A NHK approach towards the total synthesis of the cornexistins

QD Chemistry

Aimon, Anthony ; Clark, James Stephen

University:University of Glasgow

Department:School of Chemistry

关键词: Cornexistin, Hydroxycornexistin, NHK, herbicide, herbicidal activity, Nozaki, Hiyama, Kishi, nine-membered ring, medium sized ring, total synthesis;   

Others  :  http://theses.gla.ac.uk/4572/1/2013AimonPhD.pdf

来源: University of Glasgow

【 摘 要 】

Cornexistin and hydroxycornexistin were both isolated from the fungus Paecilomycesvariotii. They were found to possess significant herbicidal activity, which triggered theinterest of agrochemicals companies. Their structures consist of a nine-memberedcarbocyclic ring fused to a cyclic anhydride with various oxygen functionalitiesdecorating the nine-membered core.Previously, the synthesis of (±)-5-epi-hydroxycornexistin was successfully achieved inthe group, using a Stille-coupling reaction between a chloride and stannane fragments,followed by a key ring-closing metathesis reaction to form the core of the ninememberedring. However, the desired stereochemistry on the C-5 centre could not beinstalled despite the use of a variety of methods.A new strategy, involving an intramolecular Nozaki-Hiyama-Kishi reaction wasinvestigated, leading to the formation of an advanced intermediate for the synthesis ofhydroxycornexistin. The reaction proved efficient and X-ray crystallography was used toconfirm the desired formation of the natural C-5 configuration of cornexistins. Thestereoselectivity of the reaction was considered and alternative methods to improve thediastereoisomeric ratio were attempted.The asymmetric synthesis of hydroxycornexistin was studied, using an advanced modelsubstrate and an efficient strategy for the asymmetric syntheses of both Stille-couplingpartners was performed. The synthesis of the chloride fragment involved a crossmetathesisreaction and a [3,3]-sigmatropic rearrangement reaction as main steps ofthe reaction sequence. Using a chiral auxiliary, the stannane fragment was obtainedwith excellent enantiomeric excess. Finally, the sequence leading to the synthesis ofthe NHK precursor was accomplished.