An iterative approach to the stereocontrolled total synthesis of bahamaolide A and mycapolyol E

  • Sheenagh G Aiken

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Polyketide natural products are of particular interest due to their highly specific and potent biological activity and structural diversity. The recurring motifs, such as (deoxy)propionate or acetate, often present in this class of molecules can be synthesised through iterative processes.

Bahamaolide A and mycapolyol E contain an extended 1,3-polyol, comprising nine or ten stereodefined 1,3-related hydroxyl groups, respectively; to date, the total synthesis of these compounds has not been reported. Herein the application of an iterative protocol to construct the 1,3-polyol is described; specifically, asymmetric diboration of a terminal alkene followed by primary-selective homologation of the resulting 1,2-bis(boronic ester) with an enantiopure carbenoid bearing a pendent alkene primed to undergo subsequent diboration. When performed iteratively this enabled the synthesis of a 1,3-poly(boronic ester) with exquisite levels of stereocontrol. Functional group interconversions were not necessary between iterations, since the boronic esters themselves masked the hydroxyl functionality, which was revealed in a later stereospecific oxidation.

This was employed in a bidirectional manner to prepare the 1,3-polyol in bahamaolide A. Diboration–homologation–diboration proved a step-efficient approach to rapidly access a C2-symmetric octa(boronic ester) from 1,4-pentadiene. The octa(boronic ester) was desymmetrised through sequential homologation at the terminal primary boronic esters before poly(oxidation) where eight boronic esters were converted to the corresponding polyol in one
operation. Cross-metathesis then a Horner-Wadsworth-Emmons reaction proceeded with high selectivity for six E-alkenes. The first total synthesis of bahamaolide A was completed in fourteen steps (LLS).

The 1,3-polyol in mycapolyol E is not C2-symmetric and so the iterative protocol was applied unidirectionally. The C5 stereocentre in mycapolyol E was assigned through synthesis of both diastereomers of the eastern fragment and comparison of NMR data with the isolated natural product. This work discusses the optimised synthesis of the three fragments, their combination through lithiation–borylation reactions and endgame model studies.
Date of Award21 Jun 2022
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorVarinder K Aggarwal (Supervisor) & Laura M Chavda (Supervisor)

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