Synthesis of two 6-s-cis locked stereoisomeric analogues of the steroid hormone 1α,25-dihydroxyvitamin D3:: 1α,25-dihydroxy-19-nor-previtamin D3 and 1β,25-dihydroxy-19-nor-previtamin D3

An efficient synthesis of A-ring precursors 8 and 9 from inexpensive commercially available (-)-quinic acid has been developed. A-Ring synthon 8 has been obtained through a short sequence (eight steps) in high overall yield (30%). One key step in the synthesis of A-ring precursor 9 is the selective deprotection of a silyl ether in an alpha,beta-unsaturated ester 12. However, of note is the excellent yield of the Mitsunobu process on derivative 15, which takes place with the total inversion of configuration, giving ester 16. Coupling of A-ring synthons 8 and 9 with the appropriate CD-rings/side chain fragment 7, provides access to 6-s-cis locked analogues of the steroid hormone 1 alpha,25-(OH)(2)-D-3: 1 alpha,25-(OH)(2)-19-nor-pre-D-3 (3) and novel 1 beta,25-(OH)(2)-19-nor-pre-D-3 (4). (C) 2000 Elsevier Science Ltd. All rights reserved.