Oxidative Fragmentation of Pregna-14,16-dien-20-ones to 14β-Hydroxyandrost-15-en-17-ones

Abstract

Two methods have been developed for efficient conversion of pregna-14,16-dien-20-ones into 14 beta-hydroxyandrost-15-en-17-ones. One procedure consists of treatment of the ring-D dienone successively with sodium borohydride and singlet oxygen. The reaction is illustrated by the conversion of pregna-14,16-dien-20-one 1 into 14 beta-hydroxyandrost-15-en-17-one 3, via the corresponding allylic alcohol 2. Although this two-step procedure is simple, it provides 3 in relatively low yield, accompanied by a smaller amount of the isomeric 14 alpha-hydroxyandrost-15-en-17-one 6. An alternative one-step conversion is achieved by treatment of dienone 1 with a peroxyacid in the presence of a strong protic acid. This process is illustrated by the two-step conversion of dienone 1 into hydroxy ketone 11 in 51% overall yield (Scheme 5) and by the analogous conversion of dienone 13 into hydroxy ketone 24 in 61% overall yield (Scheme 11).

Chemical Synthesis of the Cardiotonic Steroid Glycosides and Related Natural Products

“…Heathcock and co-workers have described a practical method (Scheme 1a) [26] for the conversion of an inexpensive plant-derived sapogenin (11) into a 14b-hydroxy-androstane, potentially useful for subsequent elaboration to complex cardiotonic glycosides. Sarsasapogenin (11) is first converted into the D [16,17] progesterone (20-oxopregnane) derivative 12 by means of a modified-Marker degradation [27] protocol.…”

“…Treatment of 25 with peroxy-A C H T U N G T R E N N U N G acid results in attack of the oxidant by furan at the less-hindered a-position (C5' of the furan) followed by nucleophilic addition of hydroxide to the remaining a site (C2'). The dearomatized intermediate (not shown) is then oxidized further to the hydroxylactone (26), which can be reduced with sodium borohydride to the butenolide 27. The C15-b-hydroxy group now serves as a handle for oxidative functionalization of C14 (with inversion of configuration).…”

3β,12β,14α-Trihydroxypregnan-20-one

“…For the synthesis, see: Templeton & Yan (1992); Fell & Heathcock (2002). For background on hecogenin, see: Ranu & Samanta (2003).…”

“…The title compound was obtained by oxidation and reduction of the corresponding 3β,12β-diacetoxypregnan-20-ethylenedioxy-14-ene, which was prepared from hecogenin (Fell & Heathcock, 2002;Ranu & Samanta, 2003). We have undertaken the X-ray crystal structure determination of (I) in order to establish its molecular conformation and relative stereochemistry.…”

“…The title compound was prepared according to the literature method (Fell & Heathcock, 2002;Templeton & Yan 1992).…”