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Title: Synthetic studies on 20-methylisobacteriochlorins
Author: Taylor, D. A.
ISNI:       0000 0001 3503 2799
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1986
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This dissertation describes the synthesis of the ring B imide of vitamin B12 and its subsequent use in the preparation of the A/D precursor of 20-methylsirohydrochlorin. The latter, in its reduced form, is a key intermediate in vitamin B12 biosynthesis. The synthetic strategy was based on a photochemical cyclization and was similar to the approach used to prepare sirohydrochlorin. The initial intention was to prepare racemic ring B imide using a thio-Claisen rearrangement in order to set up the relative stereochemistry at the two adjacent asymmetric centres, and then to prepare the imide from the resulting thioamide. This was completed successfully for the simpler ring C imide of vitamin B12 with gem-dimethyl groups, but it was carried out for ring B imide itself. The Michael addition of hydrogen cyanide to Hagemann's ester, effected using trimethylsilyl cyanide and triethylaluminium, led to a mixture of diastereoisomers. The methoxycarbonylation of the favoured trans-cyanoester proved to be problematic and was achieved only in a low yield. The planned strategy had been to prepare a derivative of the resulting β-ketoester and to subject this to a reverse-Dieckmann reaction in order to produce the propionate and acetate side chains. This was not carried out, however, and a new approach was sought. A resolved diacid, prepared from Hagemann's ester, was used successfuly to synthesize (-)-ring B imide. An imidoisoxazole, prepared from this diacid, was treated with aqeuous alkali; this cleaved the isoxazole and the resulting α-cyanocyclohexanone was hydrolysed and underwent the reverse-Dieckmann ring opening to afford the imide. (-)-Ring B imide was used to prepare, selectively, 'left hand' monothio-ring B imide. The latter was coupled with a phosphonium salt via a thio-Wittig reaction to form a meso-cyano bicyclic lactam. This was reduced to its amine which was then formylated. The resulting formamide was dehydrated to give an isonitrile, which was reduced to give the required meso-methyl bicyclic lactam. This lactam is the A/D precursor of the natural 20-methylisobacteriochlorins and was obtained as a mixture of epimers and double bond isomers. These were separated for characterization.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemistry