Conversion of D-glucose to (+)-desthiobiotin

Although the structure of biotin contains three centers of chirality, and thus the molecule exists in eight stereoisomeric forms, many texts ignore the configuration of the biologically active form and others show an incorrect one. The evidence from chemical degradations, stereospecific chemical syntheses, and X-ray crystalographic structure determination by the anomalous dispersion technique, leading to the absolute configuration of naturally occurring (+)-biotin is reviewed.

The use of carbohydrates for establishing, by synthesis, the absolute configuration of branched aliphatic alcohols is demonstrated by the synthesis and degradation of carbohydrate derivatives that contain two branch points. Benzyl 4,6-O-benzylidene-2,3-dideoxy-3-C-ethyl-2-C-hydroxymethyl-α-d-glucopyranoside (23) and -mannopyranoside (24) were formed from benzyl 2,3-anhydro-4,6-O-benzylidene-α-d-mannopyranoside (17) by a reaction sequence that involved ring-opening with ethylmagnesium chloride, oxidation, epimerisation, methylenation, and hydroboronation. The gluco isomer 23 was converted into (+)-(R)-2,3-bisacetoxymethylpentyl acetate (1) by sequential hydrogenolysis, borohydride reduction, periodate oxidation, borohydride reduction, and acetylation. The synthesis of 1 provides confirmatory evidence for the absolute configuration of the alkaloid pilocarpine (2). Unidentified products, and not the expected free-sugars, were obtained by acidic hydrolysis of methyl 4,6-O-benzylidene-2,3-dideoxy-3-C-ethyl-2-C-hydroxymethyl-α-d-glucopyranoside (8) and -mannopyranoside (9). Convenient syntheses of benzyl α-d-glucopyranoside derivatives are described.

This chapter illustrates the practical applications of carbohydrates in asymmetric synthesis. The chapter also describes the application of carbohydrates for the synthesis and configurational proof of other biologically important molecules. Carbohydrates provide excellent chiral frameworks for mechanistic studies of asymmetric synthesis and serve as readily available and easily modified sources of asymmetric centers. The main essence of asymmetric synthesis is the creation of asymmetric centers under the influence of other asymmetric centers, in such a way that the resulting enantiomers or diastereoisomers are formed in unequal proportions. Asymmetric reactions can be divided into three types—namely, type 1 reactions in which optically active compounds are formed from achiral substrates and chiral reagents, or from achiral substrates and achiral reagents in chiral solvents, type 2 reactions in which new asymmetric centers are created in molecules that already possess one asymmetric center or more and in which the new asymmetric center may be liberated from the parent molecule by simple hydrolytic reactions, and type 3 reactions in which new asymmetric centers are created immediately adjacent to existing asymmetric centers in molecules that contain one asymmetric center.