The Synthesis and Glycoside Formation of Polyfluorinated Carbohydrates

Abstract

Fluorinated carbohydrates have found many applications in the glycosciences. Typically, these contain fluorination at a single position. There are not many applications involving polyfluorinated carbohydrates, here defined as monosaccharides in which more than one carbon has at least one fluorine substituent directly attached to it, with the notable exception of their use as mechanism-based inhibitors. The increasing attention to carbohydrate physical properties, especially around lipophilicity, has resulted in a surge of interest for this class of compounds. This review covers the considerable body of work toward the synthesis of polyfluorinated hexoses, pentoses, ketosugars, and aminosugars including sialic acids and nucleosides. An overview of the current state of the art of their glycosidation is also provided.

1. Introduction

Carbohydrates have essential roles in Nature as energy sources, structural matter, and as molecular recognition elements in cellular processes.¹ Interactions between carbohydrates and proteins (such as enzymes, lectins, and antibodies) play a role in numerous biological processes related to health, reproduction, and disease, including fertilization, cell–cell interactions, and cell-pathogen interactions.²⁻⁴ Pathogen-specific glycans are recognized by the immune system, eliciting an immune response.⁵⁻⁸ The functioning of the enzymatic machinery responsible for carbohydrate modifications and their glycosidation is crucial to life, with many diseases originating in the malfunctioning of carbohydrate-related processes. Hence, the roles of protein–carbohydrate and carbohydrate–carbohydrate interactions, and how to manipulate them, are therefore intensively investigated.⁹⁻¹⁷

Fluorination of carbohydrates has long been one of the strategies to investigate protein-carbohydrate interactions, for example to investigate the contributions of individual sugar alcohol groups,¹⁸⁻²⁰ or in the design of mechanism-based inhibitors.^21,22 The favorable NMR properties of the ¹⁹F nucleus have been exploited to investigate protein–carbohydrate binding at the molecular level with ever more sophisticated NMR experiments.^14,23−30 Fluorination has also been used to investigate intermolecular glycan–glycan hydrogen bonding in carbohydrate materials.³¹

The high hydrophilicity and metabolic susceptibility of carbohydrates generally results in low binding affinities and bioavailabilities, which reduces their application in drug discovery programs. This has led to the development of glycomimetics^32,33 and the use of multivalent conjugates.³⁴⁻³⁷ However, fluorination of carbohydrates increases their enzymatic and chemical stabilities, and reduces their hydrophilicities, making this modification attractive for drug discovery purposes.^33,38−40 This extends to applications such as synthetic carbohydrate vaccines.⁴¹⁻⁴⁶

Carbohydrate analogues also have applications in molecular imaging, with ¹⁸F-2-deoxy-2-fluoroglucose currently being the most widely used PET tracer used for cancer and inflammatory disease diagnosis.⁴⁷⁻⁴⁹ The stability of 2-deoxy-2-fluoroglucose imparted by the fluorine atom is a key reason for its success.

In most of the aforementioned applications, monodeoxyfluorinated sugars are involved, including sugars in which a single carbon atom contains two or three fluorine substituents, whether part of a disaccharide/glycan or not. However, dideoxy-difluorinated sugars, notably 2-deoxy-2-fluorinated glycosyl fluorides, 2-deoxy-2,3-difluorinated sialic acids, and 5-fluorinated glycosyl fluorides, have been extensively investigated as mechanism-based glycosylation inhibitors.²¹ Glycoenzyme inhibition data of some of these sugars inspired the “polar hydrophobicity” concept formulated in 1998.^50,51 This in turn has led to the investigation of the lipophilicity of fluorinated carbohydrates, with the first fluorosugar lipophilicities, obtained by a newly developed and convenient ¹⁹F NMR based log P determination method, reported in 2016.⁵²

Nevertheless, the synthesis of polyfluorinated carbohydrates has a long history, with major initial applications being the study of ¹⁹F NMR spectroscopic properties and sugar conformations.⁵³⁻⁵⁵ The first dideoxy-difluorinated sugars, 3,5-dideoxy-3,5-difluoro-d-xylose,⁵⁶ and 2-deoxy-2-fluoro-α-d-glucopyranosyl fluoride, and -β-d-mannopyranosyl fluoride,⁵⁷ were synthesized in 1969, while the first trideoxy-trifluorinated sugars, 1,6-di-O-acetyl-2,3,4-trideoxy-2,3,4-trifluoro-d-glucose and -galactose, were synthesized in 1989.⁵⁸ The first tetradeoxy-tetrafluorinated sugar, with four hydroxyl groups replaced by fluorine, was reported in 1982,⁵⁹ and the first tetrafluorinated sugar with just two hydroxyl groups replaced, was reported in 2004.⁶⁰ The most heavily fluorinated monosaccharide so far, 2,3,4-trideoxy-2,2,3,3,4,4-hexafluoroglucose, came on the scene in 1998.⁵⁰

This review aims to provide a comprehensive overview of the synthesis of polyfluorinated carbohydrates published in the peer-reviewed literature. Polyfluorinated sugars are defined here as having >1 deoxyfluorination site, resulting in >1 fluorinated carbon atom within a monosaccharide, whether further glycosylated or not. It is organized first by sugar type (aldohexoses, pentoses, ketosugars, and aminosugars, with sialic acids being a separate section), and then by the carbons that are fluorinated. The focus is on the synthetic route(s) to polyfluorinated sugars. Their glycosidation is included as well, but only selective examples are included of other further functionalizations. While the synthesis of polyfluorinated nucleosides is included, nucleoside formation of polyfluorinated sugar donors is not exhaustively covered. Reviews discussing fluorinated nucleosides are available.⁶¹⁻⁶⁵

Where relevant, improvements in synthetic procedures are mentioned, or old/redundant syntheses of precursors or early intermediates are updated. Syntheses of sugars will usually be shown starting from currently available, relatively inexpensive starting materials. This text generally aims to show the full synthesis of each polyfluorinated sugar derivative, but to avoid repetition of synthetic steps leading to common intermediates, the second structure in a synthetic scheme may be an advanced intermediate already discussed elsewhere, with a reference to the relevant scheme. However, it is not within the scope of this contribution to comprehensively review the synthesis of sugar precursors, whether monofluorinated or not. In general, it is aimed to show an efficient route to precursors for which a full experimental data set is available.

6-Deoxy-6-fluorogalactose and 6-fluorofucose have the same structure, as do 6-deoxymannose and rhamnose. These will be regarded as galactose/mannose analogues when in the d-configuration, and as fucose/rhamnose analogues when in the l-configuration, given that their synthesis can be very different.

Additional deoxygenation is not considered, with the exception for deoxygenation at the 6-position. Iminosugars, inositols, carbasugars, and C-glycosides are not included.

Several reviews covering the synthesis of fluorinated carbohydrates (mostly monofluorinated or geminal difluorinated), have been published within the last 10 years.⁶⁶⁻⁶⁹ A number of older reviews are also available,⁷⁰⁻⁸² including discussion of the material’s NMR properties.^54,55 While many reviews do include aspects of polyfluorinated carbohydrates, this review aims to provide an updated comprehensive overview of their synthesis.

2. Short Overview of Fluorinating Agents

In this section, the fluorination agents that feature in this review are briefly introduced.

2.1. Electrophilic Fluorination Agents

The electrophilic fluorinating agents featuring in this review are listed in Figure 1. Fluorine (F₂) is a highly reactive and toxic gas, usually used diluted with an inert gas (N₂, He), and nowadays only employed by specialized laboratories. Trifluoromethyl hypofluorite (CF₃OF), the reaction product of carbon monoxide with F₂, is a highly toxic gas. Both are sources of electrophilic fluorine, and in carbohydrate chemistry have been mainly used for the reaction with glycals before the invention of more convenient electrophilic fluorinating agents. In contrast, xenon difluoride (XeF₂), prepared from xenon and fluorine, is a solid. It is a milder fluorinating agent and although still very reactive, it requires use under an inert atmosphere.⁸³ The development of N–F based electrophilic fluorination agents by a number of groups in the mid-1980s completely transformed the area of electrophilic fluorination,⁸⁴ with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectFluor, also abbreviated as F-TEDA-BF₄), developed by the Banks group,^85,86 also used extensively in in carbohydrate chemistry.⁸⁷ It is synthesized via reaction of F₂ and DABCO. A milder electrophilic fluorination agent is N-fluorobenzenesulfonimide (NFSI), which was introduced in 1991 by the Differding group at Ciba-Geigy.^88,89 This reagent is also derived from F₂, by reaction with benzenesulfonimide, and is a crystalline powder. Relative reactivity scales that also include other electrophilic fluorination reagents have been determined.⁹⁰⁻⁹²

Figure 1.

Electrophilic fluorinating agents featuring in this review.

2.2. Nucleophilic Fluorination Agents

The nucleophilic fluorinating agents featuring in this review are listed in Figure 2. Anhydrous HF (aHF) is the primary source for all fluorination reagents, being obtained by sulfuric acid treatment of fluorospar (CaF₂), sourced from mining operations.⁹³ It is thus very inexpensive; however, it is extremely toxic, difficult to use, and etches glassware. It is nowadays mostly used in combination with an organic base.⁹⁴ Anhydrous HF has seen use in carbohydrate chemistry for the synthesis of glycosyl fluorides, until a convenient method was developed using the milder Olah’s reagent by the Noyori and the Szarek groups.^95,96 Olah’s reagent (pyridinium poly(hydrogen fluoride), HF-py, also abbreviated as PPHF) is a mixture of 70% HF in pyridine (py),⁹⁷ equivalent to a 9:1 HF/py molar ratio, and is widely used in organic chemistry as a nucleophilic fluorinating agent.^94,98 Another HF-derived reagent is Et₃N·3HF, triethyl amine trishydrofluoride (TREAT-HF).⁹⁹ While it has seen much use as fluorination agent through nucleophilic substitution reactions with activated alcohols and epoxides, as well as for halofluorination reactions, it has limited nucleophilicity.^94,100 The addition of Et₃N causes equilibration to Et₃N·2HF and Et₃N·HF, which were shown to lead to more nucleophilic reagents.^101−103 It is worth adding that a combination of HF with the nonbasic 1,3-dimethyl- 3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), leading to the hydrogen-bonded complex HF·DMPU, has been developed as a useful HF-derived reagent by the Hammond group.¹⁰⁴

Figure 2.

Nucleophilic fluorination reagents featuring in this review.

Alkali metal fluorides such as potassium and cesium fluoride (KF, CsF) have been widely used as inexpensive fluorinating agents, despite their limited solubility in organic media. It has been found that the use of bulky alcohols as solvents, such as t-BuOH, is beneficial for fluorinations with these reagents, including in carbohydrate applications.¹⁰⁵ This has been attributed to stabilization of the fluoride anion by hydrogen bonding to provide a “controlled” environment balancing fluoride basicity and nucleophilicity. While tetraalkylammonium fluorides such as Bu₄NF have enhanced solubility in organic solvents, its fluoride reactivity is also beneficially modified by using t-BuOH as solvent. The Kim group developed TBAF(t-BuOH)₄ as an isolable reagent with excellent fluorination properties,^106,107 and the Gouverneur group has developed other types of hydrogen-bonded fluoride reagents.^108−110

The combination of HF and KF, leading to potassium hydrogen difluoride (KHF₂), a reagent first used in fluorosugar synthesis,¹¹¹ has proven to be a useful reagent for epoxide opening, although elevated temperatures are typically required.¹¹² Silver fluoride (AgF) is soluble in acetonitrile and DMF,¹¹³ and has also seen use for glycosyl fluoride synthesis from glycosyl bromides or chlorides.⁷⁶ Silver tetrafluoroborate (AgBF₄) is soluble in water and many organic solvents, and is involved in a wide variety of transformations.¹¹⁴ Silver-based reagents use the precipitation of silver salts (such as silver bromide) as the driving force when used in halogen displacement reactions.

Finally, tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) is a mild fluoride donor shown by the Szarek group to efficiently displace triflates in fluorosugar synthesis,¹¹⁵ although elimination products were observed in some cases. This reagent is also a useful alternative to the more basic TBAF for silyl ether cleavage.^116,117

Nucleophilic fluorination by displacement of sulfonates is typically an S_N2 reaction, with steric hindrance (often by protecting groups) an important consideration for the success of the reaction. In addition, the transition state of this reaction features two polar bonds, and in a carbohydrate context, the interaction between the resulting dipoles with those of C–O bonds in adjacent positions is also an important factor. This had been recognized early on in carbohydrate synthesis, with the formulation of the Richardson-Hough rules¹¹⁸ (recently updated by the Hale group to include triflate displacements,¹¹⁹ including for furanoses¹²⁰). A summary is included in a recent review dealing more generally with controlled inversion strategies in carbohydrate synthesis.¹²¹ These rules are important to consider, given fluoride is a weak nucleophile, and its basicity can facilitate elimination side reactions.

The nucleophilic opening of epoxides with fluoride is a widely used process to synthesize fluorosugars. Regioselectivity is generally determined by the possibility to proceed via a chairlike transition state (the so-called Fürst-Plattner effect),^122,123 which has proven to be especially useful with opening of epoxides within 1,6-anhydrosugars. With more conformationally flexible substrates, steric hindrance and the electron withdrawing effect of the anomeric center are typical factors determining regioselectivity.

2.3. Deoxyfluorination Agents

Deoxyfluorination reagents (Figure 3) represent a class of nucleophilic fluorination reagents that are also able to activate an alcohol into a leaving group, and by doing so, release fluoride which can then act as the nucleophile to effectively cause a “deoxyfluorination” reaction. Some reagents are able to convert a carbonyl group to a CF₂-moiety, in which case the term ‘deoxofluorination’ is used.

Figure 3.

Deoxyfluorination reagents featuring in this review.

Sulfur tetrafluoride (SF₄) was the original (and very effective) deoxyfluorination agent, but its very high toxicity and gaseous nature prohibit its use in research laboratories. A number of SF₄ derivatives have been developed, of which diethylaminosulfur trifluoride (DAST, Figure 3) has been the most important. It is fair to say that the availability of DAST has been a key turning point in the development of organofluorine chemistry. It was developed by Middleton in 1975,¹²⁴ and to the best of our knowledge, was already first applied two years later for the synthesis of fluorinated sugars by the Korytnyk group (6-deoxy-6-fluoroglucose).¹²⁵ However, DAST has the potential to decompose violently when heated above 80 °C,¹²⁶ and in 1999, di(2-methoxyethyl)aminosulfur trifluoride (DeoxoFluor) was introduced by the Lal group as a broad-spectrum deoxyfluorination agent with enhanced thermal stability, and very similar reactivity as DAST.^127,128

Both DAST and DeoxoFluor are liquids which slowly decompose over time. Stable, crystalline derivatives such as diethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E, pronounced “crystalfluor”), essentially the product of reaction from DAST with BF₃, have been introduced by the Couturier team at OmegaChem.^129−131 Because its reactive fluoride is now sequestered by BF₃, a promoter such as Et₃N·3HF or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is required for the reaction.

Nonsulfur based deoxyfluorination agents include 1,1,2,2-tetrafluoroethyl-N,N-diethylamine (TFEDMA),¹³² which is also volatile, and N,N-diethyl-α,α-difluoro(m-methylbenzyl)amine (DFMBA, Figure 3),^133,134 which was shown to have a high thermal stability. Nonafluorosulfonyl fluoride (NfF, also known as perfluorobutylsulfonate PBSF) is another deoxyfluorinating agent, with which alcohol activation and fluoride displacement occur in the same reaction mixture. Additives are required for efficient reaction, such as hindered or non-nucleophilic bases,^135,136 Et₃N·3HF/Et₃N,¹⁰³ and tetrabutylammonium triphenyldifluorosilicate.¹³⁷

Given the extensive use of DAST in fluorosugar chemistry, with its reactive nature in some cases leading to rearrangement reactions, it is worth discussing mechanistic aspects of this reaction. A possible deoxyfluorination mechanism is shown in Scheme 1. The availability of a pair of electrons on the nitrogen atom allows fluoride elimination to intermediate A, which essentially is the reactive part of XtalFluor-E. This is intercepted by an alcohol, which leads to B upon proton loss. Such intermediates have been isolated,¹³⁸ and invoked as leaving groups in a subsequent nucleophilic substitution with fluoride,^124,139 but the presence of HF could lead to protonation to give C, which could undergo substitution with fluoride. Alternatively, B could lose another fluoride to give D, which can then undergo nucleophilic substitution with fluoride. In many DAST reactions, an amine is added as additive, which would act as proton scavenger to promote formation of D. When XtalFluor-E is used, there is no free fluoride to scavenge the proton released in the formation of B, essentially leading to the formation of the strong acid HBF₄, leading to C.¹³⁰ Interestingly, this intermediate C was suggested not to be a good electrophile for reaction with fluoride, leading to side reactions, including reaction with another equivalent of alcohol to form symmetrical ethers, and loss of diethyl amine, ultimately leading to the formation of symmetrical sulfites (not shown).¹³⁰ This can be mitigated by adding an external fluoride source, such as Et₃N·3HF, or also by adding a base such as DBU, preventing the formation of C. Hence, formation of intermediate D with release of another fluoride is promoted, which can then undergo reaction with the released fluoride to give E.^130,140

Scheme 1. Possible Mechanism for DAST/DeoxoFluor and XtalFluor-Mediated Deoxyfluorination of Alcohols.

In DAST-mediated reactions a competition between S_N2 and S_N1 processes is often observed, certainly in the presence of structural factors that stabilize carbenium intermediates. In carbohydrates, apart from the anomeric position, an S_N2 process with inversion of configuration is typically observed, hence the aforementioned Richardson-Hough rules also apply. However, the strong electrophilic nature of the intermediates and the rigidity imparted by the sugar ring frequently cause elimination and rearrangement processes, which will be illustrated throughout the review.^81,141−146

Finally, it is worth mentioning that there are many other deoxyfluorination agents available that do not feature in this review.^{140,147−149}

3. Aldohexoses: Fluorination at Two Positions

3.1. Fluorination at Positions 1 and 2

3.1.1. Difluorinated at Positions 1 and 2

There have been many reports describing the synthesis of 1,2-difluorinated sugars, either as synthetic intermediates for 2-fluorinated sugar derivatives, or as desired substrates for enzyme or NMR studies. Only those reports that describe the isolation of the 1,2-difluorinated sugars will be detailed here and will be discussed for each type of sugar according to their fluorination method.

3.1.1.1. 1,2-Difluorinated Glucose/Mannose Derivatives

The early work regarding the synthesis of 2-deoxy-2-fluoroglucosyl fluoride mainly centered around the development of effective syntheses of 2-deoxy-2-fluoroglucose, of which it is a possible precursor. Initial approaches involved the reaction of glucals with fluorine and CF₃OF. The reaction of commercially available tri-O-acetyl-d-glucal 1 with F₂ to give 1,2-difluorinated glucose and mannose derivatives has been described by the Fowler group (Scheme 2).¹⁵⁰ Fluorine reacts in a syn-addition fashion with a slight preference from the α-face to give the gluco-compound 2 as the major isomer. These compounds are stable to chromatography and could be separated. The Satyamurthy group has investigated the solvent-dependency of the facial selectivity of the fluorine addition to 1, and found that apolar solvents lead to a greater α-2/β-3 ratio (as measured by the ratio of their hydrolysis products 2-deoxy-2-fluoroglucose and -mannose).¹⁵¹ The Schrobilgen group reported that when 1 was reacted with F₂ in anhydrous HF, no 2-fluorinated glucose or mannose products were formed, but that after hydrolysis of the 1,2-difluorinated fluorination product, 2-deoxy-2-fluoroallose was obtained (not shown).¹⁵² This was explained by protonation of the C-3 OAc group, which then resulted in a cyclization with the 4OAc group, which after hydrolysis resulted in inversion of configuration at C-3. No 2-fluorinated allosyl fluoride was isolated however.

Scheme 2. Synthesis of 1,2-Difluorinated Sugars by syn-Fluorine Addition¹⁵⁰.

The Withers group used this procedure to synthesize 2-deoxy-2-fluoromaltosyl fluoride and -maltotriosyl fluoride as inactivators of α-glycosidase enzymes (Scheme 3).¹⁵³ The required peracetylated maltal 5 can be obtained in three standard steps from maltose involving peracetylation, conversion of the anomeric acetate into the anomeric bromide 4, and Zn-mediated elimination of the C-2 OAc group.^154−156 The addition of fluorine proceeded with a decreased facial selectivity (α-6/β-7 1.3:1) compared to triacetyl glucal, ascribed to the presence of the (1 → 4)-linked glucose tetraacetate. Chromatographic separation afforded 6 in 20% yield, which was successfully deprotected to give 8. In a similar way, the maltotriose derivative 9 was isolated in 37% yield, and then deprotected to give 10.

Scheme 3. Application of syn-Fluorination to 1,2-Difluorinated Di- and Tri-saccharides¹⁵³.

The reaction of triacetyl-d-glucal with CF₃OF was investigated by the Foster group and was found to lead to a mixture of four separable compounds (Scheme 4).^57,157 The 2-deoxy-2-fluorinated glucosyl and mannosyl fluorides α-2 and β-3 are formed, alongside trifluoromethoxylated byproducts 11 and 12. The reaction also proceeds via syn-addition, with increased facial selectivity toward the gluco-compounds compared to F₂.¹⁵¹ The glycosyl fluorides and trifluoromethyl glycosides can be hydrolyzed in strong acid, for example, α-2 and 11 were converted into 2-deoxy-2-fluoroglucose in 85 and 91% yield, respectively, and 12 to 2-deoxy-2-fluoromannose in 67% yield (not shown).⁵⁷

Scheme 4. Synthesis of 1,2-Difluorinated Sugars by syn-CF₃OF Addition^57,157.

The Kent group employed this procedure with peracetylated lactal 13 (Scheme 5).¹⁵⁸ Many syntheses of lactal are available, for example via peracetylation of lactose, anomeric bromination, and elimination with Zn.¹⁵⁹ Compared to a reaction with peracetylated glucal, reaction of 13 with CF₃OF was reported to require a higher temperature, and proceeded with a different facial selectivity. The syn-addition products arising from the β-face approach, the 2-epilactosyl products 14 and 16, are now the major isolated isomers, which was explained by the steric influence of the second monosaccharide ring. These observations are consistent with the observed stereoselectivity difference between the reaction of peracetylated glucal and maltal with F₂ (cf. Schemes 2 and 3). The difluorinated compounds 16 and 17 were then deprotected to give 2-deoxy-2-fluoro-β-epilactosyl fluoride and -α-lactosyl fluoride 18 and 19.

Scheme 5. Application of syn-Addition of CF₃OF to d-Lactal¹⁵⁸.

The Korytnyk group investigated the use of xenon difluoride as alternatives for F₂ and CF₃OF (Scheme 6A).^160,161 Three products were obtained, with acetylated 2-deoxy-2-fluoroglucosyl fluoride α-2 as the major isomer. Its β-anomer β-2 and the β-anomer of the corresponding mannosyl product β-3 were isolated in small amounts. The Quayle group obtained a total yield of 91% for this reaction, with less than 10% of β-2 and β-3 combined.¹⁶² A benzene–ether solvent mixture was found to be optimal, with the use of ether alone leading to a very slow reaction. To avoid BF₃-catalyzed Ferrier-type rearrangements, this reagent had to be added slowly to the reaction mixture. The presence of β-2 was shown not to arise from BF₃-catalyzed anomerization, which indicates that the XeF₂ reaction is not a concerted syn-addition process.¹⁶¹

Scheme 6. Synthesis of 1,2-Difluorinated Sugars by XeF₂ Addition^160−163.

The Bornemann group applied this process in the synthesis of the 1,2-difluorinated maltose 8 (Scheme 6B), but in dichloromethane as solvent.¹⁶³ The formation of both anomers of 2-deoxy-2-fluoromaltyl fluoride was reported in a 40% combined yield. After separation, α-6 was deprotected to give 8, which was used for enzyme studies.

The Withers group reported a direct conversion of the mannose derivative 24 using DAST (Scheme 7A).¹⁴³ This intermediate was synthesized in five steps from mannose, first by obtaining the peracetylated α-mannosyl bromide 21, then by ortho-ester formation 22, and after a protecting group switch to 23, hydrolysis of the ortho-ester. Treatment of 24 with DAST leads to the 2-deoxy-2-fluorinated β-glucosyl fluoride derivative 26 in 30% isolated yield, with the monofluorinated α-mannosyl fluoride α-25 as the other isolated product. This reaction outcome was explained by initial conversion of A to both anomeric mannosyl fluorides β-25 and α-25, but with the second deoxyfluorination process only proceeding for the β-anomer β-25, due to the—commonly observed—reluctance of α-configured mannose derivatives to undergo nucleophilic substitution at C-2. In the case of α-25, similar to the Richardson-Hough rules,^118,119 and as established more generally for S_N2 reactions adjacent to fluorine,^164−166 the strong C–F dipole was thought to cause unfavorable dipole interactions with the transition state of the S_N2 reaction at C-2. Hence, activated intermediate 27, which would be formed by reaction of α-25 with DAST, does not react and is hydrolyzed in the workup to give back α-25.

Scheme 7. Direct Conversion of 2-Deprotected Mannopyranose with DAST to 2-Deoxy-2-fluoro-β-glucosyl Fluoride Derivatives^143,167.

The Stick group applied this dideoxy-difluorination reaction with the disaccharide 28 (Scheme 7B) after benzyl hydrogenolysis, to give the 2-fluorinated β-laminaribiosyl fluoride 29 as the only isolated product in 66% yield.¹⁶⁷

The Dax group found that reactions of glycals with SelectFluor in the absence of water led directly to 2-fluorinated glycosyl fluoride derivatives (Scheme 8A).¹⁶⁸ This reaction proceeds via syn-addition of SelectFluor to give adducts 39, which can then react with nucleophiles to effect substitution at the anomeric center,¹⁶⁸ including glycosidations.¹⁶⁹ In the absence of other nucleophiles, the tetrafluoroborate counterions in SelectFluor can act as fluoride donors. As such, glycals 1,30–32 gave mixtures of inseparable 2-deoxy-2-fluoro-α-glycosyl- and -α-mannosyl fluorides 33–35 and 36–38 in yields between 25 and 45%, and in ratio’s depending on the nature of the protecting groups.¹⁶⁸ When starting from the glycal derivatives of maltose, lactose, and cellobiose 5,13, and 40 (Scheme 8B),¹⁶⁸ the resulting C-2-epimers were separable, with the 2-deoxy-2-fluoro-α-maltosyl-, -lactosyl-, and -cellobiosyl fluorides 6, 17, and 41 obtained in a lower yield compared to their 2-epi derivatives 7, 16, and 42. When the SelectFluor reaction is carried out in a nitromethane (or DMF)–water mixture, as illustrated with the commercially available tri-O-acetyl-d-glucal 1 (Scheme 8C), then the hemiacetals 43/44 are obtained.^168,170 In this case, water acts as nucleophile to react with 39. The Priebe group reported this reaction on a large scale, in which α-2 and α-3 were still found to be minor products in the reaction mixture.¹⁷¹

Scheme 8. Synthesis of 1,2-gluco/manno Difluorides Using SelectFluor¹⁶⁸.

In addition to the direct difluorination methods described above, sequential methods have also been employed. Starting from 2-deoxy-2-fluoroglucose 45 (Scheme 9A), obtained as mentioned with Scheme 4 from the hydrolysis of 2/11, the Foster group synthesized the glycosyl bromide 46 via the peracetate, which was subjected to AgF to afford β-2 with the β-anomer as the only reported product.^172,173 The Withers group used this procedure as well,¹⁷⁴ with the peracetate intermediate 47 (Scheme 9B) obtained from tri-O-acetyl-d-glucal via treatment with SelectFluor in acetic acid (as opposed to nitromethane or water as shown in Scheme 8). This directly afforded a mixture of separable acetates 47 and 48. From 47, anomeric bromide formation and fluoride displacement led to 14 in 85% yield.¹⁷⁴ Alternatively, DAST-mediated deoxyfluorination with 3,4,6-tri-O-acetyl-2-deoxy-2-fluoroglucose 43 was investigated as well.¹⁷⁵ It was synthesized from the mixture of 2-fluoroglucose anomers 47 by treatment with methanolic ammonia to effect anomeric deprotection. Treatment with DAST then gave 2, but as a mixture of anomers.¹⁷⁵

Scheme 9. Sequential Syntheses of 2-Deoxy-2-fluoro Glucosyl Fluoride^{172,174,175,179}.

It should be said that the reaction of tri-O-acetyl-d-glucal with SelectFluor in aqueous medium is currently the most employed method to obtain 47, despite a separate acetylation step being required to separate the gluco- and manno isomers, often as a mixture of anomers.¹⁶⁸ Given the importance of this method, some typical results are summarized in Scheme 9C. The gluco/manno ratio, as well as the ratio of their respective anomers, varies according to the reaction conditions, although it should be noted that typically isolated yields are reported (as opposed to analyses on crude reaction mixtures). With aqueous nitromethane as solvent (a,b), the gluco-product is the major isomer.^168,171 In aqueous DMF at room temperature,¹⁷⁶ a high gluco/manno ratio was obtained. However, when the reaction was carried out at 40 °C, the opposite result was reported.¹⁷⁷ The reaction in aqueous acetone also delivered the manno-product as major isomer, albeit in a lower ratio.^175,178

Finally, the Withers group applied the sequential SelectFluor/DAST difluoride introduction in the synthesis of the disaccharide 58 (Scheme 9D).¹⁷⁹ Tri-O-acetyl-d-glucal 1 was first converted to the 3,6-di-O-benzylated glucal 49,¹⁸⁰ to which SelectFluor addition in nitromethane with acetic acid as nucleophile led to the separable 50 and 51 in, respectively, 29% and 25% yield.¹⁷⁹ Glycosylation of 51 with donor 52 gave disaccharide 53, after which the trichloroacetamide group was reduced to the acetamide 54. Benzyl hydrogenolysis and reprotection of the uncovered alcohols as acetate gave 55, which was then selectively deprotected at the anomeric position. DAST-mediated deoxyfluorination afforded 57 as the only reported anomer. Finally, global deprotection gave 58.

Overall, some of the synthetic routes described above give access to both 2-deoxy-2-fluoroglucosyl fluoride anomers 2 as pure compounds, as well as to the β-anomer of 2-deoxy-2-fluoromannose 3. The 2-deoxy-2-fluoromannose α-anomer α-3, obtained as described in Scheme 8, could not be separated from the α-anomer of 2-deoxy-2-fluoroglucose α-2. The Foster group described an anomerization process to access the α- from the β-anomer, by treatment with liquid HF at low temperature (Scheme 10), a process which turned out to be complete in 15 min on the 650 mg scale.¹⁷²

Scheme 10. Anomerization to Obtain Pure Tri-O-acetyl-2-deoxy-2-fluoromanno-α-pyranosyl Fluoride^172,173.

3.1.1.2. 1,2-Difluorinated Quinovose/Rhamnose Derivatives

The Kent group described the addition of CF₃OF with 3,4-di-O-acetylated l-rhamnal 59 (Scheme 11A).¹⁸¹ The rhamnal derivative can be synthesized from rhamnose by peracetylation, anomeric bromide formation, and elimination, for example by the conditions shown.¹⁸² The reaction led to the l-quinovose derivatives 60 and 61 as the major addition products, with the l-rhamnose derivatives 62 and 63 as the minor products. As part of work aimed at the synthesis of fluorinated oleandrose analogues, the Lukacs group described a direct DAST-mediated 1,2-dideoxy difluorination of the l-rhamnose derivative 65 (Scheme 11B),¹⁸³ itself synthesized from l-rhamnose.^184,185 This reaction gave a separable mixture of 4-O-benzoyl-2-deoxy-2-fluoro-3-O-methyl-β-l-quinovosyl fluoride β-67 and the corresponding α-l-rhamnosyl fluoride α-66 in excellent overall yield. In full accordance with the corresponding dideoxy difluorination of the d-mannose derivative 24 (cf. Scheme 7), deoxyfluorination at the anomeric position precedes reaction at C-2, with the second deoxyfluorination only occurring when the anomeric fluorine substituent is in the equatorial position, so only β-66 reacts and α-66 is recovered after the workup.

Scheme 11. Direct and Sequential Vicinal Difluorination Approaches to 1,2-Difluorinated Quinovose and Rhamnose Derivatives^181,183.

