Chloro–formyl steroids as precursors for hybrid heterosteroids: synthesis, spectroscopic characterization, and molecular and supramolecular structures

Abstract

Two new functionalized steroids containing both chloro and formyl substituents in ring A, and intended as precursors for the synthesis of hybrid systems, have been synthesized from ketosteroid precursors. 3-Chloro-2-formyl-17,17-dimethyl-18-nor-5α-androstane-2,13-diene, (I), and methyl 3-chloro-4-formyl-12-oxo-5β-cholan-3-ene-24-oate, C26H37ClO4, (IV), have been synthesized using Vilsmeier reactions with 17β-hydroxy-17α-methyl-5α-androstan-3-one and methyl 3,13-dioxo-5β-cholan-24-oate, respectively. These products have been fully characterized using IR spectroscopy, 1H and 13C NMR spectroscopy, and high-resolution mass spectrometry, and in the case of (IV), a single-crystal X-ray diffraction study. Crystal structures have also been determined for the known analogues 3-chloro-2-formyl-17-oxo-5α-androst-2-ene, C20H27ClO2, (II), 3-chloro-2-formyl-5α-cholest-2-ene, C28H45ClO, (III), and the absolute and relative configurations are assigned for all four compounds (I)–(IV): when the fusion between rings A and B is trans, 3-chloro-2-formyl products are formed, but when this ring fusion is cis, a 3-chloro-4-formyl product results. The formation of (I) involves not only chloroformylation at ring A, but also dehydration and the 1,2 migration of a methyl group at ring D. In each of (II), (III) and (IV), rings B and C adopt almost perfect chair conformations, while ring A adopts a half-chair conformation. Ring D adopts an envelope conformation in each of (II) and (III), albeit differently folded in the two compounds, while in (IV), it adopts a half-chair conformation. A single C—H...O hydrogen bond links the molecules of (II) into C(6) chains which are linked into sheets by means of carbonyl–carbonyl interactions. The molecules of (IV) are linked into simple C(7) chains, again by a single C—H...O hydrogen bond, but there are no direction-specific interactions in (III) that are structurally significant.