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.
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!