Synthesis of 3α,6β,17,20α-tetrahydroxy-5β-pregnan-11-one 6-hemisuccinate, a hapten for immunoassay of 3α,17,20α-trihydroxy-5β-pregnan-11-one (‘pregnanetriolone’)

Abstract

3α,6β,17,20α-Tetrahydroxy-5β-pregnan-11-one 6-hemisuccinate (4) has been synthesised by two distinct routes. In the first of these, introduction of a 6β-hydroxy substituent into 17α-hydroxypregn-4-ene-3,11,20-trione followed by catalytic hydrogenation of the Δ⁴-olefinic bond gave 6β,17α-dihydroxy-5β-pregnane-3,11,20-trione. The 5β-configuration was confirmed by an X-ray crystallographic analysis of the derived 6-hemisuccinate. Subsequent selective reduction at C-3 and C-20 by sodium borohydride in the presence of cerous chloride gave the required compound (4), although in low overall yield. To avoid the problem of non-specificity in the reduction at C-20, alternative routes were explored from precursors already possessing the essential 17,20α-diol system, protected as the isopropylidene derivative or by acetylation as appropriate. Hydroboration-oxidation of 3,3-ethylenedipxy-17,20α-isopropyl-idenedioxypregn-5-en-11-one gave the 6β-hydroxy derivative of 5β-configuration, verified by dehydration (POCl₃–pyridine) to the 6-ene derivative. Further routine transformations including succinoylation of the 6β-hydroxy derivative, deprotection at C-3 and in the side chain, and reduction of the 3-oxo group, gave the required compound (4).