Synthetic Approaches to the Trichothecene, T-2 Tetraol

Kerr, Fraser Witton (1989) Synthetic Approaches to the Trichothecene, T-2 Tetraol. PhD thesis, University of Glasgow.

Abstract

The trichothecenes are a group of structurally complex sesquiterpenoids of considerable environmental importance. It is difficult to obtain many of these compounds in significant amounts from natural sources, and much effort has been directed towards devising efficient, practicable syntheses of these molecules and their analogues. This research project has concentrated on the synthesis of T-2 tetraol, one of the most highly oxygenated trichothecenes. Diels-Alder reaction between isoprene and coumalyl chloride (260, R=Cl) followed by in situ conversion to methyl ester (266) established the cis-fused AB ring system of T-2 tetraol. Dimethyl lithium cuprate addition to (266) gave the 1,4-addition product (259) as a single methyl epimer. Stereoselective epoxidation produced (280) in good yield. Epoxide rearrangement using BF3. Et2O gave ketone (283) which was converted into ketal (258). Alternatively, a one pot epoxide-ketal conversion could be used to transform (280) into (258). Oxidation of (258) was accomplished using the MoOPH reagent of Vedejs. Corey oxidation of the epimeric mixture of a-hydroxy lactones gave enol lactone (288). Allylation of (288) furnished enol ether lactone (289), a two step reduction of which using the method of Kraus gave pyran (291). LiAlH4 reduction of (291) gave the unstable neopentyl alcohol (292), Claisen rearrangement of which produced allyl ketone (294) as a 3.2:1 mixture of alpha-allyl:beta-allyl epimers as determined by G. L. C. and n.o.e. experiments. Protection of the free alcohol (294) as the silyl ether (302) followed by catalytic osmylation gave diol (320), which was cleaved with ethereal periodic acid to yield noraldehyde (303). Aldol cyclisation then gave the tricyclic ketol (306) which was protected as its tetrahydropyranyl ether (333). Installation of the 12,13-alkene was achieved by means of a Wittig reaction. Selective removal of the THP ether gave olefinalcohol (332) and thence ketone (336). Alpha oxygenation, followed by hydride reduction,generated (346), possessing the required ring C trans-3alpha,4beta-diol system. Deketalisation, epoxidation, dehydrogenation, reduction and finally deprotection are the operations necessary to complete the synthesis of T-2 tetraol in racemic form.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Organic chemistry
• Date of Award: 1989
• Depositing User: Enlighten Team
• Unique ID: glathesis:1989-77831
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jan 2020 11:53
• Last Modified: 14 Jan 2020 11:53
• URI: https://theses.gla.ac.uk/id/eprint/77831