New Methods for the Homologation of Boronic Esters and Their Application in Synthesis

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

The asymmetric synthesis of organic molecules is of fundamental importance to the design and preparation of new drug and agrochemical compounds. The treatment of a boronic ester with a metal carbenoid, termed a homologation reaction, is a useful strategy for accessing stereodefined boronic esters, which can participate in a plethora of transformations. This thesis reports the development of three new methods for the homologation of boronic esters and details their application towards the synthesis of complex molecules.

Firstly, enantio- and diastereopure α-sulfinyl benzoate building blocks were explored as carbenoid precursors for the homologation of boronic esters. A range of functionalised αsulfinyl benzoates were prepared in enantioenriched form by using either a lithiation‒ transmetallation‒trapping approach or through alkylation chemistry. These building blocks were transformed into stereodefined Mg and Li carbenoids, through sulfoxide‒metal exchange, and were found to homologate boronic esters in a highly stereospecific fashion. This homologation process was rendered iterative, which allowed a molecule bearing three contiguous stereocentres to be accessed as a single stereoisomer.

Secondly, lithiated terminal epoxides were explored as reagents for the preparation of βoxyboronic esters. Our goal was to use this transformation, in conjunction with a preestablished homologation protocol, to access polypropionate motifs, which are frequently encountered in the polyketide family of natural products. However, due to a poor reactivity profile and issues regarding the stability of β-oxyboronic esters, this strategy was abandoned.

Finally, lithiated epoxysilanes were used to achieve the vinylidene homologation of boronic esters. This reaction allowed access to a diverse range of sp3-rich vinyl boronic esters, many of which would be difficult to prepare by other means. A divergence in mechanism was observed for some sp2-hybridised starting boronic esters, which were found to deliver the corresponding vinyl silane products. This mechanistic divergence was probed using computation, which revealed that the reaction outcome could be rationalised by considering the stabilisation of negative charge in the transition-state of the elimination step. The vinylidene homologation reaction was applied to achieve a short and stereoselective synthesis of the proposed structure of machillene, however the NMR data of our synthetic sample did not match that which was reported. Our efforts towards the structural revision of machillene are discussed.
Date of Award23 Jan 2020
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorVarinder K Aggarwal (Supervisor)

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