The Lukacs group also reported a sequential approach in which the anomeric fluoride is introduced first (Scheme 11B). Reaction of α-64 with DAST results in the two inseparable anomeric quinovosyl fluorides α-68 and β-68, for which the anomeric benzyl group has migrated to the 2-position with inversion of configuration,¹⁸³ a rearrangement originally described by the Lemieux group from 2-iodinated glycosides,¹⁸⁶ and later more or less simultaneously described by a number of groups (Nicolaou, Withers, Kovac, and Lukacs) when using DAST.^{77,141−143,187} Removing the benzyl group allowed activation of the OH-2 as triflate (no conditions/yields provided), leading to the separable α-69 and β-69. Displacement with fluoride was then achieved in both cases, with a lower yield for α-70 vs β-70 due to the electronic influence of the adjacent axial anomeric fluoride in α-69 hampering the deoxyfluorination.^119,188

3.1.1.3. 1,2-Difluorinated Galactose Derivatives

Vicinal fluorinations starting from galactal derivatives are shown in Scheme 12. With tri-O-acetyl-d-galactal 71 (Scheme 12A), reaction with CF₃OF led to the four types of compounds also seen with glucal. The syn-addition products from the α-face, α-72 and 73, were obtained as major isomers, with the β-talose derivatives 74 and 75 being the minor isomers.^189,190 The yields represent the amounts of recrystallized material, with the authors noting that chromatographic isolation from the mother liquors would lead to higher yields for the galacto-derivatives. Dwek et al. reported yields of 55% and 40% for α-72 and 73 as the only isolated products for this reaction (not shown).¹⁹¹ Nevertheless it is clear that the galacto:talo ratio is much larger than the gluco:manno ratio, which can be ascribed to the increased steric hindrance of the galactal 4-position compared to that of glucal.¹⁹⁰ Compound α-72 was deprotected to give 2-deoxy-2-fluoro-α-d-galactosyl fluoride 76.¹⁶¹

Scheme 12. Vicinal Difluorinations with Galactal Derivatives^{160,161,189−192,194,195}.

Reaction of 71 with XeF₂ was investigated in detail by the Korytnyk group (Scheme 12B).^160,161 A very similar stereochemical outcome compared to d-glucal is now obtained, with the α-2-fluorogalactosyl fluoride product α-72 being the major product alongside small amounts of its β-anomer, and of the product arising from β-face attack, being the β-talose derivative 74. The Wong group reported a 78% yield of α-72 for this reaction.¹⁹² Geilen et al. achieved the reaction with XeF₂ in CFCl₃ without Lewis acid catalysis, although the 1,2-difluoride was not isolated and immediately hydrolyzed to 2-deoxy-2-fluorolagactose (in 63% yield, not shown).¹⁹³ Interestingly, they did not observe the formation of any talose isomers.

The Dax group reported that difluorination of 71 with SelectFluor was very selective as well (Scheme 12C), with α-72 isolated as the only product in 52% yield.¹⁹⁴

A sequential approach with 3,4,6-tri-O-benzyl-2-deoxy-2-fluorogalactose 78 has also been reported (Scheme 12D).¹⁹⁵ This material can be obtained via SelectFluor addition to the corresponding galactal 77, but with water added to the reaction mixture.^196,197

3.1.1.4. Difluorinated Fucose Derivatives

The synthesis of both 1,2-difluorinated fucose anomers has been described via 3,4-di-O-acetyl-l-fucal 80 (Scheme 13). Fucal 80 can be synthesized from l-fucose via peracetylation, anomeric bromide formation, and elimination.¹⁹⁸ Direct difluorination of 80 using CF₃OF was described by the Kent group (Scheme 13A), giving the α-configured 2-fluorofucosyl fluoride α-81 as the major product, alongside the unavoidable trifluoromethyl glycoside byproduct 82.¹⁹⁹ Korytnyk used XeF₂ addition to achieve direct 1,2-difluorination, leading to α-81 as the major product, with a minor amount of the β-anomer.¹⁶¹ Performed at room temperature, a 53% yield of α-81 was obtained, but starting the process at low temperature improved the yield to 62%. Deprotection then afforded 2-deoxy-2-fluoro-α-d-fucosyl fluoride α-83. Alternatively, the Wang group achieved a sequential fluorination approach (Scheme 13B) to give the other anomer.²⁰⁰ The fucal derivative 80 was fluorinated in anhydrous SelectFluor, with bromide as an additional nucleophile to directly afford the 2-fluorinated anomeric bromide 84.^194,198,201 Bromide displacement with fluoride proceeded with inversion of configuration to give β-89 as the only reported anomer, and deprotection then afforded 2-deoxy-2-fluoro-β-d-fucosyl fluoride β-83.²⁰⁰

Scheme 13. Synthesis of Both 1,2-Difluorinated Fucose Anomers via a Direct and a Sequential Approach^161,199,200.

3.1.1.5. 1,2-Difluorinated Uronic Acid Derivatives

The Withers group reported a synthesis of 2-deoxy-2-fluoro-β-d-glucopyranosyluronic acid 86 starting from the 1,2-difluorinated glucose derivative β-20 (Scheme 14).¹⁷⁴ TEMPO-mediated oxidation of the primary alcohol in β-20 led to the corresponding glucuronic acid, which was protected as phenacyl ester 85 to aid purification. Its hydrogenolysis then afforded 86.

Scheme 14. Synthesis of 1,2-Difluorinated Uronic Acid Derivatives^174,202.

The corresponding iduronic acid derivative 92 could also be prepared from 85.²⁰² Acetylation led to 87, which was subjected to radical bromination conditions leading to 88. Tributyl tin hydride-mediated radical reduction of the bromide led to a 1:1 mixture of C-5 epimers, which could be separated. The iduronic ester 89 was hydrogenolyzed to give 90, after which the acetates were cleaved. However, pure 92 could only be obtained after reprotection of the carboxylic acid, chromatography, then deprotection.

3.1.1.6. DAST-Mediated Rearrangement

Based on the possible rearrangement initiated by DAST-mediated deoxyfluorination at the OH-2 position,^142,143 the Castillòn group developed a synthetic approach toward 1,2-difluorinated sugar derivatives based on a DAST-mediated rearrangement process starting from 2-uloses (Scheme 15A).²⁰³ DeoxoFluorination of α-93 was shown to lead to 94. Given that the methoxy group ends up on the other pyranose face, it is proposed that the rearrangement occurs immediately upon DAST-activation of the carbonyl (95), followed by fluoride substitution of the resulting axial activated alcohol group (96) with inversion of configuration. When the corresponding β-anomeric substrate β-93 (Scheme 15B) was subjected to DAST, a much faster reaction occurred, giving the expected gem-difluorinated 97 in good yield, with the equatorial anomeric substituent unable to initiate neighboring group participation. However, the ketone 98 derived from rhamnose (Scheme 15C) did lead to the rearrangement product 99,²⁰⁴ which was explained by facile ring inversion of 98. Indeed, with a protecting group locking the pyranose conformation as in 100 (Scheme 15D), the gem-difluorination product 101 was obtained.

Scheme 15. Synthesis of 1,2-Difluorinated Derivatives via a DAST-Mediated Rearrangement Process^203,204.

3.1.2. Trifluorinated at Positions 1 and 2

3.1.2.1. 1,1,2-Trifluorinated

As part of a study investigating the effect of different fluorine substitutions on the rates of glycosidation and deglycosylation upon reaction with glycosidase enzymes, the Withers group synthesized 2-deoxy-1,2-difluoro-d-glucopyranosyl fluoride 107 (Scheme 16) starting from the 2-fluorinated glucosyl bromide 46.²⁰⁵ This is prepared from the corresponding tetraacetate α-48, which was obtained as shown in Scheme 9C from commercially available tri-O-acetyl-d-glucal.¹⁷⁷ Conversion of α-48 to the corresponding glycosyl bromide 46 was achieved by acetylation and HBr treatment.^172,206 Halide exchange with inversion of configuration led to 102, which was subjected to radical bromination. This reaction was not selective, leading to bromination at both C-1 and C-5. The inseparable mixture of 103 and 104 was subjected to silver fluoride. Upon being stirred overnight, only 104 reacted to give 105, after which the unreacted 103 could be isolated cleanly. Interestingly, only the bromide at C-5 was displaced, with inversion of configuration. Subjecting 103 to the same AgF-mediated halide exchange reaction, but now for 10 days, led to displacement of both anomeric halides,²⁰⁷ giving 106. The slow displacement at C-1 is a result of the electron withdrawing effect of the fluorination at C-2. Deprotection led to 2-deoxy-1,2-difluoro-d-glucopyranosyl fluoride 107 in 10% yield from 102.

Scheme 16. Synthesis of 2-Deoxy-1,2-difluoro-d-glucopyranosyl Fluoride²⁰⁵.

3.1.2.2. 1,2,2-Trifluorinated

The synthesis of 1,2,2-trifluorinated compounds has been achieved via fluorination of 2-fluoroglycal derivatives. Adamson et al. investigated the reaction between the 2-fluoroglucal derivative 108 and CF₃OF (Scheme 17A).²⁰⁸ The fluoroglucal was synthesized from the 2-deoxy-2-fluoroglucosyl bromide 46, for which the synthesis was shown above in Scheme 16, by base-mediated elimination.¹⁶² The reaction of 108 with CF₃OF under the same conditions as for the corresponding glucal (cf. Scheme 4) resulted in a similar reaction outcome in that both the glucosyl fluorides and the trifluoromethyl glucosides were formed, with the α-anomer being the major product in both cases.

Scheme 17. Synthesis of 1,2,2-Trifluorinated Sugar Derivatives^154,185,208.

The Lukacs group reported a similar outcome for the reaction of the 2-fluororhamnal derivative 115 (Scheme 17B),¹⁸⁵ with α-116 isolated as the major product. With XeF₂ as the reagent, α-116 and β-116 were isolated in excellent yield. The fluororhamnal was synthesized from the advanced intermediate 64,¹⁸³ with first installation of an equatorial anomeric substituent to facilitate deoxyfluorination of the axial OH-2. This was achieved by using stannylene acetal methodology, and DAST-treatment of β-63 afforded the 2-deoxy-2-fluoroquinovose derivative 113 in excellent yield. Anomeric deprotection and acetylation was followed by anomeric bromination, upon which bromide elimination then gave the 2-fluororhamnal 115.

The synthesis of 1,2,2-trifluorinated maltose as a nonhydrolyzable mimic of maltose-1-phosphate was achieved by Thanna et al. (Scheme 17C),¹⁵⁴ with 2-fluoromaltal 119 as key intermediate. Its synthesis started from maltose as shown in Scheme 3. Reaction of peracetylated maltal 5 with SelectFluor followed by heating with acetic acid delivered 118 as a mixture of four stereomers.²⁰⁹ A two-step procedure in which 5 was first reacted with SelectFluor in water followed by acetylation was lower-yielding (not shown).¹⁵⁴ From 118, formation of the corresponding glycosyl bromide was followed by E2-elimination of the anomeric bromide to give peracetylated 2-fluoromaltal 119 alongside unreacted 120, whose mannose stereochemistry prevented bromide elimination.^154,209 Reaction of the 2-fluoromaltal derivative 119 with SelectFluor in nitromethane without an added nucleophile resulted in both peracetylated 2-deoxy-2,2-difluoromaltosyl fluoride anomers α-121 and β-121 in an 1.1:1 ratio of isolated yields, with hydrolyzed byproduct 122. This byproduct could be converted to α- and β-121 by a DAST-mediated deoxyfluorination, albeit in low yield. Finally, protecting group aminolysis gave 2-deoxy-2,2-difluoro-α-maltosyl fluoride α-123 and 2-deoxy-2,2-difluoro-β-maltosyl fluoride β-123. The 2-fluoromaltal derivative 119 was also reacted with XeF₂ to give a 12% yield of anomers 121 (not shown).

3.2. Fluorination at Positions 1 and 3

The synthesis of 3-dideoxy-3-fluoro-α-glucosyl fluoride 129 was achieved from 3-deoxy-3-fluoroglucose 126 by a number of groups (Scheme 18).^59,210−212 This starting material is commercially available but expensive. It can be synthesized from glucose diacetonide in 4–5 steps (compare Scheme 56, compound 413),^139,213,214 but a shorter alternative developed by Giguère involves selective benzylation of levoglucosan to give 124 followed by a 2-step retentive deoxyfluorination to 125 and anhydro-bridge opening.^215,216 Acetylation of the resulting 126 led to the peracetate 127, from which the anomeric acetate mixture was converted to the α-configured glucosyl fluoride α-128 by treatment in liquid HF in good yield. Acetate removal then gave 129.^59,211,212 The corresponding β-anomeric glucosyl fluoride was obtained through conversion of α-127 to the anomeric bromide 130, followed by treatment with AgF in acetonitrile. This gave β-128 in 77% yield.²¹⁰

Scheme 18. Synthesis of 3-Dideoxy-3-fluoro-glucosyl Fluorides^59,210−212.

Scheme 56. Synthesis of 3,6-Dideoxy-3,6-difluoro-β-d-glucopyranose³¹¹.

3.3. Fluorination at Positions 1 and 4

The 1,4-difluorinated derivatives of glucose and galactose have been reported. Again, the anomeric fluoride is introduced last, and hence the 4-deoxy-4-fluoroglucose and -galactose precursors are obtained first. These, and their peracetates, are commercially available but expensive. Both anomeric glycosyl fluorides of 4-deoxy-4-fluoroglucose, 141, can be prepared selectively from the corresponding peracetate 136 (Scheme 19), which in turn can be obtained from levoglucosan.²¹⁷ Its selective tosylation at the 2,4-positions gave 131,^215,218 which upon deprotonation of the OH-3 selectively formed the 3,4-epoxide 132.^219−222 Photolytic cleavage of the tosyl group was used to deprotect the OH-2 group to give 133.²¹⁷ The Linclau group later used the Robins procedure²²³ to remove the tosyl group in 132 in equally high yield.²²⁴ This was followed by regioselective epoxide opening with fluoride to give 134 in good yield.²¹⁷ The regioselectivity of the epoxide opening is governed by the so-called Fürst-Plattner effect,¹²² which originates from the formation of a chairlike transition state which cannot be obtained upon reaction at C-3. A more direct synthesis of 134 was possible from the monotosylate 135 using the same conditions. This reaction proceeds by in situ conversion of 135 to epoxide 133 by the basic fluoride, followed by epoxide opening. Monotosylation of levoglucosan was reported to be very low yielding and unselective,²²⁵ but a reasonable yield of 135 could be obtained on gram scale with prior formation of the 2,4-stannylene acetal. However, chromatographic separation of the corresponding 2,4-di-O-tosylate (6%) and the 2-O-tosylate (17%) side products was required.^226,227 Acetolysis of 134 gave 136 in excellent yield. Alternatively, 136 can be synthesized from methyl α-d-galactopyranoside 137,²¹⁴ starting with a regioselective benzoylation to give 138.²²⁸ Fluorination with inversion of configuration affords the 4-deoxyfluorinated glucose derivative 139.^214,229,230 These two steps have been conducted on the kilogram scale.²³¹ Deprotections then give 4-deoxy-4-fluoroglucose 140,²¹⁴ which is acetylated to give 136.^214,232 Treatment of 136 with liquid HF led to the α-anomeric fluoride α-141.²¹⁷ The β-anomeric fluoride β-141 was obtained in a 2-step procedure via the anomeric bromide.

Scheme 19. Synthesis of (Peracetylated) 4-Deoxy-α and -β-glucopyranosyl Fluorides²¹⁷.

The galactosyl fluorides α- and β-144 were obtained in the same way from the peracetylated 4-deoxy-4-fluorogalactopyranose 143 (Scheme 20).²³³ There are many different syntheses toward 143 starting from methyl glucoside, with various protecting group manipulations to allow selective fluorination of OH-4 (either directly with DAST or using a variety of leaving groups), but the example shown from the Giguère group, starting from levoglucosan, is perhaps the most convenient.²²⁷ Selective 4-O-tosylation as described in Scheme 19 is followed by MOM-protection of the remaining alcohol groups. Fluorine displacement to give 142 can be achieved in modest yield, and a one-pot deprotection operation leads to the peracetate 143,²²⁷ which can then be converted to α- and β-144.²³³ Alternatively, the tosylate group can be removed using sodium naphthalenide (92%, not shown), and fluorination can be achieved in much higher yield (80%) using Et₃N·3HF via the triflate.²³⁴

Scheme 20. Syntheses of (Peracetylated) 4-Deoxy-α and -β-galactopyranosyl Fluorides²³³.

3.4. Fluorination at Positions 1 and 5

3.4.1. Difluorinated at Positions 1 and 5

Fluorination at C-5 has been well-investigated given the use of 5-fluorosugar derivatives as mechanism-based inhibitors of glycosidase enzymes,^21,235,236 as pioneered by the Withers group.²¹ Its introduction is a two-step process, starting with a radical bromination at C-5.^237,238 Given that halide introduction at C-5 prevents selective reactions at the anomeric position,²³⁹ glycosyl fluorides are used as substrates when additional fluorination at the anomeric position is required.

Both anomers of 5-fluoroglycosyl fluoride 152 have been synthesized (Scheme 21).

Scheme 21. Synthesis of 5-Fluororinated Glucopyranosyl Fluoride and Idopyranosyl Fluoride^{154,235,239,247}.

The substrate β-glucosyl fluoride 147 can be obtained by a number of means,²⁴⁰ for example treatment of the anomeric bromide 145 with KHF₂ or with AgF (not shown) in MeCN,^241−243 or treatment of 2,3,4,6-glucose tetraacetate 146 with DFMBA.¹³³ The 2,3,4,6-tetra-O-benzoyl-β-glucosyl fluoride β-148 has been synthesized from 149 by deoxyfluorination with DAST.²⁴⁴ Radical bromination of β-147 led to β-150,^{207,235,239,245} with only a small amount (4%) of anomeric bromination byproduct (not shown).²⁰⁷ Halide exchange with AgBF₄ proceeded with retention of configuration to give β-151, with use of Et₂O as the solvent found to be superior over toluene.²³⁹ Acetate aminolysis then gave β-152.²³⁵ The bromination of the tetrabenzoate β-148 was reported to be slower, but better yields were obtained.²³⁹

Radical fluorination of the α-configured glucosyl fluoride α-147 (Scheme 21B), which can be obtained in one step from 155,^{95,96,154,246} proceeded equally well with no anomeric bromination,^154,207 but this reaction on the corresponding tetrabenzoate was reported not to give clean conversion (not shown).²³⁹ Halide exchange was not hindered by the axial fluoride at C-1 and proceeded with retention as well, giving α-151. However, when AgF or AgBF₄ were reacted with α-150 in MeCN, inversion of configuration took place, leading to the l-ido configured 156.¹⁵⁴ All attempts to isomerize 156 to α-151 using HF-py or with Lewis acids were not successful. Deprotection of α-151 and 156 yielded α-152 and 157 respectively.^{154,235,239,247}

The Withers synthesis of the α-configured 5-fluorogalactosyl fluoride 162 is shown in Scheme 22.²⁴⁸ Reaction of peracetylated galactose 158 with HF-py afforded the corresponding α-galactosyl fluoride 159,^246,249 which was brominated at C-5 to give 160 in similar yields as shown above. Halide exchange at C-5 proved not possible with AgF but was achieved with AgBF₄ in toluene, leading to 161 with retention of configuration, albeit in a low yield. Interestingly, when Et₂O was used as the solvent, a 1:1 mixture of 161 and the corresponding l-altrose epimer (not shown) was obtained, resulting from inversion of configuration at C-5. Aminolysis finally provided 5-fluoro-β-d-galactopyranosyl fluoride 162.

Scheme 22. Synthesis of 5-Fluoro-β-d-galactopyranosyl Fluoride²⁴⁸.

The sequence starting from α-configured peracetylated mannosyl fluoride 164, which can be obtained from mannose pentaacetate 163,²⁴⁶ is shown in Scheme 23.²⁵⁰ Radical bromination to 165 again proceeded with similar yields compared to the aforementioned glycosyl fluorides. Halide exchange was effected with AgF, which proceeded with inversion of configuration to give the l-gulose derivative 166. Deprotection of 166 yielded 5-fluoro-β-l-gulopyranosyl fluoride 167, which was shown by ¹H NMR analysis to adopt a boat-like conformation. Interestingly, treatment of 166 with BF₃-etherate caused epimerization at C-5 toward the more stable mannosyl derivative 168, which upon aminolysis led to 5-fluoro-α-d-mannopyranosyl fluoride 169. This compound was shown to adopt a ⁴C₁ chair conformation in solution (¹H NMR analysis), as well as in the solid state (X-ray crystallographic analysis).

Scheme 23. Synthesis of 5-Fluoro-α-d-mannopyranosyl Fluoride and 5-Fluoro-β-l-gulopyranosyl fluoride²⁵⁰.

For the synthesis of 5-fluorinated uronic acids (Scheme 24),²⁵¹ the carboxylic acid protecting group needed to be removable under conditions that were mild enough for the difluoride to survive, while also being compatible with the radical bromination and fluorination conditions. This ruled out methyl, benzyl, and silyl esters. In the event, after alcohol acetylation of glucuronic acid and anomeric deprotection, the Withers group used a phenacyl protecting group, leading to 172. Then, the introduction of the anomeric fluoride was achieved with DAST to give a mixture of anomers, predominantly the β-anomer 172. Radical bromination to give 173 proved to be much faster compared to the corresponding peracetylated glucosyl fluoride, which was ascribed to the stabilization of the intermediate C-5-radical by the carboxyl group. Halide exchange proceeded both with inversion and retention, leading to 174 and 175.²⁵¹ Both were deprotected in two separate steps to give 5-fluoro-β-d-glucopyranosyl uronic acid fluoride 178 and 5-fluoro-α-l-idopyranosyl uronic acid fluoride 179.^202,251

Scheme 24. Synthesis of 5-Fluoro-β-d-glucopyranosyl and -α-l-idopyranosyl Uronic Acid Fluorides^202,251.

3.4.2. Trifluorinated at Positions 1 and 5

The synthesis of the trifluorinated 1,5-difluoroglycopyranosyl fluorides has also been achieved by the Withers group.²⁰⁵ Tetraacetylated β-acetyl chloride 180 (Scheme 25), synthesized from β-d-glucose pentaacetate 155 by treatment with thionyl chloride,²⁵² was subjected to the radical bromination process. This gave predominantly the 1-brominated product 181, alongside 14% of the corresponding C-5-bromination product (not shown).^207,245 Reaction with AgF resulted in exchange of both anomeric halides to give 182.²⁰⁷ A subsequent radical bromination led to 183, which was subjected to a halide exchange reaction, giving both of the 1,1,5-trifluorinated products with retention (184) and inversion (185) of configuration in low yields.²⁰⁵ Both were deprotected to give 1,5-difluoro-d-glucosopyranosyl fluoride 186 and 1,5-difluoro-l-idopyranosyl fluoride 187.

Scheme 25. Synthesis of 1,5-Difluoro-d-glucosopyranosyl and -l-idopyranosyl Fluorides²⁰⁵.

3.5. Fluorination at Positions 1 and 6

3.5.1. Difluorinated at Positions 1 and 6

3.5.1.1. 1,6-Diluorinated Glucose Derivatives

The Kovac group reported a direct synthesis of 6-deoxy-6-fluoroglucosyl fluoride from 2,3,4-tribenzylated glucose 189 (Scheme 26).¹⁴⁴ This was prepared by a modified selective acetylation procedure reported by Eby et al. starting from tetrabenzylated glucose 188, followed by acetate hydrolysis.²⁵³ Treatment of 189 with DAST gave the desired 190 and 191, which were separable, with the addition of Et₃N required to obtain a good yield. Without addition of base, the 3,6-anhydro derivative 192 was isolated as the major product, with the C-3 OBn oxygen displacing the activated OH-6 group after ring inversion. Treatment of methyl 2,3,4-tri-O-benzyl galactopyranoside with DAST was also found to give the 3,6-anhydro derivative.^145,254 In this case the required ring inversion for cyclization will have been facilitated by its anomeric configuration, as it resulted in the β-glucosyl fluoride becoming axial. The action of base was proposed to deprotonate any formed HF, thereby ensuring that fluoride substitution at C-6 outcompeted cyclization.

Scheme 26. Direct Fluorination Strategy for the Synthesis of 6-Deoxy-6-fluoroglucosyl Fluorides¹⁴⁴.

A sequential synthesis approach for both anomeric glucosyl fluorides has also been reported, with 1,2,3,4-tetra-O-acetyl-6-deoxy-6-fluoro-β-d-glucopyranose 194 as a key intermediate (Scheme 27A).²⁵⁵ This is synthesized from 193,¹²⁵ for which a one-step synthesis from glucose pentaacetate 155 involving selective 6-deacetylation with Cp₂ZrCl₂ is now available.²⁵⁶ Treatment of 194 (as an anomeric mixture) with anhydrous HF at low temperature resulted in a mixture of products, from which α-195 and a partially deprotected byproduct 196 were isolated. The β-anomer can be accessed by prior conversion of 194 to the anomeric bromide 197, and subsequent treatment with silver fluoride. Deprotection of α- and β-195 with ammonia affords the α- and β-6-deoxy-6-fluoroglucopyranosyl fluorides α-198 and β-198.

Scheme 27. A Sequential Fluorination Approach to 1,6-Difluorinated Sugar Analogues^255,257.

Following similar methodology, the Driguez group synthesized a 1,6-difluorinated maltose analogue (Scheme 27B), with the 1,6-anhydromaltose hexaacetate 200 as key intermediate.²⁵⁷ This can be obtained from maltose by reaction with 2-chloro-1,3-dimethylimidazolinium chloride 199,^258,259 followed by acetylation.²⁶⁰ Selective opening of the 1,6-anhydro-bridge was achieved with dichloromethyl methyl ether in the presence of ZrCl₄, leading to 201. This was immediately treated with acetic acid and silver acetate to install the anomeric acetate, and then with hydrochloric acid in methanol for the selective hydrolysis of the 6-O-formyl group. This gave 202, which was deoxyfluorinated with DAST and then treated with HF-py to install the anomeric fluoride to give 204.

3.5.1.2. 1,6-Difluorinated Galactose Derivatives

The Mori group described the synthesis of benzylated 6-deoxy-6-fluorogalactosyl fluoride 209 starting from 205 (Scheme 28A),²⁶¹ which is obtained via a standard 3-step sequence involving tritylation, benzylation, and trityl hydrolysis of methyl α-d-galactopyranoside (not shown). Attempted deoxyfluorination with XtalFluor gave the 3,6-anhydro byproduct 206 as the major product, a side reaction also observed by Kovac as described in Scheme 26. Reaction with DAST also led to 206, even as the only observable product. As described by Kovac,¹⁴⁴ addition of base enabled deoxyfluorination at the 6-position to give 207, albeit in a moderate yield. From 207, anomeric acetolysis followed by methanolysis of the resulting acetate gave 208, which was then subjected to anomeric deoxyfluorination to give 209 as a 2:3 α/β mixture of anomers.

Scheme 28. Sequential Fluoride Introduction for a 1,6-Difluorinated Galactose Derivative^261,262.

A short synthesis of peracetylated 6-deoxy-6-fluoro-α-galactopyranosyl fluoride 212 was reported by the Miethchen group (Scheme 28B).²⁶² Starting from commercially available 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose 210, deoxyfluorination is best effected by conditions established by the Hoffman-Roeder group to give 211,^196,263 upon which treatment with anhydrous HF in the presence of acetic anhydride gave 212.²⁶²

3.5.2. Trifluorinated at Positions 1 and 6

The Edwards group reported a synthesis of 6-deoxy-6,6-difluoro-α-d-glucosyl fluoride 217 starting from 213 (Scheme 29).²⁶⁴ Pfitzner-Moffatt oxidation with diisopropyl carbodiimide (DIC), directly followed by treatment of the resulting C-6-aldehyde hydrate with DAST, gave 214 in a low yield. Dealkylation by acetolysis resulted in the peracetate 215, which was converted to the glycosyl fluoride 216. Alcohol deprotection then gave 217, which was directly used in enzyme assays.

Scheme 29. Synthesis of 6-Deoxy-6,6-Difluoroglucosyl Fluoride²⁶⁴.

3.6. Fluorination at Positions 2 and 3

3.6.1. Difluorinated at Positions 2 and 3

3.6.1.1. 2,3-Difluorinated Glucose Derivatives

The synthesis of 2,3-dideoxy-2,3-difluoroglucose 225 was first reported by the Linclau group,²⁶⁵ followed by a Giguère synthesis featuring an improved deoxyfluorination procedure.²¹⁵ Both syntheses involve the Cerny epoxide 219 as a key intermediate (Scheme 30). This can be synthesized either from levoglucosan in four steps, via 132,^{219,221,222,227} or starting from glucal in three steps.^266−269 Regioselective fluoride opening of the epoxide 219 with potassium hydrogen difluoride in ethylene glycol led to 221 in yields of 65 to 74%,^265,270,271 but an improved 83% yield was obtained with the addition of KF as an extra fluoride source.²⁷² In the original report of this epoxide opening, the formation of the regioisomer 222 in 3% yield was detailed.²⁷¹ Fluorination of 221 at the 3-position using DAST proceeded with retention of configuration to give 223, thanks to a neighboring group participation involving the 4-O-benzyl group. The original conditions involving refluxing a DAST solution in toluene⁵⁸ gave a yield of 86%.²⁶⁵ Safer conditions involving DeoxoFluor in THF at 100 °C for 1.5 h under microwave irradiation gave a similar yield (87%),²⁷³ and a subsequent improvement by first obtaining the triflate intermediate 224 followed by displacement using TREAT-HF in triethyamine gave a 95% yield over two steps.²⁷² This was followed by 1,6-anhydro-bridge opening and debenzylation with BCl₃ in water to give 2,3-dideoxy-2,3-difluoro-glucose 225.^215,265

Scheme 30. Synthesis of 2,3-Dideoxy-2,3-difluoro-d-glucose^215,265.

3.6.1.2. 2,3-Difluorinated Galactose Derivatives

The synthesis of the corresponding 2,3-difluorinated galactose analogue 229 was reported by the Linclau group from the advanced intermediate 223 (Scheme 31).²⁷⁴ Deprotection of 223 leads to 226 using hydrogenolysis.⁵⁸ While these conditions result in an excellent yield,⁵⁸ they can be difficult to reproduce. The Giguère group showed that alternative deprotection conditions involving TiCl₄ were effective as well.²⁷⁵ Inversion of the OH-4 by triflation, nucleophilic substitution with benzoate, and transesterification provides 228 in excellent yield.⁵⁸ The inversion was also shown via a Lattrell-Dax reaction²⁷⁶ in equally excellent yield.²⁷⁵ Opening of the 1,6-anhydro-bridge with BCl₃ led to 2,3-dideoxy-2,3-difluoro-d-galactose 229, and with Ac₂O in H₂SO₄ to the corresponding peracetylated 230.²⁷⁴ The latter could be fully deprotected to give 229 (not shown), or selectively deprotected at the anomeric position to give 231.

Scheme 31. Synthesis of 2,3-Dideoxy-2,3-difluoro-d-galactose²⁷⁴.

Given the importance of galactofuranoses,^277−279 suitable protection of 229 to achieve ring isomerization was also investigated (Scheme 32).²⁷⁴ In contrast to a precedent from the Liu group, who showed that acetylation of 2-deoxy-2-fluorogalactose in pyridine at 100 °C gave a 1.6:1 ratio of pyranose to furanose (not shown),²⁸⁰ submitting 229 to these conditions only furnished traces of the furanose 232. However, in accordance with precedent from Hricovíniová of protection of galactose with 2,2-dimethoxypropane,²⁸¹229 could be converted to the furanose acetonide 234, which was the thermodynamically more stable acetonide as shown by the isomerization of 233 to 234. After anomeric protection as acetate 235, however, acetonide hydrolysis conditions caused anomeric deprotection, initiating ring isomerization back to the pyranose 229. Finally, it was discovered that direct acetylation of 235 with bismuth triflate as catalyst did not lead to ring isomerization, and the furanose triacetate 232 was obtained as a suitable precursor for glycosylation reactions.

Scheme 32. Protection of 2,3-Dideoxy-2,3-difluoro-d-galactose to Obtain the Furanose Form²⁷⁴.

