Asymmetric Synthesis of S(IV) and S(VI) Stereogenic Centers

Abstract

Sulfur can form diverse S(IV) and S(VI) stereogenic centers, of which some have gained significant attention recently due to their increasing use as pharmacophores in drug discovery programs. The preparation of these sulfur stereogenic centers in their enantiopure form has been challenging, and progress made will be discussed in this Perspective. This Perspective summarizes different strategies, with selected works, for asymmetric synthesis of these moieties, including diastereoselective transformations using chiral auxiliaries, enantiospecific transformations of enantiopure sulfur compounds, and catalytic enantioselective synthesis. We will discuss the advantages and limitations of these strategies and will provide our views on how this field will develop.

1. Introduction

Sulfur-containing functional groups have been playing important roles in drug development since the discovery of prontosil, the first synthetic antibacterial sulfonamide, in the 1930s.¹⁻⁵ Sulfonamide, sulfone, thiol, and thioether are representative nonchiral examples of such functional groups. On the other hand, sulfur is also able to form diverse chiral structures due to its multiple oxidation states, including many S(IV) and S(VI) stereogenic centers, which are usually neglected by drug discovery programs (Scheme 1).^6,7 These stereogenic centers are underexplored as pharmacophores even though they can significantly increase the structural diversity and complexity of drug candidates.

Scheme 1. Diverse S(IV) and S(VI) Stereogenic Centers.

Among these sulfur stereogenic centers, sulfoxides are well studied, and several sulfoxides such as esomeprazole and armodafinil are marketed drugs (Scheme 2). Chiral sulfoximines⁸⁻¹¹ are known to have outstanding physiochemical properties and have been introduced into several clinical drug candidates such as BAY 1251152, AZD6738 and BAY 1000394.¹²⁻¹⁴ This promising pharmacophore motivates the exploration of other sulfur stereogenic centers.¹⁵⁻¹⁸ Unlike achiral functional groups, sulfoximine, sulfonimidamide, sulfondiimine, and sulfondiimidamide can be chiral and contain extra nitrogen atoms bonded to their sulfur center. These nitrogen atoms provide more interaction sites and additional modification sites. Due to the increased interest in these sulfur stereogenic centers in drug discovery, many strategies have been developed for their synthesis.¹⁹⁻²² However, most reported methodologies are only able to generate racemic products.²³⁻²⁸

Scheme 2. Selected Bioactive Molecules with Sulfur Stereogenic Centers.

Asymmetric synthesis of S(IV) and S(VI) stereogenic centers is still challenging and in its infancy. Present asymmetric strategies mainly utilize stoichiometric amounts of chiral reagents or chiral auxiliaries. Although much effort has been expended on the development of catalytic strategies, reaction scope and product diversity are often limited. This perspective summarizes different strategies for the construction of enantioenriched sulfur stereogenic centers. Methodologies using chiral auxiliaries, enantiospecific transformations using enantioenriched sulfur compounds, and catalytic enantioselective synthesis will be included. Enantioselective synthesis of sulfoxides using chiral transition-metal catalysts through asymmetric oxidation of thioethers is well-known and will only be discussed briefly. We hope that our discussions will provide insights and inspire further development of this field.

2. Construction of Sulfur Stereogenic Centers Using Chiral Auxiliaries

The use of chiral auxiliaries is the most common strategy for the construction of enantioenriched sulfur stereogenic centers. One well-known and commercially available auxiliary is l-menthol, which leads to Andersen’s sulfinate upon the addition of sulfinyl chloride (Scheme 3).²⁹ Often, one of the diastereomers is a solid and can be easily isolated through crystallization. This enantioenriched sulfinate ester is versatile and can be stereospecifically transformed to other sulfur stereogenic centers. Nucleophilic substitution with different nucleophiles gives chiral sulfoxides and sulfinamides with inversion of the sulfur stereocenter. In another example, the Shi group used (R)-N-benzyl-1-phenylethanamine as an auxiliary to prepare chiral sulfinamide (Scheme 4).³⁰ Similar to Andersen’s sulfinate, one of the diastereomers of the sulfinamide was easily separated by crystallization. The enantioenriched sulfinamides were excellent precursors for the preparation of chiral sulfinate esters.

Scheme 3. Synthesis of Andersen’s Sulfinate Using l-Menthol As Chiral Auxiliary.

Scheme 4. Sulfinamide Synthesis with an Enantiopure Amine as the Chiral Auxiliary.

Several other useful chiral auxiliaries have been developed over the last few decades for the preparation of enantioenriched sulfinates, sulfinamides, sulfites, and sulfuramidites (Scheme 5).³¹⁻³⁵ Their S–O or S–N bonds can then be easily cleaved during nucleophilic substitutions. Some of these sulfur stereogenic centers contain two labile groups, which can be substituted using two different nucleophiles in sequence, allowing the sulfur stereogenic centers prepared to be highly diverse.

