Total synthesis of naturally occurring α-tocopherol. Assymetric alkylation and asymmetric epoxidation as means to introduce (R)-configuration at C(2) of the chroman moiety

Article abstract of DOI:10.1002/hlca.19900730431

Based on the reductive, stereospecific ring closure of (2R,4'R,8'R)-α-'Tocopherylquinone' or corresponding analogues with a short, functionalized side chain (B, Scheme 1) to 1 resp. the chroman system of 1 (C), two different approaches for the introduction of the required tertiary methyl-substituted alcohol structure in the side chain of the aromatic precursors (A, Scheme 1) were developed. The first approach uses asymmetric alkylation in three different versions featuring a) diastereoselective steering with chiral auxiliaries I-IV (Scheme 2) attached as esters to α-keto acids, b) intermediate transfer of chirality in an ester enolate (from 18, Scheme 4) derived from an optically active α-hydroxyacid, c) enantioselective alkylation of phytenal (20) and subsequent ring closure with chirality transfer (Schemes 5-7). The second approach is based on the asymmetric epoxidation of β-metallylalcohol (Sharpless epoxidation), the corresponding epoxyalcohol being converted in situ to the (S)- or (R)-chlorodiol (S)- and (R)-29, respectively, for isolation (Schemes 8 and 9). Nucleophilic epoxide opening with a (3R,7R)-3,7,11-trimethyldodecyl (C₁₅**) and an ArCH₂ unit in appropriate sequence is used to assemble the C-framework of the target molecule via corresponding epoxide intermediates from either chlorodiol. Combined with the use of the methoxymethyl-ether function for protection of the hydroquinone system, the epoxide approach provides a short route to 1 (Scheme 10).