Development and strategic application of metal-mediated methods in the synthesis towards Agariblazeispirol C

Student thesis: Doctoral Thesis

Abstract

Within our research team, significant efforts towards the total synthesis of the natural product agariblazeispirol C (1) has been conducted. In our synthetic programme, and as aligned with the broader interests of our team, we proposed that the key core skeleton of the target could be constructed through a combination of two effective metal-mediated cyclisation processes. More specifically, intramolecular Heck and Pauson-Khandannulation techniques have been employed to construct the core structure of the desired natural product, leaving the installation of an oxygenated five carbon side-chain as the final requirement to complete the target. Througout this overall programme of work, each individual reaction sequence has been fully explored and strategic synthetic steps have been established, and optimised, to provide access to advanced intermediates. Disclosed in this thesis is an extensive exploration of the asymmetric intramolecular Heck cyclisation reaction to deliver an enantioenriched 6,6-bicyclic system (rings B and C).This established the first quaternary stereocentre within the natural product, ultimately, dictating the overall diastereoselectivity in the downstream synthesis. Indeed, high enantioselectivityof the asymmetric Heck reaction was achieved via substantial optimisation processes, including a comprehensive chiral ligand screen – allowing the cobalt-mediated Pauson-Khand cyclisation to be studied next in our programme of work. This demanding cyclisation required the formation of the two cyclopentyl rings (rings D and E), constructing the overall polycyclic network containing a further quaternary centre within the congested system. In this regard, efficient cyclisation of two distinct Pauson-Khand precursors has delivered the overall core of the natural product as a single diastereomer, confirmed by X-ray crystallography. Exploration of the final synthetic manipulations to allow for the installation of the required oxygenated side-chain has been initiated, with promising methodology having emerged to allow the final target to be accessed. [See print copy for diagram]
Date of Award11 Aug 2020
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde & EPSRC (Engineering and Physical Sciences Research Council)
SupervisorWilliam Kerr (Supervisor) & Nick Tomkinson (Supervisor)

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