3.6.1.3. 2,3-Difluorinated Mannose Derivatives

A synthesis of the 2,3-difluorinated mannose derivative 244 (Scheme 33) was reported by the Giguère group, with epoxide 238 as the key intermediate.²⁸² This epoxide was synthesized via advanced intermediate 218, which was obtained in three steps from levoglucosan,²²¹ via mesylation and then slow addition of NaOMe, which significantly improved the yield of this reaction.^221,283 The methoxide reacts with the 2-OTs group at the sulfur atom to generate the corresponding alkoxide, which then displaces the 3-OMs group to form the epoxide. This reaction was further improved by the use of dichloromethane as the solvent instead of chloroform.²²⁷ The epoxide 238 is then regioselectively opened with KHF₂ to give 239, after which the OH-2 group is activated to the triflate 240 and displaced by fluoride to give 241.²⁷⁵ Deprotection, acetolysis, and acetate methanolysis then gave 2,3-dideoxy-2,3-difluoro-d-mannose 244.²⁸²

Scheme 33. Synthesis of 2,3-Dideoxy-2,3-difluoro-d-mannose²⁸².

3.6.1.4. 2,3-Difluorinated Talose Derivatives

The advanced intermediate 242 (cf. Scheme 33) was also used for the synthesis of the 2,3-difluorinated talose 248 (Scheme 34). Lattrell-Dax inversion²⁷⁶ at C-4 to give 246(275) was followed by 1,6-anhydro-bridge acetolysis to 247, then acetate hydrolysis to give 2,3-dideoxy-2,3-difluoro-d-talose as a mixture of pyranose and furanose tautomers 248 and 249.²⁸²

Scheme 34. Synthesis of 2,3-Dideoxy-2,3-difluoro-d-talose²⁸².

The synthesis of 4-O-acetyl-2,3,6-trideoxy-2,3-difluoro-α-l-talopyranose bromide 262 was described by the Tsuchiya group, starting from methyl α-l-fucopyranoside 250 (Scheme 35).²⁸⁴ After selective protection as its acetonide, which enabled separation of the anomers of 251,²⁸⁵ the α-anomer was used to continue the synthesis. Position 2 was acetylated using a standard procedure,²⁸⁶ giving compound 252, and the acetonide was subsequently hydrolyzed to give 253. Selective tosylation at the equatorial position and benzylation of position 4 gave 255, upon which treatment with sodium methoxide in methanol gave the l-gulo-2,3-epoxy derivative 256. Fluorination of 256 was achieved with KHF₂ in ethylene glycol by selective epoxide opening, giving the 2-fluoro-l-idopyranose derivative 257.²⁸⁵ Deoxyfluorination of 257 using DAST led to a complex mixture, but activation of position 3 as triflate 258 followed by nucleophilic substitution using tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) as the fluoride source successfully led to 2,3,6-trideoxy-2,3-difuoro-α-l-talopyranoside 259.²⁸⁴ Hydrogenolysis and acetolysis gave a mixture of α- and β-261 (α/β ratio: 2.5:1), and bromination of α-261 gave crystalline 2,3,6-trideoxy-2,3-difluoro-α-l-talopyranosyl bromide 262.

Scheme 35. Synthesis of 2,3,6-Trideoxy-2,3-difluoro-α-l-talopyranosyl Bromide²⁸⁴.

3.6.2. Tetrafluorinated at Positions 2 and 3

The synthesis of 2,3-dideoxy-2,2,3,3-tetrafluorinated sugar derivatives was reported by Linclau et al. using a de novo approach, starting from commercially available fluorinated building block 263 (Scheme 36).^287,288 Radical abstraction of iodine from 263 by a single electron transfer initiated by dithionite homolysis led to addition to alkene 264, which resulted in 265 after the atom transfer propagation step. Elimination at low temperature with wet DMF led to the alkene 266 in excellent yield and stereoselectivity. A Sharpless asymmetric dihydroxylation reaction gave the syn-diol 267 in excellent yield. Due to the alkene deactivation by the fluorination,²⁸⁹ increased levels of osmium and ligand were required, but the ligand could be easily recovered.²⁹⁰ Subsequent recrystallization led to essentially enantiopure material. Selective protection was achieved by deprotonation of the most acidic alcohol group of 267 followed by benzylation, leading to 268 with minimal diprotection (5%, not shown). Formylation then gave the cyclization precursor 269, which upon bromine–lithium exchange to 270 allowed cyclization to the protected tetrafluorinated sugar derivative 271. Hydrogenolysis then led to 2,3-dideoxy-2,2,3,3-tetrafluoro-d-threo-hexopyranose 272.^287,288

Scheme 36. Synthesis of 2,3-Dideoxy-2,2,3,3-tetrafluoro-d-threo-hexopyranose^287,288.

Protection of the other alcohol group in 267 allows synthesis of furanose derivatives.^288,291 Reaction with MOM-Cl (Scheme 37) gave 273 as the major regiosiomer in 70% yield, as a result of the most nucleophilic alcohol group reacting in preference. With TESCl as the electrophile, 274 was obtained in 80% yield. The regioisomers 275 and 276 were obtained in 11% and 6% yields, respectively, and both reactions also returned fully protected product (5% with MOM, 10% with TES, not shown). Formylation and bromine–lithium exchange then allowed cyclization to give 279 and 280 depending on the protection.^288,291 Interestingly, with TES protection a rearrangement took place to give the more stable pyranose analogue 281 as a side product.²⁸⁸

Scheme 37. Synthesis of 2,3-Dideoxy-2,2,3,3-tetrafluoro-d-threo-hexofuranose Derivatives^288,291.

The corresponding gluco-configured diastereomer 286 was also synthesized from 266 (Scheme 38) and required inversion of configuration of one of the alcohols. Because adjacent fluorination hampers the S_N2 reactions,^{143,164−166} inversion of the C-5 (sugar numbering) alcohol was targeted. This required carrying out the asymmetric dihydroxylation using the pseudoenantiomeric ligand and was achieved in similar yield and enantioselectivity, with recrystallization leading to highly enantioenriched ent-267. Inversion at C-5 was successfully achieved via a cyclic sulfate intermediate 282 in good yield, with 15% of a separable side-product arising from competing elimination (not shown). From 283, 286 was obtained via the same four steps as described in Scheme 36.^287,288

Scheme 38. Completion of the Synthesis of 2,3-Dideoxy-2,2,3,3-tetrafluoro-d-erythro-hexo-pyranose (“Tetrafluorinated Glucose”)^287,288.

Perfluoroalkyl lithium species are unstable and rapidly lead to fluoride elimination. Clearly, the rate of cyclization toward 271 and 285 outstrips the rate of elimination. Konno and co-workers even achieved an intermolecular addition of a lithiated 287 to the protected glyceraldehyde 288 under Barbier conditions (Scheme 39),²⁹² which allows a shorter sequence to 272 and especially 286. A key condition was that LiBr-free MeLi was used. This intermolecular reaction afforded a 43:57 mixture of coupling adducts 289 and 290, which were separated by column chromatography.²⁹³ Subsequently, acid catalyzed deprotection yielded triols 291 and 292, which following ozonolysis spontaneously cyclized to afford the target sugars 286 and 272. Despite only being described on a small scale, this three-step sequence constitutes the most efficient route to tetrafluoro glucose 286 and galactose 272, obtained in 24% and 38% overall yields, respectively. However, a large excess of MeLi and aldehyde 288 is required (2.4 equiv each) due to competing addition of MeLi to the electrophilic aldehyde 288.

Scheme 39. A Shorter Synthesis of 2,3-Dideoxy-2,2,3,3-tetrafluoro-d-erythro-hexo-pyranose (“Tetrafluorinated Glucose”) 2,3-Dideoxy-2,2,3,3-tetrafluoro-d-threo-hexo-pyranose (“Tetrafluorinated Galactose”)²⁹².

This methodology was further extended by the same group to the corresponding 6-deoxygenated sugar derivatives 298 and 299 (Scheme 40) using the ethyl lactate derived 293 as the electrophile. Chromatographic separation of the resulting diastereomers 294 and 295, followed by ozonolysis and hydrogenolysis, led to 298 and 299 in excellent yields.

Scheme 40. Synthesis of 2,3,6-Trideoxy-2,2,3,3-tetrafluoro-d-erythro-hexo-pyranose (“Tetrafluorinated Quinovose”) 2,3,6-Trideoxy-2,2,3,3-tetrafluoro-d-threo-hexo-pyranose (“Tetrafluorinated Fucose”)²⁹².

3.7. Fluorination at Positions 2 and 4

3.7.1. Difluorinated at Positions 2 and 4

3.7.1.1. 2,4-Difluorinated Glucose Derivatives

The first synthesis of 2,4-dideoxy-2,4-difluoroglucose was reported by the Cerny group (Scheme 41A).²⁷¹ Starting from 221, obtained from levoglucosan as discussed in Scheme 30, hydrogenolysis and selective tosylation afforded 301, whereupon the second fluoride was installed after another epoxide introduction. This led to 303 in modest yield. Interestingly, the two fluorine atoms could be introduced directly from 132,^219,220 albeit in low yield (5%), which nevertheless is higher than the overall yield via 302. Acid-catalyzed hydrolysis then gave the target sugar 304.

Scheme 41. Approaches to 2,4-Dideoxy-2,4-difluorinated Glucose^{215,217,271,297}.

Another synthesis of the pivotal 2,4-difluorinated intermediate 303 was published around the same time by Barford et al.,²¹⁷ also starting from levoglucosan (Scheme 41B), but with the first fluorine introduction at C-4 involving intermediate 134 as described in Scheme 19. This was tosylated to give 305 and subsequent treatment with base gave epoxide 306. This was then opened with fluoride to give 303 in 59% yield. Direct treatment of 305 with KHF₂ in boiling ethylene glycol, which relied on in situ epoxide formation, only proceeded to give 303 in 8% yield. A shorter synthesis of 305 was later published by the Voznyi group by opening of the epoxide 132 with 2,4,6-collidine·HF.²⁹⁴

A good-yielding direct synthesis of 303 has only been recently achieved by the Giguère group,^275,295 and then by our group,²⁹⁶ from the easily accessible ditosylate 131 (Scheme 41C). Using this procedure, Giguère achieved three-step synthesis of 304 in excellent yield via opening of the 1,6-anhydro-bridge in 303 with a strong Lewis acid.²¹⁵

3.7.1.2. 2,4-Difluorinated Allose Derivatives

A 2,4-difluorinated allose derivative was also prepared from 303 by the Cerny group (Scheme 42).²⁹⁸ The required C-3 alcohol inversion was achieved by oxidation to give the ketone as the hydrate 308, followed by NaBH₄ reduction. The original oxidation conditions involved the use of CrO₃, but the oxidation was found to work with TCCA/TEMPO,²⁹⁶ or with DMP as well.²¹⁵ Ring opening of the thus obtained allose derivative 309 was not possible using 1% aq. pTSA, but acetolysis under perchloric acid did give triacetate 310, albeit in low yield. Deacetylation then gave the free 2,4-dideoxy-2,4-difluoroallose 311.²⁹⁸

Scheme 42. Synthesis of 2,4-Dideoxy-2,4-difluoroallose²⁹⁸.

3.7.1.3. 2,4-Difluorinated Talose Derivatives

The synthesis of 2,4-dideoxy-2,4-difluorotalose is possible from glucose through deoxyfluorination with inversion of configuration at C-2 and C-4. The Cabrera-Escribano group described the treatment of both anomers of methyl 3,6-di-O-benzyl glucopyranoside 312 with DAST (Scheme 43A) to achieve exactly that.²⁹⁹ However, while deoxyfluorination was observed at the 4-position, a ring contraction occurred at the 2-position to give epimers 313 and 314, regardless of the anomeric configuration. A ring contraction had not been reported by the Somawardhana and Card groups in their deoxyfluorination experiments of unprotected methyl glucosides.^300−302 Presumably the presence of a benzyl group in 312, which is less electron withdrawing compared to an alcohol group activated by DAST, allows the intramolecular S_N2 reaction by the endocyclic oxygen at C-2 (cf. 315), with deoxyfluorination at C-4 likely to take place after the furanose ring is obtained (see later Scheme 144).

Scheme 43. Synthesis of a 2,4-Dideoxy-2,4-difluorotalose Derivative^299,303.

Scheme 144. Investigations on the Direct DAST-Mediated Difluorination of a Branched Nitrosugar^299,443.

The Gouverneur group did achieve a synthesis of a 2,4-difluorinated talose derivative by a sequential fluorination method starting from known 316 (Scheme 43B),³⁰³ synthesized in two steps from methyl α-d-glucoside (not shown).³⁰⁴ Fluorination of 316 at the 2-position by displacement of the corresponding triflate 317 had been described.³⁰⁵ However, while this S_N2 reaction using TBAF·3H₂O in acetonitrile proceeds well with the β-anomer, a low 30% yield had been reported for the desired α-anomer. Extensive optimization led to a significantly improved yield of 318 (77%), by in situ conversion of TBAF·3H₂O to TBAF·(t-BuOH)₄ via stirring in t-BuOH in the presence of 317. Because selective benzylidene acetal reduction in 318 was not successful, it was hydrolyzed and the OH-6 was selectively protected as the pivaloate ester 320 (11% of diester). Having established that 320 did not react with DAST, no doubt because the axial F-2 group prevented S_N2 reaction with an equatorial C-4 leaving group, a second triflation with subsequent fluoride displacement was carried out, giving 322 with a 43% yield for the displacement step. The difficult substitution also led to the isolation of desulfonylated product 320 (8%), starting material 321 (13%), and a range of other byproducts (not shown). Finally, hydrogenolysis gave 323, which was used in intramolecular hydrogen-bond studies.³⁰⁶

3.7.2. Trifluorination at Positions 2 and 4

The Gouverneur group also synthesized racemic 2,4-dideoxy trifluorinated sugar derivatives (Scheme 44),³⁰⁷ using a de novo synthesis approach starting from a difluorinated building block 324, featuring a 6-endo-dig gold-catalyzed ring formation. A Reformatski reaction with (benzyloxy)acetaldehyde 325 led to racemic 326, upon which alkyne introduction via the corresponding Weinreb amide intermediate (±)-327 gave the cyclization precursor (±)-328. A high-yielding ring formation was achieved with the Gagosz catalyst, with the obtained dihydropyran ring (±)-329 nicely set up for electrophilic fluorine introduction at C-2. Reduction of the keto group to give (±)-330 was moderately selective (83:13) in favor of the desired C-3 configuration, and the diastereomers could be separated after pivaloyl protection. Due to the deactivation by the fluorine atoms, reaction of the glycals with SelectFluor required heating, but excellent yields were obtained. Starting from the pivaloate (±)-331, a 5:1 ratio of gluco:manno stereochemistry (±)-332, (±)-333 was obtained, separable after acetylation to (±)-334 and (±)-335. From (±)-cis-330, in which the 3-O-pivaloyl group was removed, the gluco:manno ((±)-336 and (±)-337) ratio was reduced to 3:2, with a better overall yield. Acetylation to (±)-338/(±)-339 again allowed separation. In both cases, (±)-335 and (±)-339 were obtained as α-anomers. When the reaction was conducted in nitromethane/methanol the corresponding methyl acetals (±)-340 and (±)-341 were formed directly, and were separable by chromatography.

Scheme 44. Synthesis of Racemic 2,4-Dideoxy-2,4,4-trifluorinated Sugar Derivatives³⁰⁷.

3.8. Fluorination at Positions 2 and 5

There is no reported synthesis available of a 5-fluorinated 2-deoxyfluorinated hexose sugar, although a 2,5-difluorinated glucose derivative has been obtained as a byproduct in the synthesis of 2-deoxy-1,2-difluoroglucopyranosyl fluoride 4 (Scheme 16).

3.9. Fluorination at Positions 2 and 6

3.9.1. Difluorinated at Positions 2 and 6

3.9.1.1. 2,6-Difluorinated Glucose Derivatives

The first 2,6-difluorinated glucose derivative, nucleoside analogue 349, was reported in 1978 by Etzold et al.³⁰⁸ The synthesis started from 1-glucosyl thymine 343 (Scheme 45), which can be obtained from glucose peracetate 155 in two steps.^309,310 Tosylation was only moderately selective at the 6-position, and the mixture was acetylated to then separate the 2,6-ditosylated byproduct. This gave 344 in 61% yield.³¹⁰ Fluorination with KF in ethylene glycol at high temperature was described to give the deacetylated 6-fluoroderivative 345. Position 2 could now be activated as the p-toluenesulfonylate, giving 346 in 40% yield. After acetylation to give 347, reaction with triethylamine in ethanol with inversion of configuration at C-2 gave the 2,2′-anhydro-nucleoside 348. Reaction with HF under AlF₃-catalysis in dioxane in a steel reactor gave the desired 2,6-dideoxy-2,6-difluoro glucopyranose 349 in 11% yield.^308,310

Scheme 45. Synthesis of 1-(2′,6′-Dideoxy-2′,6′-difluoroglucosyl)thymine³⁰⁸.

The first synthesis of the free 2,6-dideoxy-2,6-difluoro-d-glucose sugar 352 was reported by Withers (Scheme 46),³¹¹ starting from trifluoromethyl 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-α-d-glucopyranose 11, which was obtained from 3,4,6-tri-O-acetyl-d-glucal 1 by reaction with fluoroxytrifluoromethane (cf. Scheme 4).¹⁵⁷ Deacetylation of 11 with NaOMe in MeOH to 350 allowed a selective reaction with DAST at the primary alcohol to give 351. Acid-catalyzed hydrolysis then gave 2,6-dideoxy-2,6-difluoro-d-glucopyranose 352 in 76% yield.³¹¹

Scheme 46. Synthesis of 2,6-Dideoxy-2,6-difluoro-d-glucopyranose³¹¹.

A synthesis of 352 avoiding the use of CF₃OF was reported by Giguère et al. (Scheme 47).²¹⁵ Intermediate 221, obtained in five steps as discussed above (Scheme 30), was fully benzylated to give 353. Anhydro-bridge acetolysis without benzyl removal led to 354 in 98% yield. Differentiation of the acetate groups was achieved by glycosidation to give 355, after which acetyl deprotection allowed deoxyfluorination at C-6 with DAST. This afforded compound 357 without any observation of 3,6-anhydro side-product formation (cf. Schemes 26 and 28). In addition to the presence of base, presumably the configuration of the F-2 group, which will be antiperiplanar with the C-3 OBn bond in the ¹C₄ conformation required for 3,6-anhydro formation, will have deactivated the O3 for nucleophilic attack at the activated OH-6 group. Deprotection of 357 then led to 2,6-dideoxy-2,6-difluoro-d-glucose 352.

Scheme 47. Synthesis of 2,6-Dideoxy-2,6-difluoro-d-glucose²¹⁵.

3.9.1.2. 2,6-Difluorinated Galactose Derivatives

In 2012, the Hoffmann-Röder group reported a synthesis of a protected 2,6-dideoxy-2,6-difluoro-d-galactopyranose 361 (Scheme 48).⁴³ Starting from 1,2:3,4-di-O-isopropylidene galactose 210, deoxyfluorination at C-6 (cf. Scheme 28B), acetolysis, and HBr treatment gave the corresponding galactopyranosyl bromide 358.¹⁹⁶ Zn-mediated reductive elimination of the 1-bromo and 2-acetoxy groups led to 6-deoxy-6-fluoro-galactal 359 in 89% yield. After an acetate-to-benzyl protecting group switch, electrophilic fluorination using SelectFluor in aqueous medium afforded 3,4-di-O-benzyl-2,6-dideoxy-2,6-difluoro-d-galactose 361 in 97% yield.⁴³

Scheme 48. Synthesis of a 2,6-Dideoxy-2,6-difluorogalactopyranose Derivative⁴³.

3.9.1.3. 2,6-Difluorinated Fucose Derivatives

This synthesis, published in 2020 by the Wang group (Scheme 49),¹⁹⁸ is very similar to the 2,6-difluorinated galactose synthesis discussed above, but starting from l-galactose. Reaction with zinc chloride, sulfuric acid, and acetone gave 1,2:3,4-di-O-isopropylidene-α-l-galactopyranose ent-210 in 85% yield. Deoxyfluorination of ent-211 with DAST in the presence of 2,4,6-collidine according to Hoffmann-Röder’s procedure (cf. Scheme 28B),¹⁹⁶ but in refluxing dichloromethane as opposed to under microwave conditions, led to ent-211 in a slightly lower yield. Acid-catalyzed hydrolysis followed by acetylation gave the peracetylated 6-fluoro-l-fucose 362 in 92% yield over two steps. Treatment of 362 with hydrogen bromide and subsequent reductive elimination afforded 6-fluoro-l-fucal ent-359, which was subjected to SelectFluor, and protected to give peracetylated 2,6-difluoro-l-fucose 363.¹⁹⁸

Scheme 49. Synthesis of Peracetylated 2-Deoxy-2,6-difluorofucose¹⁹⁸.

3.9.1.4. 2,6-Difluorinated Mannose Derivatives

The synthesis of a 2,6-difluorinated mannose derivative was reported by the Lowary group from 2-deoxy-2-fluoro-α-mannose peracetate 49 (Scheme 50),³¹² which is most efficiently prepared from 3,4,6-tri-O-acetylglucal 1 involving reaction with SelectFluor, followed by acetylation to achieve separation from the 2-fluoroglucose stereomers as shown in Scheme 16.^170,177 Anomeric deprotection and activation as the trichloroacetimidate 364(313) allowed mannosylation with acceptor 365 to give the monofluorinated disaccharide 366.³¹⁴ Deacetylation to 367 allowed selective fluorination at the 6′-position (with S_N2 reaction at the 3- and 4- positions prevented by the axial C-1 and C-2 substituents, respectively) and, after benzyl hydrogenolysis, the 2′,6′-dideoxy-2′,6′-difluorinated dimannoside 368 was obtained.³¹²

Scheme 50. Synthesis of Octyl 2,6-Dideoxy-2,6-difluoro-α-d-mannopyranosyl-(1→6)-α-d-mannopyranoside³¹².

3.9.1.5. 2,6-Difluorinated Altrose Derivatives

Studies by the Tsuchiya group regarding the regioselective opening of 2,3-anhydroallopyranoside derivatives such as 372 led to the synthesis of 2,6-dideoxy-2,6-difluoroaltrose derivatives (Scheme 51).³¹⁵ The epoxy intermediate 370, which can be obtained from methyl glucoside 369 in four steps via selective OH-3 tosylation, base-mediated epoxide formation,³¹⁶ and hydrolysis,³¹⁷ was selectively methylated at the 4-position to give 371.³¹⁵ Its deoxyfluorination led to 372, which was further fluorinated by reaction with KHF₂ in ethylene glycol to give an inseparable mixture of the altro-derivative 373 and the gluco-derivative 374 in a 2:3 ratio.³¹⁵ The surprisingly low ratio may be due to the electronic influence of the more electronegative anomeric center (cf. Scheme 95A below), disfavoring substitution at C-2 despite the chairlike conformation associated with the latter.

Scheme 51. Synthesis of a 2,6-Dideoxy-2,6-difluoroaltrose Derivative³¹⁵.

Scheme 95. Linear Synthesis of 2′,3′-Dideoxy-2′,3′-difluorinated Ribonucleosides Starting from Nucleosides Using Sequential Fluorination via Epoxide Opening^364,368,369.

3.9.2. Tetrafluorinated at Positions 2 and 6

The tetrafluorinated derivative 386 (Scheme 52) was synthesized by the Takagi group from methyl-α-d-lyxopyranoside 375 using a head-to-tail strategy through the addition of a CF₃ group at the precursor C-1 position.³¹⁸ Hence, nucleophilic fluorination of 375 at C-4 with inversion of the configuration was achieved through a reaction with DAST, to afford 4-deoxy-4-fluoro-β-l-ribopyranoside 376 in an excellent yield. The observed regioselectivity mirrored that of the fluorination of methyl α-mannoside as reported by Somawardhana (see below, Scheme 65), with the OH-2 group promoting fluorination at C-4.³⁰¹ Benzylation of 376 with benzyl bromide to give 377 was followed by anomeric hydrolysis to give the reducing sugar 378, the major α-anomer of which is depicted (4:1 ratio in chloroform). Treatment with 1,3-propanedithiol and BF₃·OEt₂ gave the ring-opened dithioacetal 379, and protection of the terminal alcohol as the acetate, followed by deprotection of the aldehyde group, gave 381 ready for trifluoromethylation. This was achieved by reaction with Me₃SiCF₃ and catalytic TBAF,³¹⁹ which after hydrolysis of residual TMS-ether formed in situ led to a mixture of epimers 382 and 383. The d-allitol derivative 383, which was undesired in this case, could be converted to 382 by alcohol inversion. Deacetylation of 382 allowed oxidation to the aldehyde, which was achieved in chemoselective fashion thanks to the reduced reactivity of the trifluorocarbinol group.³²⁰ The aldehyde spontaneously converted to the corresponding α-l-talopyranose, isolated as the anomeric acetate 385, upon which hydrogenolysis delivered 386. In parallel, 383 went through the same route to give the β-d-allose 387 (not shown).

Scheme 52. Synthesis of 2,6-Dideoxy-2,6,6,6-tetrafluorinated Talose and Allose Derivatives³¹⁸.

Scheme 65. Direct Dideoxy Difluorination Reactions toward 4,6-Difluorinated Talose Derivatives^{229,230,301,302,333}.

3.10. Fluorination at Positions 3 and 4

3.10.1. Difluorinated at Positions 3 and 4

The synthesis of the 3,4-dideoxy-3,4-difloro glucose 392 (Scheme 53) was initially described by the Linclau group,²²⁴ and later improved by the Giguère group,²¹⁵ starting from known 133 (cf. Scheme 19). Benzylation of the alcohol group was achieved by adding the NaH base to a premixed solution of 133 and BnBr while keeping the temperature at 0 °C to avoid the Payne rearrangement.³²¹ Epoxide opening using a 1:1 mixture of KHF₂/KF resulted in the formation of 389 in 85% yield. The alcohol 389 was then treated with DAST in refluxing CH₂Cl₂ for 20 h resulting in the dideoxy difluorinated levoglucosan analogue 390 in 54% yield, while the use of DeoxoFluor in toluene at 70 °C for 2 h gave compound 390 in 67% yield, together with only 3% of unreacted 389, and 4% of byproduct 391, which arose from neighboring group participation of O6. An improved fluorination was reported by Giguère: a 2-step triflation and fluoride substitution with HF·3HF.^215,272 Finally, concomitant deprotection of OH-2 and opening of the anhydro-bridge were achieved with BCl₃ to give the desired difluorinated glucose analogue 392.^215,224

Scheme 53. Synthesis of 3,4-Dideoxy-3,4-difluoro-d-glucopyranose^215,224.

The synthesis of 3,4-dideoxy-3,4-difluorogalactose 397 was published by the Linclau group (Scheme 54).²⁷⁴ Starting from known crystalline tosylate 132 (cf. Scheme 19), reaction with sodium hydroxide and ethanol gave the 1,6:2,3-dianhydro derivative 393. As described by Karban et al.,¹⁴⁶ reaction of the epoxide 393 with DAST gave the desired compound 394 (61% yield) along with the byproduct 395 (26%). The fluoride-mediated epoxide opening of 394 gave the desired difluorinated 396 in 31% yield. Opening of the 1,6-anhydro-bridge was achieved using BCl₃ to form the corresponding glycosyl chloride, which was directly hydrolyzed to give 397, in 36% yield. A much higher-yielding procedure involved TMSOTf-catalyzed acetolysis to give 398, which could then be deprotected to give 397 in 81% yield over two steps.

Scheme 54. Synthesis of 3,4-Dideoxy-3,4-difluoro-d-galactopyranose²⁷⁴.

3.10.2. Tetrafluorinated at Positions 3 and 4

The synthesis of 3,4-dideoxy-3,3,4,4-tetrafluorinated sugar derivatives was reported by Linclau et al. using a fluorinated building block approach (Scheme 55).²⁸⁸ Sharpless asymmetric dihydroxylation of 287 required modification with enhanced levels of OsO₄ and ligand to accommodate the reduced reactivity of the deactivated alkene (cf. Scheme 36), as well as the use of (DHQ)₂PYR instead of the usual (DHQ)₂PHAL ligand. This gave 399 in an excellent yield and, as expected for terminal alkenes, moderate enantioselectivity after 9 days.²⁹⁰ Protection of the primary alcohol led to 400, and its functionalization with (S)-Naproxen allowed separation of the thus formed diastereomers to get, after ester cleavage, 400 in >99% enantiopurity. The expensive (S)-Naproxen could be recovered and recycled. Protection of the secondary alcohol group by DDQ-mediated cyclization gave 402 as a mixture of acetal diastereomers,²⁸⁸ which could now be lithiated and reacted with cinnamaldehyde. This addition was not diastereoselective and gave 403 as a 1:1:1:1 mixture of diastereomers. Acetal hydrolysis and alkene ozonolysis led to the formation of the desired tetrafluorinated sugar derivatives 405 and 406, which were not separable. Selective silylation at the primary position, anomeric alkylation with 2-naphthyl methyl bromide, and silyl removal gave the separable 409 and 410, each of which could now be deprotected to give the pure 405 and 406.²⁸⁸

Scheme 55. Synthesis of 3,4-Dideoxy-3,3,4,4-tetrafluoro-d-threo-hexopyranose 405 and 3,4-Dideoxy-3,3,4,4-tetrafluoro-d-erythro-hexopyranose 406(288).

3.11. Fluorination at Positions 3 and 6

3.11.1. 3,6-Difluorinated Glucose Derivatives

The Withers group reported a synthesis of 3,6-dideoxy-3,6-difluoro glucopyranose 418 (Scheme 56) from glucose diacetonide 411.³¹¹ Conversion to the corresponding allose 412 using an oxidation–reduction sequence was then followed by DAST-mediated deoxyfluorination at C-3 to give 413.^139,214 Selective deprotection of the terminal acetonide in 413 was achieved using sulfuric acid in methanol, giving 414 in 93% yield. Direct fluorination at C-6 was unsuccessful and only led to a 5,6-cyclic sulfite byproduct 415. Hence, a three-step protecting group manipulation sequence was carried out to give 416. Treatment with DAST gave the difluorinated product 417, which upon deprotection gave the 3,6-dideoxy-3,6-difluoro-d-glucopyranose 418. Successive acetylation of the free hydroxyl groups, bromination of the anomeric position, and displacement with acetate gave the peracetylated 3,6-dideoxy-3,6-difluoro-β-d-glucopyranose 419 in 79% yield over four steps.

As discussed in Scheme 51, a 3,6-dideoxy-3,6-difluorinated glucose was also obtained by fluoride opening of the 6-deoxy-6-fluoro-2,3-epoxy allose derivative 372 with potassium hydrogen difluoride in ethylene glycol, which gave a mixture of inseparable methyl 2,6-dideoxy-2,6-difluoro-4-O-methyl-α-d-altropyranose 373 and methyl 3,6-dideoxy-3,6-difluoro-4-O-methyl-α-d-glucopyranose 374 in 65% yield (Scheme 57).³¹⁵

Scheme 57. Synthesis of a 3,6-Dideoxy-3,6-difluoro Glucopyranoside Derivative³¹⁵.

Giguère’s group prepared 3,6-dideoxy-3,6-difluoroglucopyranose 418 (Scheme 58), starting from commercially available levoglucosan.²¹⁵ Conversion to 125 as detailed in Scheme 18 was followed by 1,6-anhydro-bridge opening and selective acetolysis, giving compound 420 in 98% yield. The anomeric position was protected using glycosidation with allyloxytrimethylsilane to afford intermediate 421. This allowed acetate removal at C-6, followed by deoxyfluorination to afford 423. Final deprotection with BCl₃ afforded the desired 3,6-difluoroglucose analogue 418 in 75% yield.²¹⁵

Scheme 58. Synthesis of 3,6-Dideoxy-3,6-difluoro-α-d-glucopyranose²¹⁵.

3.11.2. 3,6-Difluorinated Allose Derivatives

The Somawardhana group reported that reaction of unprotected methyl β-d-glucopyranoside β-369 with neat DAST at room temperature (Scheme 59A) gave 3 main products: methyl 3,6-dideoxy-3,6-difluoro-β-d-allopyranoside 424 in 32% yield, methyl 4,6-dideoxy-4,6-difluoro-β-d-glucopyranoside 425 in 8% yield, and methyl 6-deoxy-6-fluoro-β-d-glucopyranoside 426 (no yield reported).³⁰¹

Scheme 59. Synthesis of 3,6-Dideoxy-3,6-difluoro-allopyranosides Using Direct and Sequential Difluorination^301,302,322.

