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Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi-Sakurai reaction

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Ross Philip Wilkie, Andrew Neal, Craig Andrew Johnston, Nicholas Voûte, Christopher Stuart Lancefield, Matthew Stell, Federico Medda, Edward Frank Makiyi, Emma Turner, Oluwarotimi Stephen Ojo, Alexandra Martha Zoya Slawin, Tomas Lebl, Peter Mullen, David James Harrison, Chris M Ireland, Nicholas James Westwood

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Abstract

The synthesis of dehaloperophoramidine, a non-halogenated derivative of the marine natural product perophoramidine, is reported. The key steps included a [3,3]-Claisen rearrangement and an epoxide opening/allylsilylation (modified Hosomi-Sakurai) reaction to install the contiguous all-carbon quaternary stereocentres with the required relative stereochemistry. The first five steps were carried out on seventy gram scale without the need for chromatography. Resolution of the [3,3]-Claisen product gave samples of the highly enantiomerically-enriched ketones which are flexible starting points for the synthesis of a number of complex ring structures. A regio- and diastereo-selective iodocyclisation was then used to differentiate between two allyl groups enabling the synthesis of the target molecule by two different routes. A detailed comparison of the trifluoroacetic acid salt of the synthetic dehaloperophoramidine with authentic material was carried out including a key doping experiment. Biological testing showed that (±)-dehaloperophoramidine was cytotoxic to HCT116, HT29 and LoVo colorectal carcinoma cells with comparable activity to that reported for the halogenated perophoramidine. This demonstrated for the first time that the halogens are not essential for the biological activity of this alkaloid class.

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Original languageEnglish
Pages (from-to)10747-10750
JournalChemical Communications
Volume52
Issue number71
Early online date5 Aug 2016
DOIs
Publication statusPublished - 14 Sep 2016

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