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Organic Chemistry Highlights

Total Synthesis

Monday, April 2, 2012
Douglass F. Taber
University of Delaware

The Reisman Synthesis of (-)-Maoecrystal Z

(-)-Maoecrystal Z (3) was isolated as a minor consituent from the Chinese medicinal herb Isodon eriocalyx. The synthesis of 3 reported (J. Am. Chem. Soc. 2011, 133, 14964. DOI: 10.1021/ja2073356) by Sarah E. Reisman of the California Institute of Technology, featuring as a key step the cyclization of 1 to 2, is a tribute to the power of one-electron reduction for carbon-carbon bond construction.

The synthesis began with a Myers alkylation, to prepare 6. The amide was reduced to the alcohol with the convenient ammonia-borane complex, and the alcohol was carried on to the iodide 7.

The first carbocyclic ring of 3 was prepared by classic chemistry, the condensation of dimethyl malonate 9 with mesityl oxide 8, followed by selective removal of one of the ketone carbonyls. A salt-free Wittig reaction followed by hydrolysis, resolution and reduction then completed the synthesis of 12.

Exposure of 12 to peracid led to the epoxide 13 as an inconsequential mixture of diastereomers. The one-electron Nugent/RajanBabu/Gansäuer protocol was low yielding with methyl acrylate, but dramatically improved when the trifluoroethyl acrylate 14 was used as the acceptor. The lactone 15 was formed as a single diastereomer. Alkylation of 15 with 7 followed by oxidation gave 16, which was deprotected and oxidized to give 1.

The cascade cyclization of 1 presumably proceeded by intitial one-electron reduction of the more accessible aldehyde. The cyclization of the resulting radical onto the alkene may have been assisted by complexation of the lactone carbonyl with the required second equivalent of SmI2. The Sm enolate so prepared then added to the second aldehyde, to give 2. This cyclization sets one quaternary and three ternary stereogenic centers.

Attempted monoprotection of 2 was not successful, so the bis acetate was prepared and ozonized, and the aldehyde was condensed with the Eschenmoser salt to give 17. Careful monohydrolysis then completed the synthesis of (-)-Maoecrystal Z (3).

D. F. Taber, Org. Chem. Highlights 2012, April 2.