Vitamin B,2 synthesis

The high nucleophilicity of sulfur atoms is preserved, even if it is bound to electron withdrawing carbonyl groups. Thiocarboxylales, for example, substitute bromine, e.g. of a-bromo ketones. In the presence of bases the or-acylthio ketones deprotonate and rearrange to episulfides. After desulfurization with triphenylphosphine, 1,3-diketones are formed in good yield. Thiolactams react in the same way, and A. Eschenmoser (1970) has used this sequence in his vitamin B]2 synthesis (p. 261). 

Regioselectivity of enolisation is still important. Acid (33) was used in a (very early ) stage of Woodward and Eschenmoser s vitamin B 2 synthesis. Disconnection gives an unsymmetrical ketone (8) and reactive, non-enolisable (34). Reaction in acid (page 154) ensured enolisation on the more substituted side of (8). 

Fohc acid is a precursor of several important enzyme cofactors required for the synthesis of nucleic acids (qv) and the metaboHsm of certain amino acids. Fohc acid deficiency results in an inabiUty to produce deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and certain proteins (qv). Megaloblastic anemia is a common symptom of folate deficiency owing to rapid red blood cell turnover and the high metaboHc requirement of hematopoietic tissue. One of the clinical signs of acute folate deficiency includes a red and painhil tongue. Vitamin B 2 folate share a common metaboHc pathway, the methionine synthase reaction. Therefore a differential diagnosis is required to measure foHc acid deficiency because both foHc acid and vitamin B 2 deficiency cause... 

The study of the biosynthesis of vitamin B 2 is a saga whose resolution, due primarily to Battersby (80—83) and Scott (84,85), requited an effort on the same magnitude as the total synthesis. It was only when recent molecular biology tools became available to complement en2ymology, isotopic labeling, chemical synthesis, and spectroscopy that solution of this problem became possible. 

Cobalt is one of twenty-seven known elements essential to humans (28) (see Mineral NUTRIENTS). It is an integral part of the cyanocobalamin [68-19-9] molecule, ie, vitamin B 2> only documented biochemically active cobalt component in humans (29,30) (see Vitamins, VITAMIN Vitamin B 2 is not synthesized by animals or higher plants, rather the primary source is bacterial flora in the digestive system of sheep and cattle (8). Except for humans, nonmminants do not appear to requite cobalt. Humans have between 2 and 5 mg of vitamin B22, and deficiency results in the development of pernicious anemia. The wasting disease in sheep and cattle is known as bush sickness in New Zealand, salt sickness in Florida, pine sickness in Scotland, and coast disease in AustraUa. These are essentially the same symptomatically, and are caused by cobalt deficiency. Symptoms include initial lack of appetite followed by scaliness of skin, lack of coordination, loss of flesh, pale mucous membranes, and retarded growth. The total laboratory synthesis of vitamin B 2 was completed in 65—70 steps over a period of eleven years (31). The complex stmcture was reported by Dorothy Crowfoot-Hodgkin in 1961 (32) for which she was awarded a Nobel prize in 1964. 

Woodward-Eschenmoser method, 4, 431-440 neo-Vitamin B,2, 4, 421 Vitamin C — see Ascorbic acid Vitamin E — see a-Tocopherol Vitamin K epoxide, 7, 119 synthesis, 1, 439 Vitamins heterocyclic... 

Equations 4-8 illustrate some mild methods that can be used to cleave amides. Equations 4 and 5 indicate the conditions that were used by Woodward and Eschenmoser, respectively, in their synthesis of vitamin B,2- Butyl nitrite," nitrosyl chloride, and nitrosoniurn tetrafluoroborate... 

The important biological role of the isobacteriochlorins has decisively influenced the development of synthetic approaches leading to the isobacteriochlorin class of compounds. All of the naturally occurring isobacteriochlorins contain geminally dialkylated structural parts in the saturated pyrrole rings, which require special approaches for their synthesis. Until the discovery of siroheme and sirohydrochlorin, this structural element could only be found in vitamin B,2. Using the synthetic potential, which was invented during numerous syntheses of... 

Sapphyrins were discovered serendipitously by Woodward33 during the course of synthetic studies directed towards the total synthesis of vitamin B, 2. The sapphyrins were the first example of expanded porphyrins in the literature. Due to sapphyrin exhibiting a deep-blue color in the crystalline state and intense green in solution. Woodward coined the expression sapphyrin with reference to the deep-blue color of sapphire stones. 