The same year, the Card group also published direct fluorination of unprotected glucosides using DAST,³⁰² but with CH₂Cl₂ as the solvent, at −40 °C (Scheme 59B). Methyl β-d-glucopyranoside β-369, phenyl β-d-glucopyranoside 427, and p-nitrophenyl β-d-glucopyranoside 428 gave their corresponding 3,6-dideoxy-3,6-difluoro-allopyranoside products in 51%, 70%, and 78% yields, respectively. There was no mention of fluorination at the 4-position. This dideoxy difluorination process was reported to be facile, and the remarkable regioselectivity explained by activation of all alcohol groups by DAST with the primary position reacting first, leading to 431 (Scheme 59C). The reactivity at the 2- and 4-positions is reduced due to the presence of an antiperiplanar C–O bond, as well as to the higher electron withdrawing effect of the acetal center. With a β-configured glycoside, approach of the fluoride nucleophile toward C-3 is unhindered, hence leading to a facile reaction.

A sequential fluorination approach for the synthesis of a 3,6-dideoxy-3,6-difluoroallose derivative 436 has also been reported,³²² starting from 7-β-d-glucopyranosyl theophylline 432 (Scheme 59D). Positions 4 and 6 were first protected as the acetonide,³²³ which allowed for selective fluorination of position 3 using DAST to give 434 in 43% yield. Benzoyl protection of position 2 and acetonide removal, to give 435,³²⁴ was then followed by fluorination of position 6 in 50% yield.³²²

3.12. Fluorination at Positions 4 and 6

3.12.1. 4,6-Difluorinated Galactose Derivatives

The synthesis of 4,6-dideoxy-4,6-difluorinated galactose is possible in one step from α-configured glucosides (Scheme 60). The Somawardhana group reported that reaction of methyl α-d-glucopyranoside α-369 with neat DAST gave the 4,6-difluorinated methyl galactoside α-425 in 60% yield (a).³⁰⁰ Reducing the number of equivalents (b) also led to α-425 in 60% yield, this time with 9% of the monofluorinated methyl glucoside α-426.³⁰¹ While the Card group initially reported that when dichloromethane is used as solvent only α-426 is obtained (c),²²⁹ they later found that stirring at room temperature for 3–4 days led to the difluorinated α-425 in 40–46% yield.^302,325 Similar observations were made with phenyl α-glucoside α-427, which transformed to 437 in neat DAST, and to 438 when dichloromethane was used as solvent.³⁰² The regioselectivity of the difluorination reaction was explained as follows (also see Scheme 59 with the explanation of the selectivity starting from the β-anomer):³⁰¹ activation of all glucoside alcohol groups would occur, with the primary position reacting fast, to the 6-deoxy-6-fluorinated derivative 439. Reaction at the 3-position is sterically hindered by the axial anomeric substituent, and reaction at the 2-position is disfavored due to the electron withdrawing acetal center. This makes the 4-position the next-fastest to react, leading to 440. Now, reaction at the 2-position is additionally hindered by the axial fluorine at C-4, and workup then leads to α-425.

Scheme 60. Direct Dideoxy Difluorination of α-Glucosides^{300−302,325}.

Deoxyfluorinations at the 4- and 6-positions not relying on DAST have also been developed. These require protection at C-2 and C-3, although the anomeric configuration is now not important. The Szarek group converted 441 (Scheme 61A), which can be obtained from methyl β-glucoside in three standard steps (not shown), in a one-pot operation to 443 via the bis-triflate 442 in moderate yield with TASF.¹¹⁵ The Richardson group investigated the synthesis of fluorinated trehalose derivatives via di-O-mesylate fluorination. Starting from 444 (Scheme 61B), which can be obtained from trehalose in three steps, mesylation gave the fluorination substrate 445.³²⁶ Treatment of 445 with excess TBAF in refluxing acetonitrile for 1 h only led to monofluorination, resulting in 446 which, after mesylate methanolysis and deprotection, gave 6-deoxy-6-fluorotrehalose 447. In contrast, refluxing 445 for 4 days yielded the difluorination product 448 in 71% yield,³²⁷ which after deprotection resulted in 4,6-dideoxy-4,6-difluoro-α-d-galactopyranosyl-α-d-glucopyranoside 449.

Scheme 61. Difluorination of Glucoside Derivatives at the 4- and 6-Positions via Displacement of Sulfonates^{115,327,329,330}.

The Richardson group also synthesized the 4,4′,6,6′-tetramesylated trehalose derivative 451 as a substrate, from the readily available 450 (Scheme 61C).³²⁸ Subjecting the tetramesylate 451 to 8 equiv of TBAF in refluxing acetonitrile for 1 h led to the formation of the difluorinated 452 in moderate yield. After methanolysis with methoxide and benzyl hydrogenolysis, this resulted in the 6,6′-dideoxy-6,6′-difluorotrehalose 453. In contrast, when 451 was heated for 5 days with a larger excess of TBAF, the tetrafluorinated 454 was obtained in 62% yield.³²⁹ Hydrogenolysis then gave 4,6-dideoxy-4,6-difluoro-α-d-galactopyranosyl 4,6-dideoxy-4,6-difluoro-α-d-galactopyranoside 455.

Finally, the same group also investigated difluorination on the dimesylated sucrose derivative 456 (Scheme 61D),³³⁰ the reaction of which with either TBAF in refluxing acetonitrile or KF in refluxing ethylene glycol gave the difluorinated 457.

3.12.2. 4,6-Difluorinated Glucose Derivatives

Direct DAST-mediated dideoxy difluorination leading to 4,6-difluorinated gluco-configured derivatives requires galactoside protection at the 2,3-position. Hence, the 2,3-di-O-acetate 458 (Scheme 62A) was shown by the Withers group to lead to 461 in a moderate 31% yield,³¹¹ but the Hoff group reported much higher yields from the benzoate α-459, either using DAST/DMAP at room temperature or with DeoxoFluor at reflux temperature.^230,325 With the 2,3-butanedioxyacetal protected 460, the Linclau group obtained a lower yield (47%),³²⁵ which is to a certain extent offset by its more efficient preparation (1 step from methyl α-galactoside) as opposed to three steps for 458/α-459.

Scheme 62. DAST-Mediated Dideoxy Difluorination Approaches to 4,6-Difluorinated Glucose Derivatives^{230,311,325,331}.

The diacetate 461 was converted to its glycosyl chloride, and then to the β-triacetate 464.³¹¹ The benzoate α-462 was debenzoylated to give 465, which was also obtained by hydrolysis of the butanediacetal protecting group in 463.³²⁵ Anomeric acetolysis and acetate methanolysis then gave 4,6-dideoxy-4,6-difluoro-d-glucopyranose 467. Interestingly, the acetolysis reaction also yielded a ring opened 1,1-diacetoxy containing product 466.³²⁵

With the 2,3-positions protected, DAST-mediated deoxyfluorination at the 4 and 6-positions is also possible from β-galactosides. The Magnusson group applied this process to the corresponding methyl 2,3-di-O-benzoyl-β-galactopyranoside β-459 (Scheme 62B), albeit with only 1.05 equiv of DAST.³³¹ Even so, it was found that the difluorinated β-462 is still isolated in 12% yield, alongside 54% of the 6-fluorinated product 468, which gives an indication of the reactivity at the 4-position.

Difluorination using 4,6-di-O-mesylate derivatives has also been explored. The Richardson group synthesized 4,6-dideoxy-4,6-difluorosucrose 471 (Scheme 63) via displacement of the dimesylate 470 with TBAF. This dimesylate was synthesized from 456 (see Scheme 61) by nucleophilic substitution with sodium benzoate, benzoate methanolysis, and mesylation. Compared to the corresponding dimesylate 456, fluorine substitution with 470 proved more difficult, with an unidentified elimination product isolated as well.³³⁰ Fluoride displacement of the 4,6-dimesylated galacto-configured trehalose derivatives 472 and 473 was reported to give mainly elimination products.^327,329

Scheme 63. Synthesis of 4,6-Difluorinated Glucose Derivatives by Mesylate Displacement³³⁰.

Finally, a sequential approach has also been used. The Card group obtained 139 (Scheme 64A) in two steps from methyl α-d-galactoside 137 (as described in Scheme 19), which was then debenzoylated to give 474.³⁰² Treatment with DAST gave the 4,6-difluorinated glucoside 465 in good yield. The same approach was followed by the Saulnier/Balasubramanian group at Bristol Myers Squibb toward the antitumor compound analogue 475,³³² and also by the Giguère group in their synthesis from levoglucosan (Scheme 64B).²¹⁵ The intermediate 389, obtained in five steps as described in Scheme 53, was fully protected, and the resulting 476 subjected to anhydro-bridge opening to give 477. Protection at the anomeric position to give 478 allowed selective deprotection at C-6, upon which deoxyfluorination resulted in 480. Global deprotection then gave 4,6-dideoxy-4,6-difluoroglucose 467.

Scheme 64. Sequential Fluorination Approach to 4,6-Difluorinated Glucose Derivatives^215,302.

3.12.3. 4,6-Difluorinated Talose Derivatives

The Somawardhana and Card groups achieved the conversion of unprotected methyl α-mannopyranoside 481 (Scheme 65A) to the 4,6-difluorinated talopyranoside 482 in excellent yields, either in neat DAST (72%, not shown),³⁰¹ or with dichloromethane as the solvent (80%).^229,333 The reaction was reported to be more facile than reaction with methyl α-glucopyranoside (see Scheme 60). The Hoff group reported that under very similar reaction conditions 482 was isolated in only 48% yield (Scheme 65B),²³⁰ and that cyclic sulfite 483 was also obtained, which may be due to a difference in workup conditions. Nevertheless, the combined yield of 75% does indicate the ease of mannose difluorination.

The Card group further reported that this double fluoride displacement was so facile that monofluorination at the 6-postion of 481 could not be achieved,³⁰² in contrast to the reaction with methyl α-glucopyranoside (see Scheme 60). This was explained by the involvement of intermediate 484 (Scheme 65C), which would allow an intramolecular fluoride delivery to displace the activated OH-4 group. This was further investigated by subjecting the 2,3-di-O-methyl mannoside 485 to the reaction conditions, which indeed only returned the monofluorinated 486. It is nevertheless surprising that in the reaction of 481 with DAST, no neighboring group participation of the trans-diaxial anomeric methoxy group, with subsequent formation of the glycosyl fluoride, has been reported (the Somawardhana group reported an unidentified side product in 1% yield).³⁰¹ In order to achieve the synthesis of 6-deoxy-6-fluoromannosides, the reaction was also carried out with 487, which has a more easily removable protecting group at the 2,3-positions. However, only low yields of 488 were obtained, with the formation of side-product 489 explained by methanol displacement of the activated OH-6 during the workup. Subjecting 487 to DAST with a longer reaction time did lead to the 4,6-difluorinated talose derivative 490, albeit in a low yield.³⁰²

3.13. Fluorination at Positions 5 and 6

A 5,6-difluorinated UDP-galactosyl derivative 499 was synthesized by the Liu group to investigate the mechanism of UDP-galactopyranose mutase.³³⁴ The fluorine at the 5-position was not introduced via a radical bromination step (as seen for the other 5-fluorinated derivatives discussed above), but by using Coward’s 5,6-epoxide fluoride opening.³³⁵ Starting from methyl α-d-galactoside 137 (Scheme 66),³³⁴ a standard protection–deprotection sequence was followed by C-6-bromination to give 491. Displacement of bromide by phenyl selenide (generated in situ) led to 492, upon which the anomeric dibenzyl phosphate group was introduced after anomeric hydrolysis to 493. Elimination of the resulting selenide 494 to give the C-5–C-6 exocyclic double bond 495 allowed formation of the corresponding epoxide which, upon treatment with HF-py, led to regioselective opening to give both C-5-fluoro epimers 496 and 497. These were separable, and the desired major isomer was subjected to DAST to get the vicinal difluoro moiety in 498. Deprotection and UDP introduction finally gave 499. The Coward methodology allowed a C-5 fluoride introduction that was compatible with the phosphate protecting group. This sequence of events was necessary given the phosphate was introduced via the hemiacetal, and given the instability of reducing 5-fluoropyranoses, C-5 fluorination was required after the desired anomeric functionalization was completed.³³⁵

Scheme 66. Synthesis of UDP-6-Deoxy-5,6-difluoro-α-d-galactopyranose³³⁴.

4. Aldohexoses: Fluorination at Three Positions

4.1. Fluorination at Positions 1,2,5

The Withers group synthesized the trifluorinated idose derivative 502 (Scheme 67) as a glycosidase inactivator, starting from the 1,2-difluorinated glucose derivative β-2. This can be accessed as detailed in Schemes 6 and 9 either from tri-O-acetyl glucal 1 in one step (CF₃OF) albeit in low yield (12%), or in three steps involving reaction with SelectFluor and AgF-mediated fluorine introduction of the corresponding glucosyl bromide, or from 2-deoxy-2-fluoroglucose 45 also via its glycosyl bromide. Radical bromination was selective for the 5-position to give 500 only, and fluoride displacement with inversion of configuration led to the l-ido configured 501, with both reactions seemingly unaffected by the presence of the fluorine at the 2-position. Deprotection then gave 2-deoxy-2,5-difluoro-α-l-idopyranosyl fluoride 502.²⁰⁵

Scheme 67. Synthesis of 2-deoxy-2,5-difluoro-α-l-idopyranosyl Fluoride²⁰⁵.

4.2. Fluorination at Positions 1,2,6

The Withers group synthesized the 1,2,6-trifluorinated glucose 506 as a potential imaging probe for glucocerebrosidase (Scheme 68) starting from β-20 (see section 3.1.1).³³⁶ Selective tritylation and protection of the remaining alcohol groups gave 503, from which the trityl group was then removed to expose the OH-6 group ready for deoxyfluorination. This could be achieved with DAST to give 505 in excellent yield, and deprotection then gave 2,6-dideoxy-2,6-difluoro-β-d-glucopyranosyl fluoride 506. Alternatively, ¹⁸F radiolabeling at the 6-position was achieved via the triflate 507 via Kryptofix 2.2.2/K₂CO₃ assisted nucleophilic fluorination with fluoride-18, followed by acetate deprotection. A 9% radiochemical yield for 6-[¹⁸F]-506 was reported, for a synthesis/purification time of 2 h and 43 min.

Scheme 68. Synthesis of 6-[¹⁸F]-2,6-dideoxy-2,6-difluoro-β-d-glucopyranosyl Fluoride³³⁶.

4.3. Fluorination at Positions 2,3,4

4.3.1. Trifluorinated at Positions 2,3,4

4.3.1.1. 2,3,4-Trifluorinated Glucose Derivatives

The first synthesis of fully deprotected 2,3,4-trideoxy-2,3,4-trifluoro-d-glucopyranose was achieved by the O’Hagan group via a de novo synthesis approach, with 515 as a key advanced intermediate (Scheme 69).³³⁷

Scheme 69. Synthesis of an Advanced Precursor toward 2,3,4-Trideoxy-2,3,4-trifluoro-d-glucopyranose³³⁹.

A first-generation approach to generate 515 started from aldehyde 288, made from periodate cleavage of 1,2:5,6-di-O-isopropylidene-d-mannitol 508. The addition of deprotonated benzyl propargyl ether gave the adduct 509 in low stereoselectivity, which could be improved by employing ClTi(Oi-Pr)₃ as a nonchelating Lewis acid.³³⁸ Propargylic alcohol reduction with LiAlH₄ gave 510. Deoxyfluorination was then performed on the diastereomeric mixtures with tetrafluoroethyl dimethylamine (TFEDMA) in dichloromethane. It was found that this reaction proceeded with significant S_N1 character, giving all four possible allylic fluoride regio/stereomers in similar ratios regardless of the ratio of alcohols. The desired stereomer 511 could be obtained pure in 11–13% yield.³³⁹ Epoxidation gave the two diastereomers 512 and 513 in 89% yield. This mixture was treated with Et₃N·3HF to give the separable diastereoisomers 514 and 515 in, respectively, 16 and 29% yield, with the desired stereomer being the minor isomer.³³⁷

A second generation approach to 515 was successful in avoiding the formation of stereomeric mixtures (Scheme 70).³⁴⁰ It started from the commercially available butynediol 516, which was selectively mono- protected with TBDMS chloride, and reduction of the resulting derivative with Red-Al gave trans-allylic alcohol 517 in 91% yield. Sharpless epoxidation of allylic alcohol 517 provided epoxide (2R,3R)-518 in 62% yield in 89% ee. Swern oxidation of epoxide 518, followed by the reaction with triethyl phosophonoacetate, gave ester 519 in 52% yield over the two steps. Treatment of enone 519 with Et₃N·3HF resulted both in deprotection of the TBDMS group, and in the opening of the epoxide to provide, after diol protection as acetonide, the first fluorinated intermediate 511. The opening of the epoxide proceeded in a 10:1 regioselectivity, and the protection as the acetonide allowed separation of the regioisomers, giving pure 511. Reduction of the ester with DIBAL-H gave an allylic alcohol as a suitable substrate for a Sharpless epoxidation to introduce the remaining stereochemistry. This led to epoxide 512 in a 10:1 stereomeric ratio. After protection of the free alcohol, Et₃N·3HF-mediated opening of the epoxide generated 515 in 46% yield as a single diastereoisomer.

Scheme 70. O’Hagan’s Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoro-d-glucopyranose^337,340.

Then treatment of 515 with DeoxoFluor gave the trifluoroacetal 520 in 53% yield. Deprotection of the benzyl was performed using Adinolfi’s method to give the deprotected trifluoroacetal 521 in 61% yield. This was oxidized with Dess-Martin periodinane to give an α-fluoroaldehyde 522 which was directly reacted with SnCl₂ in dichloromethane to cleave the acetonide and perform the cyclization to generate 2,3,4-trideoxy-2,3,4-trifluoro-d-glucopyranose 523 in 58% yield over two steps. This synthesis was completed in 15 synthetic steps in an overall yield of 0.37%.

In 1989, the Lukacs group had reported the synthesis of the protected 2,3,4-trideoxy-2,3,4-trifluoro-d-glucopyranose 525 (Scheme 71).⁵⁸ This synthesis started from levoglucosan, proceeding via the key intermediates 223 and 228, described in Schemes 30 and 31. Reaction of 228 with DAST in dichloromethane occurred with inversion of configuration to give 524 in excellent yield. Opening of the 1,6-anhydro-bridge and acetyl protection were performed with acetic anhydride and sulfuric acid, giving the desired compound 525 in 93% yield

Scheme 71. Sarda Synthesis of Peracetylated 2,3,4-Trideoxy-2,3,4-trifluoro-d-glucopyranose⁵⁸.

However, the final DAST-mediated fluorination was found difficult to reproduce. Linclau et al. found that deoxyfluorination gave an inseparable mixture of inversion and retention of configuration (Scheme 72), with 30% of the galacto-configured 526 formed.²⁹⁶ Slower addition of DAST led to a much improved ratio, but at the expense of yield. This was also found by Giguère et al., who obtained 526 as the major product under microwave conditions.¹⁰² They eventually found a successful alternative, in that triflation followed by the addition of in situ formed Et₃N·1HF yielded 524 in excellent yield.¹⁰² They also reported that the use of TBAF·3H₂O was successful in displacing the triflate (not shown).²⁷⁵

Scheme 72. Deoxyfluorination of 20(102,296).

The Linclau group later reported a shorter synthesis of 2,3,4-trideoxy-2,3,4-trifluoro-d-glucopyranose employing 309 as a key intermediate (Scheme 73).²⁹⁶ Fluorination of 309 to give 524 was achieved with the use of nonafluorobutyl sulfonyl fluoride (NfF) in the presence of Et₃N·3HF as the external fluoride source. Finally, BCl₃-mediated opening of the 1,6-anhydro-bridge gave the desired 523 in excellent yield. This constituted a six-step synthesis of 2,3,4-trideoxy-2,3,4-trifluoro-d-glucose 523 from levoglucosan in 24% overall yield.²⁹⁶ Giguère et al. reported a similar synthesis of 523 using an alternative fluorination method.²¹⁵ Here, 309 was first converted to the corresponding triflate, allowing nucleophilic fluorination to give 524, which was immediately subjected to acetolysis to give 525 in 14% yield over three steps. Acetyl hydrolysis with HCl afforded the desired compound 523 in quantitative yield.

Scheme 73. Linclau and Giguère Syntheses of 2,3,4-Trideoxy-2,3,4-trifluoro-d-glucopyranose^215,296.

4.3.1.2. 2,3,4-Trifluorinated Galactose Derivatives

The synthesis of peracetylated 2,3,4-trideoxy-2,3,4-trifluoro-d-galactopyranose 529 (Scheme 74A) was first described by Lukacs, from the intermediate 226 also used for their corresponding glucose synthesis.⁵⁸ Treatment of 226 with DAST was reported to give 526, after which 1,6-anhydro-bridge acetolysis led to 529. Alternatively, Giguère carried out the deoxyfluorination via the triflate 227 by reaction with TBAF·3H₂O.²⁷⁵ The thus formed 526 was then directly converted to 529 in 63% overall yield. Using in situ formed Et₃N·1HF, fluoride displacement went cleanly in 82% yield.¹⁰² Acetate hydrolysis of 529 was described by Giguère to give 2,3,4-trideoxy-2,3,4-trifluoro-d-galactopyranose 530 in excellent yield.

Scheme 74. Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoro-d-galactopyranose^{58,102,275,296}.

Opening of the 1,6-anhydro-bridge directly to give the free trifluorinated galactose was reported by Linclau et al., using BCl₃ (Scheme 74B).²⁹⁶ This was carried out on the mixture of 524 and 526 (see Scheme 72), and the trifluorinated derivatives 523 and 530 proved just about separable by preparative HPLC.

4.3.1.3. 2,3,4-Trifluorinated Talose Derivatives

The synthesis of 2,3,4-trideoxy-2,3,4-trifluoro-d-talopyranose 534 (Scheme 75) was realized by the Giguère group from the advanced intermediate 246, which had been used for the synthesis of 2,3-dideoxy-2,3-difluorinated talose (Scheme 34).²⁷⁵ Interestingly, deoxyfluorination of 246 with DAST was shown to proceed with retention of configuration to give 531 in 47% yield.¹⁰² When this reaction was immediately followed by acetolysis, losses due to evaporation of the volatile 531 were avoided, and 533 was obtained in 77% yield.²⁷⁵ Fluorination at C-4 via the corresponding triflate 532 using Et₃N·3HF also led to retention of the configuration,¹⁰² but 3% of the inversion product was also isolated (not shown). Acetolysis of the mixture thus obtained led to 533 in 54% yield over three steps. Deprotection finally gave 2,3,4-trideoxy-2,3,4-trifluoro-d-talopyranose 534.²⁷⁵

Scheme 75. Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoro-d-talopyranose²⁷⁵.

4.3.1.4. 2,3,4-Trifluorinated Mannose Derivatives

For the 2,3,4-trifluorinated mannose synthesis (Scheme 76), further investigation of the fluorination of the triflate 532 by the Giguère group led to the use of Et₃N·1HF, which gave the product 535 resulting from inversion of configuration as the major product,²⁷⁵ although the talo-configured derivative 531 resulting from retention of configuration and the elimination side product 536 were formed in appreciable quantities.¹⁰² Acetolysis of 535 led to 537, and final deprotection gave 2,3,4-trideoxy-2,3,4-trifluoro-d-mannopyranose 538.²⁷⁵

Scheme 76. Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoro-d-mannopyranose²⁷⁵.

4.3.1.5. 2,3,4-Trifluorinated Altrose Derivatives

The synthesis of 2,3,4-trideoxy-2,3,4-trifluoro-d-altropyranose 542 was reported by O’Hagan as part of their first generation 2,3,4-trideoxy-2,3,4-trifluoro-d-glucopyranose synthesis (cf. Scheme 69).³³⁷ In this synthesis, 514 was obtained as a byproduct originating from an unselective epoxidation reaction. Treatment of 514 with DeoxoFluor (Scheme 77) led to the introduction of the third fluorine to give 539 in 60% yield. Deprotection of the primary alcohol was followed by oxidation with Dess-Martin periodinane to give the aldehyde 541, which was directly reacted with SnCl₂ in dichloromethane to effect cyclization to generate 2,3,4-trideoxy-2,3,4-trifluoro-d-altropyranose 542 in 48% yield over two steps.

Scheme 77. Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoro-d-altropyranose³³⁷.

4.3.1.6. 2,3,4-Trifluorinated Allose Derivatives

The Giguère group also disclosed the synthesis of a number of 2,3,4-trifluorinated allose derivatives (Scheme 78),²⁹⁵ from the difluorinated levoglucosan derivative 303 that was efficiently obtained in a 2-step procedure as described in Scheme 41C.^275,296 Introduction of the third fluorine atom via triflation and treatment with Et₃N·3HF led to 544, upon which acetolysis resulted in the formation of 545.²⁹⁵ Deprotection then gave 2,3,4-trideoxy-2,3,4-trifluoro-d-allopyranose 546.²⁷⁵

Scheme 78. Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoro-d-allopyranose^275,295.

From 545, anomeric protection via allyloxylation gave a mixture of separable anomers 547, and the α-anomer was deacetylated to allow oxidation with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and (diacetoxyiodo)benzene (BAIB) to the alluronic acid 549, which was isolated as its methyl ester 534. Alternatively, deoxyiodination led to 551, which was subsequently reduced with tris(trimethylsilyl)silane (TTMSS) under 2,2′-azobis(2-methylpropionitrile) (AIBN) initiation to give the 6-deoxy-trifluorallopyranoside 552.²⁹⁵

4.3.2. Hexafluorinated at Positions 2,3,4

DiMagno reported an enantioselective de novo approach for the synthesis of a hexafluorinated sugar derivative, starting from the commercially available fluorinated building block 553, here illustrated with the l-sugar derivative 559 (Scheme 79).^50,51 Diethyl hexafluoroglutarate 553 was reacted with 1 equiv of furanyl lithium, leading to the keto ester 554 in 60% yield. Enantioselective reduction of the keto group using (−)-DIPCl resulted in the intermediate 555, the ester group of which was directly reduced with NaBH₄ to the corresponding aldehyde, causing cyclization to give the lactol 556 in good yield. After anomeric protection, the aromatic moiety was oxidized to a carboxylic acid, which was selectively reduced to the primary alcohol in 557. The moderate enantioselectivity required further resolution, which was achieved by various crystallizations of the (R)-Naproxen derivative 558. Finally, methanolysis of both ester groups gave the l-sugar derivative 559. The synthesis with (+)-DIPCl and (S)-Naproxen was shown to lead to the corresponding d-sugar derivative.

Scheme 79. Synthesis of the 2,2,3,3,4,4-Hexafluorinated Sugar Derivative^50,51.

4.4. Fluorination at Positions 2,3,6

The synthesis of 2,3,6-trideoxy-2,3,6-trifluoro-d-glucopyranose 563, by the Giguère group, involved the advanced intermediate 223 (Scheme 80), already described for the synthesis of 2,3-difluorinated sugars (cf. Scheme 30).²⁷² Acetolysis of the 1,6-anhydro-bridge without cleaving the benzyl ether was achieved with TESOTf as catalyst, leading to 560. Differentiation of the two acetate groups in 560 was possible with a TMSOTf-catalyzed anomeric allylation to 561, which allowed acetate removal and fluorination at the 6-position to give 562. Anomeric deprotection via acid hydrolysis then led to 563.²⁷²

Scheme 80. Synthesis of 2,3,6-Trideoxy-2,3,6-trifluoro-d-glucopyranose²⁷².

4.5. Fluorination at Positions 2,4,6

The synthesis of the 2,4,6-trifluorinated glucose derivative 568 followed the same strategy as described above for the 2,3,6-derivative, and started from 303 (Scheme 81),²⁷² itself obtained in two steps from levoglucosan (cf. Scheme 41C). Hence, upon protection of the OH-3 group to 564, selective acetolysis and anomeric differentiation to 566, acetate methanolysis allowed deoxyfluorination at the 6-position to give 567. Deprotection then gave 2,4,6-trideoxy-2,4,6-trifluoroglucopyranose 568 in 85% yield.²⁷²

Scheme 81. Synthesis of 2,4,6-Trideoxy-2,4,6-trifluoro-d-glucopyranose²⁷².

4.6. Fluorination at Positions 3,4,6

A synthesis of 3,4,6-trideoxy-3,4,6-trifluoro glucopyranose 572 by Giguère et al. is shown in Scheme 82, which involved the advanced intermediate 390 (cf. Scheme 53).²⁷² Triethyl silyl triflate-catalyzed acetolysis of the 1,6-anhydro-bridge in 390 provided compound 569 in 63% yield. After protection of the anomeric center as glycoside 570, deoxyfluorination at C-6 was achieved with a deprotection–deoxyfluorination sequence, giving compound 571 in 85% yield over two steps. Final deprotection under acidic conditions allowed the formation of product 572.²⁷²

Scheme 82. Synthesis of 3,4,6-Trideoxy-3,4,6-trifluoro-α-d-glucopyranose²⁷².

5. Aldohexoses: Fluorination at Four Positions

5.1. Fluorination at Positions 1,3,4,6

The Sidhu group at Monsanto published a synthesis of the first tetradeoxy-tetrafluorinated sugar derivative with 3-deoxy-3-fluoro-α-d-glucosyl fluoride 129 (Scheme 83), discussed above in Scheme 18, as a key intermediate.⁵⁹ Treatment of 129 with neat DAST and subsequent acetylation gave 573 in 48% yield. Deprotection gave the desired 3,4,6-trideoxy-3,4,6-trifluoro-α-d-galactopyranosyl fluoride 574 in 96% yield.⁵⁹

Scheme 83. Synthesis of 3,4,6-Trideoxy-3,4,6-trifluoro-α-d-glucosyl Fluoride⁵⁹.

5.2. Fluorination at Positions 2,3,4,6

The Giguère group published a synthesis of 2,3,4,6-tetradeoxy-2,3,4,6-tetrafluoro-α-d-galactopyranoside derivatives (Scheme 84),^273,275 which involved the advanced intermediate 529 (discussed above in Scheme 74A). To achieve C-6 fluorination, an aryl group was first installed to block the anomeric position. The α-galactosyl bromide 575 was slowly generated (2 days) using an excess of hydrogen bromide in acetic acid from 529. Treatment of 575 with methyl p-hydroxybenzoate gave the β-galactoside 576. Deprotection at position 6 was now possible to give 577. Deoxyfluorination via the corresponding triflate 578 proved difficult, with elimination to 579 and to 580 being the major reaction pathways.²⁷⁵ Only a trace amount of desired tetrafluorinated product was detected. The doubly eliminated 580 was easily obtained from 579. However, a DAST-mediated deoxyfluorination generated 2,3,4,6-tetradeoxy-2,3,4,6-tetrafluorohexopyranoside 581 in 57% yield.^273,275 The benzoate aglycone was ultimately transformed into the corresponding carboxylic acid 582 with the use of aqueous 1 M LiOH solution.

Scheme 84. Synthesis of 2,3,4,6-Tetradeoxy-2,3,4,6-tetrafluoro-α-d-galactopyranoside Derivatives^273,275.

A similar synthesis was employed for 2,3,4,6-tetradeoxy-2,3,4,6-tetrafluoro-α-d-thiogalactopyranoside 584 (Scheme 84B). The aglycone was installed using the same strategy as before, leading to compound 583 via bromide 575, followed by de-O-acetylation. Due to the instability of the thionaphthyl moiety under the DAST-mediated deoxyfluorination conditions, the triflation method needed to be applied, which gave 584 in 9% yield. The major side product of this transformation was the elimination of the C-6 leaving group as explained above.²⁷³

The tetrafluorinated allose derivative 585 (Scheme 85) was synthesized from the advanced intermediate 548, the synthesis of which was described in Scheme 78, by deoxyfluorination.²⁹⁵

Scheme 85. Synthesis of the 2,3,4,6-Tetradeoxy-2,3,4,6-tetrafluoro-α-d-allopyranoside Derivative²⁹⁵.

6. Pentoses: Two Hydroxyl Groups Replaced by Fluorine

6.1. Fluorination at Positions 1 and 2

The Dwek group reported that the reaction of 3,4-di-O-acetyl-d-xylal 586 (Scheme 86) with fluoroxytrifluoromethane led to 3,4-di-O-acetyl-2-deoxy-2-fluoro-β-d-lyxopyranosyl fluoride 587 and 2-deoxy-2-fluoro-α-d-xylopyranosyl fluoride 589 in 42% and 5% yield, respectively, alongside their trifluoromethyl glycosides 588 and 590.¹⁹¹ Deprotection of 587 gave 2-deoxy-2-fluoro-α-d-lyxopyranosyl fluoride 591 in 81% yield.³⁴¹ The α-d-lyxo configured 587, 588, and 591 were all found to exist in the ¹C₄ conformation, and the xylose derivatives 589 and 590 in the ⁴C₁ conformation.

