The lithiation–borylation reaction
: in situ IR spectroscopy studies & automation on a batch platform

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

The homologation of boronic esters using lithiated Hoppe-type diisopropylcarbamates and Beak-type 2,4,6-triisopropylbenzoate (TIB) esters represents an efficient process for the formation of carbon–carbon bonds in a highly stereoselective manner. This process is referred to as lithiation–borylation.
Studying this reaction using in situ IR spectroscopy has revealed reaction times for a series of alkyl carbamates and TIB esters. Alkyl TIB esters undergo lithiation faster than their corresponding carbamates, and the lithiated alkyl carbamates undergo faster borylations than the lithiated TIB esters. It is discussed how the size and coordinating ability of each directing group could lead to these differences. Varying solvent has also provided evidence on the factors that affect lithiation and borylation. Using in situ IR spectroscopy, the lithiation–borylation of alkyl TIB esters has been further optimised, where lithiations are now performed in toluene and borylations with the addition of THF.
Boranes, boronic esters and borate esters all react with lithiated TIB esters at a similar rate providing further evidence for a pre-complexation event between the lithium carbenoid and the Lewis basic oxygen atoms. The use of a proximal aromatic group leads to rapid borylations of diamine-ligated lithiated carbenoids, providing further evidence for a cation– interaction between the aromatic group and lithium atom of the carbenoid. By generating the lithiated species under diamine-free conditions, the effects of various additives have been explored.
In situ IR spectroscopy was then employed to study the lithiation–borylation of a set of O-cycloalkyl TIB esters (cyclopropyl through to cyclohexyl). Only the cyclobutyl TIB ester underwent the full process in practical yields. It is described as occupying a “Goldilock’s zone” where the ring is small enough to allow facile deprotonation without decomposition, but large enough to allow 1,2-migration to occur.
The lithiation–borylation reaction has been optimised on a Chemspeed batch automation platform using a model boronic ester. We have shown homologations with either LiCH2Cl (the Matteson reaction) or a lithiated benzoate (derived from the -stannyl benzoate) proceed in ~90% yield per step over 2 steps. Set up time for 4 reactions can be as little as 30 minutes with 1 iteration performed per day.
A new automated synthesis of (+)-kalkitoxin analogues was designed. The starting point for the synthesis (a thiazoline bearing boronic ester) was synthesised in the lab in 6 steps starting from protected L-cysteine. The final steps of the total synthesis are Morken amination of a boronic ester, amidation and then methylation of the amide. We have shown the 3-step sequence works well on the automated platform for phenethyl boronic acid pinacol ester (42% over 3 steps) however for a model thiazoline bearing boronic ester the thiazoline undergoes rapid (1 h) isomerization to the thiazole (isolated in 46% over 3 steps) under the basic conditions required for the amination.
Date of Award28 Sep 2021
Original languageEnglish
Awarding Institution
  • The University of Bristol
SponsorsAstraZeneca, Cambridge, UK
SupervisorVarinder K Aggarwal (Supervisor), Eddie Myers (Supervisor) & Craig P Butts (Supervisor)

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