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Totally Synthetic by Paul H. Docherty, 20 July 2006

Total Synthesis of Deoxyharringtonine


J. D. Eckelbarger, J. T. Wilmot, D. Y. Gin, J. Am. Chem. Soc. 2006, 128, 10370-10371.

DOI: 10.1021/ja063304f

There is ring expansion-action in this latest paper from David Gin, regarding the total synthesis of (-)-deoxyharringtonine, an anti-leukemia alkaloid. Starting from simple starting materials, they created the complex 7,5,5 system very quickly, using the ring-strain inherant in aziridines to open to a 7-member ring via a cyclisation.

This was then N-alkylated with Me3SiCH2I, which permited O-acylation with PivCl. The silyl group was then removed, generating a short-lived nonstabilized azomethine ylide. A stereo- and regioselective 1,3-dipolar cyclisation onto the PhSO2CH=CH2 led to the spiro-pyrrolidine. An impressive set of steps, creating two rings and completing the carbocyclic core of the target.

Other cool steps include a Yb(OTf)3 mediated mono-acylation of the free diol, and use of SmI2 to remove the sulfonate group. The side-chain (a non-trivial component, which produced in an impressive sequence) was then attached using Yamaguchi conditions, resulting in the desired product. The work is full of interesting reactions, and is a great read.