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Totally Synthetic by Paul H. Docherty, 10 October 2006

Total Synthesis of Sylvaticin


T. J. Donohoe, R. M. Harris, J. Burrows, J. Parker, J. Am. Chem. Soc. 2006, 13704-13705.

DOI: 10.1021/ja0660148

There is a lot of oxidation in this latest JACS paper from Tim Donohoe, completing the first total synthesis of sylvaticin, a potent antitumor agent and nanomolar cytotoxicity target. The focus is, of course, the tetrahydrofuran rings, with a spacer of four carbons, and with neighbouring hydroxyls. Their route hinges upon an interesting oxidative cyclisation, developed within the group and detailed in a previous methodology paper.

The sequence starts with the synthesis of the cyclisation substrate, with the bulk of the work done by a pair of asymmetric dihydroxylations performed on a commercially avaliable tetraene. The low yield for this reaction can be attributed to the isomeric nature of the starting material. Clevage of the alkene was also low-yielding, but recycling the tetraol biproduct increased this, allowing Wittig olefination and completion of the cyclisation precursor.

Cyclisation, as completed in the previous paper, resulted in a excellent yield of the desired product (the notes mention use of cinnamic acid as reducing agent - taking Os(VIII) to Os(VI) via dihydroxylation). Creation of the more complex sidechain was completed in six step and reasonable yield, via cross metathesis, diimide reduction, and deprotection. A great showcase for a top THF-producing reaction.