Organometallic Routes to Novel Steroids Containing Heterocyclic C-17 Side-Chains

Abstract

A range of novel steroid analogues bearing a C-17 side-chain containing a 20R-hydroxyl group and a variety of heterocyclic substituents have been prepared by organometallic additions to 3-methoxypregnenolone. X-ray crystallography has been used to establish that the organometallic additions proceed with excellent Felkin-Anh control. This methodology has been extended, by use of the Achmatowicz rearrangement and ring-closing metathesis approaches, to prepare pyrandione and δ-lactone steroidal analogues reminiscent of the withanolide natural products.

Natural withanolides, an update

“…X-ray crystallography was used to establish the stereochemistry of the dione 583 and the lactone-steroid 584 . 274…”

Recent syntheses of steroidal derivatives containing heterocycles

“…Treatment of compound 89 with glacial acetic acid gave the triazolopyrimidinyl androstane derivative 90 in 64% yield (Scheme 19). In 2016, Vitellozzi et al 44 prepared a range of novel steroid analogues bearing a C-17 side-chain containing a 20R-hydroxyl group and a variety of heterocyclic substituents by organometallic additions to 3-methoxypregnenolone. This methodology was extended, by use of the Achmatowicz rearrangement and ring-closing metathesis approaches, to prepare pyrandione and δ-lactone steroidal analogues reminiscent of the withanolide natural products.…”

Divergent synthesis of complex withanolides enabled by a scalable route and late-stage functionalization

“…In direct contrast, only five semi-syntheses have been reported, none of which were demonstrated to be either divergent or scalable: jaborosalactones A, B, and D (11); withaferin A and 27-deoxywithaferin A (12); withanolide D (13); withanolide E (14); and withanolide A (15). There are also various reports of partial motif construction (16)(17)(18)(19)(20)(21)(22)(23) and derivatization efforts (8). As a consequence of the limited synthetic success, almost all primary material used in biological or clinical research are obtained from natural sources, which not only involves time-consuming extraction and separation protocols but also limits effective medicinal chemistry and discovery studies beyond simple derivatizations of isolated natural products.…”