Strategic redox relay enables a scalable synthesis of ouabagenin, a bioactive cardenolide

Abstract

Here, we report on a scalable route to the polyhydroxylated steroid ouabagenin with an unusual take on the age-old practice of steroid semisynthesis. The incorporation of both redox and stereochemical relays during the design of this synthesis resulted in efficient access to more than 500 milligrams of a key precursor toward ouabagenin-and ultimately ouabagenin itself-and the discovery of innovative methods for carbon-hydrogen (C-H) and carbon-carbon activation and carbon-oxygen bond homolysis. Given the medicinal relevance of the cardenolides in the treatment of congestive heart failure, a variety of ouabagenin analogs could potentially be generated from the key intermediate as a means of addressing the narrow therapeutic index of these molecules. This synthesis also showcases an approach to bypass the historically challenging problem of selective C-H oxidation of saturated carbon centers in a controlled fashion.

Figure 1

(A) Biosynthesis of highly complex steroid ouabagenin; (B) Selected examples of polyhydroxylated steroids; (C) Retrosynthetic analysis of ouabagenin.

Scheme 1

Construction of the ouabagenin core. Reagents and conditions: (a) hv, SDS solution, 120 h, 68%; (b) hv, NIS (3 equiv), Li₂CO₃ (3.5 equiv), MeOH, PhCH₃, 23 °C, 20min, 85%; (c) TiCI₄ (1 M in CH₂CI₂, 1 equiv), CH₂CI₂, −10 °C, 15 min; AgOAc (1.5 equiv), THF, 50 °C, 2 h (71% overall); (d) H₂O₂ (35 wt. % in H₂O, 6 equiv), 3 NaOH (1 equiv), MeOH, 0 °C, 75 min; (e) SeO₂ (1.1 equiv), PhCI, 90 °C, 10 h; (f) H₂O₂ (35 wt. % in H₂O, 6 equiv), 3 M NaOH (1 equiv), MeOH, 0 °C, 75 min (50% over 3 steps); (g) Al-Hg, sat. NaHCO₃, −5 °C, 1 h (56%); (h) PPTS (0.2 equiv), CaSO₄ (2.5 equiv), Me₂CO, 23 °C, 20 h; (i) LiBEt₃H (1 M in THF, 1.1 equiv), THF, −78 °C, 30 min (63% over 2 steps); (j) Li (60 equiv), NH₃, THF, −78 °C, 30 min; (k) PPTS (1.5 equiv), Me₂CO, 70 °C, 16 h (69% over 2 steps); (I) TMSOTf (3 equiv), Et₃N (4 equiv) CH₂CI₂, 0 °C to 23 °C, 30 min; Pd(OAc)₂ (1.2 equiv), MeCN, 23 °C, 3 h, then FeCI₃ (1 equiv), 0 °C, 10 min; (m) SiO₂, DIPEA (55 equiv), C₇F₈, 45 min (55% over 3 steps) (n) Co(acac)₂, PhSiH₃ (3 equiv), O₂, dioxane, 23 °C, 3 h, 86%; (o) conc. HCl (1 equiv), CH₂CI₂, 23 °C, 1 h, 87%.

Scheme 2

Completing the synthesis of ouabagenin. Reagents and conditions (a) N₂H₄ (10 equiv), Et₃N (10 equiv), 4:1 CH₂CI₂:EtOH, 50 °C, 5 h; l₂ (3 equiv), Et₃N(4 equiv), THF, 10 min; (b) 17 (4 equiv), [Ph₂PO₂][NBu₄] (4 equiv), Pd(PPh₃)₄ (0.15 equiv), CuTC (3 equiv), DMF, 23 °C, 2 h (42% over 2 steps); (c) CoCI₂.6H₂O (2.5 equiv), NaBH₄ (5 equiv), EtOH, 0 to 23 °C, 20 min; (d) Barton’s base (1.5 equiv), C₆H₆, 100 °C, 10 min (70% over 2 steps); (e) conc. HCl (2 equiv), MeOH, 23 °C, 30 mir (90%).

Scheme 3

Late-stage functionalization of deconjugated enone. Reagents and conditions: Fe₂(ox)₃ (4 equiv), Selectfluor (4 equiv), NaBH₄ (6.4 equiv), 3:4:2 MeCN:THF:H₂O, 0 °C, 20 min (51%)