Cortistatins transannular cycloaddition

Craft and Gung have disclosed the first transannular (4-1-3) cycloaddition of a symmetrical substrate using an allene function catalyzed by Pd(ll) in reaction with a furan group. The substrate itself is produced by a Grubbs I RCM, and the nonsymmetrical product should be a useful intermediate for the cortistatins (Scheme 33) [70]. 

Craft and Gung developed a paUadium-catalyzed transannular [4+3] cycloaddition route in which all of the rings of cortistatins are prepared in one step from a single macrocyclic precursor (Scheme 19.50) [114]. Exposure of macrocyclic allene 233 to a catalytic amount of palladium (II) acetate in the presence of excess lithium bromide resulted in the formation of 238 as a single isomer in 37% yield. This is the first report of a transannular [4+3] cycloaddition. The proposed mechanism is shown in Scheme 19.50. The formation of allene-palladium complex 234 affords a a-allylpalladium intermediate, which rapidly isomerizes to the 7i-allylpalladium intermediate 235. This can then undergo intramolecular cycloaddilion via an endo (compact) transition strucmre 236 to give bromonium ion 237. The loss of a proton results in the formation of the observed product 238. Cycloadduct 238 was readily converted into the tetracyclic core skeleton of cortistatins 239 by selective reduction of the olefin formed by cycloaddition with furan, followed by reductive debromination. 

SCHEME 19.51 Gold-catalyzed transannular [4+3] cycloaddition approach to cortistatins. 

The first transannular [4 + 3] cycloaddition was reported by Craft and Gung in the synthesis of the oxabicyclo[3.2.1] octene ABCD ring system of cortistatins." The reaction... 

Craft DT, Gung BW. The first transannular [4+3] cycloaddition reaction synthesis of the ABCD ring structure of cortistatins. Tetrahedron Lett. 2008 49 5931-5934. 

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