Efficient Stereocontrolled Access to 15- and 16-Hydroxy Steroids

Abstract

Four epimeric 15‐ and 16‐hydroxy steroids have been stereoselectively synthesized from epi‐androsterone. The key intermediate is the 3β‐[(tert‐butyldimethylsilyl)oxy]‐5α‐23,24‐bisnorchol‐16‐en‐22‐ol (10), which allows both efficient D‐ring functionalization and the possibility of facile side‐chain construction. In the course of this synthesis, we have found that the stereochemical outcome of the C‐15 carbonyl reduction is strongly dependent on the C‐16 and C‐17 hybridization.

Exploiting the Facile Release of Trifluoroacetate for the α-Methylenation of the Sterically Hindered Carbonyl Groups on (+)-Sclareolide and (−)-Eburnamonine

“…See representative reaction procedure C. The tert -butyl-dimethylsilyl androsterone 38 was prepared according to the literature procedure . SiO 2 flash chromatography (2% EtOAc in hexanes) afforded the title compound as a colorless solid (47 mg) in 59% yield: mp 150–152 °C; 1 H NMR (500 MHz, CDCl 3 ) δ 6.04 (m, 1H), 5.35 (m, 1H), 3.54 (tt, J = 10.8, 5.0 Hz, 1H), 2.55 (dd, J = 15.5, 6.5 Hz, 1H), 2.19–2.12 (m, 1H), 1.87–1.83 (m, 1H), 1.77–1.54 (m, 6H), 1.48–1.24 (m, 9H), 1.12–0.91 (m, 4H), 0.88 (s, 9H), 0.83 (s, 3H), 0.75–0.67 (m, 1H), 0.04 (s, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ 209.3, 144.9, 118.8, 72.3, 54.9, 49.0, 48.3, 45.3, 38.9, 37.4, 36.1, 34.9, 32.2, 31.9, 31.4, 29.6, 28.8, 26.3 (3), 20.8, 18.6, 14.5, 12.7, −4.2 (2); IR (film) ν max 2927, 2854, 1728, 1641, 1091 cm –1 ; HRMS (EI) m / z calcd for C 26 H 44 O 2 Si (M + H) + 417.3189, found 417.3186; [α] 25 D +11.9 ( c 2.1, CHCl 3 ).…”

Synthetic Approach to the Core Structure of Oleandrin and Related Cardiac Glycosides with Highly Functionalized Ring D

“…13 The Suzuki−Miyaura cross-coupling reaction 14 of 7 and 3-furyl boronic acid in the presence of tetrakis-(triphenylphosphine)palladium(0) afforded 8 in a 72% yield with 10 mol % of the catalyst (at 0.1 g scale; 62% yield with 5% of the catalyst at 5−10 g scale). 12,15 Hydroboration of 8 using borane−THF complex in THF affected selectively the aliphatic double bond 16 and occurred on the less shielded α-face of the ring D. 17 The product was, without isolation, oxidized with alkaline hydrogen peroxide to afford the 17β-(3-furyl)-16α-hydroxy derivative 9 as the single product (84% yield). The hydroxy group in 9 was oxidized with the Dess−Martin periodinane 18 to provide 16-one 10.…”

α-Hydroxylation at C-15 and C-16 in Cholesterol: Synthesis of (25R)-5α-Cholesta-3β,15α,26-triol and (25R)-5α-Cholesta-3β,16α,26-triol from Diosgenin

“…Marino functionalized D rings of steroids with a C-15β hydroxyl by alkyl cyanocuprate addition to a 1,3-diene mono-β-epoxide system . De Riccardis found that reduction of the C-15 carbonyl is stereoselective, affording the C-15α hydroxyl group when C-16 and C-17 are sp 2 hybridized . Recently, we reported two methods for the transposition of C-16β hydroxyl to the 15α position, as well as a successful synthesis of the aglycone of 26- O -deacetyl pavoninin-5 ( 1a ) via the 15α-hydroxy-16-ketone, using the Barton deoxygenation reaction on the 16-alcohol .…”

“…Introduction of the C-16α hydroxyl by oxidation of the C-16β hydroxy to the 16-one followed by KBH 4 afforded in poor yield a mixture of C-16α and C-16β hydroxy compounds in a 1:9 ratio . An ene reaction on a ( Z )-16-pregnene has afforded a bisnorchol-16-en-22-ol, which upon hydroboration−oxidation gave the C-16α-hydroxy steroid …”