Biotin precursors

Methods 7 and 8 were used to remove the benzyl group from a biotin precursor. 

Biotin Precursor of the coenzyme biocytin. Deficiency leads to dermatitis in humans. 

HCO2H, 50-60°C, 74-91% yield. This method was used to remove the a-methylbenzyl group from an amide. Methods 7 and 8 were used to remove the benzyl group from a biotin precursor. 

The cycloaddition of the following nitrone in a synthesis of a biotin precursor is an exception in that it affords the all-civ cycloadduct as the major product (d.r. 65 35)110. 

Few examples of catalytic hydrogenation of partially saturated thiophene derivatives are known, because sulfur normally poisons the catalyst. Nevertheless, hydrogenations are sometimes possible when a larger amount of catalyst is used. One example, with a high degree of diastereoselectivity, is hydrogenation of the biotin precursor l18. 

Because of the high aromatic stabilization of the thiophene nucleus and the tendency of sulfur to poison the catalyst, the hydrogenation of thiophenes is extremely difficult. In general, harsh conditions and high catalyst concentrations are required53. Hydrogenation occurs with excellent cis diastereoselectivity. as shown in the reduction of the biotin precursor 154. 

I Sanyal, SL L.ee, DH Flint. Biosynthesis of pimeloyl-CoA, a biotin precursor in E. coli, follows a modified fatty acid synthesis pathway C-labeling studies. J Am Chem Soc 116 2637-2638, 1994. 

The three hydroxy compounds, 6, , were prepared, to be tested as biotin precursors. Their synthesis, starting from 4-methyl-5"(w-carboethoxyvaleryl)-imidazolone-2, 3, (4) is summarized in scheme 2. 

The (+)-biotin precursor (13) has been conveniently prepared from... 

Certain factors and product precursors are occasionally added to various fermentation media to iacrease product formation rates, the amount of product formed, or the type of product formed. Examples iaclude the addition of cobalt salts ia the vitamin fermentation, and phenylacetic acid and phenoxyacetic acid for the penicillin G (hen ylpenicillin) and penicillin V (phenoxymethylpenicillin) fermentations, respectively. Biotin is often added to the citric acid fermentation to enhance productivity and the addition of P-ionone vastly iacreases beta-carotene fermentation yields. Also, iaducers play an important role ia some enzyme production fermentations, and specific metaboHc inhibitors often block certain enzymatic steps that result in product accumulation. 

Biotin is produced by a multistep pathway in a variety of fungi, bacteria, and plants (50—56). The estabUshed pathway (50,56) in E. coli is shown in Figure 6. However, Htde is known about the initial steps that lead to pimelyl-Co A or of the mechanism of the transformation of desthiobiotin to biotin. Pimelic acid is beheved to be the natural precursor of biotin for some microorganisms (51). 

The total synthesis of biotin (1) described in this chapter provides an impressive example of the intramolecular nitrone-olefin [3+2] cycloaddition reaction. Aiming for a practical process, the Hoff-mann-La Roche group utilized relatively simple and inexpensive starting materials, and ingeniously controlled the crucial [3+2] cycloaddition reaction to give only one stereoisomer by confining the cycloaddition precursor to a ten-membered ring. 

The Strecker reaction has been performed on the aldehyde 182 prepared from L-cysteine [86] (Scheme 28). The imine was formed in situ by treatment with benzylamine, then TMS cyanide was added to afford prevalently in almost quantitative yield the syn-diamine 183, which is the precursor of (-l-)-biotin 184. The syn selectivity was largely affected by the solvent, toluene being the solvent of choice. Since the aldehyde 182 is chemically and configurationally unstable, a preferred protocol for the synthesis of 183 involved the prehminary formation of the water-soluble bisulfite adduct 185 and the subsequent treatment with sodium cyanide. Although in this case the syn selectivity was lower, both diastereomers could be transformed to (-l-)-biotin. 

A precursor for biotin, 7-keto-8-aminopelargonic acid, is also prepared by acylation of nitromethane, followed by the selective reduction of the nitro group, as shown in Eq. 5.14.27... 

