Biotin stereoisomers

The structure of biotin was determined in the early 1940s by Kogl in Europe and by dn Vigneand and coworkers in the United States. Interestingly, the biotin molecule contains three asymmetric carbon atoms, and biotin could thus exist as eight different stereoisomers. Only one of these shows biological activity. 

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 chemical structure of biotin (hexahydro-2-oxo-IH-thieno [3,4-d] imidazol-4-valeric acid) is shown in Fig. 1. Of the eight stereoisomers, only d-(+)-biotin occurs naturally and is biologically active. 

The product of the reaction in Entry 8 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxy group is determined by the structure of the oxazoline ring formed in the cycloaddition. Entry 9 portrays the early stages of synthesis of the biologically important molecule biotin. The reaction in Entry 10 was used to establish the carbocyclic skeleton and stereochemistry of a group of toxic indolizidine alkaloids found in dart poisons from frogs. Entry 11 involves generation of a nitrile oxide. Three other stereoisomers are possible. The observed isomer corresponds to approach from the less hindered convex face of the molecule. 

Biotin is composed of an imidazolidone ring joined to a tetrahydrothiophene ring (Fignre 19.17). The latter possesses a valeric acid side chain. The unique stereoisomer occurring in natnre is d(+)-biotin. 

Propionyl-CoA is first carboxylated to form the d stereoisomer of methylmalonyl-CoA (Pig. 17—11) by propionyl-CoA carboxylase, which contains the cofactor biotin. In this enzymatic reaction, as in the pyruvate carboxylase reaction (see Pig. 16-16), C02 (or its hydrated ion, HCO ) is activated by attachment to biotin before its transfer to the substrate, in this case the propionate moiety. Formation of the carboxybiotin intermediate requires energy, which is provided by the cleavage of ATP to ADP and Pi- The D-methylmalonyl-CoA thus formed is enzymatically epimerized to its l stereoisomer by methylmalonyl-CoA epimerase (Pig. 17-11). The L-methylmal onyl -CoA then undergoes an intramolecular rearrangement to form succinyl-CoA, which can enter the citric acid cycle. This rearrangement is catalyzed by methylmalonyl-CoA mutase, which requires as its coenzyme 5 -deoxyadenosyl-cobalamin, or coenzyme Bi2, which is derived from vitamin B12 (cobalamin). Box 17—2 describes the role of coenzyme B12 in this remarkable exchange reaction. 

Biotin contains three chiral centers and therefore has eight stereoisomers.1819 Of these, only one, the dextrorotatory (-i-)-biotin, is biologically active.19 20 The vitamin is readily oxidized to die sulfoxide and sul-fone. The sulfoxide can be reduced back to biotin by a molybdenum-containing reductase in some bacteria (see also Chapter 16, Section H).20a Biotin is synthesized from pimeloyl-CoA (see chapter banner, p. 719 and Eq. 24-39). Four enzymes are required. Two of them, a... 

The structural formula (Figure 9-23) contains three asymmetric carbon atoms, and eight different stereoisomers are possible. Only the dextrorotatory D-biotin occurs in nature and has biological activity. Biotin occurs in some products in free form (vegetables, milk, and fruits) and in other products is bound to protein (organ meats, seeds, and yeast). Good sources of the vitamin are meat, liver, kidney, milk, egg yolk, yeast, vegetables, and mushrooms (Table 9-27). 

Biotin contains three chiral centers and therefore has eight stereoisomers. Of fhese, only one, fhe dextrorotatory (+)-biotin, is biologically active. ... 

Chemistry. Biotin consists of two 5-membered rings cis-fusedto each other that can be drawn either as the keto (urea)or enolic form (Fig. 8.40). The enolic d-isomer is the active stereoisomer, but many times commercial multivitamin products contain the synthetic racemic c ,Z mixture. There is no activity with the 1-stereoisomer. 

The normal situation seen with vitamins that have two or more stereoisomers is only one isomer is active. Thus a racemic (usually represented as d,D mixture contains 50%of the activity compared with an equimolar amount of the active isomer. Examples where only one isomer is active includes d-pantothenic acid, D-biotin, and D-ascorbic acid. 

The structure of biotin has three asymmetric carbons and can therefore exist as eight potential stereoisomers, but only the 4-biotin form is both biologically... 

Analogous transformations yielded the missing fourth stereoisomer of biotin, dl-epi-hiotin (m.p. 190-191°). This compound was formed when the... 

Biotin is a sulfur-containing bicyclic compound in which tetrahydrotiophene and imidazolidone rings are fused and there is a valeric acid as the side chain. From the eight possible stereoisomers, only the dextrorotatory (D-(+)-biotin) is ordinarily found in nature and is the only one biologically active. This compound is sensitive to heat. Biotin is widely distributed in nature in the free form or covalently bound to proteins or peptides. Good sources of biotin are organ meats, egg yolks, and milk. 

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