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

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 (4S,5R)-cinnamyl hemiester 4h, the direct precursor to (3aS,6aR)-lactone 5 with high enantioselectivity. A one-pot installation of the 4-carboxybutyl side chain was accomplished by a Fukuyama coupling reaction of (3aS,6aR)-thiolactone 6 with the organozinc reagent prepared from ethyl 5-bromopentanoate.

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(4S,5R)-1,3-Dibenzyl-2-oxo-5-[(3-phenylallyloxy)-carbonyl]imidazolidine-4-carboxylic acidC28H26N2O5Ee = 98%[α]D22.1=+7.6 (c 1.0, CH3OH)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5R)

Ethyl(3aS,4S,6aR)-5-(1,3-Dibenzyl-2,3,3a,4,6,6a-hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-5-yl)pentanoateC26H32N2O3S[α]D22.1=-24.1 (c 1.0, CH3OH)Source of chirality: asymmetric synthesisAbsolute configuration: (3aS,4S,6aR)

(+)-BiotinC10H16N2O3S[α]D22.3=+91.3 (c 1.0, 0.1 N NaOH)Source of chirality: asymmetric synthesis