Scheme 5. Sulfinates, Sulfinamides, Sulfites, and Sulfuramidites Carrying Chiral Auxiliaries.

3. Enantiospecific Transformations of Sulfur Stereogenic Centers

There are limited choices of commercially available enantiopure sulfur compounds. Several known compounds are the Andersen’s sulfinate, 4-methylbenzenesulfinamide, tert-butanesulfinamide (Ellman’s sulfinamide),³⁶ and tert-butanethiosulfinate (Scheme 6). Their enantiospecific transformations are the workhorses for the construction of sulfur stereogenic centers.

Scheme 6. Examples of Commercially Available Enantiopure Sulfur Compounds.

In the above-mentioned nucleophilic substitutions of sulfinates and sulfinamides, oxidation states of sulfur centers are not changed. Several groups have developed efficient approaches for transforming S(IV) to S(VI) stereogenic centers without erosion of enantiopurity. For example, enantiospecific imidation of chiral sulfoxides is an effective method for synthesis of sulfoximines (Scheme 7, eq 1).³⁷⁻⁴⁰ Various imidation reagents have been developed for the generation of nitrene, and the addition of transition-metal catalysts usually improves reaction efficiencies through formation of metal–nitrene intermediates. Another strategy is the enantiospecific oxidation of chiral sulfilimines (Scheme 7, eq 2).^41,42 The attractiveness of these methodologies relies on the ease of accessing enantioenriched chiral sulfoxides and sulfilimines.

Scheme 7. Stereospecific Imidation and Oxidation of S(IV) Compounds for the Synthesis of Sulfoximines.

A strategy toward sulfoximines is the S-alkylation of enantioenriched sulfinamides. This is a challenging approach, as alkylation usually prefers more nucleophilic nitrogen or oxygen sites, and only limited substrates with steric hindrance at nitrogen sites prefers alkylation at the sulfur site (Scheme 8).

Scheme 8. Chemoselectivity in the Alkylation of Sulfinamide.

Recently, the Maruoka group developed a new approach for the chemoselective and enantiospecific S-alkylation of chiral sulfinamides (Scheme 9, eq 1).⁴³ This approach utilized chiral tert-butanesulfinamide derivatives, which were obtained from commercially available Ellman’s sulfinamides. The steric and electronic properties of the nitrogen atom were adjusted by modifying with various substituents to promote S-alkylation. Finally, through the use of NaH and 15-crown-5, the sulfur atoms of the sulfinamides selectively substitute alkyl halides to form enantioenriched sulfoximines. Moreover, the tert-butyl group of the generated sulfoximine could be readily removed by trifluoroacetic acid to afford enantioenriched sulfinamides.

Scheme 9. Chemoselective and Enantiospecific S-Alkylation/S-Arylation of Enantioenriched Sulfinamides.

Subsequently, the Maruoka group also reported conditions for the S-arylation of chiral sulfinamides (Scheme 9, eq 2).⁴⁴ The new conditions utilized diaryliodonium salts with a copper catalyst and tolerated a wide range of aryl groups. Similarly, the tert-butyl group was also easily removed to form various aryl sulfinamides. Reversing the sequence of arylation and alkylation gave opposite enantiomers of sulfoximine (Scheme 9, eq 3). This is a practical and versatile method for synthesis of chiral sulfoximines with different substituents.

Sulfonimidoyl halides (Scheme 1) are potential precursors for S(VI) stereogenic centers; however, there are few reports on their asymmetric synthesis. The Bull and Lücking group studied the enantiospecific synthesis and transformations of sulfonimidoyl fluorides (Scheme 10).⁴⁵ Commercially available 4-methylbenzenesulfinamide was protected with a tert-butyloxycarbonyl group and subsequently deprotonated with NaH (Scheme 10, eq 1). The sulfur stereogenic center of the resulting amide salt was obtained with no loss of enantiopurity. Fluorination of the amide salt gave sulfonimidoyl fluoride, which was efficiently transformed to sulfonimidamide through nucleophilic substitution with piperidine. While reaction with electrophilic fluoride is enantiospecific with minimal loss of enantiopurity, the nucleophilic substitution with piperidine suffered a huge loss of enantiopurity. It was speculated that the fluoride that was released during the reaction was the source of racemization (Scheme 10, eq 2). In order to avoid this, different solvents and additives were investigated (Scheme 10, eq 3). In the fluorination step, the use of the polar and protic ethanol as solvent preserved the enantiopurity with reduced yield, which was improved by the addition of potassium acetate as a soluble inorganic base. In the substitution step, the use of LiBr preserved the enantiopurity. The soluble LiBr was proposed to precipitate insoluble fluoride and inhibit the racemization. A key difficulty in this study is obtaining enantiopure sulfinamides; in this case, only the one example, which is commercially available, was investigated.

