Catalytic Enantioselective Synthesis of Chiral Organofluorine Compounds: Alcohol-Mediated Hydrogen Transfer for Catalytic Carbonyl Reductive Coupling

Abstract

Alcohol-mediated carbonyl addition has enabled catalytic enantioselective syntheses of diverse fluorine-containing compounds without the need for stoichiometric metals or discrete redox manipulations. Reactions of this type may be separated into two broad categories: redox-neutral hydrogen auto-transfer reactions wherein lower alcohols and n-unsaturated pronucleophiles are converted to higher alcohols and corresponding 2-propanol mediated carbonyl reductive couplings.

Graphical Abstract

I. Introduction

Due to the favorable biological properties of organofluorine compounds, fluorinated structural motifs appear ubiquitously across commercial pharmaceutical and agrochemical ingredients¹ and many powerful methods that now exist for their synthesis.² In the course of our ongoing exploration into transfer hydrogenative carbonyl addition,³ we have developed a suite of catalytic enantioselective methods for the formation of chiral organofluorine compounds wherein π-unsaturated reactants are converted to transient organometallic nucleophiles via alcohol-mediated hydrogen-transfer. Two reactions types have emerged: hydrogen auto-transfer processes, wherein primary alcohols serve both as reductant and carbonyl proelectrophile (enabling conversion of lower alcohols to higher alcohols), and related 2-propanol-mediated reductive couplings of discrete carbonyl reactants. Such transfer hydrogenative carbonyl additions may be differentiated from “borrowing hydrogen” processes, which promote formal alcohol substitution.⁴ Most importantly, unlike many classical carbonyl additions, the present alcohol-mediated processes circumvent the use of stoichiometric organometallic reagents, which pose issues of safety, require multistep syntheses, generate stoichiometric quantities of metallic byproducts and are non-cryogenic. In this account, we provide a comprehensive survey of catalytic enantioselective methods for the synthesis of chiral organofluorine compounds via alcohol-mediated carbonyl addition with an emphasis on preparative capabilities (Scheme 1). For detailed discussions of reaction mechanism and stereochemical models, the reader is referred to the primary literature citations.

Scheme 1.

Organofluorine compounds via enantioselective alcohol-mediated carbonyl addition.

II. Chiral Organofluorine Compounds via Alcohol-Mediated Carbonyl Addition

In 2008, cyclometallated π-allyliridium C,O-benzoate complexes bound by chiral chelating phosphines were shown to catalyze highly enantioselective alcohol-mediated carbonyl allylations⁵ and crotylations⁶ using allyl acetate and α-methyl allyl acetate, respectively, as pronucleophiles. In 2011, using the cyclometallated π-allyliridium C,O-benzoate complex modified by (R)-Cl,MeO-BIPHEP, related carbonyl (α-trifluoromethyl)allylations using a-trifluoromethyl allyl benzoate as pronucleophile were developed (Scheme 2).⁷ In reactions conducted from the alcohol oxidation level, moderate to good yields of the CF₃-bearing homoallylic alcohols were generated with excellent levels of anti-diastereo- and enantioselectivity. Using 2-propanol as terminal reductant under otherwise equivalent conditions, an identical set of adducts is accessible from the aldehyde oxidation level with comparable levels of anti-diastereo- and enantioselectivity. Finally, in carbonyl (α-trifluoromethyl)allylations of enantiomerically enriched chiral γ-stereogenic alcohols, high levels of catalyst-directed stereoinduction are observed (eq. 1).

Scheme 2.

anti-Diastereo- and enantioselective iridium-catalyzed carbonyl (α-trifluoromethyl)allylation.

(eq. 1)

To illustrate the utility of the reaction products, the compound obtained upon (α-trifluoromethyl)allylation of 1,4-aminobutanol was transformed to two useful N-containing building blocks (Scheme 3). Specifically, exposure to ozone followed by NaBH₄ furnished a 1,3-diol, which was converted to the indicated p-toluenesulfonate in a site-selective fashion. Conversion of the p-toluenesulfonate to the CF₃-bearing piperidine was then accomplished in accordance with a related literature procedure.^8,9 Alternatively, the p-toluenesulfonate can be eliminated and the resulting olefin can be subjected to diastereoselective ruthenium-catalyzed hydrogenation to provide the syn-trifluoro-isopropyl-substituted secondary alcohol as a single diastereomer.¹⁰

Scheme 3.

CF₃-Bearing building blocks obtained via (α-trifluoromethyl)allylation of aminobutanol.

The cyclometallated n-allyliridium C,O-benzoate complex modified by (R)-Cl,MeO-BIPHEP was also effective in promoting highly enantioselective carbonyl (2-fluoro)allylations (Scheme 4).¹¹ Using commercially available (2-fluoro)allyl chloride as pronucleophile, benzylic, allylic and aliphatic alcohols were converted to the corresponding homoallylic alcohols in good to excellent yield with uniformly high levels of enantioselectivity. Using 2-propanol as terminal reductant under otherwise identical conditions, corresponding aldehyde reductive couplings of (2-fluoro)allyl chloride occur with roughly equivalent levels of enantioselectivity (not shown). In all cases, small quantities of defluorinated side products were observed (3–10% yield), which were easily removed upon chromatographic isolation of the product. Diastereoselective hydrogenation of the vinyl fluoride-containing products was readily achieved at ambient pressures of hydrogen gas using the Crabtree catalyst.¹² In this way, syn-3-fluoro-1-alcohols are formed from primary alcohols in the absence of stoichiometric organic or metallic byproducts.

