Lewis base-catalysed enantioselective formal cycloadditions and rearrangements

Abstract

This thesis describes the use of chiral nitrogen-based Lewis base catalysts in transformations such as cycloadditions and rearrangements. Cinchona alkaloids were employed as catalysts within a formal [4+2]-cycloaddition of trifluoromethyl- substituted α,β-unsaturated ketones and allenoates. Either 1,1,1-trifluorobut-3-en-2- ones or 4,4,4-trifluorobut-2-en-1-ones were used to selectively introduce a trifluoromethyl moiety in the 4- or 6-position within a dihydropyran scaffold. The reaction proceed successfully to give a range of dihydropyran products with (hetero)aryl- and alkyl-substituted trifluoromethyl ketones in up to 81% yield and 98% e.e. The dihydropyran products can be derivatised using selective hydrogenation methods to give tetrahydropyrans in high yield and diastereoselectivity without loss of stereointegrity.

Furthermore, isothioureas were applied in the [2,3]-sigmatropic rearrangement of 3- fluorocinnamyl substituted quaternary ammonium salts. A broad range of substituents at either the nitrogen or the cinnamyl group has been evaluated showing the generality of this process. Enantioenriched amino acid derivatives containing a tertiary flourinated carbon centre were produced in high yield and good enantio- and diastereoselectivity (up to 76%, 94:6 d.r., 96% e.e.).

It was attempted to extend the scope of this reaction to the [2,3]-Sommelet-Hauser rearrangement of benzylic ammonium salts, which proved to be difficult. A range of conditions as well as variety of substituted benzyl substrates were investigated but no rearrangement product could be isolated.

The further extension of the scope of the [2,3]-rearangement using allylic ammonium salts with 3-methylcinnamyl substitution was investigated. Mixtures of enantioenriched products derived from [2,3]- and [1,2]-rearrangement were observed. The fomation of the [1,2]-product led to the further investigation of this rearrangement.

Applying ammonium salts bearing bulky 3,3-disubstituted allyl groups a selective [1,2]-rearrangement has been observed. The optimisation of this process is discussed and products were obtained in up to 68% yield and 58% e.e. This represents the first catalytic enantioselective [1,2]-rearrangement of ammonium salts.

Date of Award	21 Jun 2017
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Andrew David Smith (Supervisor)