An improved asymmetric total synthesis of (+)-biotin via the enantioselective desymmetrization of a meso-cyclic anhydride mediated by cinchona alkaloid-based sulfonamide

Abstract

The highly enantioselective total synthesis of (+)-biotin 1 via the Hoffmann–Roche lactone–thiolactone strategy has been achieved starting from cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid 2 with an overall yield of 35%. Two contiguous stereogenic centers at C-3a and C-6a were established through a rapid cinchona alkaloid-based sulfonamide-mediated enantioselective alcoholysis of meso-cyclic anhydride 3 to afford (4 S,5 R)-cinnamyl hemiester 4h, the direct precursor to (3a S,6a R)-lactone 5 with high enantioselectivity. A one-pot installation of the 4-carboxybutyl side chain was accomplished by a Fukuyama coupling reaction of (3a S,6a R)-thiolactone 6 with the organozinc reagent prepared from ethyl 5-bromopentanoate.