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

Doctoral Thesis


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University of Cape Town

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.

Includes bibliographical references