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New thionation experimental conditions and new reagents for the synthesis of thioamide analogues of protected amino acids and peptides are presented. The interaction of thiocarbonyl analogues of model substrates of (alpha)-chymotrypsin and leucine aminopeptidase were also studied. Optically active dithioester derivatives of protected amino acids were prepared and used as thioacylating agents. / The synthesis of four thioamide-containing analogues of the chemotactic tripeptide f-Met-Leu-Phe was accomplished. The conformational properties of these novel analogues were studied by ('1)H and ('13)C NMR spectroscopy. Their biological activity was also evaluated in vitro and the results interpreted in terms of their molecular properties. / The regioselectivity of the new thionation methodology allowed for the rapid and efficient synthesis of the four possible monothioamide positional isomers of {Leu('5)}-enkephalin. Their biological activity was studied both in vitro and in vivo. / Amidoxime and amidrazide analogues of the peptidic bond were also obtained using thioamides as intermediates.

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This thesis is divided into two parts: Part 1 (i) The Synthesis of a Biologically Active Analogue of Antibiotic A-32390A Methodology for the preparation of vinyl formamides from thiooximes has been developed for use with α-carboxy systems and successfully applied to the synthesis of (2S, 3S)-2,3-di-[hydroxybutane]-1,4-di-[2-isocyano-3-methyl-but-2-enoate], a vinyl isonitrile that is a biologically active analogue of the natural product, antibiotic A-32390A. In addition trifluoromethane sulfonic anhydride has been shown to be an effective reagent for the dehydration of vinyl formamides to vinyl isonitriles in these systems. (ii) The Synthesis of (±)-Isonitrin C (Trichoviridin) Further application of the methodology for the synthesis of vinyl formamides from thiooximes allowed for the effective preparation of 1α-(1'-^t-butyldimethylsilyloxyethyl)-2β, 3β-epoxy-4-en-4-isocyano-cyclopentan-1β-ol, a key intermediate in the syntheses of the naturally occurring vinyl isonitriles, (±)-isonitrin A and (±)-isonitrin B. New methodology was developed for the synthesis of the epoxy-isonitrile functionality of (±)-isonitrin C (trichoviridin). Masking of the isonitrile functionality of 1α-(1'-^t-butyldimethylsilyloxyethyl)- 2β, 3βp-epoxy-4-en-4-isocyano-cyclopentan-1β-ol by formation of the corresponding dibromoimine was followed by epoxidation of the C-C double bond with methyl (trifluoromethyl)dioxirane and removal of the bromine groups to regenerate the isonitrile moiety. Deprotection afforded (±)-isonitrin C (trichoviridin). (iii) Mechanism of the Thiooxime Rearrangement Some insight into the mechanism of the thiooxime rearrangement was obtained by ¹³C n.m.r. experiments and elucidation of the reaction by-products. Part 2 A flexible route to optically pure γ-keto-α-amino acids using carbon based nucleophilic ring opening of activated monocyclic β-lactams has been established. Nucleophiles examined include lithiated sulfones, Lipshutz higher order organocuprates and lithiated phosphonates. This methodology has been applied to a high yielding synthesis of the naturally occurring potent ACE inhibitor WF-10129. The stereochemistry of WF-10129 was established, by synthesis of all possible diastereomers, to be S at all stereocentres.

This thesis is divided into two parts: Part One describes synthetic approaches to the naturally occurring antibiotic Lactivicin (1) and its acylamino derivatives, involving the condensation of protected L-cycloserine with 2-oxoglutaric acid. The phenoxyacetyl-amino derivative (2) exhibited antibacterial activity. A method was developed for the selective deprotonation of the endocyclic amide of the protected cycloserine; the resulting anion was then quenched with various electrophiles. In this manner, the Lactivicin analogues (3) and (4) were prepared. Whilst (3) was biologically inactive, (4) showed appreciable antibacterial activity. [See pdf file for chemical structures (1)-(4)]. Part Two details the use of N-benzoylamino-2-bromoglycine methyl ester, a glycidyl radical precursor, as a novel a-amino acid synthon. Its synthetic utility in free radical reactions was demonstrated with 2-functionalised allylstannanes as allyl transfer reagents, to produce a range of substituted a-allylglycines. Using this procedure, the naturally occuring amino acid, 4-methyleneglutamic acid, was prepared in its racemic form. Studies on the extension of this methodology to the asymmetric synthesis of a-amino acids are also described. A synthesis of (alpha)-allenylglycine, a previously undocumented amino acid, was developed. The synthetic route involves the Lewis acid mediated reaction of propargyltriphenylstannane with N-benzoylyamino-2-bromoglycine methyl ester, followed by aqueous acidic deprotection.

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Bibliography : leaves 166-183. / v, 198 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Chemistry, 1993?