Asymmetric, organocatalytic, three-step synthesis of gamma-hydroxy-(E)-alpha,beta-unsaturated sulfones and esters.

While studying the metabolites of certain vitamin D3 analogs, we became interested in the synthesis of γ-hydroxy-α,β-unsaturated sulfones and esters. γ-Hydroxy-α,β-ethylenic sulfones have previously been used as substrates in stereocontrolled processes such as conjugate additions and cycloaddition reactions,1 as substrates for preparation of enatiomerically pure polypropionate chains or amino alcohol units,2 and also as intermediates in alkaloid syntheses.3 γ-Hydroxy-α,β-enoates have been used as sources of α,β-epoxyesters, which are highly versatile functionalities and can be converted into a number of compounds by opening the oxirane4 and as intermediates in natural product syntheses.5 Use of both of these γ-hydroxy-α,β-unsaturated systems as substrates for stereoselective radical reactions has been explored.6 General methodologies for the asymmetric synthesis of these systems, however, are limited in scope.7 Based on the utility of such systems in highly stereocontrolled processes1 and as intermediates in natural product syntheses,3,5 we set out to design a simple, asymmetric general strategy for their synthesis. Recent reports on the organocatalytic, asymmetric α-selenenylation of aldehydes in high yields (>85%) and high enantiomeric excess (>95%)8 gave us an entry point to control absolute stereochemistry in our γ-hydroxy-α,β unsaturated systems. Such α-selenylated aldehydes could easily undergo an aldol type reaction with an electron withdrawing group (EWG)-stabilized carbanion to give a diastereomeric pair of γ-selenyl-β-hydroxy sulfones or esters. Oxidation of the selenide and treatment with mild base could give a β,γ-epoxide which, upon further treatment with base could rearrange into the desired enantiomerically enriched γ-hydroxy-α,β unsaturated ester or sulfone with the overall inversion of stereochemistry (Scheme 1). Scheme 1 Synthesis of γ-hydroxy-α,β-unsaturated sulfones and esters from α-selenyl aldehydes11 In order to examine the scope of this reaction, we chose three aldehydes (3-phenylpropanal, hexanal, and 3,3-dimethylbutanal) and three EWG-stabilized methyl groups (t-butyl methyl sulfone, phenyl methyl sulfone, and ethyl acetate). Using the methodology of Tiecco and Marini8b to make α-selenyl aldehydes 3a-c, we were able to react the crude α-selenyl aldehyde9 with lithiated EWG-stabilized methyl groups 4a-c to give diastereomeric compounds 5-13 (Scheme 1, A) in 55-86% yields. γ-Selenyl-β-hydroxy sulfones and esters 5-13 underwent oxidation and spontaneous cyclization with mCPBA and K2CO3 to give the transient β,γ-epoxide which immediately rearranged in situ to yield exclusively the γ-hydroxy-(E)-α,β-unsaturated sulfone or ester 14-22 (Scheme 1, B) in 63-90% yields and excellent ee's (≥95%). The (E)-geometry of the new carbon-carbon double bond in products 14-22 was confirmed by 1H NMR spectoscopy (Jα,β = 14-16 Hz). α-Selenyl aldehyde 3c derived from 3,3-dimethylbutanal underwent reaction sequence A (Scheme 1) in high yield with all three EWG-stabilized carbanions (4a-c), but γ-selenyl-β-hydroxy ester 13 derived from reaction with ethyl aceate (4c) decomposed under the reaction conditions used in reaction sequence B (Scheme 1). Also, substituted EWG-stabilized methyl groups such as propionates were explored, but no substantial selectivity in E/Z double bond formation was seen. Our success using α-selenenylated aldehydes led us to investigate other leaving groups alpha to the aldehyde and whether a one-pot 3-step procedure might be possible (Scheme 2). Given the precedent for the enantioselective organocatalytic α-chlorination of aldehydes10 we decided to explore the feasibility of such a system in the reaction sequence. Individually, each step in the reaction sequence with an α-chloro aldehyde appeared to work, but a one-pot procedure could not be achieved successfully. Ultimately this strategy was not pursued due to the instability and volatility of the α-chlorinated aldehydes and the superior results with the α-selenyl systems. Scheme 2 Plan for one pot procedure Confirmation of absolute stereochemistry was first achieved by reducing α-selenyl aldehydes 3a-c with NaBH4 and comparing optical rotations with published values.8b An x-ray crystal structure was also obtained for γ-hydroxy-α,β-unsaturated sulfone 15, which confirms the R configuration of the γ-hydroxy carbon (Figure 1). Figure 1 Crystal structure of 15 (confirms R configuration at the γ-hydroxy carbon atom). Further proving the value of this synthetic method, scale up of the procedure to one gram was readily accomplished with no erosion of ee (97%) and in 59% overall yield for γ-hydroxy-α,β-unsaturated sulfone 14.11 γ-Hydroxy ether-α,β-unsaturated ester 23 (Scheme 3) is a key intermediate in a recent synthesis of the biologically active alkaloid (+)-α-conhydrine (24).5a Intermediate 23 was prepared in 6 steps and 32% overall yield from (S)-glycidol.5a Using the methodology described here we have prepared intermediate ester 23 in only 4 steps and in 47% overall yield and 97% ee (Scheme 4). Scheme 3 Synthesis of (+)-α-conhydrine (24) using key intermediate γ-hydroxy ether-α,β-unsaturated ester 235a Scheme 4 Formal synthesis of (+)-α-conhydrine (24) In summary, we report an efficient and generalized procedure for the synthesis of γ-hydroxy-α,β-unsaturated sulfones and esters of high enantiomeric purity that is easily scaled to amounts >1 gram. This 3-step process works on a variety of substrates with high overall yields (~50%) and excellent control of absolute stereochemistry (ee values ≥95%). We have shown the application of this methodology to a formal synthesis of the natural product (+)-α-conhydrine. Undoubtedly this methodology could be expanded to the preparation of other γ-hydroxy-α,β-unsaturated compounds with other EWGs, such as nitro or cyano.