Stereoisomers, biological activity

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. 

Alkylamines have a variety of applications in the chemical industry as starting materials for the preparation of insecticides and pharmaceuticals. Labetalol, for instance, a so-called /3-blocker used for the treatment of hi h blood pressure, is prepared by SN2 reaction of an epoxide with a primary amine. The substance marketed for drug use is a mixture of all four possible stereoisomers, but the biological activity derives primarily from the (R,R) isomer. 

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. 

Although a -trans- and 9-cis-RA are only minor metabolites of ROL and (3-carotene, they display 100-1000-fold higher biological activity. Whereas all-trans-RA binds only to RARs, 9-cis-RA binds both RARs and RXRs. The stereoisomer of all-irarcs-RA, 13-cis-RA, exhibits a much lower affinity for RARs and RXRs and exerts its molecular effects mostly through its isomerization into all-irarcs-RA. 

Conduritols and inositols are cyclic polyalcohols with significant biological activity. The presence of four stereogenic centers in the stmcture of conduritols allows the existence of 10 stereoisomers. Enzymatic methods have been reported for the resolution of racemic mixtures or the desymmetrization of meso-conduritols. For example, Mucor miehei lipase (MML) showed enantiomeric discrimination between all-(R) and all-(S) stereoisomers ofconduritol E tetraacetate (Figure 6.52). Alcoholysis resulted in the removal of the four acetyl groups ofthe all-(R) enantiomer whereas the all-(S) enantiomer was recovered [141]. 

A famous example of the use of nitro compounds in synthesis was the original synthesis of the antibiotic chloramphenicol (8), which is still used to treat tropical diseases. This synthesis also confirmed the structure of chloramphenicol and established that the (-)-thrco compound was the biologically active stereoisomer. 

Stereoselectivity, in particular, enantioselectivity, is the most important feature of enzymes. It should be stressed that enzymes are capable of recognizing any type of chirality of the substrates. It does not seem necessary to prove here how important the synthesis of sterically defined products is, because the differences in biological activity of particular stereoisomers of a given substance are well known. There are three approaches to the synthesis of enantiomerically enriched... 

The chiral copper cataly.st (see Fig. 3.54) has been used to synthesize the drug Cilastatin. The desired biological activity is found in the stereoisomer derived from (-I-) 15-2,2-... 

Tocopherol can be produced as the pure 2R,4 R,8 R stereoisomer from natural vegetable oils. This is the most biologically active of the stereoisomers. The correct side-chain stereochemistry can be obtained using a process that involves two successive enantioselective hydrogenations.28 The optimum catalyst contains a 6, 6 -dimethoxybiphenyl phosphine ligand. This reaction has not yet been applied to the enantioselective synthesis of a-tocopherol because the cyclization step with the phenol is not enantiospecific. 

The reaction of metabolically generated polycyclic aromatic diol epoxides with DNA Ua vivo is believed to be an important and critical event in chemical carcinogenesis Cl,2). In recent years, much attention has been devoted to studies of diol epoxide-nucleic acid interactions in aqueous model systems. The most widely studied reactive intermediate is benzo(a)pyrene-7,8-diol-9,10-epoxide (BaPDE), which is the ultimate biologically active metabolite of the well known and ubiquitous environmental pollutant benzo(a)pyrene. There are four different stereoisomers of BaPDE (Figure 1) which are characterized by differences in biological activities, and reactivities with DNA (2-4). In this review, emphasis is placed on studies of reaction mechanisms of BPDE and related compounds with DNA, and the structures of the adducts formed. 

Metolachlor is applied as a mixture of eight different stereoisomers, only four of which have herbicidal activity (10). This implies that the other four isomers are applied as contaminants, with no additional benefit to crop production. Whether the chirality of metolachlor influences its degradation rate is unknown. This lack of information is mainly due to the difficulty of separation and analysis of its isomers. Because the stereochemistry of compounds plays an important role in their biological activity and degradation pathways, it is valuable to investigate the influence of stereochemistry on the rate of metolachlor degradation in soil. 

Trifluoromethyl derivatives of aziridine are intensively studied as biologically active substances. (Trifluoromethyl)aziridines 4 were prepared from (trifluoromethyl)ketoximes 3 and Grignard reagents (equation 2). However, this reaction is not general. For example, reaction does not occur with phenyl and allyl Grignard reagents, but when it works the Z stereoisomer is formed . 

Having identified the (+)-stereoisomer as the biologically active isomer, several independent enantioselective syntheses of this stereoisomer were developed. The initial synthesis developed in discovery chemistry employed the diastereoselective aldol condensation pioneered by Braun as the key component. Thus, treatment of aldehyde 13 from the racemic synthesis with the magnesium enolate of (5)-(+)-2-acetoxy-l,l,2-triphenylethanol at -70 °C, afforded 17 in 60% yield as a 97 3 mixture of the / ,5 5,5-diastereomers by HPLC (Scheme 3). Ester exchange employing sodium methoxide provided the methyl ester in quantitative yield. Reaction of this ester with three equivalents of lithio-f-butylacetate at -40 °C afforded the nearly enantiomerically pure r-butyl ester analog of racemic 14 in 75% yield. 

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