STEREOCONTROLLED TOTAL SYNTHESIS OF CALCITRIOL DERIVATIVES - 1,25-DIHYDROXY-2-(4'-HYDROXYBUTYL)VITAMIN-D-3 ANALOGS OF AN OSTEOPOROSIS DRUG

The diastereomeric 2 alpha- and 2 beta-(4'-hydroxybutyl) calcitriol analogs (-)-3 and (+)-3' were prepared in only 11 chemical operations, starting with 4 + 2-cycloaddition of commercially available methyl 2-pyrone-3-carboxylate. Highlights of this convergent and stereocontrolled synthetic approach are as follows: (1) retention of reactant dienophile geometry in the product bicyclic lactone, characteristic of a concerted inverse-electron-demand Diels-Alder cycloaddition; (2) an improved decarboxylation procedure involving chemospecific allyloxide opening of a lactone ring in the presence of a methyl ester and then non-high pressure palladium-promoted allylic ester decarboxylation; and (3) use of the enantiomercially pure C,D-ring chiron (+)-14 to resolve racemic A-ring phosphine oxide (+/-)-13. Relative binding affinities of the enantiomerically pure diastereomers (-)-3 and (+)-3' to the vitamin D binding protein and to the vitamin D receptor showed some unexpected trends. Diastereomer (+)-3' surprisingly bound more effectively to the vitamin D receptor than did the established osteoporosis drug ED-71 (1).