Scheme 4.

Enantioselective iridium-catalyzed carbonyl (2-fluoro)allylation.

Commercially available solutions of fluoral hydrate or difluoroacetaldehyde ethyl hemiacetal, 75 wt% in water or 90 wt% in ethanol, respectively, can be utilized in highly anti-diastereo- and enantioselective carbonyl (α-aryl)allylations (Scheme 5).¹³ Again, the chromatographically purified cyclometallated π-allyliridium C,O-benzoate complex modified by (S)-Cl,MeO-BIPHEP was identified as the catalyst of choice. Using 2-propanol as terminal reductant and molecular sieves to remove water and ethanol, (α-aryl)allylation of both fluoral and difluoroacetaldehyde occur in good to excellent yield with high levels of diastereo- and enantioselectivity. These results are significant as nearly all enantioselective metal catalyzed additions to fluoral require anhydrous conditions involving in situ generation of gaseous fluoral, which is acutely toxic. The hydrate and hemiacetal solutions are less hazardous than their gaseous counterparts. Additionally, there is surprising paucity of catalytic enantioselective methods for formation of CHF2-bearing stereocenters.¹⁴ The ability to engage fluoral hydrate and difluoroacetaldehyde ethyl hemiacetate in highly anti-diastereo- and enantioselective (α-aryl)allylation enabled concise routes to di- and trifluoromethylated derivatives of the FDA-approved alkaloid d-hyoscyamine (dextro-atropine) (Scheme 6).¹⁵

Scheme 5.

anti-Diastereo- and enantioselective iridium-catalyzed carbonyl (α-aryl)allylation of fluoral hydrate and difluoroacetaldehyde ethyl hemiacetal.

Scheme 6.

Syntheses of CF₃- and CHF₂-bearing derivatives of d-hyoscyamine (dextro-atropine).

The use of methanol as a feedstock in metal catalyzed C-C coupling is an important objective in chemical synthesis.¹⁶ Following the development of non-asymmetric allene-methanol C-C couplings,¹⁷ it was found that iridium complexes modified by PhanePhos catalyze the enantioselective reductive coupling of CF₃-allenes with methanol via hydrogen auto-transfer.^18,19 Products of hydrohydroxymethylation are formed exclusively as the branched regioisomers with excellent levels of enantiomeric enrichment (Scheme 7). In this process, methanol dehydrogenation provides formaldehyde and an iridium hydride. Allene hydrometalation then delivers an allyliridium species that undergoes formaldehyde addition to furnish a homoallylic iridium alkoxide. Alkoxide exchange with another equivalent of methanol releases the product and closes the catalytic cycle. This transformation enables catalytic enantioselective formation of acyclic CF₃-bearing quaternary carbon stereocenters without stoichiometric metals or byproducts.²⁰ The utility of this method was highlighted in syntheses of chiral carboxylic acids that incorporate CF₃-bearing quaternary carbon stereocenters (Scheme 8).

Scheme 7.

Enantioselective iridium-catalyzed reductive coupling of methanol with CF₃-allenes via hydrogen auto-transfer.

Scheme 8.

Syntheses of enantiomerically enriched carboxylic acids that incorporate CF₃-bearing quaternary carbon stereocenters.

Iridium complexes modified by PhanePhos are also effective catalysts for the 2-propanol-mediated reductive coupling of 1,1-disubstituted allenes with fluoral (Scheme 9).²¹ In this way, branched CF₃-substituted secondary alcohols bearing acyclic quaternary carbon stereocenters²⁰ are formed with high levels of anti-diastereo- and enantioselectivity. The utility of this method was illustrated by the construction of CF₃-substituted oxetanes and azetidines (Scheme 10). The oxetane formation proceeds via secondary to primary methanesulfonate transfer, which accounts for the divergent diastereoselectivity of these processes. Iridium-PhanePhos complexes were uniquely effective in the allene-mediated C-C coupling described herein.^18,21 Investigations into the reaction mechanism suggest the chromatographically stable, cyclometallated iridium-(R)-PhanePhos complex, (R)-Ir-PP-I, is the active catalyst. Generation of the cyclometallated complex in situ provides a slightly more active catalyst that does not incorporate the bidentate acetate counterion, which appears to impede conversion (Scheme 11).

Scheme 9.

Enantioselective iridium-catalyzed reductive coupling of fluoral with allenes mediated by 2-propanol.

Scheme 10.

Synthesis of an enantiomerically enriched CF₃-substituted oxetane and CF₃-substituted azetidine.

Scheme 11.

The catalytically competent cyclometallated iridium-PhanePhos complex (R)-Ir-PP-I.

III. Summary and Outlook

Carbonyl addition has played a fundamental role in chemical synthesis since the inception of organic chemistry as a field. However, traditional methods have typically relied on the use of stoichiometric carbanions, which must be preformed and deployed under cryogenic conditions and incur issues of safety, waste generation and functional group compatibility. By harnessing the reducing power of alcohols, we have demonstrated that carbonyl additional can be accomplished from transient organometallic nucleophiles in the absence of stoichiometric metals under non-cryogenic conditions.³ As summarized herein, adaptation of these methods for the synthesis of chiral organofluorine compounds enables access to novel fluorine-containing compounds that would otherwise be difficult to prepare. For application of this chemistry on scale, it will be important to reduce catalyst loadings, as successfully accomplished in related iridium-catalyzed alcohol aminations.²² The focus of future studies will be on the development of related C-C couplings, including alcohol-mediated carbonyl arylations and related cross-electrophile reductive couplings.