Partial Synthesis of Vitamin B12 Coenzyme and Analogues

Smith, E. Lester; Mervyn, L.; Johnson, A. W.; Shaw, Neil

doi:10.1038/1941175a0

Cited by 113 publications

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“…Obviously, such a method would promise to be specifically useful for the synthesis of Co b -[(methoxycarbonyl)methyl]cob(III)alamin (6) and related organo-cob(III)alamins, which are easily reduced and which (presumably) are not stable in the presence of cob(I)alamin (3 À ) [11]. Earlier, Fukui and co-workers reported that cob(II)alamin (4) and MeI in aqueous solution reacted with formation of methylcob(III)alamin (2) (ca. 50%) and aquacob(III)alamin (5 ) [15].…”

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confidence: 97%

“…The redox potentials for the Co III /Co II couples of vitamin-B 12 derivatives depend strongly on the nature of the axial substituents [6 ± 10] 1 ) 4 ). As a consequence, under the strongly reducing conditions necessary for the formation of cob(I)alamin, the more easily reducible organo-cob(III)alamins can be reductively cleaved by direct electrochemical reduction [6] or by reduction with cob(I)alamin (3 À ) [7].…”

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confidence: 99%

“…For the electrochemical reduction under potentiostatic conditions, aquacob(III)-alamin chloride (5 ¥ Cl À ) was dissolved in 0.1m Bu 4 N(PF 6 ) in MeOH (see Scheme 2) and submitted to a controlled potential of À 0.45 V (vs. 0.1n CE) to give the brown solution of cob(II)alamin (4). After the addition of an excess of methylbromoacetate, the solution was further kept at À 0.45 V potentiostatically for another 32 h. Extraction of an aqueous solution of the reaction mixture with CH 2 Cl 2 separated the H 2 O-soluble alkylcob(III)alamin from the organic electrolyte salt.…”

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Reduction‐Labile Organo‐cob(III)alamins via Cob(II)alamin: Efficient Synthesis and Solution and Crystal Structures of [(Methoxycarbonyl)methyl]cob(III)alamin

Puchberger

Konrat

Kräutler

et al. 2003

Helvetica Chimica Acta

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Dedicated to Professor Jack D. Dunitz on the occasion of his 80th birthday An efficient synthesis of Cob-[(methoxycarbonyl)methyl]cob(III)alamin (6) is reported as an example of a new method for the preparation of some easily reducible organo-cob(III)alamins via the alkylation of cob(II)alamin. The procedure represents a considerable improvement compared to earlier methods that were based on an alkylation of cob(I)alamin. Thus, aquacob(III)alamin chloride (5 ¥ Cl) was reduced to cob(II)alamin (4), either by controlled potential electrolytic reduction or with an excess of sodium formate as reducing agent. The solution of 4 was then treated with an excess of methyl bromoacetate while being reductively poised potentiostatically or kept reduced by the formate, to give crystalline 6 in a yield of up to 91%. The structure of 6 in aqueous solution was mainly established by the completely assigned 1 H-and 13 C-NMR spectra ( Table 1). The NOE data ( Table 2) were best rationalized by the presence of a single main conformation of the (methoxycarbonyl)methyl ligand. Single crystals of 6 were obtained by crystallization from an aqueous solution, and the crystal structure was determined by X-ray analysis at cryotemperatures. The NMR and crystallographic data of 6 indicated similar structures in aqueous solution and in the crystal with the (methoxycarbonyl)methyl ligand preferring a −southern× orientation in each case.Introduction. ± The standard method for the preparation of biologically important organo-cob(III)alamins, such as the adenosylcobamide coenzyme B 12 (1, 5'-deoxy-5'-adenosylcob(III)alamin) and methylcob(III)alamin (2), is based on the rapid reaction of the highly nucleophilic cob(I)alamin (3 À ; vitamin B 12s ) with alkylation reagents, such as alkyl halides or alkyl tosylates [1 ± 5]. The formation of 3 À requires strongly reducing conditions, with a rather negative half-wave potential of the critical redox couple cob(II)alamin (4; vitamin B 12r )/cob(I)alamin (3 À ) (E 1/2 (4/3 À ) À 0.85 V vs. SCE (H 2 O, pH 7) [6 ± 8]. Indeed, the route via cob(I)alamin (3 À ) in general provides a convenient way for the preparation of alkyl cob(III)alamins, as most Cob-organocob(III)alamins are only reductively cleaved at potentials considerably more-negative than À 0.85 V vs. SCE 3 )

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Reduction‐Labile Organo‐cob(III)alamins via Cob(II)alamin: Efficient Synthesis and Solution and Crystal Structures of [(Methoxycarbonyl)methyl]cob(III)alamin

