FACILE STEREOSELECTIVE SYNTHESIS OF (23S,25R)-1-ALPHA,25-DIHYDROXYVITAMIN-D3 26,23-LACTONE, A MAJOR METABOLITE OF 1-ALPHA,25-DIHYDROXYVITAMIN-D3

(23S,25R)-1-alpha,25-Dihydroxyvitamin D3 26,23-lactone (1a), a major metabolite of 1-alpha,25-dihydroxyvitamin D3 2, was synthesized efficiently and stereoselectively from 1-alpha-hydroxydehydroepiandrosterone (3). The 17-oxosteroid 3 was first converted to C(22)-steroid aldehyde 9 with the natural stereochemistry at C(17) and C(20) using a stereoselective ene reaction as the key step. Then it was combined with the chiral C5 sulfone 4 having the correct stereochemistry for the lactone in 1a. Sulfone 4 was readily obtained from commercially available (R)-citramalic acid. The side-chain lactone with the natural stereochemistry at C(23) was constructed with high stereoselectivity (84%) by iodo lactonization of the DELTA(22)-26-carboxylic acid 16b under kinetically controlled conditions in the presence of gamma-collidine. The stereoselectivity of the iodo lactonization of steroidal DELTA(22)-25-hydroxy-26-carboxylic acids 16b, 24, and 25 was studied in detail, and a mechanism is proposed in which the configuration at C(25) and an added pyridine base play an important role.