Arranging an enantioselective aza-[2,3]-Wittig rearrangement

Davies, Elizabeth Anne (2009) Arranging an enantioselective aza-[2,3]-Wittig rearrangement. PhD thesis, University of Nottingham.

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The use of the aza-[2,3]-Wittig sigmatropic rearrangement in the synthesis of α,α-disubstituted α-amino acids has been investigated with the emphasis on obtaining enantioenriched rearrangement products. It was hoped that an enantioenriched precursor could form an axially chiral enolate which would impart chiral information on the product.

To access an axially chiral enolate, the rearrangement conditions of a known precursor 66 have been studied. Varying temperature had no effect on the enantioselectivity. Different bases were investigated with only KHMDS instigating rearrangement. Upon treatment with KHMDS, 66 rearranged to form the desired product as well as pyrrolidine 119. The temperature of the rearrangement was varied; at lower temperatures only 119 was isolated.

A range of precursors with potential chelating groups has been synthesised. The effect of temperature on aza-[2,3]-Wittig rearrangement of these precursors was investigated; however, rearrangement did not occur at below temperatures of around - 40 ºC and this temperature was not low enough to provide an axially chiral enolate intermediate, as evidenced by the racemic nature of the rearrangement products.

The aza-[2,3]-Wittig rearrangement of amide precursor 63 was also investigated. The only product isolated upon treatment with KH and 18-crown -6 was pyrrolidine 158.

Precursors 150 (derived from tert-leucine), and oxazoline 159 were subjected to rearrangement conditions. Deuterium quench studies showed that, in both cases, deprotonation had not occurred, possibly due to the sterically encumbered enolate that would form upon deprotonation.

Further investigations into the cyclisation of 66 showed that the probable mechanism was aza-[2,3]-Wittig rearrangement, followed by cyclisation. The resulting pyrrolidine was formed as a single diastereomer. Precursors 65, 67 and 175 also underwent cyclisation in a similar manner. The relative stereochemistry of these pyrrolidines was determined by nOe experiments.

Studies of the mechanism of cyclisation of 63 were inconclusive. It is unknown whether pyrrolidine 158 is formed by an incomplete rearrangement or a fast rearrangement-cyclisation sequence.

The utility of the cyclisation was further demonstrated by Fleming oxidation of the dimethylphenylsilyl group and protiodesilylation of 119.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Anderson, J.C.
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry > QD415 Biochemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 10701
Depositing User: EP, Services
Date Deposited: 16 Dec 2009 10:46
Last Modified: 14 Oct 2017 12:25

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