| dc.description.abstract | A formal total synthesis of 1?,24(S)- and 1?,24(R)-dihydroxyvitamin D? (14 and 13) starting from the abundantly available cholic acid (71) is described in this chapter. Cholic acid (71) was first converted into methyl 3-oxocholanate (77) via lithocholic acid (72). The modification of A and B rings was accomplished before construction of the side chain as a model study. Bromination and dehydrobromination sequence transformed the keto ester (77) into the dienone ester (79).
The ?,?-epoxy dienone (86) was obtained from the dienone ester (79) via allylic bromination and dehydrobromination followed by regioselective epoxidation of the resulting trienone. A new reagent system, Zn, KI and disodium salt of EDTA, was developed for the regioselective reductive opening of the epoxide (86) to 1?-hydroxy ester (88). Employing a similar sequence, cholesterol (92) was converted into 1?-hydroxy dienone (95), which was transformed into the diacetate (98), a known intermediate for 1?-hydroxyvitamin D?.
The generality of this reaction sequence has also been further established by the conversion of androstan-5-en-3,17-dione (102) to the triacetate (110). For the synthesis of 1?,24-dihydroxyvitamin D? (13 and 14), the ketal ester (112), which was obtained from lithocholic acid (72), was converted into the keto ketal (119) using a modified Grignard reaction. Reduction of the keto group in the keto ketal (119) followed by hydrolysis and separation furnished the hydroxy ketones (133 and 126).
The less polar 24(S)-hydroxy ketone (133) was transformed into the hydroxy dienone (134) via acetylation, bromination, dehydrobromination and the hydrolysis sequence. In a similar manner, the more polar 24(R)-hydroxy ketone (126) was converted into hydroxy dienone (145). The stereochemistry of the hydroxy group at the C-24 position in (134 and 145) has been unambiguously established by employing single-crystal X-ray diffraction analysis.
The acetate of 24(R)-hydroxy dienone (145) was converted into epoxydienone (155) via allylic bromination-dehydrobromination followed by regioselective epoxidation of the resultant trienone. In a similar manner, the acetate of 24(S)-hydroxy dienone (134) was converted into the epoxydienone (154). Reaction of the epoxide (154) with lithium in liquid ammonia generated the triol (159) via concomitant epoxide ring reductive cleavage and the 1,6- and 1,2-reduction of the dienone moiety. The triol (159) on acetylation furnished the triacetate (153), whose conversion to 1?,24(S)-dihydroxyvitamin D? (14) has already been reported by Takeshita and coworkers. | |
