Dixon, Ruth Mary (1985) Synthesis and reactions of dihydroxyalkylcobalamins: a model for vitamin B₁₂-dependent propanediol dehydratase. PhD thesis, University of Warwick.

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Abstract

A model for vitamin-B12-dependent diol dehydratase, 4,5-dihydroxy- pentylcobaloxime, was reported by Golding et al-. 31.56. This modelled the regiospecific abstraction of a hydrogen atom from Cl of a 1,2-diol by an alkyl radical in the diol dehydratase reaction, as it gave pentanal when photolysed under acidic conditions. In the present work, the same system was studied using cobalamins.
A series of dihydroxyalkylcobalamins (length of alkyl chain = 3-6carbon atoms) was prepared. Alkylcobalamins were synthesised from hydroxo- or cyanocobalamin, which was reduced to cobalamin(I) using sodium borohydride or zinc dust, and treated with the appropriate alkyl halide or tosylate.
Synthetic routes to chirally pure or racemic alkylating agents are reported in Chapter 2. An original synthesis of4-(3-iodo-2,2- dimethylpropyl)-2,2-dimethyl-1,3-dioxolan, starting from allylalcohol and 2-methylpropanal, was developed, although the compound was not isolatedpure, forreasons discussed in Chapter 2.
Alkylcobalamins were characterised by t.1.c.,IR, UV, and NMR spectroscopy. High field NMR spectroscopy was found to be the most effective technique. The purity ofalkylcobalamins could be assessed, and, furthermore, diastereoisomeric alkylcobalamins (differing only in the chiral centre on the alkyl ligand) could be distinguished. The methine protons on the corrin ligand of three cobalamins were assigned by n.O.e. difference spectroscopy. The chemical shift sand coupling constants ofa number ofalkylcobalamins are reported, and the structural information is discussed (Chapter 4).
Hitherto, the crystal structure of only one alkylcobalamin, the coenzyme, adenosylcobalamin, had been reported^.in order to ascertain whether the bond lengths and angles in the coenzyme were typical or atypical, the crystal structures of(R)- and (S)-2,3-dihydroxypropyl- cobalamin were determined (Chapter 5). The cobalt-carbon bond lengths do not differ significantly from that of the coenzyme (R 2.00(2) Å; S, 2.08(3) Å; coenzyme 2.03(2) Å), but the Co-C-C angles are both smaller than that of the coenzyme (R, 119.6 ± 1.7 °; S, 113.6 ± 2.1 °; coenzyme; 125 ± 3 °). It seems that steric strain is relieved by an increase in the Co-C-C angle rather than in the Co-C bond length.
The thermolytic and photolytic behaviour of the dihydroxyalkyl­cobalamins was investigated (Chapter 6). No evidence of the rearrange­ment of any via-diol to an aldehyde was seen, but instead ß-elimination of hydrogen led to hydridocobalamin and an olefin, in most cases. Evidence of readdition of cobalt to the olefin, and further elimination to give a rearranged olefin, was found. The various reaction pathways available to dihydroxyalkylcobalamins are discussed.
These findings provide indirect support for the hypothesis that the cobalt atom does not participate in the rearrangement step of the diol dehydratase reaction. Instead it acts as a source of alkyl radicals, which are generated by the homolysis of the (relatively weak) cobalt-carbon bond in the coenzyme.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Chemistry, Organic, Biochemistry, Vitamin B12 -- Synthesis, Vitamin B12, Vitamin B12 -- Structure-activity relationships (Biochemistry)
Official Date:	February 1985
Dates:	Date Event February 1985 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Golding, Bernard T.,|edegree supervisor.
Extent:	[14], 253 leaves : illustrations
Language:	eng

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