Total Synthesis of Complex Polyketide Natural Products Using Stereospecific Homologation of Boronic Pinacol Esters

: 'Total Synthesis of Conglobatin E and Studies Towards the Synthesis of Conglobatin F1' and 'Total Synthesis of Mycapolyol E'

Abstract

Polyketide derived natural products are often bioactive, making them attractive targets for total
synthesis. Given that these compounds usually possess complex structural architectures, with
multiple stereogenic centres, their enantioselective synthesis is often a non-trivial task.
Stereospecific homologation of boronic esters presents a means by which these stereocentres may
be set. To accomplish such transformations with complete stereocontrol, Aggarwal and co-workers
have developed a set of carbenoid precursors that can be obtained with complete enantiopurity.
The first project outlined in this thesis describes the first reported total synthesis of the macrodiolide
natural product (–)-conglobatin E i in 12 steps LLS from oxazole. The oxazole containing
stereocentres present in this target were installed through boronic ester homologation with
enantiopure carbenoid precursor ii. Subsequently, (–)-conglobatin F1 iii was targeted using an
analogous strategy. Initial efforts towards iii focused on finding a vinylic boronic ester that would
engage in all the downstream homologation and olefin installation chemistry.
The second project outlines the first reported total synthesis of the proposed structure of the
polyacetate natural product, mycapolyol E iv in 20 steps LLS. The ten 1,3-related hydroxyl
stereocentres present in iv were set using Aggarwal’s polyboron strategy. This strategy uses an
initial platinum-catalysed diboration of a terminal olefin v to provide a 1,2-bis(boronic ester) vi.
Regio- and stereospecific homologation of vi with enantiopure magnesiated carbenoid vii provides
a 1,3-bis(boronic ester) viii. After n iterations, final stereospecific oxidation reveals the 1,3-polyol
motif. This methodology provided access to hexa(boronic ester) ix, which was converted into iv in
9 further synthetic steps following an extensive optimisation campaign.

Date of Award	13 May 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Varinder K Aggarwal (Supervisor) & Adam Noble (Supervisor)