Scheme 86. Synthesis of 2-Deoxy-2-fluoro-β-d-lyxo and α-d-Xylohexapyranosyl Fluorides from d-Xylal^191,341.

Starting from 3,4-di-O-acetyl-d-arabinal 592 (Scheme 87A), 3,4-di-O-acetyl-2-deoxy-2-fluoro-β-d-arabinopyranosyl fluoride 594 and its corresponding trifluoromethyl glycoside 593 were isolated,^191,342 with 3,4-di-O-acetyl-2-deoxy-2-fluoro-α-d-ribopyranosyl fluoride 595 as a minor product.³⁴² Interestingly, both the fluorination of d-xylal 586 and d-arabinal 592 is thus reported to occur via the β-face, regardless of the configuration at C-3. This is consistent however with the outcome of the reaction of 586 and 592 with acetyl hypofluorite as reported by Dax et al. (not shown).³⁴³ The Dax group also reported a significantly improved synthesis of 594 by reaction of 592 with SelectFluor (Scheme 87B), which only gave d-arabino configured 594, alongside an undisclosed amount of 596, formed via Ritter reaction with the solvent.¹⁹⁴ Finally, the McMillan group demonstrated the conversion of glycofuranosyl bromide 598 to 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-d-arabinofuranosyl fluoride 599 via a radical-mediated halogen atom abstraction and benzophenone photosensitization involving N-fluorobenzenesulfonimide (NFSI), with excellent yield and stereoselectivity.³⁴⁴ Compound 598 can be obtained in one step from the commercially available 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-d-arabinofuranose 597.³⁴⁵

Scheme 87. Synthesis of 2-Deoxy-2-fluoro-d-arabinopyranosyl and -furanosyl Fluoride^{191,194,342,344}.

Fluorination of 2-acetoxy-d-arabinal 601 (Scheme 88A), synthesized from 600 via bromide elimination, was also shown to proceed from the β-face, leading to 2,3,4-tri-O-acetyl-2-fluoro-β-d-ribopyranosyl fluoride 603, albeit as the minor product.³⁴² The same types of compounds could be obtained by a DAST-mediated rearrangement process (cf. also Scheme 15C): treatment of 604 with DAST (Scheme 88B) led to 606 as a mixture of anomers.²⁰³ The same outcome—with a different anomeric ratio—was observed starting from 605, which has an equatorial OMe group, which was explained by the facile ring inversion of this cis-fused ring system.

Scheme 88. Synthesis of 2,3,4-Tri-O-acetyl-2-fluoro-β-d-ribopyranosyl Fluoride Derivatives^203,342.

6.2. Fluorination at Positions 1 and 3

The Hall and Foster groups published the synthesis of 2,4-di-O-acetyl-3-deoxy-3-fluoro-β-d-xylopyranosyl fluoride 611 in three steps from 3-deoxy-3-fluoro-β-d-xylopyranoside 608 (Scheme 89).²¹⁰ This compound was synthesized in seven steps from glucose diacetonide 411 involving advanced intermediate 414 (cf. Scheme 56), by its treatment with sodium periodate and sodium borohydride to give 3-deoxy-3-fluoro-1,2-O-isopropylidene-α-d-xylofuranose 607, upon which hydrolysis of the 1,2-acetonide led to 3-deoxy-3-fluoro-β-d-xylopyranose 608.²¹³ Peracetylation followed by anomeric bromination afforded 610, upon which anomeric fluorination gave the desired 2,4-di-O-acetyl-3-deoxy-3-fluoro-β-d-xylopyranosyl fluoride 611 in 46% yield over three steps.

Scheme 89. Synthesis of 2,4-Di-O-acetyl-3-deoxy-3-fluoro-β-d-xylopyranosyl Fluoride²¹⁰.

Sivets et al. reported the formation of the 1,3-difluorinated arabinose derivative 612 (Figure 4) as a byproduct of a deoxyfluorination reaction (see Scheme 103 below), which was however fully characterized.³⁴⁶

Figure 4.

Structure of 5-O-benzoyl-3-deoxy-3-fluoro-2-O-methyl-α-d-arabinofuranosyl fluoride.³⁴⁶

Scheme 103. Direct Difluorination Approaches with Methyl 5-O-benzoyl Arabinofuranoside^{346,385−387}.

The Qing group published an enantioselective synthesis of a 1,3,3-trifluorinated pentose as donor 622 for nucleoside synthesis (Scheme 90) using a de novo synthesis approach starting from glyceraldehyde acetonide 288.^347,348 The addition of 1,1-difluoroallyl indium led to 613 in excellent yield in a 7.7:1 diastereomeric ratio in favor of the anti-diastereomer, which decreases to 5.7:1 in 614 after benzylation, which was attributed to NaH-mediated epimerization of 614. Next, the alkene was dehydroxylated. Under Upjohn conditions, a 1:1 ratio of diastereomers at the newly formed stereocenter was obtained, but under Sharpless conditions with (DHQ)₂PYR, a 4.4:1 ratio was obtained in favor of 616. After protection of the terminal alcohol to 617, the acetonide was hydrolyzed and the resulting diol cleaved with periodate, causing the furanose 618 to form in excellent yield. Interestingly, the diastereomeric ratio at C-2 turned out to be >35:1, up from 5.7:1 at the benzyl ether center in 617. This was attributed to an epimerization process at C-2. Anomeric acetylation followed by debenzylation gave 619. The enantiomer of 619 was obtained in the same way from 616 (not shown).³⁴⁸ Attempted OH-2 deoxyfluorination to give 620 failed. Instead, neighboring group participation of the anomeric acetate involving displacement of the activated OH-2 intermediate took place, giving 621, which then reacted with fluoride to give the β-configured furanosyl fluoride 622. Nucleoside formation from 622 was successful (not shown).³⁴⁸

Scheme 90. Synthesis of 3-Deoxy-3,3-difluoro-α-d-erythro-pentofuranosyl Fluoride³⁴⁸.

6.3. Fluorination at Positions 1 and 5

The Withers group reported the synthesis of a number of 5-fluorinated pentopyranosyl fluorides as part of a mechanistic study.³⁴⁹ Like the synthesis of 5-fluorinated hexopyranosyl fluoride derivatives (section 3.1), the anomeric fluoride was introduced first. Hence, treatment of β-d-xylose tetra-O-acetate 623 (Scheme 91) with neat anhydrous HF led to the formation of both anomeric xylopyranosyl fluorides 624, which were separable.³⁵⁰ Using Olah’s reagent (HF-py), this reaction was reported to only lead to the α-anomer in 95% yield (not shown).⁹⁵ From β-624, radical bromination was selective for the 5-position, with the formation of the axial bromide β-625 as the only monobrominated product, alongside the 5,5-dibrominated xylose derivative 626. Fluorination of β-625 led to a mixture of β-627 and β-628, but only the desired β-627 was isolated. Deprotection furnished (5R)-5-fluoro-β-d-xylopyranosyl fluoride β-629. Fluorination from 626 led to 630 in good yield, and deprotection then gave 5,5-difluoro-β-d-xylopyranosyl fluoride 631.

Scheme 91. Synthesis of 5-Fluorinated Xylopyranosyl Fluorides³⁴⁹.

From the α-configured xylopyranosyl fluoride α-624, radical bromination only gave the monobrominated α-625. Treatment with AgBF₄ in toluene now gave the two fluoride epimers at C-5 α-627 and α-628. After separation, their deprotection gave (5R)-5-fluoro-α-d-xylopyranosyl fluoride α-629 and (5S)-5-fluoro-α-d-xylopyranosyl fluoride 632.³⁴⁹

6.4. Fluorination at Positions 2 and 3

The chemistry of 2,3-dideoxy-2,3-difluoropentoses is intimately linked with that of its nucleosides. Hence, nucleoside chemistry is included, although the emphasis is not on nucleobase introduction, but on establishing the 2′,3′-fluorination pattern. Where applicable, approaches that introduce both fluorine before nucleobase introduction will be mentioned first.

6.4.1. Difluorinated at Positions 2 and 3

6.4.1.1. Riboconfigured

The synthesis of a 2,3-dideoxy-2,3-difluorinated ribose derivative 641 was described by Mikhailopulo, with subsequent transformation to an adenosine analogue (Scheme 92).³⁵¹ Treatment of d-lyxose with 0.5% HCl in methanol resulted in methyl lyxofuranoside formation, which was protected as its acetonide followed by separation of the anomers 633.³⁵² Tosylation of the OH-2 group to 634(353) and acetonide hydrolysis led to the 2,3-anhydro lyxofuranoside derivative β-635. An improved large-scale synthesis of β-635 and its α-anomer, in which a 93% yield was obtained for the conversion of xylose to 633, and which were not separated until after epoxide formation, is available.³⁵⁴ Protection of the remaining alcohol in β-635 then led to benzyl ether β-636.^353,355,356 Epoxide opening with fluoride resulted in the formation of the 2-fluorinated xylose derivative 637 in 23% yield, and in the 3-fluorinated arabinose derivative β-638 in 31% yield.³⁵⁵ However, the De Clercq group reported that in their hands, only β-638 was obtained, also in 31% yield.³⁵⁶ Tosylation of β-638 to give 639(356) allowed for displacement with fluoride, giving 640 in 24% yield.³⁵¹ Direct deoxyfluorination of 637 gave 640 in 17% yield.³⁵¹ The low yields can be attributed to the congested environment, with unfavorable dipole interactions. Benzyl hydrogenolysis then gave methyl 2,3-dideoxy-2,3-difluoro-d-ribofuranoside 641. Finally, glycosylation of adenine was achieved after benzoyl protection, giving 642, with only the formation of the β-anomer reported.

Scheme 92. Convergent Synthesis of a 2,3-Dideoxy-2,3-difluorinated Ribose Derivative Using a Sequential Fluorination Approach³⁵¹.

A number of nucleosides based on 2′,3′-dideoxy-2′,3′-difluoro-d-ribofuranose have been prepared with at least one fluorine introduction achieved after nucleobase introduction. The most direct method was reported by Coe et al.³⁵⁷ Uridine 643 was converted to the 2,3-dehydro derivative 645 (Scheme 93) via the corresponding ethylidene acetal intermediate 644.³⁵⁸ Reaction of 645 with diluted fluorine gas resulted in diastereoselective vicinal syn-fluorination at the furanose double bond to give the ribo-configured 646, but the uracil moiety was also fluorinated at the 5-position. Presumably the uracil double bond was also difluorinated, followed by a fluoride elimination. The byproduct of this reaction was 647, suggesting fluorination at the uracil ring was the fastest process.

Scheme 93. A Direct Fluorination Approach to Give 5-Fluoro-2′,3′-dideoxy-2′,3′-difluoro uridine³⁵⁷.

The Herdewijn group also reported a synthesis of 2′,3′-dideoxy-2′,3′-difluoro uridine starting from uridine 643 (Scheme 94), which involved two successive alcohol inversions before deoxyfluorination.³⁵⁹ Inversion at C-2 was achieved by conversion to the 2,2′-anhydro uracil derivative 648.³⁶⁰ This allowed protection of the remaining alcohol groups as trityl ethers, which required forcing conditions. Anhydro opening with hydroxide then resulted in inversion at C-2 to give d-arabinofuranosyluracil 649.³⁶¹ Interestingly, 2′-deoxy-2′-chlorouridine 650, resulting from opening of the anhydro group by the chloride that was released upon trityl protection, was initially reported as the main product of this sequence.³⁶² From 649, DAST-mediated deoxyfluorination installed the F-2 group, and a detritylation-selective OH-5 tritylation sequence then gave 652 with the OH-3 available for reaction. Inversion of configuration was achieved with a triflation, hydroxide displacement sequence, leading to the 2-fluoro-d-xylo derivative 653. The second DAST-mediated deoxyfluorination produced 654 in a much higher yield compared to the equivalent DAST reaction of the OH-3 in 637, despite the mild conditions and short reaction time (see Scheme 92). This was followed by deprotection which then gave the desired 2′,3′-dideoxy-2′,3′-difluoro uridine 655, which in fact was the first synthesis of a difluororibose based nucleoside.³⁵⁹ A similar synthesis of 2′,3′-dideoxy-2′,3′-difluoro thymidine, with similar yields, was also reported by the same group.³⁶³

Scheme 94. Synthesis of 2′,3′-Dideoxy-2′,3′-difluoro Uridine Starting from Uridine Using DAST-Mediated Sequential Fluorination³⁵⁹.

A number of groups have described the synthesis of 2,3-dideoxy-2,3-difluororibose-based nucleosides from their parent ribonucleosides via a 2,3-anhydro approach (cf. Scheme 92). The Watanabe group was the first to demonstrate this short synthesis method (Scheme 95A).³⁶⁴ Thymidine 656 was protected at the primary alcohol, and dimesylated to give 641. Treatment with hydroxide, in which an intermolecular displacement was followed by cyclization, led to the 2,3-lyxo-configured anhydro nucleoside 658. Opening with fluoride was not regioselective, but separation of the regioisomers 659 and 660 was not required as the subsequent DAST-mediated deoxyfluorination led to the same product 661 in an overall 45% yield. The Kumar group also reported the fluoride opening of 658, which was synthesized in a similar way as shown here,³⁶⁵ with isolated yields of 20% and 7% for 660 and 659.³⁶⁶ The opening at the 3′-position was found to predominate, which was explained for 2,3-lyxo-epoxides by the influence of the electron withdrawing effect of the anomeric center.³⁶⁷ This was also illustrated for the lyxo-anhydro uridine derivative 662 with the 3-fluoroarabino nucleoside 663 as the major product (Scheme 95B),³⁶⁶ which was further deoxyfluorinated to give tritylated 2′,3′-dideoxy-2′,3′-difluoro uridine 654.³⁶⁸ This C-2-deoxyfluorination proceeded in lower yield than the corresponding C-3-deoxyfluorination as shown with 653 in Scheme 94.

Finally, the synthesis of a (protected) 2′,3′-dideoxy-2′,3′-difluorinated adenosine with the epoxide strategy was shown by the Aldrich group (Scheme 95C).³⁶⁹ The required 2′,3′-anhydro substrate 665 was synthesized from adenosine 664 by tritylation of the ribose OH-5 and the adenine amino group, followed by triflation of both remaining alcohols, and epoxide formation.³⁷⁰ Fluoride opening of 665 gave a 3:1 ratio of regioisomers with the 3′-fluoro-arabino651 as the expected major product.³⁶⁹ These were not separated, and DAST-mediated deoxyfluorination, which was conducted at a higher temperature than that of 663, with a much better yield as a result, led to the formation of 668 with concomitant detritylation at the OH-5 group (but not of the nucleobase).

Finally, the Dyatkina group at Janssen Biopharma synthesized the branched nucleoside 673 with 2’3′-ribo-difluorination (Scheme 96).³⁷¹ Starting from α-633, synthesized as shown in Scheme 92,³⁵⁵ conversion to the 2′,3′-anhydro derivative α-635 was achieved via tosylation, acetonide removal, and cyclization, which was then protected as the benzyl ether α-636.^353,354,356 Opening of the epoxide with fluoride now proceeded with complete regioselectivity to give α-638,³⁷² which will be due to the combined steric and electronic effects of the α-configured anomeric center.³⁶⁷ Tosylation of the OH-2 group allowed inversion of configuration with sodium benzoate in moderate yield.³⁷¹ However, this allowed introduction of the nucleobase to isolate the β-nucleoside in 72% yield. Tritylation of the amino group then gave 670. The benzoate group was removed, the resulting alcohol was oxidized, and the subsequent Grignard reaction afforded 671 as the only reported diastereomer. DAST-mediated deoxyfluorination led to 672 as a single diastereomer, which was converted to 2′,3′-dideoxy-2′,3′-difluoro-2′-C-methylguanosine 673.³⁷¹

Scheme 96. Linear Synthesis of a C-2-Branched 2′,3′-Dideoxy-2′,3′-difluorinated Guanosine Using Sequential Fluorination via Epoxide Opening³⁷¹.

6.4.1.2. Lyxo-configured

The synthesis of d-lyxo-configured nucleosides was achieved by the Marquez group in 1995.³⁷³ In a first approach (Scheme 97), the fluorination was planned before nucleoside formation.³⁷⁴ Intermediate 607 was obtained from glucose diacetonide 411 in six steps as detailed above in Scheme 89. Protection of the primary alcohol group as the benzoate and acetal methanolysis gave the d-xylo derivative 675 as a 3:2 ratio of anomers. This was deoxyfluorinated with DAST to give methyl 5-O-benzoyl-2,3-dideoxy-2,3-difluoro-d-lyxofuranoside 676 as a single α-anomer. It was noted that reflux temperature was required to achieve conversion, which was attributed to repulsive dipole–dipole interactions between the cis-vicinal fluorines.^{143,164−166} This contrasts with the low/room temperature DAST reactions required to arrive at the ara- and even the ribo- configurations. Unfortunately, nucleoside introduction attempts with 676 led to decomposition, and with attempts to form the anomeric bromide, a d-xylo configured rearrangement product 677 with loss of F-2 was obtained. It was proposed that the electron withdrawing effect of the fluorines hampered reaction at the anomeric center, and that instead neighboring group participation of the antiperiplanar anomeric OMe group facilitated loss of HF, leading to 678. This could be in equilibrium with the oxonium ion 679, leading to 680 upon bromide addition. The anomeric configuration of 680 could not be ascertained, but only the β-nucleoside 677 was obtained upon subsequent glycosidation.

Scheme 97. Synthesis of a 2,3-Dideoxy-2,3-difluoro-d-lyxofuranoside Derivative, and Its Unsuccessful Nucleobase Introduction³⁷⁴.

Hence, the nucleobase was introduced before the second fluorine (Scheme 98).³⁷³ Uracil introduction with 598 only gave the β-anomer 681, and benzoyl aminolysis led to 682.³⁷⁵ Selective rebenzoylation at the 5′-position and tert-butyl dimethyl silyl (TBDMS) protection of the 3′position, to give 684, allowed uracil protection as the N³-benzoyl derivative 685. This was required to avoid the very facile cyclization of pyrimidine nucleosides with activated trans-positioned alcohols at C-2 or C-3, which leads to the corresponding anhydro derivatives. The silyl group was then removed with fluoride, allowing DAST-mediated deoxyfluorination of the 3′OH group with concomitant N³-benzoyl cleavage to give the d-lyxo configured nucleoside 687. Interestingly, although the yield was low, this DAST reaction proceeded at −40 °C despite the resulting highly congested substitution in 686, and the dipole repulsion from F-2.

Scheme 98. Linear Synthesis of a 2′,3′-Dideoxy-2′,3′-difluorinated d-lyxo Configured Nucleoside with Nucleobase Introduction Preceding the Second Fluorination³⁷³.

6.4.1.3. Xylo-configured

Gosselin et al. reported the synthesis of 2′,3′-dideoxy-2′,3′-difluoroxylofuranosyl nucleosides starting from glucose diacetonide 411 (Scheme 99A),³⁷⁶ the conversion of which to the advanced intermediate 674 is shown in Scheme 97. Direct acetolysis of 674 led to the open chain aldehyde–diacetate as a major byproduct (not shown), but acetonide hydrolysis followed by nucleophilic acetate formation resulted in the desired 688. Its condensation with silylated thymine under Vorbruggen conditions afforded the nucleoside derivative 689 as the only reported anomer. Acetate hydrazinolysis revealed the OH-2 group, but attempted deoxyfluorination with DAST to arrive at the ribo-configured 2′,3′-difluorinated nucleoside failed, because the activated intermediate was intercepted by the (unprotected, cf. Scheme 98 for the relevance of this) thymine carbonyl to give the 2,2′-anhydro derivative 691. Hydrolysis of the anhydro-bridge then led to the lyxo-configured 692, upon which deoxyfluorination proceeded in excellent yield to give, after benzoate removal, 1-(2′,3′-dideoxy-2′,3′-difluoro-β-d-xylofuranosyl)thymine 694.³⁷⁶

Scheme 99. Linear Synthesis of (2′,3′-Dideoxy-2′,3′-difluoro-β-d-xylofuranosyl) Nucleosides via 2,2′-Anhydro Intermediates^376,377.

A related, shorter synthesis was reported by the Marquez group (Scheme 99B).³⁷⁷ The 5-tritylated 2,2′-anhydrouridine derivative 695 was synthesized in two steps from uridine 643 (no yields were given). The remaining hydroxyl group in 695 was then displaced with fluorine to give 696, after which the synthesis converged with the Gosselin synthesis: anhydro hydrolysis allows for a second fluorination to the difluorinated xylo-derivative 697, which upon deprotection gave 1-(2′,3′-dideoxy-2′,3′-difluoro-β-d-xylofuranosyl)uracil 698 (no yields were given).³⁷⁷

The Aldrich group reported the synthesis of 2′,3′-dideoxy-2′,3′-difluoro-β-d-xylofuranosyl)adenosine 708 starting from adenosine 664 (Scheme 100).³⁶⁹ The fluorine at C-2 was introduced first, as published by the Pankiewicz group.³⁷⁸ Adenosine was first subjected to tritylation, with the 2,5-di-O-trityl protection product isolated in 26% yield. The primary trityl group was selectively cleaved, leading to 699 with concomitant adenine deprotection. Protection of the alcohols as benzyl ethers was followed by removal of the 2-O-trityl group. Inversion of configuration at C-2 in 700 via an oxidation–reduction protocol was not successful, and instead an S_N2 reaction with sodium acetate on the corresponding triflate 701 was carried out. This afforded, after acetate aminolysis, the required arabino-configuration in 702. DAST-mediated deoxyfluorination proceeded in excellent yield, resulting in 703. Interestingly, when the 3′,5′-hydroxyl groups were protected as trityl ethers, the DAST reaction resulted in the formation of 705 as a side-product (30% yield). The bulky trityl group hampers fluoride approach at C-2, promoting an E2 elimination process involving the antiperiplanar H-1 in 704. With benzyl protection, elimination was not observed. Benzyl hydrogenolysis gave 2-deoxy-2-fluoroadenosine 706.³⁷⁸ Protection of the primary alcohol, with concomitant adenine amine protection, then allowed deoxyfluorination at C-3 to give 707. Final deprotection afforded 1-(2′,3′-dideoxy-2′,3′-difluoro-β-d-xylofuranosyl)adenosine 708.³⁶⁹

Scheme 100. Linear Synthesis of 9-(2′,3′-Dideoxy-2′,3′-difluoro-β-d-xylofuranosyl) Adenine via Sequential Fluorine Introduction of Adenosine³⁶⁹.

Finally the Goss group reported a direct DAST-mediated deoxyfluorination with 5-protected uridine (Scheme 101).³⁷⁹ The substrate 709 was synthesized via acetonide protection of the ring alcohols, benzylation at OH-5, and acetonide hydrolysis. Reaction of DAST with the diol led to the formation of (protected) 1-(2′,3′-dideoxy-2′,3′-difluoro-β-d-xylofuranosyl) uracil 714 in 11% yield, alongside the corresponding C-2-monofluorinated derivative 716 in 53% yield. This outcome was explained by reaction of the OH-2 group with DAST, leading to 710. This was intercepted by a uracil carbonyl group leading to the 2,2′-anhydro derivative 711, similar to what was observed in the Gosselin synthesis (690 → 691, Scheme 99). However, because the uracil benzyl protecting group maintained the positive charge, 711 then reacted with fluoride to give the 2′-fluorouridine derivative 712. This can be compared with uracil protection using a benzoyl group (cf. Scheme 98), which deactivates the heterocycle from 2,2′-anhydro formation. From 712, a second activation by DAST gave 713, which could either undergo displacement with fluoride to give 714 or be intercepted again by the uracil carbonyl to give the 2,3′-anhydro compound 715. This did not undergo S_N2 reaction with fluoride at C-3 to give (protected) 2′,3′-dideoxy-2′-3′-difluorouridine, but was hydrolyzed during the basic workup to give 716.

Scheme 101. A direct DAST-Mediated Deoxyfluorination Approach to 2′,3′-Difluorinated Nucleosides³⁷⁹.

6.4.1.4. Arabino-configured

The conversion of 5-protected methyl xylofuranoside with DAST to arrive at 2,3-dideoxygenated 2,3-difluorinated araninofuranosides was investigated extensively by Sivets and Mikhailopulo. Their sequential approach is shown in Scheme 102.³⁸⁰ Starting from commercially available 1,2-O-isopropylidene-α-d-xylofuranose 717, selective protection as the 5-O-methyl carbonate 718 allowed activation of OH-3 as the mesylate 719. Acetonide acetolysis and methanolysis of the resulting 1,2-di-O-acetate, with concomitant anomeric methylation, gave 720. Treatment with base initiated epoxide formation, at which stage the anomers were separated.³⁸¹ The ribo-epoxide α-721 was benzylated,³⁸² and reacted with KHF₂ in ethylene glycol at reflux temperature. This led to the 2-fluorinated arabinofuranoside 724 in 42% yield, alongside a small amount of 3-fluorinated xylofuranoside 723.³⁸³ Hence, in this case the steric hindrance of the benzyloxymethyl substituent overrides the electronic influence of the anomeric center (cf. Schemes 51, 95A). Inversion at C-3 was achieved by oxidation to give 726, which unfortunately also resulted in epimerization at the 2-position to give inseparable 725 as the thermodynamically most stable isomer. Reduction of the mixture then gave the 2-fluorinated ribofuranoside 727 as the major product which, compared to the initial starting point 724, actually resulted in inversion at C-2 and not C-3. The 2-fluorinated lyxofuranoside 728 was isolated in only 22% yield (alongside 10% of 724, not shown).³⁸⁴ Deoxyfluorination of 728 gave the 2,3-difluorinated arabinofuranoside 729, after which a protecting group swap afforded methyl 5-O-benzoyl-2,3-dideoxy-2,3-difluoroarabinofuranoside 730.³⁸⁰

Scheme 102. Sequential Fluorination Approach to Give Methyl 5-O-benzoyl-2,3-dideoxy-2,3-difluoroarabinofuranoside³⁸⁰.

A direct fluorination approach was also developed, and proved much more efficient (Scheme 103). Methyl d-xylofuranoside 731 was obtained using Anker’s procedure in excellent yield.³⁵⁴ Without (possible) anomeric separation at this stage, careful benzoylation at the 5-position followed by chromatographic separation gave the two anomers α- and β-732.³⁴⁶ When α-732 was subjected to DAST, the double-inversion product 730 and the OH-3 deoxyfluorination product 733 were obtained, in yields that were dependent on the reaction time. With a 10 h reaction time, 18% of 730 and 51% of 733 was obtained. A longer time (not specified in the scheme) led to 730 in 34% yield, while the yield of 733 decreased to 19%, suggesting 733 is an intermediate in the synthesis of 730.^{346,385−387} Indeed, isolated 733 was shown to give 730 by DAST treatment in 66% yield.³⁴⁶ Alternatively, activation of the OH-2 group in 733 as imidazoylsulfonate 734 allowed fluoride displacement to give 730 in 49% yield.³⁸⁵

Treatment of β-732 with DAST led to the isolation of four compounds, of which 3-deoxy-3-fluoro-β-ribofuranoside 737 was the major, followed by 2,3-anhydro-β-ribofuranoside 736. Small amounts of the difluorinated arabinofuranoside 735 were isolated, and the formation of this α-anomer was explained by anomerization of an intermediate before deoxyfluorination at C-2. Finally, a rearrangement product 612 was also isolated, which arose through neighboring participation of the anomeric substituent to the activated OH-2 (not shown).³⁴⁶

Methyl 5-O-benzoyl-2,3-dideoxy-2,3-difluoroarabinofuranoside 730 has also been used to synthesize nucleosides, although direct condensation of 730 with nucleobases under SnCl₄ activation was low-yielding.³⁸⁰ Hence, 730 was acetolyzed to give 738 (Scheme 104), which was converted to the more reactive glycosyl bromide 739, which has generally been the substrate of choice for nucleobase introductions.^{346,380,385,388} For example, the reaction of 739 with deprotonated purines gave good yields of the corresponding nucleoside derivatives. Using the sodium salt of 2,6-dichloropurine led to a 2.9–4:1 anomeric ratio of β- to α-740,^385,388 which was improved by using the corresponding potassium salt to 9:1.³⁸⁸ In contrast, the reaction of 739 with the potassium salt of 2-fluoroadenine led to a 1:1 anomeric ratio of 741.³⁴⁶ Their deprotection then gave 742.

Scheme 104. Synthesis of 9-(2′,3′-Dideoxy-2′,3′-difluoro-β-d-arabinofuranosyl) Purines^{346,380,385,388}.

A number of linear approaches to 2′,3′-difluorinated arabinofuranosyl nucleosides have also been reported. In the Schinazi approach (Scheme 105),³⁸⁸ this started from a 3-fluorinated ribofuranosyl precursor 737, for which the synthesis in three steps from d-xylose was shown in Scheme 103. Acetylation of OH-2 gave 743, and acetolysis of the anomeric position provided 744. Coupling with silylated 2,6-dichloropurine 745 in a mixture of acetonitrile and dichloroethane (DCE) under TMSOTf activation led to 746 in excellent yield as the only isolated anomer. The acetate group was now hydrolyzed to give 747, and deoxyfluorination resulted in the desired nucleoside β-740 in moderate yield.³⁸⁸

Scheme 105. Linear Synthesis of 2′,3′-Difluorinated Arabinofuranosyl Nucleosides Starting from a C-3-Fluorinated Precursor³⁸⁸.

Alternatively, the Martin group achieved a linear synthesis using a 2-fluorinated building block (Scheme 106A).³⁷⁵ Starting from 1-(2′-fluoro-β-d-arabinofuranosyl)uracil 682, synthesized as already shown in Scheme 98, selective tritylation at the 5′-position allowed formation of the mesylate 748. Treatment with base caused cyclization to give the 2,3′-anhydro derivative 749, which upon further treatment with base hydrolyzed to give the lyxofuranosyluracil derivative 750, although this process led to a significant amount of elimination to give 751 as the major product. DAST treatment of 750 then introduced the second fluorine, which, in contrast to the second fluorination to arrive at the lyxo-configuration (Scheme 98),³⁷³ proceeded smoothly to give 752. This was subseqeuently deprotected to give 1-(2′,3′-dideoxy-2′,3′-difluoro-β-d-arabinofuranosyl)uracil 753.³⁷⁵

Scheme 106. Linear synthesis of 2′,3′-Difluorinated Arabinofuranosyl Nucleosides Starting from a C-2-Fluorinated Precursor^364,375.

A shorter process, in which the 2,3′-anhydro opening was directly achieved with fluoride, was developed by the Watanabe group (Scheme 106B).³⁶⁴ In a similar way as shown in Scheme 98, 2′-fluoro-5-methyl-β-d-arabinofuranosyluracil (FMAU) 754 was obtained.³⁸⁹ Selective benzoylation and mesylation gave 755, upon which treatment with DBU led to the 2,3′-anhydro 756. Treatment of 756 with HF under AlF₃-catalysis³⁹⁰ in a steel vessel at 170 °C gave a moderate yield of the desired difluorinated arabino nucleoside 757, which was then deprotected to give 1-(2′,3′-dideoxy-2′,3′-difluoro-β-d-arabinofuranosyl)uracil 758.³⁶⁴

6.4.2. Tetrafluorinated at Positions 2 and 3

The Linclau group developed an enantioselective de novo synthesis to 2,3-dideoxy-2,2,3,3-tetrafluorinated pentoses (Scheme 107).^60,290 As shown earlier in Scheme 55, the diol 399 was obtained in 79% ee by an asymmetric dihydroxylation reaction, and could be crystallized to enantiopurity after naphthyl methyl protection and derivatization with (S)-Naproxen. In this case, the tetrafluorinated pentose synthesis was carried out with a benzyl protecting group.^60,288 Hence, after Sharpless asymmetric dihydroxylation to 399,²⁹⁰ benzylation of the primary alcohol, functionalization with (S)-Naproxen to effect separation of the thus formed diastereomers, and ester cleavage gave 759 in >99% enantiopurity.^288,290 As before, the expensive (S)-Naproxen could be recovered and recycled. Formylation of 759 to give 761 then allowed cyclization via lithiation, giving 762 in 78% yield. Removal of the benzyl group resulted in ring tautomerization to give 2,3-dideoxy-2,2,3,3-tetrafluoro-d-glycero-pentopyranose 763.⁶⁰

Scheme 107. Synthesis of 2,3-Dideoxy-2,2,3,3-tetrafluorinated Pentofuranose and -pyranose^60,290.

