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Durham e-Theses
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Doctoral thesis, Durham University.

PDF (PhD Thesis of Adam D. J. Calow) - Accepted Version


This thesis describes the asymmetric synthesis of γ-amino alcohols through the asymmetric copper-catalysed β-boration of α,β-unsaturated imines.

An introduction is given into the area of β-boration/borylation (or boron conjugate addition, BCA) of electron-deficient alkenes, which forms the basis of the literature review within this thesis.

The β-boration of α,β-unsaturated imines (formed in situ to circumvent problems with isolation) has been studied and the intermediate β-boryl imines have been transformed to γ-amino alcohols in one-pot (‘one-pot methodology’). An interesting side reaction was observed when methanol was present during the final oxidation step of the methodology. Indeed, evidence suggests that slight methanol oxidation gives rise to the formation of 1,3-oxazines (which can be made readily from γ-amino alcohols and aqueous formaldehyde) during this late stage oxidative step.

Additional in situ IR spectroscopy (ReactIR), 1H NMR and DFT studies were performed to understand the factors which govern direct addition-elimination vs. conjugate addition of primary amines to enones and enals, with the aim of using this information to prepare α,β-unsaturated imines in situ. It was found that most enones and enals have a kinetic preference towards the direct addition of primary amines, but enones such as methyl vinyl ketone show that the kinetic preference is towards conjugate addition. DFT calculations support this observation by showing that there is a conformational effect which favours direct- over conjugate-addition, i.e. enones and enals that adopt the s-trans conformation show a lower energy barrier of addition (kinetic preference) via the direct addition pathway with primary amines. Conversely, enones and enals that adopt the s-cis conformation show a lower energy barrier of addition (kinetic preference) via the conjugate addition pathway with primary amines.

A base-free (alkoxide) β-boration methodology was developed, which allows enones to be transformed to γ-amino alcohol by the addition of a primary amine, Cu2O, BINAP ligand, B2pin2 and MeOH to the starting enone, with subsequent reductive and oxidative transformations. Evidence suggests that the reaction proceeds via the α,β-unsaturated imine (formed in situ) and, in addition, the absence of the alkoxide base reduces the possibility of any alternative β-boration pathways (e.g. organocatalytic), leading to the highly enantioselective protocol (up to 99% e.e.).

Enals are prone to direct borylation under the standard β-boration-type methodology and low e.e. values. It is shown herein that the use of a sterically bulky N-benzyl imine auxiliary can be used (formed from the reaction between an enal and benzhydrylamine) to favour selective β-boration and, indeed, high e.e. can be obtained using a relatively cheap and stable DM-BINAP ligand-copper catalyst system (up to 97% e.e.).

The optimised one-pot methodology was applied towards the total synthesis of (R)-Fluoxetine in 45% yield (96% e.e.) and (S)-Duloxetine in 47% yield (94% e.e.), whereby the intermediate β-boryl N-benzhydryl imine can be readily exchanged by methylamine addition to form the appropriate N-methyl precursor.

Item Type:Thesis (Doctoral)
Award:Doctor of Philosophy
Keywords:gamma-amino alcohol, asymmetric synthesis, catalysis, imine formation, alpha,beta-unsaturated imines, conjugate addition, borylation, boration, Fluoxetine synthesis, Duloxetine synthesis
Faculty and Department:Faculty of Science > Chemistry, Department of
Thesis Date:2015
Copyright:Copyright of this thesis is held by the author
Deposited On:04 Feb 2015 09:59

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