Watson, William Peter (1974) Some chemistry of the nitro group in the context of a possible synthesis of vitamin B₁₂. PhD thesis, University of Warwick.

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Abstract

This thesis describes new nitro-chemistry in studies related to a possible synthesis of Vitamin B12 as proposed by J. W. Cornforth. Some of the Vitamin B12 intermediates possess special nuclear magnetic resonance properties when examined as their nitronate anions. Some synthetic studies of fluorinated compounds as potential substrates for glyceroldehydrase, an enzyme requiring 5' -deoxyadenosyl cobalamin (Coenzyme B12 ), are also described ..

The Introduction discusses the chemical synthesis of corrins, together with some of the prominences of the Eschenmoser-Woodward synthesis of Vitamin B12. A brief account of the possible synthesis of Vitamin B12 proposed by Cornforth is also given. The chemistry of the related B12 coenzymes is summarised in a section on the enzymatic reactions requiring a 5' -deoxyadenosyl cobalamin as a cofactor, The current proposals for the mechanism of action of glyceroldehydrase and dioldehydrase are also compared.

The Cornforth approach to Vitamin B12 was to utilise the reaction of an anion with a germinal bromonitro or dinitro compound in order to join precursors of ring A and ring D. Chapters I and II describe the synthesis of suitable precursors and models for these radical-anion coupling reactions, and attempts to realise an intermolecular coupling of ring A and ring D intermediates. The synthesis of 4-carboxamidodiethylmalonyl-3-methyl-3-(2', 2' -brornonitroethyljcyclo-hexanone ethylene ketal and 4-(2',2' -dinitro)n -butoxycarbonyl-3-(2' -nirroethyl )- 3-methyl ccyclohexanone are described together with attempts to use these intermediates for intramolecular coupling purposes. In chapter I, the attempted coupling of hindered geminal halogenonitroso compounds with nitronate anions is also described.

Attempts to incorporate an intramolecular Michael addition into the synthesis, for the linking of ring A and ring D precursors are the subject of chapter III. The synthesis of amide derivatives of Hagemann's ester (4-ethoxycarbonyl-3-methyl cyclohex-2-enone ) containing a nitro-enamide residue as the 4-substituent,to examine this scheme was unsuccessful. The corresponding hydrazide analogues, for example, 3-methyl cyclohex-3-ene-1-one ethylene ketal 4-carboxylic acid 3'-nitrobutylidene hydrazide, are more readily accessible and some reactions are described.

In chapter IV, interesting long range deshielding effects are noted in the 1H n, m. r. spectra of the nitronate anions derived from 4-alkoxycarbonyl-3- methyl-3-(2 '-nitroethyl) cyclohexanones, ring A precursors for coupling studies. The deshielding effect associated with the nitronate anion is a useful probe in conformational analysis, and shows the axial conformer of 2-substituted cyclo- hexane nitronate anions to be preferred. Also the 13C n. m, r. spectra of several nitronate anions show large solvent dependent chemical shift difference which correlate with differing electronic distibution in the anions in solvents of different protonating ability.

Chapter V is an account of the synthesis of potential substrates and inhibitors for the enzyme glyceroldehydrase. 3,3, 3-Trifluoro-1, 2-propanediol is a substrate for the enzyme and is converted to 3,3, 3-trifluoropropionaldehyde isolable as its 2, 4-dinitrophenyl hydrazone. Attempts to synthesise authentic 3,3, 3-trifluoro- propionaldehyde and the effects of the CF3 group are also discussed. The reaction between 3,3, 3-trifluoro-1, 2-propanediol and glyceroldehydrase is readily monitored by 19F n. m. r. allowing an examination of reaction intermediates. The synthesis of several bromopropanols and some preliminary investigations as to their reactions with glyceroldehydrase are also noted.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Vitamin B12 -- Synthesis
Official Date:	1974
Dates:	Date Event 1974 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Cornforth, John Warcup,1917-2013
Sponsors:	Science Research Council (Great Britain) ; Shell UK Oil (Firm)
Extent:	ix, 160 leaves : illustrations
Language:	eng

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