Scheme 10. Enantiospecific Synthesis and Transformations of Sulfonimidoyl Fluorides.

The Bull group subsequently investigated the influence of different N-protecting groups on the enantiospecificity of the fluorination and Grignard substitutions (Scheme 11).⁴⁶ For the fluorination step, Boc and Piv protection gave products with complete enantiospecificity, while Cbz protection resulted in slight racemization. On the other hand, methyl carbamate protection gave products with complete racemization. For the substitution reaction with Grignard reagents, Boc and Piv also worked the best and gave chiral sulfoximines with high yields and complete enantiospecificity. Various aryl and alkyl sulfonimidoyl fluorides were enantiospecifically substituted using Grignard reagents. The authors proposed that magnesium halide counterion scavenged fluoride ion, which was speculated to cause the racemization of sulfonimidoyl fluorides.

Scheme 11. Influence of N-Protecting Groups on Enantiospecific Fluorination and Substitution.

The Zuilhof group developed the sulfur(VI) fluoride exchange reaction (SuFEx) of sulfonimidoyl fluorides (Scheme 12).⁴⁷ They investigated the enantioselectivity of the nucleophilic substitution reactions of enantiopure sulfonimidoyl fluorides. They separated the enantiomers of sulfonimidoyl fluoride with preparative HPLC and utilized phenols and phenolates as the nucleophiles. When the electron-poor 4-methyl-2-nitrophenol (a) was used, mostly racemic substitution products were obtained. As a comparison, a good nucleophile like p-cresol (b) gave products with 73% and 71% ee values, respectively, following substitution of ent-1 and ent-2. Further investigations with 10 equiv of p-cresol increased the ee value to 95%. The excess amount of p-cresol might compete with the nucleophilic fluoride ion, which was proposed to result in the decreased enantiopurity. Finally, with phenolates, the sodium salts of both electron-rich and electron-poor phenols gave substitution products with complete enantiospecificity. Possibly, the sodium ion scavenged fluoride ion to preserve the enantiopurity.

Scheme 12. Nucleophilic Substitution of Sulfonimidoyl Fluorides.

DBU was added as the base.

DBU was not added.

Ten equivalents of p-cresol was used.

In summary, enantiospecific transformations of the sulfur stereogenic centers include nucleophilic substitution, imidation, oxidation, arylation, alkylation, and halogenation. These transformations are crucial for diversification of existing sulfur stereogenic centers. However, a loss of enantiopurity is inevitable in some reactions; thus, the improvement of these methods to make them more efficient and practical is an urgent task for our community.

4. Catalytic Enantioselective Synthesis of Sulfur Stereogenic Centers

The chiral auxiliary strategy often resulted in wastage due to additional steps in preparation and removal of the auxiliary. Enantiospecific transformation of enantiopure sulfur stereogenic centers is limited by the number of commercially available sources of these compounds. Catalytic enantioselective transformations are still the most efficient and desirable strategy to access enantiopure stereogenic centers on sulfur. Catalytic enantioselective oxidation and imidation of prochiral thioethers are the most well developed. Kinetic resolution as well as dynamic kinetic resolution, desymmetrization, and deracemization of racemic starting materials are also keenly investigated strategies.

4.1. Enantioselective Oxidation

Synthesis of enantioenriched sulfoxides with chiral transition-metal catalysts is well studied and summarized in previous reviews.^19,48−53 Notable enantioselective oxidation systems are those using Ti(O-iPr)₄ as the catalyst and modulate with different chiral ligands such as diethyl tartrate, BINOL, salen, Schiff base, and porphyrin. These ligands are also well studied with many other metals such as Al, V, Cu, and Fe. In this Perspective, we will discuss selected advances that utilize enantioselective oxidation to construct sulfur stereogenic centers with organocatalysts, enzymes, and polyoxometallic catalysts. We will also highlight interesting developments using electrochemical conditions.

The List group reported the enantioselective oxidation of thioethers with hydrogen peroxide, catalyzed with Brønsted acid (Scheme 13).⁵⁴ This efficient methodology utilized confined imidodiphosphoric acids C1 and has broad substrate scope, rivaling the best metal-catalyzed alternatives. Various substituted aryl groups and alkyl groups of different sizes were well tolerated. The authors successfully demonstrated the usefulness of this methodology through the synthesis of (R)-sulindac. The Tang and Li group similarly utilized chiral Brønsted acid C2 as catalyst for the enantioselective synthesis of chiral sulfinamides (Scheme 14, eq 1).⁵⁵ Various aryl and alkyl sulfenamides were oxidized to form the corresponding sulfinamides with high enantioselectivity. Further transformations of Boc-protected sulfinamides with Grignard reagents or amines gave the corresponding enantioenriched sulfoxides and sulfinamides (Scheme 14, eq 2).

Scheme 13. Chiral Imidodiphosphoric Acid-Catalyzed Asymmetric Oxidation.

Scheme 14. Enantioselective Synthesis of Sulfinamides Using Brønsted Acid Catalyzed Oxidation.

The advantages of enzyme catalysis include mild conditions, environmental friendliness, and high efficiency. The Xu and Yu group reported an efficient synthesis of esomeprazole using enzymatic enantioselective sulfoxidation (Scheme 15).⁵⁶ The prazole sulfide monooxygenase (AcPSMO) was used together with the redox cofactor NADPH, which was regenerated using another enzyme BstFDH, with CO₂ as the byproduct. This enzymatic reaction was scaled to 120-L and produced 0.39 kg of esomeprazole which was isolated with 99.9% enantiomeric excess.

Scheme 15. Enzymatic Enantioselective Sulfoxidation.

Polyoxometalates are anionic metal–oxygen clusters of early transition metals (V, Nb, Ta, Cr, Mo, W, etc.). Many polyoxometalates are able to activate molecular oxygen or hydrogen peroxide for oxidation reactions.⁵⁷⁻⁵⁹ Different from other typical transition-metal-catalyzed reactions, in which the enantioselectivity is controlled with chiral ligands, enantioselective reactions with anionic polyoxometalate catalysts were solved using chiral cationic catalysts. Recently, the Tan group used a chiral dicationic bisguanidinium C3 to form ion-pair catalysts with tungstate⁶⁰ or molybdate⁶¹ for the enantioselective oxidation of thioethers with H₂O₂ as the oxidant (Scheme 16). This efficient method was applied to the synthesis of (S)-lansoprazole and armodafinil. The activity of the polyoxometalates was adjusted using different inorganic additives, such as NH₄H₂PO₄ and KHSO₄. Mechanistic studies include the investigations of the active catalytic species with Raman spectroscopy and DFT calculations. For the molybdate-catalyzed oxidation, the proposed bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pair was successfully characterized using single-crystal X-ray crystallography.

Scheme 16. Asymmetric Oxidation Catalyzed by Polyoxometalates.

In recent years, we have witnessed the rapid development of electrochemistry in organic synthesis. Electrochemical oxidations and reductions can proceed without the use of stoichiometric reagents and thus have the potential to reduce the amount of waste generated significantly. The enantiocontrol of electrochemical synthesis is highly challenging and quite limited.⁶² The Miller group and the Nonaka group reported some success with enantioselective oxidation of thioethers with chemically modified electrodes (Scheme 17). In 1976, the Miller group modified the electrodes with phenylalanine methyl ester or camphoric acid, obtaining oxidized products with moderate ee values of 2.5% and 1.4%, respectively (Scheme 17A,B).⁶³ In 1984, the Nonaka group investigated the modification of electrodes with poly amino acid (Scheme 17C).⁶⁴ The poly-l-valine coated electrode worked well in the anodic oxidation of thioethers. The resulting sulfoxides were obtained with up to 93% ee value. Although these pioneering works were done 30 years ago, practical enantioselective anodic oxidation of thioethers is still unrealized, and more development is greatly needed.

Scheme 17. Enantioselective Anodic Oxidation.

4.2. Enantioselective Imidation

Enantioselective imidation of thioethers is highly attractive but is hampered by the difficulty to control nitrene intermediates. The Bolm group utilized N-(p-tolylsulfonyl)imino phenyliodinane as the imidation reagent for the enantioselective imidation of thioethers (Scheme 18).⁴¹ A combination of iron(III) 4-chloro-2,6-dimethyl-3,5-heptanedionate and (R,R)-PhPyBOX C4 gave chiral sulfilimines with high enantioselectivity. Various aryl substitutions, including heterocycles, were well tolerated. In comparison, the Lebel group reported a Rh-catalyzed enantioselective imidation of thioethers, using chiral N-mesyloxycarbamate as the imidation reagent (Scheme 19).⁴² A combination of catalytic dirhodium(II) tetrakis(N-1,8-naphthoyl-tert-leucinate) (Rh₂[(S)-nttl]₄), DMAP, and bis(DMAP)CH₂Cl₂ was proposed to generate a Rh^II–Rh^III complex as the active species.

Scheme 18. Fe-Catalyzed Enantioselective Imidation.

Scheme 19. Rh-Catalyzed Enantioselective Imidation.

The Bach group, instead, reported a Ag-catalyzed enantioselective imidation, which used a chiral phenanthroline with hydrogen bonding sites as the ligand (Scheme 20).⁶⁵ Various substituted quinolones and pyridines were well tolerated, and the corresponding heterocyclic sulfimides were obtained with high enantioselectivity. Mechanism studies and DFT calculations suggest that one molecule of chiral ligand C5 and one molecule of achiral ligand 1,10-phenanthroline are bonded to the silver atom to induce high enantioselectivity.

Scheme 20. Ag-Catalyzed Enantioselective Imidation.

4.3. (Dynamic) Kinetic Resolution

Kinetic resolution (KR) and dynamic kinetic resolution (DKR) of racemic sulfur stereogenic centers through oxidation, reduction, hydrogenation, amidation, and C–H functionalization have developed rapidly in recent years and provided a viable approach for the enantioselective synthesis of these moieties.

The Uemura group developed the asymmetric oxidation to prepare chiral sulfoxides using Ti(IV)/(R)-BINOL complex as catalyst.^66,67 In the kinetic resolution of sulfoxides (Scheme 21, eq 1),⁶⁷ the sulfoxides were obtained with high enantioselectivity. However, this method was not efficient enough, with yields of up to 26%. Subsequently, the Chan group reported a tandem enantioselective sulfoxidation–kinetic resolution process for sulfoxides using Ti(IV)/(S)-BINOL complex as catalyst (Scheme 21, eq 2).⁶⁸ While the enantioselective oxidation only afforded the desired sulfoxide with low enantioselectivity, it could be coupled with a subsequent kinetic resolution process. In this manner, the desired sulfoxides were obtained with high enantiopurity but at the expense of yield for the extra oxidation.

Scheme 21. Kinetic Resolution Using Ti-Catalyzed Oxidation.

While kinetic resolution through oxidation is more common, there are less examples using reduction. The Míšek group found that methionine sulfoxide reductase A was an excellent biocatalyst for the reductive kinetic resolution of racemic sulfoxides (Scheme 22).⁶⁹ With only 0.1 mol % of the enzyme, the kinetic resolution gave chiral sulfoxide with more than 99% ee value at 50% conversion. The selectivity factor was so high that the conversion can be kept at 50% for several hours. Remarkably, a wide range of substituted phenyl groups and alkyl groups were well tolerated under the conditions.

Scheme 22. Kinetic Resolution Using Enzyme-Catalyzed Reduction.

The kinetic resolution of vinyl sulfoxides through asymmetric hydrogenation of alkene was also reported. The Vidal–Ferran group achieved the process using Rh complexes with phosphine–phosphite ligands C6 as catalyst (Scheme 23).⁷⁰ This approach efficiently generated enantioenriched vinyl sulfoxides and their corresponding hydrogenated products with high enantioselectivity.

Scheme 23. Kinetic Resolution Using Rh-Catalyzed Hydrogenation.

Conversion (C) was determined by ¹H NMR.

The selectivity factor (s) = ln[1 – C(1 + ee^P)]/ln[1 – C(1–ee^P)], ee^P = ee value of the product.

The Bolm group developed the kinetic resolution of sulfoximines using the N-heterocyclic carbene (NHC) catalyst C7 (Scheme 24).⁷¹ The stereoselective amidation reaction with enals proceeded smoothly with diphenoquinone (DQ) as the oxidant. This methodology worked well with various substituted phenyl alkyl sulfoximines. By changing the structure of the carbene catalyst, the opposite enantiomer of sulfoximine was also efficiently obtained. Gram-scale synthesis of biologically active compounds was achieved to demonstrate the utility of this methodology.

Scheme 24. Kinetic Resolution Using NHC-Catalyzed Amidation.

The selectivity factor (s) = ln[(1 – C)(1–ee^S)]/ln[(1 – C)(1 + ee^S)], C = (ee^S)/(ee^S + ee^P), ee^S = ee value of the substrate, ee^P = ee value of the product.

The Cramer group developed Rh(III)-catalyzed C–H functionalization reaction for kinetic resolution of sulfoximines (Scheme 25).⁷² The reaction between aryl alkyl substituted sulfoximine and diazoketoester efficiently generated enantioenriched aryl alkyl sulfoximine and cyclic benzothiazine. This kinetic resolution was able to differentiate the two enantiomers of the sulfoximnes with high selectivity. Both benzothiazines and the remaining sulfoximes were isolated with high ee values. Various substituted sulfoximines and diazo interceptors were investigated, and a wide substrate scope was demonstrated.

Scheme 25. Kinetic Resolution through C–H Functionalization.

The selectivity factor (s) = ln[(1 – C)(1–ee^S)]/ln[(1 – C)(1 + ee^S)], C = (ee^S)/(ee^S + ee^P), ee^S = ee value of the substrate, ee^P = ee value of the product.

The main disadvantage of kinetic resolution of racemates is that the maximum theoretical yield of the desired enantiopure product is 50%. Dynamic kinetic resolution (DKR) is one strategy to circumvent this disadvantage. In DKR, additional conditions are required for the starting materials to undergo racemization rapidly, and this will increase the maximum theoretical yield to 100%. The Dong group reported a DKR of allylic sulfoxides through an enantioselective Rh-catalyzed hydrogenation that is using a Mislow [2,3]-sigmatropic rearrangement for their racemization (Scheme 26).⁷³ This reaction utilized the low pressure of hydrogen gas to decrease the relative rate of enantioselective hydrogenation so that it is comparable to the rate of racemization. This DKR-generated product efficiently with high yields and enantioselectivities. A deuterium scrambling experiment and computational studies suggested that Rh-mediated oxidative addition of allylic sulfoxide gave a rhodium π-allyl sulfenate intermediate, which generated the racemized allylic sulfoxide through reductive elimination.

Scheme 26. DKR through Rh-Catalyzed Hydrogenation.

Chiral sulfinate esters are linchpin intermediates for the preparation of other sulfur stereogenic centers. In the previous section, we discussed the ease of using of stoichiometric amounts of commercially available enantiopure alcohols as chiral auxiliaries for formation of enantiopure sulfinate esters. However, catalytic enantioselective synthesis of sufinate esters with achiral alcohols is still highly desirable to expand the scope and accessibility of this class of important intermediates.

Ellman and Miller reported the DKR of tert-butanesulfinyl chloride with achiral alcohols (Scheme 27).⁷⁴ This reaction utilized a peptide C9 as the nucleophilic catalyst, which reacted with sulfinyl chlorides to form diastereomeric N-sulfinylammonium salts. The sulfur stereogenic center of the sulfinylammonium salt rapidly racemized before being replaced diastereoselectively by an alcohol. Subsequently, the Ellman group⁷⁵ and the Toru group⁷⁶ developed the use of Cinchona alkaloids C10 as catalysts for the stereoselective sulfinylation reaction of achiral alcohols. In general, this is an efficient method for the synthesis of enantiopure sulfinate esters.

Scheme 27. DKR Using Nucleophilic Catalysis.

The Chi and Zheng group recently reported DKR of sulfoxides catalyzed using a chiral N-heterocyclic carbene (Scheme 28).⁷⁷ The X-ray structure of the substrate suggested an intramolecular chalcogen bond (ChB) between the oxygen atom of the aldehyde and the sulfur atom of the sulfoxide. The ChB-induced conformational locking effect resulted in a racemic sulfoxide and through facile conformational isomerization enabled the efficient DKR. With the NHC precatalyst C11 and diphenoquinone (DQ) as the oxidant, the aldehyde moiety activated by the ChB was prone to convert to an ester with an alcohol, providing the enantioenriched sulfoxide with high selectivity.

Scheme 28. NHC-Catalyzed DKR of Sulfoxides Enabled by Chalcogen Bond.

4.4. Desymmetrization

The number of reports on catalytic enantioselective synthesis of sulfur stereogenic centers through desymmetrization is increasing. For example, the Bolm group reported the desymmetrization of dimethyl sulfoximines (Scheme 29).^78,79 Stoichiometric chiral lithium amides were utilized as the base for the enantioselective deprotonation of the prochiral dimethyl sulfoximines. This is followed by trapping of the carbanion with TMSCl. Although only moderate enantioselectivity was achieved using the stoichiometric chiral reagent, this pioneering work inspired subsequent studies on catalytic desymmetrization.

Scheme 29. Desymmetrization Using Enantioselective Deprotonation.

The Wang group reported the desymmetrization of diaryl sulfoxides through C–H functionalization (Scheme 30).⁸⁰ The prochiral sulfoxide was an efficient directing group for the Pd-catalyzed ortho-C–H olefination. With monoprotected amino acids as ligands, chiral sulfoxides were generated with high enantioselectivity. A wide range of substitutions were well tolerated under the conditions.

Scheme 30. Desymmetrization Using Enantioselective Pd-Catalyzed C–H Functionalization.

The Cramer group developed desymmetrization of diaryl sulfoximines using Rh-complexes with chiral cyclopentadienyl ligands as catalyst (C12) (Scheme 31).⁸¹ Enantioselective activation of the ortho-C–H bond of sulfoximine was followed by addition to diazoketones, producing enantioenriched 1,2-benzothiazines. Carboxylic acids were found to coordinate with Rh and had significant effect on the enantioselectivity. Chiral tert-leucine-derived acid showed the highest improvement for the reaction. Almost at the same time, the Li group reported a similar Rh-catalyzed C–H functionalization reaction (Scheme 32).⁸² The enantioselective functionalization/cyclization sequence is suitable for a broad scope of diaryl sulfoximines and diazo compounds. With a simple adjustment of the achiral carboxylic acid and solvent, the opposite enantiomers of chiral sulfoximines were obtained, thus enabling an enantiodivergent synthesis. The authors proposed that the steric bulk of the carboxylic acids resulted in the opposite stereochemical outcome.

