Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi-Sakurai reaction
MetadataShow full item record
Altmetrics Handle Statistics
Altmetrics DOI Statistics
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.
Wilkie , R P , Neal , A , Johnston , C A , Voûte , N , Lancefield , C S , Stell , M , Medda , F , Makiyi , E F , Turner , E , Ojo , O S , Slawin , A M Z , Lebl , T , Mullen , P , Harrison , D J , Ireland , C M & Westwood , N J 2016 , ' Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi-Sakurai reaction ' , Chemical Communications , vol. 52 , no. 71 , pp. 10747-10750 . https://doi.org/10.1039/c6cc05747k
Copyright 2016 the Authors. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
DescriptionThe authors would like to acknowledge EPSRC for PhD funding through the Doctoral Training Schemes.
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.