Studies on the use of peptide auxiliaries in the meso-desymmetrization of epoxides, and the kinetic resolution of secondary alcohols

Cozett, Rudy Edgar

Studies on the use of peptide auxiliaries in the meso-desymmetrization of epoxides, and the kinetic resolution of secondary alcohols

Doctoral Thesis

2015

Publisher

University of Cape Town

Department

Department of Chemistry

Faculty

Faculty of Science

Abstract

This thesis reports on the use of amino acids and peptides as chiral ligands/catalysts in two asymmetric processes: Meso-desymmetrization of an epoxide and the kinetic resolution of secondary alcohols. Chapter 1 comprises a literature review, which gives a general overview of methods of asymmetric synthesis, followed by an overview on the existing classes of asymmetric DMAP-type acyl-transfer catalysis as the major topic of the thesis. Chapter 2 describes the synthesis and evaluation of four peptide ligands used in combination with scandium(III) triflate for the meso-desymmetrization of cyclohexene oxide. Enantioselectivities were determined by chiral HPLC, and gave results of up to 41 % ee. Chapter 3 discusses the synthesis and characterisation of three clas ses of nucleophilic DMAP-type catalysts, in which various amino acid/peptide auxiliaries were attached either α, β, or γ-to the pyridine nitrogen. The peptides contained tryptophan, chosen to exploit a potential π - π stacking interaction with the acyl-pyridinium cation. Catalysts substituted at the α and γ positions gave no kinetic resolution for 1-(2-naphthyl)ethanol 121 ; however, a dipeptide (Leu-Trp)-containing catalyst 128 substituted at the β-position gave an s-v alue of 5.3. In order to improve the selectivity, 128 was derivatised at the C-terminal to form two tripeptide-containing catalysts, and acylated at the NH group of the indole ring (141). A range of secondary alcohols were tested and selectivity factors in creased to up to 10.7 . A series of second-generation catalysts were synthesised, but s-values did not improve. An NMR study was performed to reveal a possible conformational change during the stereoselective step. Computational modelling was performed using molecular mechanics (MMFF94) and quantum mechanics (B3LYP/6-31G, M06/6-31G*, ω B97X-D/6-31G) to determine a po ssible transition-state model, which indicated a π - cation interaction of the electron-rich indole ring of a tryptophan moiety with the electron-deficient pyridinium cation as a likely determinant of stereoselectivity.

Description

Includes bibliographical references

Keywords

Chemistry

Reference:

Collections

PhD / Doctoral

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