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. 2008 Jun 11;130(23):7241-3.
doi: 10.1021/ja8023466. Epub 2008 May 14.

Synthesis of (+)-cortistatin A

Ryan A Shenvi  1 , Carlos A Guerrero, Jun Shi, Chuang-Chuang Li, Phil S Baran
Affiliations

Synthesis of (+)-cortistatin A

Ryan A Shenvi et al. J Am Chem Soc. .

Abstract

Cortistatin A is a marine steroid with highly selective and perhaps mechanistically unique antiangiogenic activity. Herein we report a synthesis of this natural product by way of "cortistatinone", an intermediate ideally suited for investigating the key pharmacophore of the cortistatin family. The synthesis begins with a terrestrial steroid and traverses a route to cortistatin A through the discovery of unique chemical reactivity. Specifically, we demonstrate the first example of a directed, geminal C-H bisoxidation, a new fragmentation cascade to access expanded B-ring steroid systems, a chemoselective cyclization to install the hallmark oxabicycle of the cortistatin family, and a remarkably selective hydrogenation reaction, which should find extensive use in future syntheses of the cortistatins and designed analogues. The synthesis displays a level of brevity, efficiency, and practicality that will be crucial in evaluating the medicinal potential of this fascinating class of marine steroids.

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Figures

Figure 1
Figure 1
Isoquinoline-bearing cortistatins A−D (1−4) and J−L (5−7) (cortistatins E−H bear pyridines or piperidines and exhibit markedly diminished potency), and a general retrosynthetic strategy to target a steroid skeleton, namely, the inexpensive, terrestrial steroid, prednisone.
Scheme 1
Scheme 1. Synthesis of the (+)-Cortistatin A Core: Cortistatinone (8)
Reagents and conditions: (a) t-BuO2H (2 equiv), DBU (2 equiv), THF, 23 °C, 72 h, 82%; (b) NH4OAc (15 equiv), Na(BH3)CN (1.2 equiv), MeOH, THF, 23 °C,18 h; then HCO2Et (74 equiv), Et3N (11 equiv), 54 °C, 12 h, 73%; (c) TBAA (5 equiv), Co(acac)2 (0.2 equiv), PhH, 90 °C, 24 h, 48%, 76% brsm; (d) Co(acac)2 (0.2 equiv), PhSiH3 (2.2 equiv), O2, THF, HC(OMe)3, 23 °C, 12 h; then TsOH•H2O (3 equiv), rt, 2 h; then K2CO3 (5 equiv), MeOH, 6 h, 65%; (e) PhI(OAc)2 (5 equiv), Br2 (5 equiv), CH2Cl2, −30 °C, 10 h; then TMSCl (5 equiv), imidazole (5 equiv), 0 °C, 15 min, 57%; (f) DBU (2 equiv), LiCl (10 equiv), THF, 23 °C, 24 h, 85%; (g) SmI2 (2.2 equiv), 1:9 DMPU:THF, 23 °C, 5 min; then TBCHD (1.1 equiv), 23 °C, 5 h; (h) LiBr (20 equiv), Li2CO3 (20 equiv), DMF, 80 °C, 1 h (65% over 2 steps); (i) AlH3 (0.5 M in THF, 5 equiv), THF, 23 °C, 1 h; then K2CO3 (4 equiv), MeOH, 23 °C, 12 h; then Ac2O (20 equiv), Et3N (40 equiv), DMAP (0.1 equiv), CH2Cl2, 23 °C, 3 h, 89%; (j) MgBr2•Et2O (1.1 equiv), 2,6-(t-Bu)2Py (2.1 equiv), PhH, 80 °C, 1 h; PPTS (5 equiv), butanone: H2O (1:1), 90 °C, 2 h; then K2CO3 (10 equiv), 23 °C, 5 h (82%).
Figure 2
Figure 2
Key transformations en route to (+)-cortistatin A and mechanistic analyses.
Scheme 2
Scheme 2. Completing the Synthesis of (+)-Cortistatin A
Reagents and conditions: (a) N2H4 (10 equiv), Et3N (10 equiv), EtOH, 50 °C, 6 h, I2 (2 equiv), Et3N (3 equiv), THF, 23 °C, 5 min; (b) 7-(trimethylstannyl)-isoquinoline (4 equiv), Pd(PPh3)4 (0.5 equiv), CuCl (10 equiv), LiCl (10 equiv), DMSO, 23 °C, 10 min, 53% (over 2 steps); (c) Raney Ni (88 wt equiv), i-PrOH, H2O, 50 °C, 1 h, 50% (ca. 100% brsm).
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National Institutes of Health, United States