Scheme 31. Desymmetrization Using Enantioselective Rh-Catalyzed C–H Functionalization.

Scheme 32. Desymmetrization Using C–H Functionalization and Enantiodivergent Synthesis of Sulfoximine.

The Shi group realized an enantioselective annulative coupling of sulfoximines using a Ru catalyst (Scheme 33).⁸³ The C–H cleavage was proposed to be the enantiodetermining step and is followed by coupling with α-carbonyl sulfoxonium ylides. Chiral binaphthyl monocarboxylic acids C14 were found to be efficient ligands for the reaction. Various chiral sulfoximines with different substitutions were obtained with excellent stereocontrol.

Scheme 33. Desymmetrization Using Ru-Catalyzed Annulative Coupling.

The Miller group developed the synthesis of chiral sulfoximines using enantioselective N-oxidation of pyridine (Scheme 34).⁸⁴ An aspartic acid-containing peptide catalyst worked well in the desymmetrization of bis-pyridyl sulfoximines with hydrogen peroxide as the oxidant. A urea-directing group was found to have a profound influence on the enantioselectivity. X-ray crystallography was used to determine the absolute configuration of the product. Within the unit cell, there were two stable conformations consisting of a vertical pyridine N-oxide or pyridine ring and a horizontal pyridyl-sulfoximine plane.

Scheme 34. Desymmetrization through Enantioselective N-Oxidation of Pyridine.

The Wang group reported the phosphonium-catalyzed desymmetrization of bisphenols through phosphinylation (Scheme 35).⁸⁵ After deprotonation, the anionic sulfoximine formed an ion pair with the chiral cationic phosphonium catalyst C15. The following enantioselective Atherton–Todd reaction with Ph₂P(O)H gave chiral sulfoximines with high enantioselectivity. Similar to the related case with sulfoxides (see Scheme 20), further mechanistic studies suggested that the minor enantiomer obtained after desymmetrization can be further transformed to the achiral diphosphinylation product through kinetic resolution. This further improved the enantiopurity of the desired chiral sulfoximine. This methodology allows the direct access to free N–H sulfoximines.

Scheme 35. Desymmetrization through Enantioselective Atherton–Todd Reaction.

The Willis group reported the enantioselective alkylation of sulfonimidamides using a Cinchona alkaloid derived catalyst C16 (Scheme 36).⁸⁶ The configuration of the sulfonimidamides was unstable because of rapid equilibrium between the tautomers. After deprotonation, a prochiral anion intermediate was generated and formed an ion pair with the chiral cationic catalyst. The desymmetrization of the anion intermediate was achieved through enantioselective alkylation of one of the enantiotopic nitrogen atoms. This is the first example of catalytic enantioselective desymmetrization of sulfonimidamides. The reaction tolerated various substitutions, and a diverse range of enantioenriched sulfonimidamides were obtained.

Scheme 36. Desymmetrization of Sulfonimidamides.

The Tan and Zhang group reported the enantioselective condensation of sulfinates and alcohols to prepare enantioenriched sulfinate esters (Scheme 37).⁸⁷ It was proposed that the sulfinate anion formed an ion pair with pentanidium C17, the chiral cation catalyst, which resulted in one of the enantiotopic oxygen atoms being enantioselectively acylated. This formed the key intermediate of the desymmetrization, which is the mixed anhydride. It was subsequently stereoinvertively substituted by alcohols at the sulfur stereogenic center. This reaction tolerated a wide substrate scope, and various substituted aryl and alkyl sulfinates were prepared. Furthermore, the mild reaction conditions allowed this approach to be suitable for late-stage functionalization of existing drugs. Several drug-derived sulfinate esters were efficiently obtained with high enantioselectivity. A key reason for this success is that numerous methods are available for introducing the sulfinate functionality on drugs at a late stage.⁸⁸⁻⁹⁰ This approach was also successfully applied to the enantioselective sulfinylation of primary and secondary alcohols, including several biologically active alcohols. In addition, the generated sulfinate esters were versatile precursors for other S(IV) and S(VI) stereogenic centers, which made this an ideal approach for the rapid diversification of existing drugs or lead compounds with chiral sulfur pharmacophores.

Scheme 37. Desymmetrization of Sulfinates.

