Tadano, Takao, Hayakawa, Yamada, Yamaguchi, Morita and Kawasaki, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800253.
Mentioned in the comments, this tidy little synthesis features one hell of a tightly functionalised ring system, with seven contiguous stereocentres and a trans- trisubstituted olefin in a ten-membered ring. The biological activity seems impressive too: cytotoxicity and immunosuppressive activity, but the potency isn’t mentioned in this paper. This is actually the first synthesis of pestalotiopsin A, even though it’s recieved plenty of attention from the Procter and Paquette groups. Retro time:
Circumventing the metathesis problems of Paquette by using a NHK coupling to put in the medium ring and a [2+2] 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. However, a closer look at the cycloaddition reveals impressive regioselectivity – but only after almost a week on the stove…
Without going into too much 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. A little aqueous acid hydrolysed the nitrile and allowed cyclisation of provide the desired gamma lactone.
However, it’s their synthesis of an enantiomerically enriched propargyl alcohol that I liked most. This prep was developed by Takano in the 80’s, and it’s utillity stems from the ease of synthesis of the starting materials, Î²-cholo epoxides, which are of course easily prepared using an SAE. 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 itself. A spot of methyl iodide then left the desired product, quickly and easily. Nice.
There’s a lot more nice chemistry in this paper, including that nice (and high-yielding) NHK, but also a bit of a protecting group dance. Smart work.
Takao, K., Hayakawa, N., Yamada, R., Yamaguchi, T., Morita, U., Kawasaki, S., Tadano, K. (2008). Total Synthesis of (Ã¢Ë†â€™)-Pestalotiopsin A. Angewandte Chemie International Edition DOI: 10.1002/anie.200800253
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