New Developments in Organoboron Incorporation, Homologation and Functionalization

  • Alexander Fawcett

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

This thesis reports contributions to three branches of organoboron chemistry: boron incorporation, boron homologation, and boron functionalization.

Firstly, a decarboxylative borylation reaction has been developed. Carboxylic acids, pre-activated as their corresponding N-hydroxyphthalimide esters, have been found to undergo a decarboxylative borylation process in the presence of bis(catecholato)diboron in N,N-dimethylacetamide solvent under blue LED irradiation to deliver, after transesterification with pinacol, stable and isolable pinacol boronic esters. These simple conditions extended to a wide range of functional group-bearing and structurally diverse carboxylic acids to give the corresponding boronic esters in mostly good to excellent yields. Mechanistic studies have revealed that a single electron transfer between the activated ester and bis(catecholato)diboron, which form a light-absorbing EDA complex, is responsible for initiating the transformation, and that the ability of the solvent to stabilize boryl radicals is critical to successful reaction.

Secondly, the Aggarwal lithiation−borylation methodology has been expanded to enable the synthesis of 1,3-diols, which were previously inaccessible due to beta-elimination of the intermediate boronate complexes. 1,2-Bis(boronic esters) were discovered to undergo stereo- and regioselective homologation using enantioenriched lithium carbenoids in the presence of bulky diamines, such as sparteine. The resultant 1,3-bis(boronic esters) were oxidized to deliver a wide range of structurally diverse secondary-secondary and secondary-tertiary 1,3-diols in good to excellent yields and perfect diastereoisomeric ratios, the latter of which is especially noteworthy since these substrates have not previously been accessible with such generality and high diastereoselectivity.

Finally, we have developed a novel, strained bicyclobutyl boronate complex that has enabled, for the first time, the reaction of C−C sigma-bonds of boronate complexes with electrophiles. We have invented a linchpin reagent, a bicyclobutyl sulfoxide, that enables the facile generation of bicyclobutyl lithium on demand, which then reacts with a boronic ester to form the bicyclobutyl boronate complex. These highly reactive intermediates have been reacted with electrophiles to produce a set of pharmaceutically-relevant 1,1,3-trisubstituted borylated cyclobutanes with excellent diastereoselectivity. Of note, electrophilic palladium(II)-aryl complexes were found to be excellent electrophiles and have enabled the addition of two modular units, a boronic ester and an aryl triflate, across a C−C sigma-bond. This reaction constitutes the first report of a C−C sigma-bond carbopalladation, albeit a highly strained one.
Date of Award6 Nov 2018
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorVarinder K Aggarwal (Supervisor)

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