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Organic Chemistry Highlights

Total Synthesis

Monday, March 5, 2012
Douglass F. Taber
University of Delaware

The Yamashita/Hirama Synthesis of Cortistatin A

A central challenge in the synthesis of the antiangiogenic Cortistatin A (3) is the stereocontrolled assembly of the cycloheptene ring. Shuji Yamashita and Masahiro Hirama of Tohoku University solved (J. Org. Chem. 2011, 76, 2408. DOI: 10.1021/jo2002616) this problem by the addition of the intermediate radical from the reduction of 1 in an intramolecular sense to the cyclohexenone of 1, to give 2.

The starting point for the synthesis was the enantiomerically-enriched enone 4, prepared from the Hajos-Parrish ketone. Alkylation gave 6, which was reduced, after some experimentation, selectively to the trans-fused ketone 7. Pd-mediated oxidation of the silyl enol ether derived from 7 gave the enone, which was homologated to the aldehyde 8 by way of the corresponding enol triflate. Condensation with dihydrorescorcinol 9 delivered the triene 10, which was carried on the iodide 1.

Unexpectedly, 1 readily epimerized at the indicated stereocenter, presumably by way of an equilibrating Claisen rearrangement. Fortunately, when the solid iodide was maintained at -30C for 12 hours, the desired diastereomer became dominant. The free radical reduction then proceeded smoothly to give 2.

To introduce the pendant isoquinoline of the natural product, 2 was protected and oxidized to 11. Reduction of the thiocarbamate derived from the tertiary alcohol 13, with H atom transfer to the more open face of the intermediate free radical, then delivered 14.

To oxidize 14 to the enone 15, the ketone was deprotonated, then exposed to the Mukaiyama reagent 15. Nucleophilic epoxidation followed by reduction, following the Nicolaou precedent, then set the stage for selective opening with dimethylamine, to complete the synthesis of (+)-Cortistatin A (3).

D. F. Taber, Org. Chem. Highlights 2012, March 5.