Pharmacology Vitamin B-12 is essential to growth, cell reproduction, hematopoiesis, nucleic acid, and myelin synthesis. Sources of vitamin B 2 include liver, meat, fish,... 

Scott, A.I. (1994) Towards a total, genetically engineered synthesis of vitamin B,2. Synlett, 871-84. 

Microbiological Synthesis of Vitamin Bt2. Microbiological synthesis affords the only known means for bulk production of pure vitamin B[2 and concentrates of the vitamin. Several reports concerned chiefly with vitamin Bi2 yields in actinomycete cultures are available (Garey and Downing 1951 Garibaldi et al. 1951 Hall and Tsuchiya 1951 Hall et al. 1951 Saunders et al. 1951). 

Leviton, A. and Hargrove, R. E. 1952. Microbiological synthesis of vitamin B[2 by propionic acid bacteria. IruL Eng. Chem. 44, 2651-2655. 

The utility of intermediary sulfur bridging has been evidenced by the Eschenmoser group [445]. An example of their method was applied in studies [446] directed towards the synthesis of vitamin B,2. 

Equations 4-8 illustrate some mild methods that can be used to cleave amides. Equations 4 and 5 indicate the conditions that were used by Woodward9 and Eschenmoser,10 respectively, in their synthesis of vitamin B,2- Butyl nitrite,11 nitrosyl chloride,12 and nitrosonium tetrafluoroborate (NO+BF4 )13 have also been used to cleave amides. Since only tertiary amides are cleaved by potassium r-butoxide (eq. 6), this method can be used to effect selective cleavage of tertiaiy amides in the presence of primary or secondary amides.14 (Esters, however, are cleaved by similar conditions.)15 Photolytic cleavage of nitro amides (eq. 7) is discussed in a review.16 n,o4/cci4 ... 

Spent liquors from streptomycin and other antibiotic fermentations contain appreciable amounts of vitamin B12. Bacterial strains producing high amounts have been specially selected for commercial production. Today vitamin B 2 is obtained from fermentations using selected strains of Propionibacterium or Pseudomonas cultures. A full chemical synthesis process for vitamin B 2 is known. However, it requires some 70 steps and for all practical purposes is of little value. 

Dr. Woodward obtained his first HPLC in 1971 and eventually his group had three. Very quickly, his group benefited from using LC and two short years later at the 1973 IUPAC Symposium (11), Dr. Woodward announced the synthesis of vitamin B 2 and emphasized the power of HPLC. At that time he became the strongest spokesman for the importance of the technique to the organic chemist and many followed his lead and quickly incorporated LC into their laboratories. Thus, Dr. Woodward played a key role in the tremendously rapid growth of HPLC. 

In the synthesis of vitamin Bj2, for example, unexpected findings emci ged that led to the understanding of an entire new class of reactions—the pericyctic reactions that are the subject of Chapter 30 in this book. From synthesizing vitamin B,2 to understanding pericyclic reactions—no one could have possibly predicted such a link at tlie beginning of the synthesis, but that is the way of science,... 

Covalent synthesis of complex molecules involves the reactive assembly of many atoms into subunits with aid of reagents and established as well as innovative reaction pathways. These subunits are then subjected to various reactions that will assemble the target molecule. These reaction schemes involve the protection of certain sensitive parts of the molecule while other parts are being reacted. Very complex molecules can be synthesized in this manner. A prime example of the success of this approach is the total synthesis of palytoxin, a poisonous substance found in marine soft corals (35). Other complex molecules synthesized by sequential addition of atoms and blocks of atoms include vitamin B 2 potentially anticancer KH-1 adenocarcinoma antigen, and epothilones A and B (36,143—145). 

The main biological and biochemical interest in cobalt concerns vitamin B,2 and a number of its derivatives, such as 5 -deoxyadenosyl cobalamin, which function as coenzyme in a number of rearrangements involving hydrogen shifts and aquocobalamin which is involved in the synthesis of methionine, methane and acetate. Vitamin in its resting state is ESR-inactive since it contains Co , but, when reduced to Co, spectra such as that shown in Figure 4.7 are obtained. This reduced form is referred to as vitamin B,2r it does not have cyanide as a sixth ligand. Its... 

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