The key enzyme in fatty acid synthesis is acetyl CoA carboxylase (see p. 162), which precedes the synthase and supplies the malonyl-CoA required for elongation. Like all carboxylases, the enzyme contains covalently bound biotin as a prosthetic group and is hormone-dependently inactivated by phosphorylation or activated by dephosphorylation (see p. 120). The precursor citrate (see p. 138) is an allosteric activator, while palmitoyl-CoA inhibits the end product of the synthesis pathway. 

An attempted synthesis of biotin using thiocarbonyl ylide cycloaddition was carried out (131,133,134). The crucial step involves the formation of the tetrahydrothiophene ring by [3 + 2] cycloaddition of a properly substituted thiocarbonyl ylide with a maleic or fumaric acid derivative (Scheme 5.27). As precursors of the thiocarbonyl ylides, compounds 25a, 72, and 73 were used. Further conversion of cycloadducts 74 into biotin (75) required several additional steps including a Curtius rearrangement to replace the carboxylic groups at C(3) and C(4) by amino moieties. 

Few examples of total syntheses have been reported that involve an intramolecular nitrile oxide cycloaddition and ensuing reduction to an aminoalcohol. The very first example was reported by Confalone et al. (334) and involved a synthesis of the naturally occurring vitamin biotin (287). The nitro precursor 284 was easily prepared from cycloheptene. When treated with phenyl isocyanate-triethylamine, cycloaddition led to the all-cis-fused tricyclic isoxazoline 285 with high stereoselectivity (Scheme 6.102). Reduction with LiAlFLj afforded aminoalcohol 286 as a... 

The B-group is a heterogeneous collection of water-soluble vitamins, most of which function as co-enzymes or are precursors of co-enzymes. The B-group vitamins are thiamin, riboflavin, niacin, biotin, pantothenic acid, pyridoxine (and related substances, vitamin B6), folate and cobalamin (and its derivatives, vitamin B12). 

Some enzymes associate with a nonprotein cofactor that is needed for enzymic activity. Commonly encountered cofactors include metal ions such as Zn2+ or Fe2+, and organic molecules, known as coenzymes, that are often derivatives of vitamins. For example, the coenzyme NAD+contains niacin, FAD contains riboflavin, and coenzyme A contains pantothenic acid. (See pp. 371-379 for the role of vitamins as precursors of coenzymes.) Holoenzyme refers to the enzyme with its cofactor. Apoenzyme refers to the protein portion of the holoenzyme. In the absence of the appropriate cofactor, the apoenzyme typically does not show biologic activity. A prosthetic group is a tightly bound coenzyme that does not dissociate from the enzyme (for example, the biotin bound to carboxylases, see p. 379). 

Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans and, therefore, must must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water-soluble, whereas four vitamins (vitamins A, D, K, and E) are termed fat-soluble (Figure 28.1). Vitamins are required to perform specific cellular functions, for example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat soluble vitamin (vitamin K) has a coenzyme function. These vitamins are released, absorbed, and transported with the fat of the diet. They are not readily excreted in the urine, and significant quantities are stored in Die liver and adipose tissue. In fact, consumption of vitamins A and D in exoess of the recommended dietary allowances can lead to accumulation of toxic quantities of these compounds. 

Vitamins and Minerals. Milk is a rich source of vitamins and other organic substances that stimulate microbial growth. Niacin, biotin, and pantothenic acid are required for growth by lactic streptococci (Reiter and Oram 1962). Thus the presence of an ample quantity of B-complex vitamins makes milk an excellent growth medium for these and other lactic acid bacteria. Milk is also a good source of orotic acid, a metabolic precursor of the pyrimidines required for nucleic acid synthesis. Fermentation can either increase or decrease the vitamin content of milk products (Deeth and Tamime 1981 Reddy et al. 1976). The folic acid and vitamin Bi2 content of cultured milk depends on the species and strain of culture used and the incubation conditions (Rao et al. 1984). When mixed cultures are used, excretion of B-complex vita-... 

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