Alternatively, the anionic cyclization to give a protected pentopyranose was also demonstrated. Similar to what was shown for the alkylation of 267 to give 268 in Scheme 36, deprotonation of 399 followed by alkylation led to the protection of the alcohol group adjacent to the fluorination giving 764 in reasonable yield. Nevertheless, < 2% of the dibenzylated or the regioisomer was isolated (not shown). Formylation of 764 gave cyclization precursor 765, whose treatment with MeLi resulted in 766. Hydrogenolysis of the benzyl group then also gave 763.²⁹⁰

Starting from 762 (Scheme 108), the Schinazi group synthesized a number of nucleosides along with their prodrugs, illustrated here for uridine.³⁹¹ While Vorbrüggen-type nucleobase introduction via the corresponding triflate of 762 proved unsuccessful, direct introduction under Mitsunobu conditions afforded the desired coupling products in moderate anomeric ratios. Anomeric separation and deprotections gave uridine analogue 768, which was then converted to its prodrug derivative 769. This worked for all five typical nucleoside derivatives (U, T, A, G, C). Conformational analysis indicated that the tetrafluorinated uracil preferred the 3′-endo conformation, unlike its 2′-3′-dideoxy analogue, which showed no preference between 2′-endo and 3′-endo. Unfortunately, none of the tetrafluorinated nucleosides or their prodrugs showed significant activity against a number of viruses.

Scheme 108. Synthesis of 2′,3′-Dideoxy-2′,2′,3′,3′-tetrafluorinated Uridine and Its Prodrug³⁹¹.

6.5. Fluorination at Positions 2 and 4

The synthesis of a 2,4-dideoxy-2,4-difluorinated d-xylopyranoside has been described by the Ellervik group (Scheme 109).³⁹² Peracetylation of l-arabinose to its pyranoside 770 was followed by anomeric bromination to give l-600.³⁹³ Glycosidation with 2-naphthol to 771 was followed by selective benzylation at the 3-position using a borinic acid catalyst. When Ag₂O was added, a 1:1 mixture of 3- and 4-benzylated sugars was obtained (not shown), but a metal-free version gave solely the desired 3-O-benzylated 772. Reaction of 772 with DAST was selective for the 4-position, albeit in modest yield. The deoxyfluorination of the corresponding benzoate proceeded in a lower 22% yield (not shown). Inversion at C-2 proceeded best via triflation followed by nucleophilic substitution with acetate, and gave 775 after removal of the acetate group. An oxidation/reduction attempt led to fluoride elimination (not shown). The second deoxyfluorination now proceeded in good yield to give 776, whereupon deprotection finally gave 2-naphthyl 2,4-dideoxy-2,4-difluoro-β-d-xylopyranoside 777.³⁹³

Scheme 109. Synthesis of a 2,4-Difluorinated Xylose Derivative³⁹³.

A number of 2′,4′-difluorinated nucleosides have also been reported. The Damha group designed 2′-deoxy-2′,4′-difluorouridine 784 as a monocyclic conformationally locked nucleoside (Scheme 110).³⁹⁴ The synthesis started from 2′-deoxy-2′-fluorouridine 651, for which the synthesis was described in Scheme 94. Selective iodination at the primary position gave 778, which was treated with base to effect elimination to 779. Iodofluorination was achieved by gradual addition of I₂/AgF in acetonitrile at 0 °C to give 780. Displacement of the iodide with benzoate proved difficult,³⁹⁵ due to the deactivating effect of fluorine toward S_N2 reactions.^164−166 As a solution, the 3-position was benzoylated and the iodide oxidized to hypoiodate, which initiated intramolecular displacement from the 3-O-benzoate group to give intermediate 782. The addition of water led to migration of the benzoate to the 5′-position, leading to 783 in 66% yield. Aminolysis of the benzoate group then gave 784.³⁹⁴

Scheme 110. Synthesis of a 2,4-Difluorinated Uridine Derivative³⁹⁴.

The Dyatkina group reported a 4′-fluorinated analogue of a 2′-fluorinated-2′-methylated nucleoside, active against HCV (Scheme 111).³⁷¹ The synthesis, which had been optimized on a large-scale, started with commercially available d-glyceraldehyde 288, also easily available from d-mannitol.^396,397 Reaction of a slight excess of 288 with the commercially available ylide 785 gave the alkene 786 in a 97:3 E/Z ratio,³⁹⁸ which was taken to the next step. Dihydroxylation was successful under OsO₄ conditions but, aiming to avoid the use of this toxic reagent on large scale, KMnO₄-mediated dihydroxylation in acetone was conducted instead. After crystallization of the crude reaction mixture, this gave diol 787 as a single diastereomer in 53% yield from 785. Fluorination was achieved after activation of the diol as cyclic sulfate ester 788, with hydrolysis of the residual sulfate requiring modified conditions (concentrated HCl in 2,2-dimethoxypropane) to prevent acetonide hydrolysis, which allowed purification of 789 via an aqueous workup. The synthesis was telescoped further by treating 789 with concn. HCl in EtOH to effect acetonide hydrolysis and lactone formation, and the resulting crude 790 was then protected as 3,5-di-O-benzoate 791 in 47% overall yield from 787.³⁹⁸ The lactone was then reduced to lactol 792,³⁹⁹ which was isolated after crystallization as the β-anomer. This proved important toward stereoselective nucleobase introduction. Bromination under Appel conditions proceeded with clean inversion of configuration, to give the α-anomeric bromide 793. Nucleoside formation was then achieved with the potassium salt of purine 794 in a 64% yield and 14:1 β/α ratio.³⁹⁹ From 795, fluorination at the 4′-position was achieved using similar methodology as shown in Scheme 110. After functionalization and protection of the nucleobase, leading to 796, the OH-5 was subjected to deoxyiodination to give 797. Elimination to 798 was followed by iodofluorination, which provided 799 as a single isomer. Following benzoylation at the 3′-position, nucleophilic substitution of the 5-iodo group with benzoate led to 800, which was further converted to a nucleoside prodrug (not shown).³⁷¹

Scheme 111. Synthesis of a 2,4-Difluorinated Nucleoside Precursor in the Synthesis of a HCV NS5B Polymerase Inhibitor³⁷¹.

6.6. Fluorination at Positions 2 and 5

Von Schütt et al. reported the synthesis of 2,5-dideoxy-2,5-difluorouridine 806 (Scheme 112).⁴⁰⁰ Starting from uridine acetonide 801 (cf. Scheme 101), tosylation at the 5-position allowed its substitution by fluoride to give 803. Acetonide removal was followed by 2,2′-anhydro formation (805). Subsequent fluorination with AlF₃/HF afforded the final compound 806 in modest yield.

Scheme 112. Synthesis of 2,5-dideoxy-2,5-difluorouridine⁴⁰⁰.

6.7. Fluorination at Positions 3 and 5

Foster et al. reported the synthesis of 3,5-dideoxy-3,5-difluoro-d-xylose, which was the first reported dideoxy-difluorinated sugar derivative in the literature (Scheme 113).⁵⁶ 3-Deoxy-3-fluoro-1,2-O-isopropylidene-α-d-xylofuranose 607, synthesized in six steps from glucose diacetonide 411 (as shown in Scheme 89), was tosylated to give 807.⁴⁰¹ Nucleophilic displacement with fluoride gave the 3,5-dideoxyfluorinated xylofuranose derivative 808,⁵⁶ whereupon mild acid hydrolysis conditions gave 3,5-dideoxy-3,5-difluoro-d-xylofuranose 810. The fluoride substitution was accompanied by nucleophilic substitution with the solvent leading to 809, and by hydrolysis leading back to 607 (5%, not shown).

Scheme 113. Synthesis of 3,5-Dideoxy-3,5-difluoro-d-xylofuranose⁵⁶.

7. Ketosugars

7.1. Erythro-2-pentulose (Ribulose)

The Anker group reported the synthesis of the 1-deoxy-1,1,1-trifluororibulosyl fluoride derivative 814 (Scheme 114).⁴⁰² Trifluoromethylation of the acetonide-protected erythronolactone 811 led to 812 as a mixture of equilibrating anomers.⁴⁰³ Mesylation afforded 813 with β-selectivity. This was stable to chromatography thanks to the inductive effect of the trifluoromethyl group. Displacement with Et₃N·2HF then gave the corresponding ribulosyl fluoride 814, largely with inversion of configuration.⁴⁰²

Scheme 114. Synthesis of a 1,1,1,2-Tetrafluorinated Ribulose Derivative⁴⁰².

7.2. Fructose

The synthesis of 1,6-dideoxy-1,6-difluorinated fructose derivatives is shown in Scheme 115. d-Fructose was tosylated at the primary positions, and converted to its acetonide 815,⁴⁰⁴ which was subjected to tosylate displacement. Guthrie et al. reported that reaction with KF in ethylene glycol at 150 °C gave 816 in 20% yield, alongside the monofluorinated 817 in 29% yield.⁴⁰⁵ Pacak et al. achieved a 40% yield of 816 in refluxing ethylene glycol while bubbling through CO₂ gas.⁴⁰⁶ With DMF as the solvent, reaction with LiF or CsF at 100 °C did not lead to any fluorination, while the use of TBAF at 80 °C gave 45% of 817 and 8% of 816 (not shown).⁴⁰⁵ However, increasing the temperature to 120 °C led to the formation of 816 in 58–61% yield with CsF or TBAF.⁴⁰⁵ The deoxyfluorination of the fructose acetonide 1-position is known to be difficult; it was reported to be unsuccessful with DAST and is best achieved via the corresponding triflate.⁴⁰⁷ Aqueous acid-catalyzed hydrolysis of 816 afforded 1,6-dideoxy-1,6-difluoro-d-fructose 818,⁴⁰⁶ while methanolysis led to the two methyl fructoside anomers of 819.⁴⁰⁵

Scheme 115. Synthesis of 1,6-Dideoxy-1,6-difluorinated Fructose Derivatives^405,406.

The synthesis of a 2,2,3,3-tetrafluorinated fructose analogue was reported by Linclau et al. using a fluorinated building block approach (Scheme 116A).²⁹⁰ Starting from 759, for which the synthesis was shown in Scheme 107, ester formation with benzyloxyethanoyl chloride led to 820, and anionic cyclization afforded the ketofuranose 821. Removal of the protecting groups was accompanied by ring tautomerization to give the ketopyranose 822. This fructose derivative was also obtained via the other possible anionic cyclization pathway from 764 (Scheme 116B), the regioisomer of 759, the synthesis of which was also depicted in Scheme 107. Ester formation to obtain 823 allowed cyclization to 824, which upon hydrogenolysis then gave 822.²⁹⁰

Scheme 116. Synthesis of a Tetrafluorinated Fructose Derivative²⁹⁰.

This methodology was used by Gouverneur et al. for the synthesis of pentaketose derivatives (Scheme 117).⁴⁰⁸ Here, 759 was esterified with aromatic acid chlorides 825a–e to give 826a–e as substrates for the anionic cyclization. MeLi-treatment of 826d,e, followed by removal of the benzyl group led to the formation of ketopyranoses 828d,e. MeLi-treatment of 826a–c, followed by reduction of the resulting hemiacetal led to 829a–c, upon which debenzylation gave the to C-nucleosides 830a–c. The anomers of 830a,b could be separated after acetylation to 831a,b.

Scheme 117. Synthesis of 3,3,4,4-Tetrafluoroaryl-C-nucleoside Analogues⁴⁰⁸.

7.3. d-Gluco-hept-2-ulose

The Thiem group reported the synthesis of a number of difluorinated hept-2-ulose derivatives.^409,410 Starting from tri-O-benzyl-d-glucal 30 (Scheme 118), reaction with SelectFluor gave the separable 2-deoxy-2-fluoroglucose 832 and -mannose 833. From 832, oxidation to the lactone 834 was followed by a Petasis olefination to give the exocyclic enol ether 835. Another reaction with SelectFluor then provided the 1,3-difluorinated heptulose 836 as the α-anomer, which was finally deprotected to give 1,3-dideoxy-1,3-difluoro-α-d-gluco-hept-2-ulopyranose 837.⁴⁰⁹ A similar reaction sequence starting from 833 gave the corresponding epimer 838.⁴¹⁰

Scheme 118. Synthesis of 1,3-Dideoxy-1,3-difluorinated hept-2-uloses^409,410.

The same group also reported the synthesis of the 1,7-difluorinated hept-2-ulose 843 (Scheme 119),⁴⁰⁹ starting from 1,2,3,4-tetra-O-acetyl-6-deoxy-6-fluoro-β-d-glucopyranose 194, for which the synthesis was shown in Scheme 27. From 195, anomeric protection as the thioglycoside, protecting group switch to benzyl, and anomeric deprotection gave 839. Lactol oxidation, Petasis olefination, and SelectFluor treatment then led to the formation of 842, which was deprotected to give 1,7-dideoxy-1,7-difluoro-α-d-gluco-hept-2-ulopyranose 843.

Scheme 119. Synthesis of 1,7-Dideoxy-1,7-difluoro-α-d-gluco-hept-2-ulopyranose⁴⁰⁹.

7.4. 2-Keto-3-deoxy-d-glycero-d-galacto-nononic Acid (Kdn)

The synthesis of a 2,3-difluorinated Kdn derivative was reported by both the Withers and Bennet groups.^411,412 The enzyme-catalyzed aldolase reaction between d-mannose and 3-fluoropyruvic acid sodium salt (Scheme 120) was reported by the Chen group to give both F-3 diastereomers in 84% combined yield,⁴¹³ with the F_ax-3 diastereomer as the major product. This aldolase reaction is a key strategy for the synthesis of 3-fluorinated sialic acids starting from d-ManNAc (see section 9). d-ManNAc is the natural substrate of the enzyme, and the reaction with d-mannose was reported to be slower; hence, an extended reaction time was needed.⁴¹² In contrast, the aldolase enzyme used by the Bennet group gave 845 as the only reported diastereomer in 83% yield. Protection of the carboxylic acid and alcohol groups followed by anomeric deprotection gave ketose 847, ready for anomeric fluorination. This was achieved with DAST⁴¹² or XtalFluor-E,⁴¹¹ and in both cases only the formation of the desired β-anomer 848 (cf. section 9.1.1) was reported. Deprotections afforded 3-deoxy-3-fluoro-d-erythro-β-l-manno-non-2-ulopyranosyl fluoride 849.⁴¹¹

Scheme 120. Synthesis of 3-Deoxy-3-fluoro-d-erythro-β-l-manno-non-2-ulopyranosyl Fluoride^411,412.

Finally, Neu5Ac aldolase-catalyzed aldol reaction between 4,6-dideoxy-4,6-difluoro talose 850 (Scheme 121), and pyruvic acid was reported to give 7,9-dideoxy-7,9-difluoro Kdn 851.³³³ Only one diastereomer was reported. The talose derivative 850 was obtained from hydrolysis of 482, the one-step synthesis of which was described in Scheme 65A.

Scheme 121. Synthesis of 7,9-Dideoxy-7,9-difluoro Kdn³³³.

8. Aminosugars

In this section, the synthesis of polyfluorinated aminosugars and their protected derivatives, including azido- or other aminofunctionalized sugars, is given.

8.1. Fluorination at Two Positions

8.1.1. Fluorination at Positions 1 and 2

8.1.1.1. Galactose Stereochemistry

Vocadlo and Bertozzi published the synthesis of 6-azido-2,6-deoxy-2-fluoro-β-d-galactosyl fluoride 858 (Scheme 122) as a probe for activity-based labeling of retaining glycosidases.⁴¹⁴ Their synthesis involved the galactosyl bromide 852, which was obtained from tri-O-acetyl-d-galactal 71. This was a two-step procedure: first via reaction with CF₃OF (as shown in Scheme 12) to give α-72, which was then converted to the glycosyl bromide 852 with HBr in acetic acid.⁴¹⁵ Alternatively, the SelectFluor procedure can be used with acetic acid as the solvent to obtain 853 (cf. Scheme 9B), which can also be converted to 852 using HBr in acetic acid.^416,417 Finally, 71 can be directly converted to 852 using Dax’ original procedure with SelectFluor and a bromide source.¹⁹⁴ The anomeric position of 852 was protected as the thioglycoside,⁴¹⁴ and subsequent acetate hydrolysis gave 854. Selective tosylation at the primary position and displacement with azide gave 855, upon which the remaining alcohols were reprotected as acetates and the anomeric position was deprotected. This led to 856, the treatment of which with DAST gave 857 as the only reported anomer (cf. α/β ratio of 14:86 for tri-O-benzyl-2-deoxy-2-fluorogalactose 79, Scheme 12), which was immediately deprotected to give 858.

Scheme 122. A Sequential Fluorination Approach to a 2,6-Dideoxy-6-azido-2-fluoro Galactosyl Fluoride⁴¹⁴.

The Jordaan group reported on the reaction of the 3-deoxy-3-aminoglucal derivative 859(418) with CF₃OF (Scheme 123), which led to the 2-cyano-2-deoxy-2-fluorogalactosyl fluoride derivative 860 alongside the corresponding trifluoromethyl galactoside 861.⁴¹⁹ Hence, the same facial selectivity compared to tri-O-acetyl galactal was observed, as shown in Scheme 12, although in that case products arising from reaction at the β-face were isolated.

Scheme 123. Direct Difluorination of a 3-Amino-2-cyano Functionalized Glycal⁴¹⁹.

8.1.1.2. Fucose Stereochemistry

The Wennekes group reported the synthesis of the analogous 6-azidofucose activity probe 867 (Scheme 124).⁴²⁰ Protection of l-galactose as shown in Scheme 49 led to ent-210, which was tosylated and converted to the peracetate 863. Installation of the Δ1,2 double bond afforded the 6-tosyloxyfucal 864, for which substitution with azide gave 865. Interestingly, it was reported that introducing the azido group before fucal synthesis caused its substitution by bromide in the anomeric bromination step, a problem not seen with the tosylate. Direct vicinal difluoride introduction with XeF₂ gave 866 as the only reported product. The excellent stereoselectivity is consistent with the analogous reaction on the corresponding tri-O-acetyl galactal 1 or di-O-acetal fucal 80 (Schemes 12 and 13), although in these cases other diastereomers were reported in minor amounts. Deprotection of 866 then gave 6-azido-2-deoxy-2-fluoro-α-l-fucosyl fluoride 867.

Scheme 124. Direct Difluorination Approach to a 6-Azido-1,2-difluorinated Fucose Derivative⁴²⁰.

The 1,2,2-trifluorinated fucosamine derivatives α- and β-882 (Scheme 125) were synthesized by the Lukacs group as intermediates in their 2,2-difluorodaunosamine synthesis.⁴²¹ Starting from d-glucose, anomeric protection as α-benzyl glucoside, followed by standard benzylidene protection gave 868. In the original report, 868 was converted to 869 via the corresponding dimesylate, which gave a very low yield (2%).⁴²² However, a procedure reported by the Magnusson group using tosyl imidazole, originally introduced by Fraser-Reid for this purpose,⁴²³ gives access to 869 in a good yield.⁴²⁴ Its azidolysis furnished azido alcohol 870,⁴²⁵ which was then treated with DAST in boiling benzene to give the desired 871 in 40% yield. Unsurprisingly, the reaction outcome was determined by the two adjacent axial substituents, ideally positioned for neighboring group participation, leading to intermediates 874 and 875. This not only resulted in the desired fluorination with retention of configuration (871, 40%), but also in the formation of the two possible rearrangement products 872 (40%), and 873 (15%). While fluoride attack at C-2 is stereoelectronically favored (chairlike transition state), it is perhaps unexpected to observe that the azido migration product 872 is formed in preference over the benzyl ether migration product 873. Acid-catalyzed deprotection of 871 and selective mesylation at the primary position afforded 876. Substitution with iodide was followed by AgF treatment to effect elimination to unsaturated compound 877. Its rapid hydrogenation led to 878 with l-fuco-stereochemistry, with simultaneous reduction of the azide but without cleavage of the benzyl groups. Amine protection as the trifluoroacetamide and benzylation of the alcohol gave 879, from which the anomeric benzyl was hydrogenolyzed and converted to acetate 880.⁴²⁵ 2-Fluorofucal synthesis by anomeric bromination and elimination was achieved, and reaction with CF₃OF under Lewis acid catalysis furnished the typical mixture of anomeric fluorides and trifluoromethyl glycosides, 882 and 883.⁴²¹

Scheme 125. Direct Difluorination of a 2-Fluorinated Glycal to Arrive at 1,2,2-Trifluorinated Sugars⁴²¹.

8.1.1.3. Glucose/Mannose Stereochemistry

The Van der Marel/Overkleeft and Wright groups both independently reported the synthesis of 6-azido-2,6-deoxy-2-fluoro-β-d-glucosyl fluoride 889 from tri-O-acetyl d-glucal 1 (Scheme 126),^426,427 which essentially only differs in the aromatic thiol used to protect the anomeric position (p-tolyl vs p-chlorophenyl). The Van der Marel/Overkleeft synthesis is shown here. The fluorine at the 2-position was introduced first, from reaction of the glucal 1 with SelectFluor (as shown in Scheme 16) to give 47.⁴²⁶ The Wright group synthesized 47 via β-2, which can be synthesized from 1 with XeF₂ (as shown in Scheme 6) through reaction with HBr.⁴²⁷ A 2-step synthesis of 47 from 2-deoxy-2-fluoroglucose is also possible, as shown in Scheme 9 (not shown). Protection of the anomeric position as the thioglycoside 884 was followed by deacetylation and selective activation of OH-6 to give 885, which allowed azide introduction.⁴²⁶ Reprotection of the remaining alcohols as acetates (886) was then required to allow, after anomeric deprotection to 887, DAST-mediated glycosyl fluoride formation. This led to a 4:1 anomeric ratio of 888, from which the desired β-anomer was isolated in 64% yield. Deprotection of β-888 with a catalytic amount of NaOMe led to 889 in quantitative yield. The use of a stoichiometric amount of NaOMe was reported to lead to a substantial amount of anomeric substitution to give 890.

Scheme 126. A Sequential Fluorination Approach to a 1,2-Difluorinated-6-azido Glucose Derivative^426,427.

The Jordaan group investigated the protected 3-deoxy-3-amino glucal 891(428) as a substrate for reaction with CF₃OF (Scheme 127).⁴¹⁹ This led to the mannosamine derivative 892 as the major and the glucosamine derivative 893 as the minor product, next to the formation of the trifluoromethyl glucoside 894. This result indicates a different facial selectivity compared to the corresponding tri-O-acetyl-d-glucal as shown in Scheme 6.

Scheme 127. A Direct Difluorination Approach to 1,2-Difluorinated-3-amino Mannose and Glucose Derivatives⁴¹⁹.

8.1.2. Fluorination at Positions 1 and 3

There are no dedicated syntheses of 1,3-difluorinated aminosugars, but it is worth mentioning observations by the Karban group regarding a 1 → 6 migration process when deoxyfluorinating the 6-position of β-configured thioglycosides (Scheme 128).⁴²⁹ This process, originally described with a 2-O-benzoylated β-configured methyl galactoside,¹⁴⁵ had been expanded by the Lin group (with β-thiophenolates), where they showed that high yields of migration can be achieved, for example in the conversion of 895 to 896 (Scheme 128A).⁴³⁰ Upon treatment of a mixture of anomers 897 (Scheme 128B, see below Scheme 139 for their synthesis), the Karban group isolated four products,⁴²⁹ with α-898 arising from clean deoxyfluorination of the α-anomer of 897, while β-898, α-899, and β-899 arose from the β-anomer of 897. The major product was the migration product α-899. However, subjecting β-900, the gluco-configured diastereomer of β-897 (Scheme 128C), to the same deoxyfluorination conditions did not lead to much migration, with only 7% of 902 observed in the mixture of inseparable products. This reflects the higher ability of the electron withdrawing equatorial substituent to destabilize a positive charge at the anomeric position, as extensively investigated by the Bols group.^431,432

Scheme 128. Formation of 1,3-Difluorinated-2-Azidohexopyranoses Based on a DAST-Induced 1 → 6 Migration Process^429,430.

Scheme 139. Synthesis of 3,6-Difluorinated GlcNAc Derivatives^429,463.

8.1.3. Fluorination at Positions 1 and 4

The Voznyi group reported a synthesis of a 1,4-difluorinated glucosamine derivative 905 from levoglucosan (Scheme 129A).²⁹⁴ After a 3-step conversion of levoglucosan to 305, as shown in Scheme 41B, treatment with ammonia initiated 2,3-anhydro formation and subsequent opening with ammonia at the usual 2-position. The resulting amine was immediately protected as trifluoroacetamide 903, followed by alcohol protection as acetate 904. 1,6-Anhydro-bridge opening with direct formation of a glycosyl fluoride was achieved with Olah’s reagent in acetic anhydride,⁴³³ to yield target 905. This transformation is usually achieved in a 2–3 step operation involving anhydro opening followed by glycosyl fluoride introduction.

Scheme 129. Synthesis of 1,4-Difluorinated Gluco- and Galactosamine Derivatives^294,429.

Again, it is worth mentioning a 1 → 6 migration reaction (cf. Scheme 128) reported by the Karban group, now starting from 4-fluorinated β-configured thioglycoside 906d (Scheme 129B).⁴²⁹ Hence, reaction of β-906d (see below, Scheme 143 for its synthesis) with DAST under microwave irradiation delivers the 1,4-difluorinated GalNAc derivative 907 in 57% yield, alongside 34% of the direct deoxyfluorination product 908.

Scheme 143. Sequential Fluorination Strategy via 1,6-Anhydro Derivatives to Access 4,6-Difluorinated GalNAc Derivatives^429,463.

8.1.4. Fluorination at Positions 1 and 5

The Withers group reported the synthesis of a 1,5-difluorinated idosamine derivative 914 (Scheme 130).⁴³⁴ Peracetylated glucosamine 909 was treated with HCl in acetic anhydride for >6 days to yield the α-glycosyl chloride 910,^435−437 the reaction of which with AgF in acetonitrile for 2 d at room temperature gave the β-glycosyl fluoride 911.⁴³⁸ Radical bromination (cf. section 3.4) led to the unstable 912, which was directly subjected to AgF in acetonitrile to effect bromide displacement with inversion of configuration to give the l-idosyl fluoride 913. This was subsequently deprotected to yield 2-acetamido-2-deoxy-5-fluoro-α-l-idosyl fluoride 914.⁴³⁴

Scheme 130. Synthesis of a 1,5-Difluorinated l-Idosamine Derivative⁴³⁴.

The Vocadlo group has synthesized the corresponding glucosamine derivatives 921 and 922 (Scheme 131).⁴³⁹ As already indicated in section 3.4 for the synthesis of 1,5-difluorinated derivatives, fluorination at C1 is required before fluorination at C-5. Hence, 916 was targeted as the first deoxyfluorination substrate and was obtained by anomeric deprotection of the per-O-acetate 915. This can be synthesized from glucosamine hydrochloride via a temporary amine protection as the p-methoxybenzylidene imine in four steps,^439,440 but a shorter, higher yielding, 2-step process as shown is now available from glucosamine.⁴⁴¹ DAST-mediated deoxyfluorination of 916 gave the β-glycosyl fluoride 917 as the only reported anomer in excellent yield.⁴³⁹ Radical bromination at the 5-position was followed by retentive bromide displacement with the AgBF₄/Et₂O conditions to give 919 in modest yield. Amine deprotection with hydrazine was possible without affecting the anomeric fluoride group, and subsequent acetylation followed by global deprotection afforded the desired 5-fluorinated glycosyl fluoride probe 921. A similar process using chloroacetic acid anhydride for the acetylation, and subsequent chloride displacement with azide gave 922.

Scheme 131. Synthesis of 1,5-Difluorinated GlcNAc Derivatives⁴³⁹.

8.1.5. Fluorination at Positions 1 and 6

The Cabrera-Escribano group investigated deoxyfluorination reactions on branched nitrosugars, which were synthesized by the Baer reaction.^299,442,443 Methyl α-d-glucopyranoside α-369 (Scheme 132) was subjected to periodate cleavage to the dialdehyde 923, whereupon treatment with nitroethane in basic medium led to a 1:1 mixture of inseparable 924 and 925. The synthesis of the latter involves epimerization at C-5.⁴⁴⁴ The stereomers were separated after formation of the benzylidene acetals α-926 and ent-β-926. Each was then converted to its corresponding thiophenyl glycoside 927, and this led in both cases to a 4:1 β/α mixture, with the compounds coming from α-926 being enantiomeric to those arising from ent-β-926. Treatment of β-927 led to a mixture with 6-deoxy-6-fluoro α-glycosyl fluoride 928 as the major product, in which the thiophenolate had rearranged to the 2-position, and 929, in which only a reaction at the anomeric center had taken place.⁴⁴² This result was confirmed with ent-β-927 as starting material.

Scheme 132. Investigation of Direct DAST-Mediated Difluorination on a Branched Nitrosugar Derivative^299,442,443.

8.1.6. Fluorination at Positions 2 and 3

The Linclau group synthesized the tetrafluorinated aminosugars 937 and 938, with the addition of lithiated 287 to the sulfinylimines 931 and 938 as the key step.⁴⁴⁵ This methodology had been developed by the Konno group, with a demonstration of the addition of lithiated 287 to the corresponding sulfinylimine of benzaldehyde.⁴⁴⁶ Hence, with 931 as substrate (Scheme 133A), synthesized from d-glyceraldehyde 288 and the sulfinamide 930, syn and anti-adducts 932 and 933 were obtained in excellent diastereoselectivity. These could be separated after acetonide methanolysis as 934 and 935, respectively. A minor (±3%) side product arising from S_N2′ substitution of a fluoride by methyl lithium was also formed (not shown). The major isomer 934 was obtained in 88% isolated yield, upon which alkene ozonolysis and auxiliary cleavage gave the aminosugar 937, which was isolated as its hydrochloric acid salt.

Scheme 133. Synthesis of Tetrafluorinated Aminosugar Derivatives⁴⁴⁵.

Based on the observation by the Linclau/Poisson groups that stereocontrol in additions to sulfinylimines derived from glyceraldehyde acetonide is exerted by the auxiliary configuration,⁴⁴⁷ addition with 938 was investigated (Scheme 133B) as well. As expected, the syn-adduct 940 was now the major stereomer, which was subsequently converted to the 4-epi aminosugar 942 in the same way as shown above.⁴⁴⁵

8.1.7. Fluorination at Positions 2 and 4

The Giguère group reported the synthesis of a number of 1,6-anhydro-2,4-dideoxy-2,4-difluoroallose derivatives via functionalization at C-3 (Scheme 134).^295,448 Using the triflate 543 as a key intermediate, for which the synthesis was discussed in Scheme 78, the azide 943 could be prepared as a first handle for functionalization via a click reaction to obtain the lipoic acid fluorinated glycoconjugate 945.²⁹⁵ The azide could also be reduced to the corresponding amine 946 as a versatile intermediate for further functionalization. Reductive amination with aldehyde 947 (derived from galactose diacetonide) gave the amino-linked fluorinated disaccharide 948, whereas peptide coupling with Cbz-protected phenylalanine 949 using isobutyl chloroformate (IBCF) as the coupling agent yielded 950.²⁹⁵ It was also demonstrated that oxime resin aminolysis was possible, leading to the C-terminal fluoroglycopeptide 951.⁴⁴⁸

Scheme 134. Synthesis of Functionalized 2,4-Difluorinated 3-Amino-1,6-anhydrohexopyranose Derivatives^295,448.

8.1.8. Fluorination at Positions 2 and 5/3 and 5

The Anker group investigated the fluorination of aminosugars, and results toward difluorinated pentoses are given in Scheme 135.^449,450 Methyl 2,3-anhydro-β-d-lyxofuranoside α-635, whose synthesis in five steps from d-xylose was discussed in Scheme 96, was converted to the N,N-dimethyl aminosugar derivative 952 with full regioselectivity.⁴⁵⁰ Following hydroxyl group mesylation, treatment with Et₃N·2HF initially gave rise to formation of aziridinium species α-954, whereupon nucleophilic substitution with fluoride took place with moderate regioselectivity to give α-955 and 956. Fluorine substitution at the 5-position, reported to be difficult, only proceeded in low yield with the more reactive tetraethylammonium hydrogen difluoride to yield 957.⁴⁵⁰ Direct treatment of 953 with Et₄NHF₂ only returned a complex reaction mixture.

