A novel and enantioselective synthesis of d-(+)-biotin via a Sharpless asymmetric dihydroxylation strategy

A novel and enantioselective synthesis of d-(+)-biotin has been accomplished starting from commercially available cyclohexanone. The key steps in the sequence are the Sharpless asymmetric dihydroxylation of a (E)-ethyl 3-(2-chlorocyclohex-1-en-1-yl)acrylate derivative to establish the stereocenters of d-(+)-biotin, the carboxyalkyl side chain is introduced by unmasking the cyclohexene by ozonolysis and enzymatic hydrolysis of a thioacetate.

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(2S,3R)-Ethyl 3-(2-chlorocyclohex-1-en-1-yl)-2,3-dihydroxypropanoateC11H17ClO4[α]D25=+5.2 (c 1.92, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (2S,3R)

(2S,3S)-Ethyl 3-azido-3-(2-chlorocyclohex-1-en-1-yl)-2-hydroxypropanoateC11H16ClN3O3[α]D25=-40.9 (c 1.32, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (2S,3S)

(2S,3S)-Ethyl 3-(((benzyloxy)carbonyl)amino)-3-(2-chlorocyclohex-1-en-1-yl)-2-hydroxypro panoateC19H24ClNO5[α]D25=-17.9 (c 1.59, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (2S,3S)

(2R,3S)-Ethyl 2-azido-3-(((benzyloxy)carbonyl)amino)-3-(2-chlorocyclohex-1-en-1-yl) propanoateC19H23ClN4O4[α]D25=+11.6 (c 1.73, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (2R,3S)

(4R,5S)-1-Benzyl 3,4-diethyl 5-(2-chlorocyclohex-1-en-1-yl)-2-oxoimidazolidine-1,3,4-tricarboxylateC23H27ClN2O7[α]D25=-8.1 (c 2.6, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (4R,5S)

(4R,5S)-Benzyl 5-(2-chlorocyclohex-1-en-1-yl)-4-(hydroxymethyl)-2-oxoimidazolidine-1-carboxylateC18H21ClN2O4[α]D25=-65.5 (c 2.0, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (4R,5S)

(4R,5S)-Benzyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-chlorocyclohex-1-en-1-yl)-2-oxoimidazolidine-1-carboxylateC24H35ClN2O4Si[α]D25=-47.5 (c 4.0, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (4R,5S)

(4R,5S)-1,3-Dibenzyl-4-(((tert-butyldimethylsilyl)oxy) methyl)-5-(2-chlorocyclohex-1-en-1-yl)imidazolidin-2-oneC30H41ClN2O2Si[α]D25=-33.1 (c 2.9, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (4R,5S)

Methyl 6-((4R,5R)-1,3-dibenzyl-5-(((tert-butyldimethyl silyl)oxy)methyl)-2-oxoimidazolidin-4-yl)-6-oxohexanoateC31H44N2O5Si[α]D25=-12.2 (c 2.0, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (4R,5R)

Methyl 6-((4R,5R)-1,3-dibenzyl-5-(hydroxymethyl)-2-oxoimidazolidin-4-yl)-6-oxohexanoateC25H30N2O5[α]D25=-11.1 (c 2.0, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (4R,5R)

Methyl 6-((4R,5R)-5-((acetylthio)methyl)-1,3-dibenzyl-2-oxoimidazolidin-4-yl)-6-oxohexanoateC27H32N2O5S[α]D25=+40.0 (c 1.0, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (4R,5R)

Methyl 6-((4R,5R)-1,3-dibenzyl-5-(mercaptomethyl)-2-oxoimidazolidin-4-yl)-6-oxohexanoateC25H30N2O4S[α]D25=+17.5 (c 2.6, CHCl3).Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (4R,5R)

(Z)-Methyl 5-((3aS,6aR)-1,3-dibenzyl-2-oxotetrahydro-1H-thieno[3,4-d]imidazol-4(2H)-ylidene)pentanoateC25H28N2O3S[α]D25=+192 (c 1, CHCl3)Source of chirality: Sharpless asymmetric dihydroxylationAbsolute configuration: (3aS,6aR)