Facile Stereoselective Synthesis of (23S,25R)-1α,25-Dihydroxyvitamin D3 26,23-Lactone, a Major Metabolite of 1α,25-Dihydroxyvitamin D3

Article abstract of DOI:10.1021/jo00027a010

(23S,25R)-1α,25-Dihydroxyvitamin D3 26,23-lactone (1a), a major metabolite of 1α,25-dihydroxyvitamin D3 2, was synthesized efficiently and stereoselectively from 1α-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 (84percent) by iodo lactonization of the Δ²²-26-carboxylic acid 16b under kinetically controlled conditions in the presence of γ-collidine.The stereoselectivity of the iodo lactonization of steroidal Δ²²-25-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.