Scheme 135. Investigations on the Fluorination of Aminopentofuranoside Derivatives^449,450.

With the β-anomer of methyl 2,3-anhydro-d-lyxofuranoside β-635, obtained in five steps from d-xylose as discussed in Scheme 92, the epoxide opening with dimethyl amine was less selective (Scheme 135B), giving a 75:25 ratio of inseparable 958 and 959.⁴⁵⁰ Mesylation of this mixture led to another inseparable mixture of 960 and 961. These converged to the same aziridinium ion β-954 upon treatment with Et₄NHF₂, which underwent regioselective opening with fluoride, with some fluorination at C-5 as well, to give β-955 and 962 in modest yields.⁴⁵⁰

With the 2,3-anhydroribofuranoside substrate β-721 (Scheme 135C), obtained in five steps from the commercially available 717 as discussed in Scheme 102, regioselective epoxide opening with ammonia followed by protection as the diallyl amine led to 963. Mesylation of the alcohols to 964 was followed by fluorination, which now proceeded first through azetidinium intermediate 965, leading first to fluorination at the 5-position. Subsequent fluorination proceeded then via an aziridinium intermediate, giving both the F-2 and F-3 products 966 and 967.⁴⁵⁰ Nevertheless, it was stressed that C-5-fluorination remained difficult. The azetidinium ion derived from the dimethylamino group, 968 (Scheme 135D), was reported to be isolable and stable, and only 16% of the 2,5-difluorinated 969 was obtained after fluorination.⁴⁴⁹ The enhanced reactivity of 965 was ascribed to steric strain between an allyl group and the anomeric methoxy group.

8.1.9. Fluorination at Positions 3 and 4

The Karban group reported the synthesis of 3,4-dideoxy-3,4-difluorinated GlcNAc and GalNAc derivatives using a sequential fluorination approach.⁴⁵¹ The GlcNAc synthesis (Scheme 136) commenced from d-mannose, which was converted first to 1,6-anhydro-β-d-mannose 971 and then its acetonide 972 using the Fraser-Reid procedure.⁴⁵² Tosylation of the alcohol,⁴⁵³ acetonide hydrolysis,⁴⁵⁴ and intramolecular tosylate substitution⁴⁵⁵ resulted in 1,6:2,3-dianhydrotalose 973. Activation of the OH-2 as a triflate allowed azide introduction to give 974, in which the use of LiN₃ proved far superior compared to NaN₃ (82% vs 48%).⁴⁵⁶ This was subjected to fluoride opening to give 975, with the side-product 976 resulting from epoxide opening by the solvent also isolated. The second fluorine introduction by DAST-mediated retentive deoxyfluorination gave the desired 977 alongside rearrangement product 978.⁴⁵¹ This rearrangement is initiated by neighboring group participation of the azido group, leading to 979. Fluoride attack at C-3 then leads to 977, while a second neighboring group participation from O6 leads to 980, upon which fluoride attack at the anomeric center results in 978. From 977, acetolysis to open the anhydro-bridge followed by azide reduction and acetylation afforded 2-acetamido-1,6-di-O-acetyl-2,3,4-trideoxy-3,4-difluoro-α-d-glucopyranose 982. Alternatively, 1,6-anhydro opening by phenyl trimethylsilyl sulfide (PhSTMS) under ZnI₂ catalysis afforded the thioglycoside 983,⁴²⁹ which was then subjected to OH-6 protection and anomeric deprotection to give 984. Azide reduction with concomitant acetylation and benzyl hydrogenolysis finally afforded 3,4-dideoxy difluorinated GlcNAc 986.

Scheme 136. Synthesis of 3,4-Difluorinated GlcNAc Derivatives^429,451.

The syntheses of the corresponding 3,4-difluorinated GalNAc derivatives proceed along similar lines (Scheme 137). The 4-O-benzylated 1,6:2,3-dianhydromannose 219, obtained in two steps from d-glucal as discussed in Scheme 30, was subjected to azide opening to give 987.⁴⁵⁷ DAST-mediated retentive deoxyfluorination gave 988 in excellent yield without any rearrangement,⁴⁵¹ in contrast to the deoxyfluorination of 975. Presumably this is due to the availability of the benzyloxy group for neighboring group participation, possibly outcompeting the azido group (however see Scheme 125). Oxidative debenzylation then allowed a second deoxyfluorination, now with inversion of configuration, to give 990. Acetolysis and azide reduction/acetylation then gave 2-acetamido-1,6-di-O-acetyl-2,3,4-trideoxy-3,4-difluoro-α-d-galactopyranose 992.

Scheme 137. Synthesis of 3,4-Difluorinated GalNAc derivatives^429,451.

Unlike the corresponding gluco-configured analogue 977 (see Scheme 136), treatment of 990 with PhSTMS/ZnI₂ was reported to lead to decomposition.⁴²⁹ Hence, 989 was subjected to PhSTMS/ZnI₂ instead, leading to 993. This was then converted to the 6-O-benzyl ether 994 to allow deoxyfluorination at C-4, which proceeded smoothly with the expected inversion of configuration to give 995. Anomeric deprotection, azide reduction/acetylation, and benzyl hydrogenolysis finally afforded 3,4-dideoxy difluorinated GalNAc 996.

8.1.10. Fluorination at Positions 3 and 6

The Picq/Anker group used the aziridinium-mediated fluorination approach, as described in Scheme 135, for the synthesis of 2,5/3,5-difluorinated pentosamine derivatives. Conversion of 997 (Scheme 138) to the 2,3-anhydro derivative 998 using the Fraser-Reid procedure⁴²³ was followed by regioselective epoxide opening with diallyl amine.⁴⁵⁸ The resulting 999 was then hydrolyzed to give 1000,⁴⁵⁹ and converted to its tri-O-mesylate 1001.⁴⁶⁰ Treatment of 1001 with Et₃N·3HF at 60 °C led to a mixture of the 3-fluorinated glucosamine derivative 1003 and the 2-fluorinated altrose derivative 1004,⁴⁶¹ an outcome that can be explained by invoking an aziridinium intermediate. Given that 1003 is the major product, this must primarily react via the half-chair 1002a. Reaction of 1003 with the more reactive Et₄NHF₂ then gave the 3,6-difluorinated derivative 1005. In an earlier publication, it was reported that heating 1001 with Et₃N·3HF at 75 °C for 4 h gave 1003 in 73% yield, with no mention of any formation of 1004,⁴⁶⁰ although it was later claimed that heating of 1001 with Et₃N·3HF at 75 °C for 26 h led to a mixture of 1003-1006 without specification of yields.⁴⁶¹

Scheme 138. Investigations on the Fluorination of 3-Amino Altropyranoside Derivatives⁴⁶¹.

The Karban group reported an approach to 3,6-dideoxy-3,6-difluorinated GlcNAc derivatives using 1,6-anhydro intermediates (Scheme 139). From 989, for which the synthesis was reported in Scheme 137, acetylation and anhydro-bridge opening with PhSTMS gave 1008 as a mixture of anomers.⁴⁶² The available OH-6 group was deoxyfluorinated to 1009, and the anomeric position deprotected to give 1010. Azide reduction with concomitant acetylation then gave 1011.⁴⁶³

Alternatively, the 4-O-benzyl-protected 1,6-anhydro derivative 988, obtained in four steps from d-glucal as discussed in Scheme 137, was treated with PhSTMS to obtain a separable mixture of thioglycoside anomers α-and β-900.⁴⁶⁴ These anomers were separated before deoxyfluorination, given the 1 → 6 migration side reaction of the β-thiophenyl anomer (see Schemes 128 and 129). Deoxyfluorination of the α-anomer led to 1012 in excellent yield,⁴⁶² and subsequent anomeric deprotection, azide reduction/acetylation, and benzyl hydrogenolysis gave 2,3,6-trideoxy-2-acetamido-3,6-difluoroglucose 1015.⁴²⁹

The Karban group also developed similar a synthesis of 3,6-difluorinated GalNAc derivative 1019 (Scheme 140). Starting again from 988, oxidative debenzylation followed by Lattrell-Dax inversion²⁷⁶ resulted in the galacto-derivative 1016, which was protected as benzyl ether 1017.⁴⁶⁴ Anhydro-bridge opening with PhSTMS gave a mixture of separable anomers 897, and the α-anomer was subjected to deoxyfluorination to give α-898.⁴²⁹ Anomeric deprotection, azide reduction/acetylation, and benzyl hydrogenolysis then afforded 2,3,6-trideoxy-2-acetamido-3,6-difluorogalactose 1019.

Scheme 140. Synthesis of 3,6-Difluorinated GalNAc Derivatives⁴²⁹.

8.1.11. Fluorination at Positions 4 and 6

8.1.11.1. Galactose Stereochemistry

The Richardson group reported the first synthesis of 4,6-difluorinated GalNAc using fluoride displacement of the required 4,6-di-O-mesylate, an approach already encountered in Scheme 61A for the synthesis of 4,6-dideoxy-4,6-difluorogalactose. Starting from d-glucosamine hydrochloride (Scheme 141A), treatment with NaOMe followed by benzoic anhydride gave 1020.⁴⁶⁵ Its α-methyl glycoside 1021 was then obtained, and the 4,6-positions were protected as benzylidene acetal 1022.⁴⁶⁶ Protection of OH-3 as benzyl ether 1023 was followed by benzylidene acetal hydrolysis to allow activation to the 4,6-di-O-mesylate 1025.⁴⁶⁷ Fluoride substitution to give 1026 could be achieved with TBAF in refluxing acetonitrile or with KF in refluxing ethylene glycol, the latter having a much shorter reaction time. Replacing the 3-O-benzyl group with an acetate and the benzamide with acetamide gave, after acetate methanolysis, methyl 2,4,6-trideoxy-2-acetamido-4,6-difluorogalactoside 1029.⁴⁶⁷

Scheme 141. Synthesis of 4,6-Difluorinated GalNAc Derivatives via Mesylate Displacements^467,469.

A similar synthesis was later published by the Korytnyk group (Scheme 141B). N-Acetyl glucosamine was converted to its benzyl glycoside 1030, and further converted to its benzylidene acetal. This was acetylated for recrystallization purposes to give 1031 as pure α-anomer.⁴⁶⁸ The acetyl group was replaced with a benzyl, after which the benzylidene acetal was hydrolyzed to give 1034.⁴⁶⁹ Reaction of 1034 with DAST was reported to be unsuccessful, owing to the low reactivity of the OH-4 group, so the alcohols were activated as mesylates, upon which reaction with TBAF in refluxing acetonitrile resulted in the formation of 1036 in excellent yield. Hydrogenolysis then gave 2,4,6-trideoxy-2-acetamido-4,6-difluorogalactose 1037.

The Dax group reported the synthesis of a 4″,6″-difluorinated kanamycin A derivative 1044 (Scheme 142) using a related approach.⁴⁷⁰ Starting from kanamycin A, the 4′′ and 6′′ positions were differentiated from the rest by first protecting the amino groups as their Boc derivatives, leading to 1038.⁴⁷¹ Cyclohexylidene acetal formation (1039) was followed by peracetylation of the remaining alcohol groups to give 1040, upon which removal of the acetal group resulted in 1041. The deprotected alcohol groups were then activated as triflates (1042), which allowed substitution with fluoride to give 1043. Global deprotection then resulted in 4″,6″-dideoxy-4″,6″-difluoro-4″-epi-kanamycin A 1044.

Scheme 142. Synthesis of 4″,6″-Difluorinated Kanamycin A Derivative via Triflate Displacements⁴⁷⁰.

The Karban group synthesized a series of 4,6-difluorinated GalNac derivatives using 1,6-anhydrosugar chemistry (Scheme 143). The benzyl group in the 1,6:2,3-dianhydro derivative 219, obtained as described in Scheme 30, was hydrogenolyzed to give 1046, which was deoxyfluorinated with retention of configuration to give 1047.^146,451 Epoxide opening with lithium azide led to 1048 in 74% yield with a small amount of regioisomer 1049 observed. The alcohol group in 1048 was now acylated to give the acetate 1050a,⁴⁷² the propionate 1050b, and the butyrate 1050c,⁴⁶³ as well as benzylated to give 1050d.⁴⁶⁴ Anhydro-bridge cleavage was effected with PhSTMS to give a mixture of separable anomers 906a–d.^463,464 Interestingly, for the propionate derivative 1050b, a rearrangement byproduct 1051 was also isolated. This is formed through activation of the azido group by ZnI₂, initiating neighboring group participation from the endoxyclic O5 (not shown).⁴²⁹ As explained with Scheme 139, the thiophenyl anomers were separated to avoid dealing with possible 1 → 6 migration side reactions arising from the β-anomer.⁴³⁰ Hence, the α-anomers α-906a–d were subjected to the DAST-mediated deoxyfluorination conditions, followed by anomeric deprotection and azide reduction/acetylation to give the 4,6-difluorinated GalNAc derivatives 1054a–d as analogues of the cytotoxic triacetylated GalNAc,⁴⁶³ and the benzyl ether 1054d. This was then fully deprotected to give 2,4,6-trideoxy-2-acetamido-4,6-difluorogalactose 1055.⁴²⁹

In Cabrera-Escribano’s investigations of fluorinations on branched nitrosugars (cf. Scheme 132), 4,6-dideoxy difluorination was also achieved from 925 (Scheme 144), which was obtained by benzylidene acetal deprotection of β-ent-926. Using the same DAST conditions as applied to 927, only deoxyfluorination at C-6 took place, leading to 1056.⁴⁴² In refluxing solvent, however, deoxyfluorination at the 4- and 6-positions took place leading to 1057,⁴⁴³ an outcome consistent with the Somawardhana result as described in Scheme 60A. However, ring contraction diastereomers 1058 and 1059 were also observed, with their structure reassigned in a later publication,²⁹⁹ via a similar process already shown in Scheme 43A. The isolation of 1058 and 1059 suggests that deoxyfluorination at C-4 does not precede ring contraction (cf. Scheme 43A).

8.1.11.2. Glucose Stereochemistry

The Richardson group also reported the synthesis of 4,6-difluorinated GlcNAc derivatives using the dimesylate fluorination approach (Scheme 145).⁴⁶⁷ Hence, the advanced glucosamine intermediate 1025, for which the synthesis is described in Scheme 141, was converted to its galactosamine analogue 1061 using nucleophilic substitution with lithium benzoate, followed by ester methanolysis (cf. Scheme 63 for another example of this approach) and mesylation. In contrast to the fluoride displacement of 1025 (cf. Scheme 141), reaction of 1061 with KF in refluxing ethylene glycol resulted in a significant amount of elimination product 1063, which is due to the availability of an antiperiplanar C–H bond at the 5-position. Other fluorination conditions, such as lowering the temperature to 100 °C or using TBAF in refluxing acetonitrile, either failed to give product or returned a complex reaction mixture with 1062 formed in <40% yield. From 1062, a protecting group change of OH-3 and conversion of the benzamide group to an acetamide afforded 1065.

Scheme 145. A Direct Synthesis of 4,6-Difluoro GlcNAc via Mesylate Displacement⁴⁶⁷.

The Ling group has synthesized the peracetylated 4,6-dideoxy-4,6-difluoro glucosamine 1076 (Scheme 146) using a sequential deoxyfluorination approach.⁴⁷³N-Acetyl glucosamine was converted to its α-benzyl anomer 1066,⁴⁷⁴ then subjected to benzoylation conditions which were selective for the 3- and 6-positions.^475,476 Inversion of the OH-4 group in the resulting 1067 was achieved by a Lattrell-Dax reaction to give 1068, followed by deoxyfluorination to give 1069.⁴⁷⁶ Benzoate methanolysis to 1070(476) was followed by a protecting group sequence to arrive at the free OH-6 in 1073, which was subjected to another deoxyfluorination to give 1074. Anomeric deprotection followed by acetylation then gave 1076.⁴⁷³

Scheme 146. A Sequential Deoxyfluorination Approach to a 4,6-Difluorinated GlcNAc Derivative⁴⁷³.

The Karban group also used a sequential deoxyfluorination approach to obtain 4,6-difluorinated GlcNAc derivatives based on 1,6-anhydrosugar chemistry (Scheme 147).^429,463 The key intermediate 975, for which the synthesis was discussed in Scheme 136, was converted to the acetate 1077a,⁴⁶² the propionate 1077b, the butyrate 1077c,⁴⁶³ and the benzyl ether 1077d.⁴⁶⁴ Anhydro-bridge opening of 1077a–c using PhSTMS was followed by separation to obtain the pure anomers, with the α-anomer now clearly the major product,^462,463 in contrast to the result obtained with the corresponding galacto-configured derivatives (see Scheme 143). In some cases, the anomers were contaminated by ring contraction products 1079. The opening of the benzyl ether 1077d led to 1078d, the anomers of which were not separated.⁴²⁹ Fluorination at OH-6 was carried out with α-1078a–c, as discussed above to avoid complications with a possible 1 → 6 migration with the β-anomers (cf. Schemes 128 and 129), to give the 4,6-difluorinated GlcNAc derivatives 1080a–c in high yield.⁴⁶³ However, when the deoxyfluorination was carried out on the mixture of benzyl anomers 1078d, an excellent yield of 1080d was obtained with no mention of migration issues.⁴²⁹ This is consistent, however, with the result shown in Scheme 128C in which there was a low level of migration product with the glucose-based substrate. Treatment of the thus obtained 4,6-difluorinated derivatives 1080 with NBS in aqueous medium gave the free hemiacetals 1081a–d, whereupon the azide group was reduced with concomitant acetylation to give 1082a–d.^429,463 The benzyl ether was then removed via hydrogenolysis to give 4,6-dideoxy-4,6-difluoroGlcNAc 1083.⁴²⁹

Scheme 147. A Sequential Deoxyfluorination Approach to 4,6-Difluorinated GlcNAc Using 1,6-Anhydropyranose Chemistry^429,463.

8.2. Fluorination at Three Positions

8.2.1. Fluorination at Positions 2,3,4

The Giguère group reported the synthesis of the 6-azido 2,3,4-trifluorinated allose derivative 1086 (Scheme 148) from advanced intermediate β-547, for which the synthesis was described in Scheme 78.²⁹⁵ Acetate hydrolysis followed by triflate activation and azide substitution led to 1086, which was successfully used in a click reaction with a dipeptide derivative (not shown).

Scheme 148. Synthesis of a 6-Azido 2,3,4-Trifluorinated Alloside Derivative²⁹⁵.

8.2.2. Fluorination at Positions 3,4,6

The Karban group disclosed the synthesis of 3,4,6-trifluorinated GlcNAc and GalNAc 1089 and 1092.⁴²⁹ Advanced intermediate 977 (Scheme 149A), for which the synthesis was discussed in Scheme 136, was treated with PhSTMS to achieve anhydro-bridge opening with the formation of separable thioglycosides. The α-anomer of 983 was reacted with DAST to effect OH-6 deoxyfluorination, giving 1087. After anomeric deprotection and azide reduction/acetylation, this gave the trifluorinated GlcNAc 1089.

Scheme 149. Synthesis of 3,4,6-Trifluorinated GlcNAc and GalNAc⁴²⁹.

Subjection of intermediate 993, obtained as discussed in Scheme 137, to deoxyfluorination conditions led to 1090 in excellent yield (Scheme 149B). Anomeric deprotection and azide conversion then gave the trifluorinated GlcNAc 1092.

9. Sialic Acids

Fluorinated sialic acids are being extensively explored and will be discussed in this section. In particular, 2,3-difluorinated sialic acids have been widely investigated as mechanism-based inhibitors. Their synthesis is possible via direct vicinal difluoride introduction (cf. sections 3.1.1, 6.1, and 8.1.1), although hazardous reagents are required. Therefore, most syntheses of 2,3-difluorinated sialic acid analogues thus adopt a sequential approach which in all cases involves obtaining C-3-fluorinated sialic acid first, followed by anomeric fluorination. Because of the number of analogues reported, often using different methods for the first and second fluorination, these fluorination steps will be discussed separately. Selected examples from the literature that feature a single F-3 introduction are also included for discussion purposes.

9.1. Nomenclature and Assignment

9.1.1. Nomenclature

The nomenclature of sialic acid and its derivatives is complex and confusing, and errors can be found in the literature. Hence, this section is included in order to ensure consistent naming of derivatives. Sialic acid, or N-acetyl neuraminic acid (Figure 5A), is a non-2-ulonic acid derivative, or non-2-ulopyranosonic acid if the ring structure is included in the name. It has no substituent at the 3-position. For its IUPAC systematic name,⁴⁷⁷ the Fisher structure is considered (Figure 5). As there are more than four chiral centers, two configurational prefixes are required for the stem name. For sialic acid, these are d-galacto and d-glycero. However, when a single fluorine (or any other substituent) is introduced at C-3, as in 1093, a new chiral center is created. Consequently, this results in different configurational prefixes. For 1093, with (3R)-configuration, this is l-manno and d-erythro. For the other C-3-diastereomer 1094, this is l-gluco and d-erythro.

Figure 5.

Nomenclature for sialic acid and 3-substituted sialic acids.

The α,β-assignment of the anomeric center is nontrivial, and furthermore changes upon introduction of a (single) substituent at C-3. Consideration of the so-called “anomeric reference atom” is required. This is the highest numbered carbon atom of the group of stereocenters within the configurational prefix alongside the anomeric center, which is also involved in the heterocyclic ring. For sialic acid and 1093, the configurational prefix encompasses four stereocenters, but in sialic acid the 3-position is ignored as it is not a chiral center. Hence, the different atoms of the configurational prefixes involved in the ring structures of sialic acid and 1093 result in a different anomeric reference atom. These are indicated in Figure 5 with a blue dot. For sialic acid, the substituents at the anomeric center and on the reference atom are trans, hence the anomer shown is the β-anomer. For 1093, the two substituents are cis, thus this is the α-anomer. Hence, while both sialic acid and 1093 have the anomeric OH group in the same axial position, their anomeric assignment is different.

In this section, this IUPAC nomenclature will be used, even if that differs from the nomenclature used in the referenced publication.

CIP nomenclature can also be used to indicate F-3 configuration (e.g., 3(R) in 1093), but this is cumbersome and not “at-a-glance”. Together with the difference in anomeric assignment compared to sialic acid, a convenient system just indicating the orientation of the fluorines on a chair conformation as axial or equatorial (e.g., 2F_ax3F_ax, Figure 5C), is sometimes used in the literature as well. This will also be adopted here for the ease of discussion.

9.1.2. Identification

Given the occasional nomenclature errors in literature experimental sections, it is useful to include a section regarding anomeric assignment of 2,3-fluorinated sialic acids at C-2 and C-3. This is possible using NMR analysis; relevant data are shown in Table 1 for the four possible 2,3-difluorinated sialic acid compounds α/β-1095/1096.^478,479 The configuration of F-3 is easily determined through the magnitude of the vicinal coupling between H-3 and H4: with F_eq-3 this is a trans-diaxial coupling with H-4 and hence ³J_H3–H4 will be around 8–10 Hz, while with F_ax-3 ³J_H3–H4 will be much smaller. Furthermore, the same is true for the vicinal F3–H-4 coupling: with F_ax-3 this is a trans-diaxial coupling and ³J_F3–H4 will be between 25 and 30 Hz, while with F_eq-3 ³J_H4–F3 will be 15 Hz or smaller (Table 1).

Table 1. Diagnostic NMR Features of 2,3-Difluorinated Sialic Acid Derivatives. Data Taken from References (478 and 479).

^aNot observed.

^bH-3 and H-4 are multiplets.

Determination of the configuration of F-2 is only straightforward in the presence of an F_eq-3 substituent, as only then are the ³J_F2–H3 coupling constants of diagnostic value. This coupling constant is 21 Hz for 2a3e and 14 Hz for 2e3e (Table 1). While H3 or H-4 can be part of a multiplet, these values are typically easily extracted from the ¹⁹F NMR spectrum. Unfortunately, ¹⁹F–¹⁹F coupling constants do not adhere to the Karplus rule, although they do have diagnostic value to distinguish 2,3-difluorinated sialic acid derivatives: the largest (absolute) value is found for the F2_axF3_eq derivative (21 Hz), which is well above the other values.

For unambiguous assignment vicinal ¹³C–¹⁹F coupling constants need to be considered, which do adhere to the Karplus rule. Hence, ³J_C–F values will be higher for equatorial fluorines compared to their axial counterparts. With F_eq-2 ³J_C4–F2 values are 6–8 Hz, while with F_ax-2 this coupling is not observed, although a value of <2 Hz is expected (Table 1). The same is seen for the ³J_C5–F3 values, which are ∼8 Hz when F-3 is equatorial and <3 Hz when axial (not shown). Interestingly, a geminal C–F coupling can have diagnostic value as well: Wray noted that ²J_C–F increases with the change of an electronegative substituent bonded to the coupled carbon from a gauche to a trans-orientation with respect to the fluorine involved in the coupling.⁵³ With 2,3-difluorinated sialic acids, this is especially useful for ²J_C3–F2 (Table 1): a value of 45 Hz is found for the trans-diaxial F2_axF3_ax compound, whereas it has a much lower value when the fluorines are gauche in 2e3a. The Wray-rule is not useful for ²J_C2–F3, presumably as there are two extra electronegative groups at C-2, but, given the stereochemistry of F-3 is easily established otherwise, this is not an issue.

Given that in most cases F-2 is introduced after installation of F-3 with known configuration, anomeric assignment is required. A summary of diagnostic coupling constants to easily achieve this is provided inFigure 6.

Figure 6.

Diagnostic NMR values to assign anomeric configuration.

9.2. Simultaneous Fluorine Introduction at C-2 and C-3

The earliest syntheses of 2,3-difluorinated sialic acid analogues employed electrophilic fluorination of the sialic acid glycal intermediate 1099 (Scheme 150), which can be obtained from sialic acid by methyl ester formation to 1097, acetylation of the alcohol groups with concomitant conversion of the hemiketal to the chloride 1098, and finally by elimination of the latter to the conjugated ester.^479−481 Reaction of 1099 with fluorine gas in acetic acid gave the 2F_ax3F_eq-difluorinated sialic acid derivative α-1100 as the major product in 36% yield, alongside the 2-acetoxy-3-fluoro diastereomers 1101 and 1102 as side products.⁴⁸² With AcOF as the fluorinating agent, 1101 was the major product and α-1100 and 1102 the minor products (34%, 7.7%, 0.5% yields, respectively, not shown). Acetate methanolysis and acid hydrolysis of α-1100 gave α-1096, which was reported to be a potent inhibitor against neuraminidase.⁴⁸²

Scheme 150. Direct Difluorination Approach with F₂ to Give the 2F_ax3F_eq Adduct⁴⁸².

This methodology was used by the Ikeda/Sato group on a sialic acid glycal modified at the 4-position (Scheme 151).⁴⁸³ Starting from peracetylated sialic acid methyl ester 1104,⁴⁸⁴ which could be obtained from sialic acid without using diazomethane via acid-catalyzed methyl ester formation followed by alcohol acetylation,⁴⁸⁵ protection of the anomeric center as the thiophenolate resulted in the formation of 1105.⁴⁸⁶ Deacetylation was followed by acetonide formation, which was selective for the terminal side-chain position. The resulting 1106 was selectively alkylated at OH-4, upon which the acetonide was hydrolyzed and all alcohols reprotected as acetates to give 1108. Activation of the anomeric substituent with dimethyl(methylthio)sulfonium triflate (DMTST) allowed its elimination with DBU to give the key glycal intermediate 1109.⁴⁸⁷ Reaction with diluted fluorine gas was reported to lead to 1110 stereoselectively, which after deprotections gave the 2F_ax3F_eq-difluorosialic acid derivative 1111. This was further converted to the human sialidase inhibitor 5-acetamido-3-cyanomethyl-2,5-dideoxy-2,3-difluoro-α-d-erythro-l-gluco-2-nonulopyranosonic acid 1112.⁴⁸³

Scheme 151. Synthesis of a 2,3-Difluorinated Sialic Acid Analogue Using a Direct Difluorination Strategy with F₂⁴⁸³.

Alternatively, reaction of glycal 1099 (synthesis described in Scheme 150) with xenon difluoride/BF₃ also leads to syn-vicinal difluorination with the same facial selectivity as the reaction with F₂, with no report of formation of F_ax-3-containing minor products (Scheme 152).^479,481 Acetate methanolysis and methyl ester hydrolysis then gave α-1096.

Scheme 152. Direct Difluorination Strategy with XeF₂^479,481.

9.3. Stepwise Introduction

9.3.1. Fluorination at C-3 from the Glycal

The reaction of the sialic acid glycal with SelectFluor was first described by the Wong group (Scheme 153A).^170,488 From the peracetylated glycal 1099, the F_ax-3 and F_eq-3 diastereomers 1113 and 1114 were obtained in a 3:1 ratio (isolated yields) in excellent overall yield. The Ito/Kanie group reported that the reaction on the perbenzylated derivative 1115, obtained via a protecting group switch from 1099 (Scheme 153B),⁴⁸⁹ was much faster and with similar yields of the F_ax-3 and F_eq-3 stereomers compared to the reaction of 1099, albeit with a slightly lower diastereoselectivity.⁴⁹⁰ This result has been confirmed by the Gilmour group.⁴⁹¹ This group also updated the original synthesis of 1115(489) by replacing diazomethane with iodomethane.⁴⁹¹

Scheme 153. Fluorine Introduction at C-3 via Reaction of Sialic Acid Glycal with SelectFluor^{170,488,490,491}.

This fluorination methodology has also been employed for 4-azido analogues, such as 1119 and 1123 (Scheme 154). The former can be obtained by Lewis acid activation of the allylic acetate in 1099, which initiates cyclization of the NAc group to form a fused oxazoline, giving 1118. Reaction with azide under acid activation at the allylic position provided the 4-azido group in 1119 with overall retention of configuration.⁴⁹² Subsequent treatment of 1119 with SelectFluor in a nitromethane–water mixture at room temperature gave the F_ax-3 derivative 1120 as the major isomer in 39% yield, alongside the F_eq-3 1121 in 18% yield (2.2:1 ratio).⁴⁹³ With the similar glycal 1123, the von Itzstein group obtained similar product yields (49% for 1124, 17% for 1125) using these room temperature conditions.⁴⁹⁴ The long reaction time confirms the unreactive nature of the acetylated glycal. Von Itzstein showed that reaction with SelectFluor at 80 °C under microwave irradiation dramatically decreased the reaction time, while increasing the product yield and ratio. In 2 h, 1124 and 1125 were obtained in a 1.7:1 ratio in 93% combined yield (58% for 1124, 35% for 1125).⁴⁹⁴ Glycal 1123 can be obtained from 1119 by switching the N-acetyl for a Boc group, which proceeds first by Boc-protection of the amide and acetamide hydrolysis, followed by the required reacetylation of the alcohol groups to get 1122. Amine deprotection followed by acylation with isobutanoyl chloride then provides 1123.^495,496

Scheme 154. Fluorine Introduction at C-3 via Reaction of 4-Azido Modified Sialic Acid Glycal with SelectFluor^493,494.

With a less electron withdrawing NHBoc group at the 4-position, as in glycal 1128 (Scheme 155), the SelectFluor reaction required 4 days at room temperature to give a 50% combined yield of 1129/1130.⁴⁹⁷ Unfortunately, no ratio was reported. The glycal was obtained from 1119 by azide reduction and subsequent Boc protection to give 1126, upon which the remaining alcohols were deprotected. After terminal acetonide formation, the OH-7 was activated to give the p-nitrophenyl (PNP) carbonate 1127.⁴⁹⁸ Reaction with 1-amino-2-azidoethane gave the corresponding carbamate, after which the acetonide protecting group was removed and the alcohols reprotected as acetates, giving 1128. The mixture of 1129/1130 was taken forward for deoxyfluorination (see Scheme 170).

Scheme 155. Fluorine Introduction at C-3 via Reaction of 4-Boc-amino Modified Sialic Acid Glycal with SelectFluor⁴⁹⁷.

Scheme 170. Deoxyfluorination of (Protected) 4-Deoxy-4-N-Boc-3-fluoro Sialic Acids⁴⁹⁷.

