Antipodal effect

Care should be exercised when attempting to interpret in vivo pharmacological data in terms of specific chemical—biological interactions for a series of asymmetric compounds, particularly when this interaction is the only parameter considered in the analysis (10). It is important to recognize that the observed difference in activity between optical antipodes is not simply a result of the association of the compound with an enzyme or receptor target. Enantiomers differ in absorption rates across membranes, especially where active transport mechanisms are involved (11). They bind with different affinities to plasma proteins (12) and undergo alternative metaboHc and detoxification processes (13). This ultimately leads to one enantiomer being more available to produce a therapeutic effect. 

Levopropoxyphene [2338-37-6] (42), the optical antipode of the dextrorotatory analgetic propoxyphene, is an antitussive without analgetic activity. The 2-naphthalenesulfonate salt has a less unpleasant taste than the hydrochloride salt, and is widely used. Clinical effectiveness has been demonstrated against pathological and artificially induced cough, but the potency is somewhat less than codeine. The compound is reported not to cause addiction. Levopropoxyphene can be prepared (62) by first resolving [ -dimethylamino-CX-methylpropiophenone with dibenzoyl-(+)-tartaric acid. The resolved... 

Parallel to the modification of the catalytic performance in Baeyer-Villiger oxidations, random mutagenesis was successfully applied to improve the stereoselectivity of CHMOAcineto hi cascs of essentially racemic sulfoxide formation. In addition, enantiodivergent clones with >98% ee for both antipodal products were identified (Table 9.5) [205]. However, improvement in stereoselectivity of mutant enzymes was often accompanied by increased formation of sulfone. This effect can also be utilized to resolve racemic sulfoxides. 

Among the difficult (and sometimes referred to as sensitive ) chromatographic separations, those of enantiomeric antipodes and racemic mixtures are of particularly great importance and of the highest interest. This is because many compounds with a therapeutic effect (and incomparably more often the synthetic species than the natural ones) appear in a clearly defined enantiomeric form and for reasons of safety, need to be isolated from their opposite counterparts. Most phar-macodynamically active compounds are equipped with polar functionalities that make them interact with biological receptors and with the other constituents of a biological environment, and it often happens that these functionahties are of the AB type. In such cases, it can be justly concluded that an almost proverbial difficulty... 

In the synthesis of the tetracyclic intermediates for the synthesis of isoarborinol and its CDE-antipode femenol, the stereochemistry of the Diels-Alder reaction can be varied using various Lewis-acid catalysts in aqueous media (Eq. 12.36).97 Their results show that the hydrophobic effects play an important role in enhancing reaction rates and can control product distribution. Novel 2,4-dialkyl-1-alkylideneamino-3-(methoxycarbonylmethyl)azetidines were obtained from aldazines and... 

This procedure describes the preparation and application of an effective chiral catalyst for the enantioselective Diels-Alder reaction.11 The catalyst is derived from optically active 1,2-diphenylethylenediamine, the preparation of which (either antipode) was described in the preceding procedure. The aluminum-based Lewis acid also catalyzes the cycloaddition of crotonoyl oxazolidinones with cyclopentadiene,11 and acryloyl derivatives with benzyloxymethylene-cyclopentadiene. The latter reaction leads to optically pure intermediates for synthesis of prostaglandins.11... 

Striking examples of this phenomenon are presented for allyl and homoallyl alcohols in Eqs. (5) to (7). The stereodirection in Eq. (5) is improved by a chiral (+)-binap catalyst and decreased by using the antipodal catalyst [60]. In contrast, in Eq. (6) both antipode catalysts induced almost the same stereodirection, indicating that the effect of catalyst-control is negligible when compared with the directivity exerted by the substrate [59]. In Eq. (7), the sense of asymmetric induction was in-versed by using the antipode catalysts, where the directivity by chiral catalyst overrides the directivity of substrate [52]. In the case of chiral dehydroamino acids, where both double bond and amide coordinate to the metal, the effect of the stereogenic center of the substrate is negligibly small and diastereoface discrimination is unsuccessful with an achiral rhodium catalyst (see Table 21.1, entries 9 and 10) [9]. 

The optimum 5,9-diMe geometry for writhing prevention is difficult to ascertain in some cases, a trans isomer is more effective (for example. Nos. 4 and 10) while in others, the cis (for example. Nos. 11 and 17). Some of these results are complicated, however, by the fact that compounds Nos. 10 and 17 show hotplate activities in mice. Again, activity differences between antipodes are consistent, (-(-pentazocine and (-(-cyclazocine being more active than corresponding (+)-forms (Nos. 2, 3 and 12,13 respectively). 

Further evidence upon the role of the 3-methyl substituent in reversed ester of pethidine is available from a recent investigation of enantiomorphs of a- and /3-prodine [280] (Table 5.11). It is to be noted that activity is governed by C-4 rather than C-3 geometry since the two more active optical antipodes (dextro a- and /3-prodine) have identical C-4 but different C-3 configurations. This result supports the view that the importance of the 3-methyl substituent lies in its influence upon the conformation of the molecule. Its effect upon activity in (-i-)-a-prodine where it is equational and favours a chair conformation is minor as seen by the similar potencies of (+)-a-prodine and 3-desmethylprodine. Both... 

The constitution of all the amino acids except diaminotrioxy-dodecanic acid is thus known, and with the exception of histidine they have all been synthesised. The separation of the synthetical compound into its optical antipodes has still to be effected in the case of several of the amino acids. 

Full details of Barton s selenofenchone (212 X = Se) and fenchylidenefeachane (212 X = 2-fenchylidene) synthesis (Vol. 6, p. 40) have been published" and Wynberg has discussed the antipodal interaction effect in the reductive dimerization of (+)- and ( )-camphor to bornylidenebornanes (Vol. 7, p. 41)," sensitized photo-oxidation of which has also been reported." The CuCl2-promoted dimerization of camphor-lithium enolate yields the expected mixture of dia-... 

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