The synthesis of (+/-)- trichoviridin, WF-10129 and a biologically active analogue of antibiotic A-32390A

Thesis



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.

Authors: Smith, M; Smith, Marie-Louise

• Publication date: 1994
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Antibiotics; Synthesis; Amino acids