Enantioselective Synthesis of (2R,49R,89R)-a-Tocopherol (Vitamin E) Based on Enzymatic Function

in chemical and biological systems, has increasingly been receiving attention in clinical and nutritional applications in human health. Therefore, attempts have been made to develop an efficient and stereocontrolled synthesis of the natural form of a-Tocopherol. In terms of synthetic strategy, we considered the final carbon–carbon bond formation stage of our approach as involving a Wittig coupling of the chiral chroman-2-carboxaldehyde congener (S )-1 with the 15-carbon phosphonium salt (3R,7R)-2. The chiral chroman part would be obtained based on the enantioselective acetylation of the racemic chroman diol (6)-6. The synthetic strategy for the side-chain moiety corresponding to the phosphonium salt (3R,7R)-2 was based on the use of the chiral isoprene unit (S )-3 in which the phenylsulfonyl group represents a reactive function capable of coupling with a ten-carbon synthon such as (3R)-3,7-dimethyloctyl iodide 4. In this paper, we wish to describe the syntheses of the chiral chroman aldehyde (S )-1 and chiral isoprene unit (S )-3 based on enzymatic acetylation and their application to the total synthesis of (2R,49R,89R)-atocopherol. 1) Synthesis of the Chiral Chroman Aldehyde (S)-1 Reduction of the commercially available (6)-chroman-2-carboxylic acid 5 with LiAlH4 was reported to give the (6)chroman-2-methanol 6 in 42% yield. In order to improve the yield of (6)-6, the following four synthetic steps were undertaken to afford (6)-6 in 81% overall yield from (6)-5. Esterification of (6)-5 with CH2N2 provided the corresponding methyl ester (6)-7 (98% yield), which was treated with benzyl bromide (BnBr) and K2CO3 in acetone to give the benzyl ether (6)-8 (93% yield). Reduction of (6)-8 afforded an alcohol (6)-9 (99% yield) which was subjected to catalytic hydrogenation to provide the desired (6)-6 in 90% yield. From a screening experiment for (6)-6 using several kinds of commercially available lipases, lipase PL-266 from Alcalgenes sp. was found to be effective and the result is shown in Table 1. When vinyl acetate was employed as the acylating reagent (entry 1), (S )-acetate 10 (67% ee) and (R)-unchanged 6 (.99% ee) were obtained in 58% and 39% yields, respectively. Deprotection of (S )-10 (67% ee) with LiAlH4 gave the (S )-6 (67% ee), which was repeatedly subjected to enzymatic acetylation to provide (S )-10 (77% yield, .99% ee) and (R)6 (18% yield, 74% ee). The enantiomeric excess (ee) of the