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Totally Synthetic by Paul H. Docherty, 27 March 2008

Total Synthesis of Pestalotiopsin A


K.-i. Takao, N. Hayakawa, R. Yamada, T. Yamaguchi, U. Morita, S. Kawasaki, K.-i. Tadano, Angew. Chem. Int. Ed. 2008, 47, 3426-3429.

DOI: 10.1002/anie.200800253

Pestalotiopsin A features a tightly functionalised ring system, with seven contiguous stereocenters and a trans-trisubstituted olefin in a ten-membered ring. The biological activity seems impressive too: cytotoxicity and immunosuppressive activity. This is actually the first total synthesis of pestalotiopsin A, even though it has received a lot of attention from the Procter and Paquette groups. A retroanalysis:

Circumventing the metathesis problems of Paquette by using a Nozaki-Hiyama-Kishi coupling (NHK) to generate the medium ring and a [2+2] cycloaddition to create the cyclobutane, there’s plenty of interesting chemistry to examine. Lets start with the [2+2] using Oppolzer’s camphorsultam chrial auxilliary to control the following reductive step. A closer look at the cycloaddition reveals impressive regioselectivity - but only after almost a week on the stove…

Without going into detail, the elaboration of this core is neat, with cleavage of the ketal allowing a substrate contolled addition of vinyl Grignard, and displacement of a tosylate with cyanide providing the one-carbon homologate. Aqueous acid hydrolysed the nitrile and allowed cyclisation to provide the desired γ-lactone.

However, it’s their synthesis of an enantiomerically enriched propargyl alcohol that I liked most. This preparation was developed by Takano in the 80’s, and it’s utillity stems from the ease of synthesis of the starting materials, β-chloro epoxides, which are of course easily prepared using a Sharpless asymmetric epoxidation. Treatment of the chloro epoxide with three equivalents of butyl lithium results first in opening of the epoxide to give the allylic alchol. A second deprotonation and elimination provides the required terminal acetylene which was promptly deprotonated. Reaction with methyl iodide gave the desired product. Nice.

There’s a lot more interesting chemistry in this paper, including a high-yielding NHK, but also some protecting group transformations. A smart total synthesis!