4.5. Deracemization

Deracemization is the conversion of racemates directly into single enantiomers. This is a highly attractive strategy but, in practice, highly difficult to execute. The Bach group reported the use of hydrogen-bonding catalyst C18, incorporated with xanthone sensitizers, for the deracemization of cyclic sulfoxides (Scheme 38).⁹¹ The configuration of chiral sulfoxide is known to be unstable upon excitation. By selective excitation and racemization of one of the enantiomers with a higher binding efficiency to the chiral catalyst, enantioenrichment can be achieved. This methodology gave chiral sulfoxides with up to 55% ee value. This stimulating work will require further studies and will be an inspiration for future chemists.

Scheme 38. Deracemization of Sulfoxide Using Hydrogen-Bonding Catalyst.

In the previous section, we discussed the reductive kinetic resolution of racemic sulfoxides using methionine sulfoxide reductase A, which was developed by the Míšek group. This concept was adapted toward cyclic deracemization, which involved another nonselective oxidant to transform the thioether to racemic sulfoxides, allowing a theoretical yield of 100% (Scheme 39). The Míšek group added 1 equiv of oxaziridine as the nonselective oxidant (Scheme 40).⁶⁹ Several chiral sulfoxides were obtained in moderate to high yields and with excellent enantioselectivity. One major disadvantage of this methodology is overoxidation of sulfoxide to sulfone. The Glueck and Winkler group demonstrated that a photocatalyst can also be utilized for the nonselective oxidation (Scheme 41).⁹² Protochlorophyllide C19 was found to mostly avoid excessive overoxidation, dramatically increasing the yield of the cyclic deracemization.

Scheme 39. Cyclic Deracemization.

Scheme 40. Deracemization by Enzymes and Oxaziridines.

Scheme 41. Deracemization by Enzymes and Photocatalysts.

Recently, the Chen and Yang group developed a multienzyme redox system for the cyclic deracemization of sulfoxides (Scheme 42).⁹³ The nonselective oxidation was a low enantioselective styrene monooxygenase (SMO) instead of a chemical oxidant. The cascade catalysis of three auxiliary enzymes regenerated the cofactors of MsrA and SMO by consuming d-glucose. This system had a wide range of substrate scope, and diverse aromatic, heteroaromatic, alkyl, and thio-alkyl sulfoxides were obtained in high yield and enantioselectivity.

Scheme 42. Deracemization by Multienzyme Redox System.

5. Conclusion

Due to the increased interest of sulfur stereogenic centers in both industry and academia, many new approaches have been developed for their asymmetric synthesis. We had discussed these synthetic methodologies in three parts, based on the different strategies.

First, strategies with chiral auxiliaries have provided reliable routes for the synthesis of sulfur stereogenic centers. However, stoichiometric amounts of chiral auxiliaries usually result in significant waste. In addition, subsequent nucleophilic substitutions usually require highly reactive metal reagents, which have unsatisfactory functional group tolerance. Chiral auxiliaries that can be easily substituted using simple nucleophiles are needed. Next, strategies using enantiospecific transformations of enantiopure sulfur compounds are limited by suitable commercially available enantiopure starting materials. While many examples lead to minimal loss of enantiopurity, milder reaction conditions are required and with higher retention of enantiopurity. Finally, there are increasing efforts to develop catalytic enantioselective strategies; particularly exciting are dynamic kinetic resolution, desymmetrization, and deracemization approaches, which have high theoretical yields. However, the scope of most methods is limited to simple aryl or alkyl substitutions. More attention should be paid to heterocyclic compounds, which are common in drugs and natural products.

In general, it is our view that catalytic enantioselective strategies should aim at delivering highly efficient synthesis of S(IV) stereogenic centers such as sulfinate esters, sulfinimidate esters, and thiosulfinate esters. These are potential linchpin compounds that can be converted to other sulfur stereogenic centers, especially S(VI) stereogenic centers. In order to complement this strategy, a range of suitable enantiospecific transformations that can be performed under mild conditions with large functional group tolerance is required.

Separately, we also consider sulfonimidoyl halide, a dark horse that requires taming. It can be prepared from enantiopure sulfur compounds and are easily substituted by alcohols, phenols, and amines. The high reactivity of sulfonimidoyl halides makes it attractive and yet challenging to obtain with high enantiopurity. The high reactivity is also usually the cause for racemization of enantioenriched sulfonimidoyl halides during reactions and leads to products with decreased enantiopurity. However, if some of these issues are solved, the outcome can be highly rewarding.

While the construction of sulfur stereogenic centers has improved, our attention needs to be focused on exploring new strategies and improving the existing methodologies so that they are useful for synthesis and modification of complex molecules, including drugs and other biologically active compounds.

Author Contributions

CRediT: All authors wrote, revised and approved the manuscript. CRediT: Fucheng Wang writing-original draft.

The authors declare no competing financial interest.