Atom transfer reactions of amino acid derivatives
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
Investigations of atom transfer reactions of amino acid derivatives are described in this thesis. Reaction of N-benzoylvaline methyl ester (29a) with sulphuryl chloride gave the β-chlorovaline derivative (30a) and lesser amounts of diastereoisomers of the r-chlorovaline derivative (31a). Studies of reactions of the valine derivatives (29a-c) with sulphuryl chloride, and of the photolyses of the corresponding N-chlorovaline derivatives (39a-c) have shown that the reaction of (29a) with sulphuryl chloride and the photolysis of (39a) involve regioselective intermolecular transfer of the respective β-valinyl hydrogens. There is no evidence of reaction at the corresponding a-positions. These reactions establish the chemical validity of a regiospecific hydrogen atom transfer proposed in penicillin biosynthesis and in the β-hydroxylation of valine residues in peptides. Factors affecting the production of amidocarboxy-substituted radicals have been investigated by examining reactions of derivatives of valine, alanine and glycine with a number of reagents. The variation in the regioselectivity of reactions of these compounds is typified by the reactions of (29a) with sulphuryl chloride and N-bromosuccinimide. Whereas the reaction of (29a) with sulphuryl chloride involves hydrogen atom abstraction from the β-position of (29a) with subsequent chlorine atom incorporation to give (30a), the reaction with Nbromosuccinimide proceeds via hydrogen atom abstraction from the α-position of (29a) and yields the dibromovaline derivative (76). The studies indicate that amidocarboxy-substituted radicals such as (34a) are considerably more stable than, for example, the tertiary alkyl radical (32a), but hydrogen atom transfer reactions may afford the less stable products if electrophilic radicals are involved in the hydrogen atom abstraction and if there is little development of radical character in the transition state of the reaction. The preferential reactivity of glycine residues in free radical reactions of proteins, peptides and other amino acid derivatives has been investigated by examination of reactions of derivatives of valine, alanine, glycine, methyl pyroglutamate and proline with NBS. The previously unexplained reactivity of glycine derivatives has been rationalised in terms of steric interactions and their effect on the conformation of the amidocarboxy-substituted captodative radical (41). The selective reactivity of glycine derivatives has been exploited synthetically. Reaction of the α-bromoglycine derivative (112a), prepared by reaction of the glycine derivative (93a) with NBS, with hexabutylditin under strictly anhydrous conditions gave the diasteroisomers of the glycine dimer (131). Otherwise the major products were the ethers (132a) and (132b). Selective functionalisation of the dipeptide (126a) at the α-glycyl position was achieved by reaction with NBS. The regioselectively labelled dipeptide (126b) was synthesised by reaction of the bromide (127) with triphenyltin deuteride.