9.3.2. Aldolase Reaction with 3-Fluoropyruvate

9.3.2.1. Unmodified ManNAc Starting Material

Sialic acid is biosynthesized by an aldol reaction between N-acetyl mannosamine (ManNAc) and sodium pyruvate, which is catalyzed by N-acetylneuraminic acid aldolase (EC 4.1.3.3). Following the patent literature, the Withers group reported that this enzyme effectively catalyzed the aldol reaction with monofluorinated pyruvate to give 1093 (Scheme 156).⁴⁷⁸ Only the formation of the F_ax-3 stereomer was reported, in excellent yield (76%). The Bennett group confirmed this result (81% yield),⁴¹¹ as did the Watts group when they isolated the protected F_ax sialic acid derivative 1131.⁴⁹⁹ However, using the same enzyme cloned from Ecoli K12,⁵⁰⁰ the Chen group obtained both F-3 diastereomers 1093 and 1094, with the F_ax-3 as the major product in a 1.2:1 ratio of isolated yields.⁴¹³ A similar result was found using aldolase from Pasteurella multocida.^501−503

Scheme 156. Enzyme-Catalyzed Aldol Reaction Leading to 3-Fluorinated Sialic Acid^{411,413,478,499,502}.

9.3.2.2. Modified ManNAc Starting Materials

The aldolase enzyme also tolerates the use of modified ManNAc substrates, which has been exploited to produce azide and alkyne containing sialic acid derivatives for bioconjugation purposes. Starting from N-(pent-4-ynoyl)-mannosamine 1133 (Scheme 157), synthesized from mannosamine hydrochloride with activated pent-4-ynoic acid 1132,⁵⁰⁴ the aldolase reaction with fluoropyruvic acid was reported by the Wong group to give a mixture of C-3 diastereomers 1134 and 1135 (F_ax/F_eq 7:1–3:1).⁵⁰⁵ Purification by chromatography was possible after esterification and acetylation to afford 1136 in 35% yield over three steps.

Scheme 157. Aldolase Reaction on a Substituted ManNAc Substrate⁵⁰⁵.

The aldolase reaction with fluoropyruvate also proceeds when the N-acetyl group in ManNAc is modified to an azido group, as in 1137 (Scheme 158), which can be achieved from mannosamine by a diazo transfer reaction.⁵⁰⁶ The Chen group reported that Pm aldolase was efficient in catalyzing this reaction to give the F_eq-3 product 1138 in 68% yield after chromatography.⁵⁰² The F_ax-3 product 1139 was formed as observed by TLC-analysis, but the yield was low and no product was isolated. The Ec aldolase was reported not to work efficiently with this substrate.

Scheme 158. Aldolase Reaction on 2-Deoxy-2-azido Mannose⁵⁰².

The 6-deoxy-6-azido ManNAc substrate 1140 (Scheme 159A) can be obtained from ManNAc either in two steps, involving selective OH-6 tosylation and displacement with sodium azide,^503,507 or in four steps when alcohol protection is included (via 1141).⁵⁰⁸ The Withers group reported that aldolase reaction of 1140 with fluoropyruvate gave, after ester formation and alcohol acetylation, the F_ax-3 isomer 1144 in 64% isolated yield and the F_eq-3 isomer 1145 in 14% yield (4.6:1 ratio).⁵⁰⁸ The Chen group also investigated 1140 (Scheme 159B).⁵⁰² With their enzymes, 1144 and 1145 were obtained in a much lower ratio (46% and 39% yield, 1.2:1 ratio), regardless of whether Ec or Pm aldolase was used.

Scheme 159. Aldolase Reaction on 6-Deoxy-6-azido ManNac^502,508.

9.3.3. Deoxyfluorination at C-2 toward 2,3-Difluorinated Sialic Acid Analogues

In all cases, a DAST-type deoxyfluorination reaction was employed to achieve the formation of 2,3-difluorinated sialic acid analogues from 3-fluorinated sialic acids.

9.3.3.1. With Unmodified 3-Fluorosialic Acid

Selective deoxyfluorination of the anomeric hydroxy group requires full protection of the other alcohol groups. Hence, 3-fluorosialic acids obtained from aldolase reactions, such as 1093 (Scheme 160A), require carboxylic acid and alcohol protection, followed by selective deprotection of the anomeric alcohol. From 1093 this sequence gave 1113, which can also be obtained as the major product from the reaction of the sialic acid glycal (1099) with SelectFluor (as shown in Scheme 153). A number of publications mention that from 1113 β-1146 as the only isolated deoxyfluorination product,^478,502 including when the safer DAST alternative XtalFluor-E was used.⁴¹¹ However, the Withers group reported a full experimental process showing that deoxyfluorination of 1113 gave a mixture of both anomeric sialyl fluorides in 96% combined yield.⁴⁷⁹ Samples of pure anomers β-1146 (18%) and α-1146 (14%) were isolated, with the remaining material in mixed fractions. Full deprotection of each anomer gave the 2F_eq3F_ax and 2F_ax3F_ax sialic acid derivatives β-1095 and α-1095.^{411,478,479,502}

Scheme 160. Anomeric Deoxyfluorination on 3-Fluorinated Sialic Acids^{411,478,479,502}.

When an equatorial F-3 substituent was present, in 1114 (Scheme 160B), only the β-deoxyfluorination product β-1100 was reported in 81–85% yield. Deprotection then gave the 2F_eq3F_eq sialic acid derivative β-1096^479,502

The F_eq-3 stereomer 1114 can be obtained from the corresponding aldolase adduct (cf. Scheme 156) by the usual protection conditions (not shown),⁵⁰² but not all available aldolase enzymes allow its synthesis. In such cases, 1114 can be obtained as shown in Scheme 161 from the XeF₂ reaction product α-1096 (cf. Scheme 152).⁴⁷⁹ Hydrolysis of the sialyl fluoride α-1096 led to F_eq-3 sialic acid 1094, which was then submitted to the carboxylic acid protection, alcohol protection, and anomeric deprotection sequence. Alternatively, 1114 can be obtained as the minor isomer from the SelectFluor-mediated fluorination of the sialic acid glycal 1099 (cf. Scheme 153).

Scheme 161. Alternative Synthesis of F_eq-3 Sialic Acid⁴⁷⁹.

9.3.3.2. With NAc-modified 3-fluorosialic acids

The Wong group reported the synthesis of 1149 as a cell-permeable probe for sialidase imaging and identification (Scheme 162).⁵⁰⁵ Compound 1136, obtained as described in Scheme 157, was selectively deprotected at the anomeric position to give 1147. In accordance with the results described in Scheme 160, DAST-mediated deoxyfluorination led to the formation of both anomers of 1148, here in a 2:1 β/α ratio. The desired β-anomer was then deprotected to give 1149.

Scheme 162. Deoxyfluorination of (Protected) N-(4-Pentynoyl-Substituted F_ax-3 Sialic Acid⁵⁰⁵.

9.3.3.3. With Deoxygenated 3-Fluorosialic Acids

The synthesis of a series of deoxygenated 2,3-difluorinated sialic acids has been reported by the Watts group.⁴⁹⁹ In all cases, deoxygenation reactions were carried out starting from isopropylidene-protected F_ax-3 sialic acid 1131, for which the synthesis is described in Scheme 156.

Deoxygenation at the 4-position was achieved by selective reaction of 1131 (Scheme 163) with phenyl chlorothionoformate to give the thiocarbonate 1150, with OH-7 being too sterically hindered to react. Reduction with tributyl tin hydride under 2,2-bis(tert-butylperoxy)butane (BTBPB) initiation afforded 1151, which was then functionalized to allow anomeric fluorination by acetal hydrolysis, peracetylation and anomeric deprotection to give 1152. DAST-mediated deoxyfluorination led to the α-anomer of 1153 as the major isomer in a 1.5:1 ratio. The configuration of β-1153 was proven using X-ray crystallographic analysis. Full deprotection of α-1153 afforded 5-N-acetyl-2,3,4,5-tetradeoxy-3-fluoro-d-glycero-α-d-galacto-non-2-ulopyranosonic fluoride 1154. Note that the deoxygenation at the 4-position alters the configurational prefixes and anomeric reference atom.

Scheme 163. DAST-Mediated Deoxyfluorination of (Protected) 4-Deoxy-3-F_ax Sialic Acid⁴⁹⁹.

For deoxygenation at the 7-position (Scheme 164), 1131 was benzoylated to give the 2,4-di-O-benzoyl product 1155 in 54% yield, alongside the fully benzoylated 1156. As reaction with phenyl chlorothionoformate led to an inseparable 1:1 mixture of the desired thiocarbonate and a rearranged byproduct (not shown), 1155 was instead reacted with 1,1′-thiocarbonyldiimidazole. Subsequent tributyl tin hydride-mediated reduction with a commercial initiator gave 1157, which was then converted through a series of protecting group manipulations to give the required deoxyfluorination substrate 1158. This reaction led to a 2:1 ratio of anomers, again with the desired anomer (β-1159) as the major product. Its deprotection then yielded 5-N-acetyl-2,3,5,7-tetradeoxy-3-fluoro-d-glycero-β-l-manno-non-2-ulopyranosonic fluoride 1160. Note that the deoxygenation at the 7-position alters one of the configurational prefixes.

Scheme 164. DAST-Mediated Deoxyfluorination of (Protected) 7-Deoxy-3-F_ax Sialic Acid⁴⁹⁹.

The synthesis of the C-8-deoxygenated derivative 1165 is shown in Scheme 165. Starting from 1131, full protection to give 1161 was followed by acetonide hydrolysis and selective protection at the primary position to give the OH-8 unprotected 1162. Deoxygenation, followed by anomeric deprotection resulted in 1163, which was subjected to deoxyfluorination to give a mixture of anomers 1164. These could be separated after ester hydrolysis and reprotection of the carboxylic acid. Deprotection of the desired major β-anomer gave 5-N-acetyl-2,3,5,8-tetradeoxy-3-fluoro-d-glycero-β-l-manno-non-2-ulopyranosonic fluoride 1165.

Scheme 165. DAST-Mediated Deoxyfluorination of (Protected) 8-Deoxy-3-F_ax Sialic Acid⁴⁹⁹.

Finally, the 9-deoxy derivative 1170 was synthesized from the tribenzoate 1156 (Scheme 166), obtained as a byproduct from the protection of 1131 as explained in Scheme 164. Acetal hydrolysis was followed by installation of the cyclic thiocarbonate 1166. Reaction of the thiocarbonyl group with iodomethane allowed the released iodide to react at C-9, which was then reduced with tin hydride. The resulting 9-deoxy derivative 1167 was fully deprotected at the alcohol groups, and then peracetylated to allow selective deprotection of the anomeric position, to afford 1168. Interestingly, deoxyfluorination gave a 1:1 mixture of anomers 1169, and the desired β-anomer was deprotected to give 5-N-acetyl-2,3,5,9-tetradeoxy-3-fluoro-d-erythro-β-l-manno-non-2-ulopyranosonic fluoride 1170.

Scheme 166. DAST-Mediated Deoxyfluorination of (Protected) 9-Deoxy-3-F_ax Sialic Acid⁴⁹⁹.

9.3.3.4. With Azido-Substituted Sialic Acid Derivatives

A series of azido-modified 2,3-difluorinated sialic acids have been synthesized.

The Withers group reported the synthesis of a series of 4-substituted 2,3-difluorinated sialic acids (Scheme 167A).^493,509 Deoxyfluorination of 1120, for which the synthesis was described in Scheme 154, gave the β-anomer 1171 in excellent yield.⁴⁹³ No formation of the α-anomer was reported. Compound 1171 was then converted to derivatives β-1172 and 1175. The synthesis of α-1172 was also described,⁵⁰⁹ although the deoxyfluorination reaction leading to the corresponding 2F_ax3F_ax isomer was not provided. The von Itzstein group reported that DAST-mediated anomeric deoxyfluorination of the similar 1124 (Scheme 167B), in which the acetamido group is replaced by an isobutyramido group, yielded both anomeric fluorides of 1176 in a 3:1 ratio, with preferential formation of the β-anomer.⁴⁹⁴ Their deprotection gave the 2,3,5,8-tetradeoxy-3-fluoro-5-isobutyrylamido-d-erythro-l-manno-non-2-ulopyranosonic β- and α-fluorides 1177.

Scheme 167. Deoxyfluorination of (Protected) 4-Deoxy-4-azido-3-fluoro Sialic Acids^493,494,509.

With an equatorial F-3 substituent (Scheme 167C), both the Withers and von Itzstein groups reported that deoxyfluorination only led to the β-anomers, regardless of the amido group.^493,494 Hence, 1121 and 1125 were converted to 1178 and 1179, which after deprotection gave 1180 and 1181. The acetamido derivatives were then converted to the neuraminidase inhibitors 1182 and 1183.⁴⁹³

The synthesis of a 2,3-difluorinated sialic acid with a modified NAc group was reported by the Chen group (Scheme 168).⁵⁰² In contrast to the Von Itzstein approach shown in Scheme 167B/C, this was achieved from the corresponding 5-azido neuraminic acid derivative 1138, for which the synthesis was described in Scheme 158. Protection of 1138 to give 1184 was followed by anomeric deprotection, which allowed deoxyfluorination to give 1185 as the only reported anomer in excellent yield. Full deprotection then gave 2,3,5-trideoxy-5-azido-3-fluoro-d-erythro-β-l-gluco-non-2-ulopyranosonic fluoride 1186. Azide reduction, amide bond formation with acetyloxyethanoyl chloride, and acetate methanolysis then provided the 2,3-difluorinated Neu5Gc analogue 1187.

Scheme 168. Deoxyfluorination of a (Protected) 5-Deoxy-5-azido-3-fluoro Sialic Acid Analogue⁵⁰².

The synthesis of 9-azido-2,3-difluorinated sialic acids has been reported by both the Withers and Chen groups (Scheme 169A).^502,508 Anomeric deprotection of 1144 (synthesis described in Scheme 159) resulted in 1188, whereupon DAST treatment formed both anomers of 1189 in a 4:1 β/α ratio of isolated yields.⁵⁰⁸ The Chen group reported only the formation of β-1189 in 74% yield from 1144 (not shown).⁵⁰² The desired β-anomer was then deprotected to give 1190 and converted to a number of probes, including the 7-hydroxycoumarin derivative 1191.⁵⁰⁸

Scheme 169. Deoxyfluorination of (Protected) 9-Deoxy-9-azido-3-fluoro Sialic Acids^502,508.

Starting from the F_eq-3 sialic acid derivative 1145 (Scheme 169B), anomeric deprotection and deoxyfluorination gave 1192 as the only reported stereomer. Deprotection gave 5-N-acetyl-2,3,5,9-tetradeoxy-9-azido-3-fluoro-d-erythro-β-l-manno-non-2-ulopyranosonic fluoride 1193.⁵⁰²

9.3.3.5. With Amino-Substituted Sialic Acid Derivatives

Instead of a 4-azido group, 2,3-difluorinated sialic acids have also been synthesized with a Boc-protected 4-amino group (Scheme 170).⁴⁹⁷ Yang et al. described a β-selective deoxyfluorination of the F_ax-3/F_eq-3 mixture 1129/1130, for which the synthesis is described in Scheme 155. This led to a mixture of F-3 diastereomers 1194/1195 that were not separated at this stage. Amine deprotection and subsequent introduction of a protected guanidine group led to 1197/1198 in 83% yield. Separation was possible at this stage, but only the yield of 1197 was reported (39%). Both 1197 and 1198 were then converted to multivalent zanamivir analogues (not shown).

10. Glycoside Formation

This section is organized according to deoxyfluorination type, and not by mechanism. A number of examples have already been mentioned in preceding sections, for example, when anomeric functionalization was required as a protecting group. These are reproduced here for the sake of completion.

The larger electron withdrawing effect of fluorine compared to that of an OH group results in a destabilization of the transition states of anomeric C–O bond forming reactions, which is pronounced when fluorination is adjacent to the anomeric position.

10.1. Donor with Fluorination at Positions 2 and 3

The Giguère group reported the glycosidation of the anomeric acetate 560 (Scheme 171) as allyl glycoside protection in order to enable subsequent fluorination at the 6-postion (see Scheme 80).²⁷² They reported that glycosidations starting from the corresponding glycosyl bromide failed, but TMSOTf-catalyzed allylation using allyl trimethylsilane proceeded to give a 44% yield under microwave heating conditions. The glycosylation failed when allyl alcohol was used, or when conventional heating was employed. Starting from a predominantly α-configured acetate, a 1:1.7 α:β mixture of 561 was obtained.

Scheme 171. Glycosyidation of a 2,3-Dideoxy-2,3-difluorinated Sugar Derivative²⁷².

For the tetrafluorinated donors 271 and 285 (cf. Schemes 36 and 38), the Linclau group explored an anomeric alkylation strategy (Scheme 172). This is a comparatively infrequently used glycosylation method in which the hemiacetal is deprotonated, and then reacts as a nucleophile with an electrophilic acceptor.⁵¹⁰ Fluorination will facilitate the deprotonation step, as the electron withdrawing effect stabilizes the conjugate base. Following precedent by the Fried group on a noncarbohydrate fluorinated cyclic hemiacetal,⁵¹¹ reaction of 271 with KOH and MeI gave the methyl glycosides in excellent yield with a modest anomeric ratio.²⁸⁷ With the corresponding C-4-epimer 285, the α-anomer of 1201 was obtained as the major product, although the conditions were slightly different.²⁸⁸ Subsequent benzyl hydrogenolysis gave the deprotected methyl glycosides 1200 and 1202.^288,512

Scheme 172. Glycosidation of 2,3-Dideoxy-2,2,3,3-tetrafluorinated Sugar Derivatives^287,288.

With NaH as base, dichloromethane as solvent, and a long chain alkyl triflate, 271 gave an inseparable anomeric mixture of 1203 with the β-anomer as the major product.²⁸⁷

10.2. Donors with Fluorination at Positions 2 and 4

The Lewis acid-mediated allylation described in Scheme 171 has also been applied to 2,4-dideoxy-2,4-difluorinated glucose donor 565 (Scheme 173A), which had also already been described above as an anomeric protection reaction (see Scheme 81).²⁷² This reaction gave a 61% yield of 566, alongside 20% of a partially deprotected glycosidation product 1204. The Giguère group also investigated anomeric alkylation methods.⁵¹³ With Ag₂O as base (Scheme 173B), excellent yields and anomeric selectivities were obtained for the glycosidation of 1205, obtained from 565 by hydrazinolysis, with methyl and allyl iodide to give 1206a,b. Glycosylation of 1-iodo-4-pentyne, however, gave only a modest anomeric ratio of 1206c. With a free OH-6 group, such as in 1207 (Scheme 173C), the reaction also worked well, with 1208 obtained in 76% yield, although the OH-6 group was partially allylated leading to 1209 in 23% yield. An interesting result was obtained with a known direct glycosidation^514,515 using a strong Lewis acid (Scheme 173D): reaction of 1205 with the podophyllotoxin derivative 1210 gave 1211 in good yield. This glycosidation was thought to proceed via the benzylic cation 1212 and, while the anomeric selectivity was relatively modest, complete facial selectivity for the reaction with 1212 was reported.⁵¹³

Scheme 173. Glycosidations with 2,4-Dideoxy-2,4-difluorinated Glucose Donors^272,513.

10.3. Donors with Fluorination at Positions 2 and 6

The Hoffmann-Röder group achieved a number of glycosylations with the 2,6-dideoxy-2,6-difluorinated galactose donor 1213 (Scheme 174).^43,516 This trichloroacetimidate donor was obtained from 361 (see Scheme 48) using standard conditions. Coupling with T_N derivatives 1214 and 1215 gave the fluorinated T_F antigen analogues 1217 and 1218 in good yield with moderate β-selectivities. Reaction with 1215 also led to a small amount (<15%) of a 3,4-bisglycosylated product (not shown). All attempts to increase the β-selectivities were fruitless.⁴³ However, complete β-selectivity was achieved for the glycosylation of 1213 with 1216,⁵¹⁶ under conditions which exploited the “nitrile-effect” by using a mixture of dichloromethane and acetonitrile at low temperature.^517,518 A trichloroacetimidate rearrangement side reaction was successfully suppressed by using an inverse addition procedure, where donor 1213 was added to a solution of 1216 and TMSOTf in CH₂Cl₂/MeCN at −78 °C. The yield of this reaction was slightly lower compared to glycosylations with nonfluorinated or C-2-monofluorinated donors, which was attributed to its lower reactivity. The disaccharide analogue 1219 was further converted to fluorinated Leishmania cap trisaccharides (not shown).⁵¹⁶

Scheme 174. Glycosylation of a 2,6-Dideoxy-2,6-difluorinated Galactose Donor^43,516.

Takagi’s group reported glycosidation of a 2,6,6,6-tetrafluorinated donor derived from 1220 (Scheme 175) with daunomycinone as the acceptor.³¹⁸ Compound 1220 was synthesized by acetylation of 386, for which the synthesis was described in Scheme 52.³¹⁸ They found that activation of the anomeric center of 1220 was difficult, which was again attributed to the electron withdrawing effect of the fluorines. Both conventional bromination of 1220 (30% HBr in AcOH or TiBr₄ in CH₂Cl₂/EtOAc) and ethyl thioglycoside formation (EtSH, BF₃·OEt₂ in CH₂Cl₂) only returned starting material. However, based on the observation that phenyl thioglycosidation [PhSSiMe₃, Bu₄NI, ZnI₂ in Cl(CH₂)₂Cl] gave a mixture of the phenyl thioglycoside and the glycosyl iodide 1221, the synthesis of the latter was successfully achieved with Me₃SiI (in toluene at 80 °C) in reasonable yield. This glycosyl iodide could be isolated after flash column chromatography and could be stored for a few days at −30 °C, again testimony to the fluorine electron withdrawing effect. Coupling of 1221 with daunomycinone under Koenigs–Knorr conditions successfully and selectively gave the α-l-glycoside 1222 in 67% yield. Interestingly, glycosidation of the corresponding glycosyl bromide donor 1223 without C-2-fluorination and with a similar acceptor led to a 1:1 ratio of diastereomers,⁵¹⁹ suggesting the directing effect of the axial fluorine in 1221. The glycoside 1222 was then further converted to doxorubicin-type analogues (not shown).³¹⁸

Scheme 175. Glycosidation of a 2,6-Dideoxy-2,6,6,6-tetrafluorinated Galactose Donor³¹⁸.

10.4. Donors with Fluorination at Positions 3 and 4

The Giguère group also employed their Lewis acid-catalyzed allylation for the anomeric protection of 569 (Scheme 176A), as mentioned before in Scheme 82 with the synthesis of 3,4,6-trideoxy-3,4,6-trifluoro-α-d-glucopyranose.²⁷² A 48% yield of a 1:1 ratio of anomers 570 was obtained.

Scheme 176. Glycosidations of Donors with Deoxyfluorination at the 3 and 4-Positions^272,288.

The Linclau group employed an anomeric alkylation for the functionalization of the tetrafluorinated 407 and 408 (Scheme 176B) to effect their separation, as explained above in Scheme 55. This anomeric alkylation was reported to be highly β-selective, with less than 3% of the α-anomers detected (¹⁹F NMR analysis). The amount of alkylation at the 2-postion was also very small, and only observed for 407 (not shown).²⁸⁸

10.5. Donors with Fluorination at Positions 3 and 6

The Karban group reported two glycosylations with donor 1012 (Scheme 177), for which the synthesis was described in Scheme 139.⁴⁶² Under N-iodosuccinimide (NIS) activation, donor 1012 reacted with acceptors 213 and 1223 to obtain anomeric mixtures of disaccharides 1224 and 1225, respectively. Anomeric separation proved difficult, further complicated by byproducts, and only the isolated yield of the anomers shown could be provided. The obtained anomeric ratios from this 3,6-difluorinated donor were higher with the less reactive acceptor 1223, but overall these glycosylations had a lower α/β ratio compared to glycosylations with the corresponding 3-fluorinated donors with ester groups at the 6-position, which was attributed to the α-directing effect of 6-O-acyl groups.

Scheme 177. Glysosylation of a 3,6-Difluorinated Donor⁴⁶².

10.6. Donors with Fluorination at Positions 4 and 6

Lucas et al. achieved glycosidation of the 4,6-dideoxy-4,6-difluorinated galactosyl bromide donor 1226 with ethylene glycol (Scheme 178), en route to carbohydrate-oligonucleotide conjugates.⁵²⁰ Only the β-anomer 1227 was reported. The Giguère group also demonstrated their BF₃·OEt₂-catalyzed glycosylation of podophyllotoxin derivative 1210 with the 4,6-dideoxy-4,6-difluorinated glucose donor 1228, as already discussed in Scheme 173. This gave 1229 with modest anomeric selecvtivity but with retention of the alcohol configuration of the aglycon.⁵¹³

Scheme 178. Glycosylations of Donors with Deoxyfluorination at the 4 and 6-Positions^513,520.

10.7. Donors with Fluorination at Positions 2, 3, and 4

Glycosidation under phase-transfer conditions of the trifluorinated galactosyl bromide donor 575 (Scheme 179) had been described as part of the synthesis of 2,3,4,6-tetradeoxy-2,3,4,6-tetrafluoro-α-d-galactopyranoside derivatives (Scheme 84).^273,275 Displacements of the bromide by both nucleophiles gave the products 576 and 583 with clean inversion of anomeric configuration. In the case of reaction with deprotonated methyl 4-hydroxybenzoate, 20% of the E2-elimination side product 1230 was also isolated.

Scheme 179. Glycosidation of a 2,3,4-Trideoxy-2,3,4-trifluorinated Galactose Donor^273,275.

In contrast, nucleophilic displacement attempts on the corresponding trifluorinated allosyl bromide 1231, generated from 545 under the usual conditions, met with failure.²⁹⁵ Reaction with methyl 4-hydroxybenzoate or with a glycosyl sulfide precursor led to the formation of the allal derivative 1232. The difference in outcome was attributed to the availability of the C-2–H bond in 1231 compared to that in 575, with the axial F-4 in 575 hindering the E2 process.²⁹⁵ Presumably, the antiperiplanar F-3 in 1231 increases the reactivity of H-2 toward elimination as well.

Investigations toward alternative glycosidation methodologies for this donor were successful and are described in Scheme 180. Microwave irradiation of 545 at 100 °C (Scheme 180A) with allyloxytrimethtyl silane under Lewis acid catalysis yielded the separable allyl alloside anomers 547 (cf. also Scheme 78), with the α-anomer isolated in 22% yield and the β-anomer in 7% yield.²⁹⁵ However, an anomeric alkylation strategy from the reducing sugar 1233 (Scheme 180B), obtained from 545 by hydrazinolysis, using primary alkyl iodide electrophiles and Ag₂O in dichloromethane resulted in excellent yields of the 2,3,4-trifluorinated allosyl glycosides 1234a–c as β-anomers only.⁵¹³ Product 1234c was accompanied by 5% of the corresponding 6-deacetylated byproduct (not shown). Reaction of 1233 with methyl 16-iodohexadecanoate and 1,4-diiodobutane gave 1234d,e in a lower yield. Unfortunately, other primary iodides such as 1235 and 1236 failed to give any product. With more hindered iodides, such as cyclohexyl iodide, the yield dropped further to 29% (1234f), and reaction with cholesterol iodide gave no product (not shown). However, reaction with secondary iodide 1237 (Scheme 180C) did give a 25% yield of the corresponding glycoside 1238 (with concomitant oxidation to the o-quinone), although in a 7.3:1 ratio at C-4 in favor of the 4S-stereomer (retention of configuration). As discussed in Scheme 173, the corresponding cation 1212 (not shown here) reacts with complete facial selectivity. Indeed, with alcohol 1210 as the acceptor, trifluoroallosylated podophyllotoxin derivative 1239 was obtained with complete retention of stereochemistry at C-4. The stereochemical outcome for the reaction of 1233 with 1237 could indicate the occurrence of an S_N2 reaction as a minor pathway.⁵¹³

Scheme 180. Successful Glycosidation Methodologies for 2,3,4-Trideoxy-2,3,4-trifluoroallose Donors^295,513.

Finally, the Giguère group also established that the reaction of 545 with allyl trimethylsilane under TMSOTf catalysis at 85 °C (conventional heating) led to the C-glycoside 1240 with complete α-selectivity (Scheme 181).²⁹⁵

Scheme 181. C-Glycosidation of a 2,3,4-Trideoxy-2,3,4-trifluoroallose Donor²⁹⁵.

11. Conclusion

There is a large body of synthetic work for the synthesis of polyfluorinated carbohydrates, with most of the positional combinations for dideoxy difluorination of pentoses and hexoses exemplified and, at least for glucose, many of the trideoxy trifluorination combinations. Dideoxy difluorination methodologies at positions 1 and 2 of pentoses and hexoses (positions 2 and 3 for sialic acids) have been extensively investigated given their applications. Applications in nucleoside chemistry have led to a large body of work toward 2′,3′-dideoxy difluorinated pentoses.

By and large, the fluorination methodologies used in polyfluorosugar synthesis are also used in the synthesis of monodeoxyfluorinated sugars. The opening of epoxides, DAST-mediated deoxyfluorination, and reaction of glycals with SelectFluor are the most common methods, and the use of 1,6-anhydrosugars has proven particularly useful for controlled fluorine introduction at positions 2–4, despite the possible rearrangements, not least because of the possibility for deoxyfluorination at the 3-position with retention of configuration.

Many older syntheses described above, dating from the pre-DAST/selectFluor era, will be easily further optimized, and in this regard further synthetic advances will undoubtedly be possible with more recently developed fluorination agents and methodologies, as well as by considering the updated Richardson-Hough rules with the use of triflate leaving groups.^119,120

The glycosidation of polyfluorinated sugars is an area where further advances are sorely needed to exploit their full potential as bioactive compounds or carbohydrate materials, both regarding glycoside formation with other sugars as well as with aglycons, including biomolecules. The modification of glycosyl donor reactivities by polyfluorination is naturally even more pronounced than with monofluorinated sugars, and perhaps the development of other methodologies than the traditional acid-catalyzed/electrophile-induced or base-mediated anomeric glycosidation will provide extra opportunities. A recent example by the Gilmour group allowing glycosidation of a 2,2-difluorinated reducing sugar appears very promising.⁵²¹ Establishing efficient protocols to employ polyfluorinated sugar donors in an automated glycan synthesis setting will be another key advancement. It is worth pointing out that enzymatic glycosyl formation with polyfluorinated donors has not yet been achieved.⁵²² Much work also remains to be done regarding establishing reactivities of hydroxyl groups in fluorinated sugar acceptors, both in chemical and enzymatic glycosylations.

Despite the large body of work involving 1,2- and 1,5-difluorinated carbohydrates, 2,3-difluorinated sialic acids, and with 2′,3′-diflluorinated nucleosides aside, there is still relatively little work to date on the investigation of biological activities of polyfluorinated carbohydrates, especially as part of glycans and multivalent constructs. This is largely due to the lack of efficient glycoside formation methodologies, and hence there are many opportunities for further development in this area.

Finally, the past few years have seen interesting results regarding how fluorination, including polyfluorination, influences key pharmaceutically relevant properties, such as lipophilicity. Clearly this is an area with great future perspectives, especially as new glycosyl formation methodologies become available. The first lipophilicities of disaccharides have only recently been reported by the Karban group.⁵²³ It will also be of interest to explore whether glycan conformation⁵²⁴ will be significantly influenced by polyfluorination.

In summary, the synthesis of polyfluorinated carbohydrates has reached an advanced state, with the synthetic frontier now being their efficient conversion into glycosides. Achieving this will unlock their potential in chemical biology, and medicinal and materials chemistry.

Biographies

Kler Huonnic received a technical degree in chemical engineering and applied physics (2017) in Lannion, France. She obtained an engineering degree in organic chemistry at ENSICAEN and a masters degree at the University of Caen in 2020. She is now a Ph.D. student at the University of Southampton where she works on the synthesis and glycosidation of fluorinated carbohydrates.

Bruno Linclau obtained his Licentiate in Sciences (Chemistry) degree from the University of Ghent (Belgium), where he also obtained his Ph.D. in 1996 with Prof. Maurits Vandewalle. He carried out postdoctoral research with Professor Dennis P. Curran at the University of Pittsburgh, Pittsburgh PA (USA) in the field of fluorous chemistry, with a fellowship from the Belgian American Educational Foundation. He joined the faculty at Southampton University in 1999, where he was promoted to full Professor in 2015. In 2021 he moved back to the University of Ghent as Senior Full Professor in Organic Chemistry. His main research interests involve investigating how fluorination modifies important properties such as conformation, lipophilicity, and hydrogen bonding of druglike structures, carbohydrates, and amino acids.

The authors declare no competing financial interest.