Stereospecific Synthesis of Enones from Boronic Esters and its Application in the Total Synthesis of 10-Deoxymethynolide

Abstract

Enones have come to occupy a privileged position as a linchpin functional group in contemporary organic chemistry and in biological systems. Consequently, strategies by which the installation of the enone functional group can be facilitated remain of interest to the chemical community. In relation to this, the low toxicity and high stability of boronic esters has led them to become versatile building blocks for organic synthesis. As such, boronic esters make for an appealing and underexplored feedstock from which the synthesis of enones can be performed. Using methoxyallene as a three-carbon building block, a generalised method for the synthesis of enones from boronic esters was achieved. This approach uses electrophile mediated lithiation-borylation chemistry to generate an intermediate allylic boronic ester which, after
oxidation, can give rise to an enone. This process was applied to primary, secondary, and tertiary boronic esters, and was shown to be completely stereospecific. By varying the electrophile used to promote the 1,2-metallate rearrangement, a facile synthesis for the preparation of a range of α-substituted enones has also been realised. Subsequent work applied this new methodology to the total synthesis of the polyketide 10-deoxymethynolide. This synthesis was successfully completed in 14 steps and demonstrated the envisioned utility of a direct conversion of boronic esters into enones when paired with other lithiation-borylation reactions. The total synthesis of 10-deoxymethynolide culminated in the application of a Fleming-Tamao oxidation which required the use of mild, but highly toxic, mercury (II) trifluoroacetate. This inspired an investigation into an alternative approach to Fleming-Tamao reactions that sought to replicate the mild reactivity of mercury (II) salts whilst avoiding the associated safety and
environmental hazards. Resultingly, a Fleming-Tamao oxidation which utilises catalytic quantities of gold (III) was developed. Preliminary investigations demonstrated that this approach could successfully be applied to both primary and secondary silanes.

Date of Award	1 Oct 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Neil A Fox (Supervisor) & Varinder K Aggarwal (Supervisor)