A Hypervalent Iodine-Induced Double Annulation Enables a Concise Synthesis of the Pentacyclic Core Structure of the Cortistatins

Abstract

A stereocontrolled synthesis of a complex pentacycle embodying the molecular architecture of the cortistatin class of natural products was achieved from the (+)-Hajos-Parrish ketone. The cornerstone of our approach is a hypervalent iodine induced tandem intramolecular oxidative dearomatization and nitrile oxide cycloaddition. The manner in which these ring formations were orchestrated has yielded a rather concise strategy for synthesis.

Synthesis of Cortistatins A, J, K and L

“…8,18,36 The synthesis of the key azido alcohol intermediate 5 was achieved in three steps from the cyclohexadienone 6, a sequence initiated by hydrosilylation with triethylsilane (2 equiv) in the presence of Wilkinson's catalyst (0.05 equiv). 37 The intermediate triethylsilyl enol ether was not isolated; rather, pyridine was added (14% by volume) followed by N-bromosuccinimide (2 equiv), forming the (3R)-bromo ketone 22 as a single diastereomer in 70% yield.…”

“…The oxabicyclic core of the latter precursor could then be disconnected by an oxidative cyclization transform, a strategy independently conceived and previously demonstrated by Sarpong and coworkers, as well as others. 8,15,16,18 To allow for a convergent assembly process, we imagined an earlier disconnection of the seven-membered B-ring by an olefin metathesis reaction, giving rise to the triene precursor 7, which we envisioned could be synthesized by coupling of the o- …”

Methodology for the Construction of the Bicyclo[4.3.0]nonane Core

“…Cortistatins, belonging to the triterpene alkaloids class, pose a particular synthetic challenge. Recent routes have been attempted, with two being successful (see Scheme 11) [34][35][36]. In 2008, Hirama proposed using 1 to undergo a Knovengel condensation/electrocyclic reaction/radical cyclization strategy to afford cortistatin A-the most potent cortistatin [34].…”

Oxidation of oximes with hypervalent iodine reagents: opportunities, development, and applications

“…A noteworthy example of this chemistry has been described by Sorensen (Scheme 12). 21 Specifically, attack of compound 39 with DIB in TFE resulted in cyclization to presumed intermediate 40, which converged to the ultimate 42 after in situ oxidation of the oxime to a nitrile oxide and INOC cyclization. Substance 42 is structurally related to the interesting natural product, cortistatin.…”