Novel side chain analogs of 1 alpha,25-dihydroxyvitamin D-3: design and synthesis of the 21,24-methano derivatives

The syntheses of the new 21,24-methane derivatives of 1 alpha ,25-dihydroxy vitamin D-3 [viz. 1(S),3(R)-dihydroxy-17(R)-(1',4'-cis-(4'-(1'hydroxy-1'- h ydroxy-1'-methylethyl)-cyclo-hexyl))-9, 10-seco-androsta-5(Z),7(E), 10(19)- triene (MC 2108) and its(1',4'-trans)-isomer (MC 2110)] are described. The key step is the establishment, by Diels-Alder reaction on a CD-ring side ch ain diene intermediate prepared from vitamin D-2, of a 1,4-disubstituted cy clohexene moiety in the side chain. Hydrogenation to a 1:1 mixture of cis a nd trans cyclohexane derivatives and separation of the two series at a stag e prior to the standard Horner-Wittig coupling with the (Hoffmann-La Roche) ring-A building block were other important steps in the syntheses of the t arget analogs. The relative configurations of intermediates were assigned b y NMR spectroscopy. MC 2108 and MC 2110 are of interest as conformationally locked side chain derivatives to probe the receptor interactions of not on ly the parent vitamin D hormone but also its biologically active symmetrica l 'double side chain' analog [21-(3'-hydroxy-3'methylbutyl)-9, 10-seco-chol esta-5(Z),7(E), 10(19)-triene-1 (S),3(R),25-triol (MC 2100)], 'both' side c hains of which can formally be traced out in the new analogs. The preferred conformations, inferred from an analysis of C-13-NMR characteristics, nota bly the chemical shift of C-17 in a series of analogs, to have the tertiary alcohol (1'-hydroxy-1'-methylethyl) substituent equatorial on the cyclohex ane chair, are confirmed by molecular modeling. (C) 2001 Elsevier Science I nc. All rights reserved.