Synthesis and conformational study of P-heterocyclic androst-5-ene derivatives

The reactions of (20R)‐3β‐acetoxy‐21‐hydroxymethylpregn‐5‐en‐20‐ol (2) and (20R)‐3β‐acetoxypregn‐5‐ene‐20,21‐diol (11) with phenylphosphonic dichloride 3 and aryl dichlorophosphates 4–6 afforded novel types of P‐heterocyclic androst‐5‐ene derivatives 7–10 and 12 as epimeric pairs. The diastereomers were separated by column chromatography and were characterized by NMR spectroscopy. Estimation of the stereostructures of the corresponding epimers by B3LYP/631G(d) DFT ab initio calculations suggested that the six‐membered hetero ring in compounds 7b and 8a–10a adopts predominantly a chair conformation, with the P‐substituents in their preferred orientation. The cyclic phosphonate moiety in 7a or 8b–10b, however, seems to exist as an equilibrium mixture of chair–distorted‐boat or chair–chair forms. The theoretical calculations indicate that the conformational equilibrium is shifted toward the distorted‐boat conformer for 7a, with a pseudoequatorial P‐phenyl substituent, whereas for 8b–10b the chair conformer with an equatorial P‐phenoxy group predominates. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:7–14, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20372