Jean-Claude Pascal

A Practical Synthesis of 14‐epi‐19‐nor‐1α,25‐Dihydroxyvitamin D3 Analogues and Their A‐ring Epimers

A practical synthesis of (2S,3aS,4aS)-2-tert-butyldimethylsilyloxybicyclo[3.1.0]hexane-3a-carbaldehyde (14a) and diastereoisomers, starting from all-cis methyl 3,5-dihydroxy-1cyclohexanecarboxylate (24) is described. Coupling with appropriate cis-hydrindanes produces the title compounds. TX 522, a member of this series, is currently in phase II clinical studies for the treatment of psoriasis. The key step involves the coupling of 14 and 16 with the respective cis-hydrindanes 9 and 7.

Asymmetrization of all-cis-3,5-dihydroxy-1-(methoxycarbonyl)cyclohexane and of the 4-methyl and 4-ethyl substituted homologues

Abstract Enantiomerically pure mono acylated derivatives of cis , cis -3,5-dihydroxy-1-(methoxycarbonyl)cyclohexane 1 , all- cis -3,5-dihydroxy-4-methyl-1-(methoxycarbonyl)cyclohexane 2 and all- cis -3,5-dihydroxy-4-ethyl-1-(methoxycarbonyl)cyclohexane 3 were obtained upon lipase catalyzed asymmetrization. PPL-catalyzed transesterification of 1 with vinyl acetate led in high yield to the ( S )-monoacetate (+)- 13 . With substrates 2 and 3 this process was slower and gave the ( R )-monoacetates (−)- 14 and (−)- 15 ; the best results were obtained with SAM II lipase. On the other hand, enantiotoposelective hydrolysis of their diacetates and especially dibutyrates gave useful results only for the 4-substituted substrates and produced the ( S )-monoesters.