Puchberger

Konrat

Kräutler

et al. 2003

Helvetica Chimica Acta

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“…1) (1)(2)(3)(4). Methylcobalamin (MeCbl) was fi rst synthesized as an analog of AdoCbl (5), and was found later to be active in the enzymatic synthesis of methionine by Escherichia coli extracts (6) and to be present in human blood plasma and other natural source materials (7). The metabolic roles and the mechanisms of action of these two forms of vitamin B12 are quite different: AdoCbl participates as a coenzyme in intramolecular group-transfer reactions and ribonucleotide reduction, whereas MeCbl participates in intermolecular methyl transfer reactions (3,4).…”

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Synthesis and Properties of Formylcobalamin and Propionylcobalamin, Novel Acylcobalamins

Toraya

Ohya

2015

J Nutr Sci Vitaminol

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Summary Formylcobalamin (formyl-Cbl), a C1-unit carrying corrinoid, and propionylcobalamin (propionyl-Cbl) were synthesized for the fi rst time, and their properties were compared with those of acetylcobalamin (acetyl-Cbl). Formyl-Cbl, acetyl-Cbl, and propionyl-Cbl were decomposed by a NH2OH treatment, forming formo-, aceto-, and propionohydroxamic acids, respectively, which offers a proof for the presence of "activated" acyl groups and for their structures of Co-acyl-Cbls. These results, together with chromatographic, electrophoretic, and spectroscopic properties, indicate that the acyl-Cbls synthesized are actually formyl-Cbl, acetyl-Cbl, and propionyl-Cbl. Spectroscopic and electrophoretic properties were consistent with the -donor strength or trans-effect increasing in the order: formylϽacetylϽpropionyl. All acyl-Cbls underwent the Co-C bond cleavage upon photoirradiation with a tungsten light bulb as well as upon treatment with alkali, forming aquacobalamin (aqCbl) and hydroxocobalamin (OH-Cbl), respectively, under air. Formyl-Cbl was thermally unstable and decomposed to aqCbl, and the thermal stability in neutral solution was much lower than in diluted HCl. In contrast, acetyl-Cbl and propionyl-Cbl were heatstable under these conditions. Formyl-Cbl was essentially unsusceptible to unbufferized KCN solution, although acetyl-Cbl and propionyl-Cbl were rapidly converted to dicyanocobalamin under the same conditions. Such abnormal behaviors of formyl-Cbl suggest that it mainly exists in a hydrated form as formaldehyde.

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“…Dorothy Hodgkin was awarded the Nobel Prize in 1964 for her pioneering use of X-ray crystallography, particularly for her work on determining the structure of insulin and vitamin B 12 . Within 10 years, the vitamin had been partially synthesized chemically [37,38]. …”

Section: Isolation Crystallization and Synthesis Of The ‘Extrinsic’ mentioning

confidence: 99%

The Discovery of Vitamin B12

Scott¹,

Molloy

2012

Ann Nutr Metab

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The discovery of vitamin B₁₂, the elucidation of its role in metabolism, and the effects and treatment of its deficiency occurred in distinct phases over more than 100 years, and it was the subject of two separate Nobel Prizes. The valuable contribution of clinical reports and studies of patients with pernicious anemia throughout the 19th century resulted in enough clinical definition to allow Minot and Murphy to put together the first hallmark study on treatment of the condition, leading them to a Nobel Prize. These researchers were not the first to suggest that an inadequacy of nutrients was the cause of pernicious anemia, but their particular input was a carefully designed intervention in well-characterized pernicious anemia patients, of a special diet containing large amounts of liver. They found consistent improvement in the clinical and blood status of all subjects, most of whom remained on remission indefinitely. After the successful intervention studies, the next advance was made by Castle who discovered that a gastric component, which he called intrinsic factor, was missing in pernicious anemia. Many years later, intrinsic factor was found to be a glycoprotein that formed a complex with vitamin B₁₂, promoting its absorption through ileal receptors. The vitamin was isolated by two groups simultaneously and was crystallized and characterized in the laboratory of Dorothy Hodgkin, contributing to her Nobel Prize in 1964. Subsequently, the various biochemical roles of vitamin B₁₂ were elucidated, including its important interaction with folate and their common link with megaloblastic anemia. Many of the early clinical studies recognized that vitamin B₁₂ deficiency also caused a severe neuropathy leading to paralysis and death, while post mortem analysis demonstrated spinal cord demyelination. Vitamin B₁₂ is still the subject of intense research and, in particular, its role in preventing these irreversible neurological lesions remains unclear.

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Partial Synthesis of Vitamin B12 Coenzyme and Analogues

Cited by 113 publications

References 6 publications

Reduction‐Labile Organo‐cob(III)alamins via Cob(II)alamin: Efficient Synthesis and Solution and Crystal Structures of [(Methoxycarbonyl)methyl]cob(III)alamin

Reduction‐Labile Organo‐cob(III)alamins via Cob(II)alamin: Efficient Synthesis and Solution and Crystal Structures of [(Methoxycarbonyl)methyl]cob(III)alamin

Synthesis and Properties of Formylcobalamin and Propionylcobalamin, Novel Acylcobalamins

The Discovery of Vitamin B12

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