Radical cyclization cascades for the construction of natural product-like architectures

UoM administered thesis: Master of Science by Research

Abstract

In 2013, several new guaiane-type sesquiterpenes were isolated from the rhizomes of Curcuma phaeocaulis Valeton (Zingiberaceae), a purple-petalled herb native to southern China. Amongst these sesquiterpenes was phaeocaulisin A which has gained interest for its promising ability to treat melanoma. Intrigued by the potential biological activity, as well as the unique acetal containing structure of phaeocaulisin A, we aim to synthesise this quaiane-type sesquiterpene via SmI2-mediated carbonyl-alkene coupling reactions as key steps. This report describes the design as well as the synthesis of a model compound used to build the core structure of phaeocaulisin A. Following the successful synthesis of the model compound, the envisaged intramolecular coupling reactions were studied to evaluate the late stages of the proposed synthetic plan. The model compound was used as a mechanistic probe to understand and optimise these challenging transformations before attempting the enantioselective synthesis of the natural product. The coupling reactions were fine-tuned to suppress the formation of side products and to furnish the desired products with complete diastereocontrol. Encouraged by the fruitful synthesis of the skeleton of phaeocaulisin A, we began to investigate its enantioselective total synthesis. Based on the strategic disconnections made during the retrosynthetic analysis, the Sharpless Asymmetric Dihydroxylation was chosen to set the absolute stereochemistry. Numerous routes were tested to deliver the elaborate enantioenriched cyclisation substrate for the first SmI2-mediated reaction. After extensive research, a Negishi carboalumination, Negishi coupling-based path was followed to synthesise the enantioenriched diol, en route to the cyclisation substrate that could be accessed in six proposed steps.

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
Award date31 Dec 2019