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.