Synthesis of (+)-Cortistatin A

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.

Hypervalent iodine reagents in the total synthesis of natural products

“…Scheme 53) by Baran and co-workers. 391 This impressive reaction, which is the first example of an alcohol-directed geminal dibromination of an unactivated methyl group, delivered the product in 57% yield after trapping the alcohol with TMSCl to avoid ether formation (Scheme 83).…”

Synthetic Strategies Directed Towards the Cortistatin Family of Natural Products

“…[11] Their collective efforts, commencing from a broad array of starting materials and guided by an assortment of creative strategies, have culminated in one semi-synthesis, [12] three total syntheses, [13][14][15] and two formal syntheses, [16] as well as a number of syntheses of the pentacyclic cortistatin core and some illuminating model studies. [17] In an attempt to present this synthetic work in a comprehensive yet palatable manner, these approaches are organized herein by the method for B ring formation.…”

“…[12] Their semi-synthetic effort began with the commercially available steroid prednisone (14), which was converted into the formamide 15 in five steps and 26 % overall yield (Scheme 2). Mukaiyama hydration of alkene 15 with Co(acac) 2 and PhSiH 3 was then followed by orthoamide formation and subsequent cleavage of the acetate to deliver the secondary alcohol 16 in 65 % yield.…”

Synthesis and Anti-Angiogenic Activity of Cortistatin Analogs

“…Unexpectedly, the undesired 5 0 -isomer was preferentially formed. A trial of the Stille coupling reaction between triflate 4 and 7-(trimethylstannyl)isoquinoline, as Baran has reported using the corresponding vinyl iodide instead of 4,4) resulted in the decomposition of both compounds. Hydrogenation of the 16,17-double bond of 8 proceeded stereoselectively on 10% Pd/C for 5 h to give 9.…”

“…Thus, 1a could be a promising selective anti-angiogenic agent. The synthesis of 1a from the steroid, prednisone, has been achieved by Baran's group, 4) and several synthetic studies have been reported. 5,6) The structure-activity relationship studies of cortistatins 7) have revealed that a) introduction of an oxygen function on the D-ring diminishes the activity, b) the isoquinoline ring is crucial, and c) the dihydroxy group on the A-ring is removable.…”