Conduritols

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]. 

Figure 6.52 Enzymatic alcoholysis of racemic conduritol E tetraacetate.

Conduritol Epoxides (1,2-Anhydroinositols) and Sugar-derived Epoxides. 364... 

If k2 > kj, the glycosyl-enzyme intermediate will accumulate, and may be trapped by the rapid denaturation of the enzyme in the presence of (saturating) amounts of substrate. With -glucoside Aj from Asp. wentii and 4-nitrophenyl [ C]-2-deoxy-) -D-irra />jo-hexopyranoside, it was possible to identify the intermediate as a glycosyl ester (acylal) of 2-deoxy-D-arabino-hexose bound to the same aspartate residue that had previously been labeled with the active-site-directed inhibitor conduritol B epoxide and with D-glucal." This constituted an important proof that the carboxylate reacting with the epoxide is directly involved in catalysis. 

The specific reaction of a conduritol epoxide requires, in addition to the acidic group for the protonation of the oxirane, a nucleophile for the formation of the covalent bond. In all cases studied so far, this is the carboxylate... 

The wide scope of the application of conduritol epoxides for the active-site-directed inhibition is seen from the data given in Table XI. Only a few... 

Kinetic Constants for the Inactivation of Glycosidases by Conduritol Epoxides Corresponding to their Respective Glycon Specificities (see Text)... 

A. Nahrstedt, W. Hosel, and A. Walther, Phytochemistry, 18(1979) 1137-1141 Resistance of the /(-D-glucosidases of Refs. 151 and 152 against inactivation by conduritol B epoxide, W. H6sel, personal communication. 

Despite a higher intrinsic reactivity, epoxides of type 35 and 36 show a lower inactivation rate kj(max), as seen in Table XI, than the conduritol epoxides. This is probably caused by the greater flexibility of the epoxyalkyl chain in the active-site cleft, and by non-productive binding in positions where the oxirane is not within reach of the catalytic groups of the active site. For epoxypropyl oligosaccharides, this would hold even when the inhibitor occupies the correct subsites. 

A new type of mechanism-based enzyme-inactivators, which are related to conduritol epoxides with respect to activation at the active site, was introduced by Tong and Ganem, " who prepared the aziridine 37 from the o-galacto analog of 1-deoxynojirimycin. Compound 37 proved to be a pp-... 

Comparison of the kinetic data for 37 with those with the same enzyme and conduritol C fra 5-epoxide (27, see Table XI) reveals an estimated 50-fold higher reactivity of 37 if based on ki(max)/Ki. (This estimate takes account of the different temperatures employed, namely, 37° in Ref. 178 and 25 ° for the data in Table XI, re-evaluation of the data given in gave... 

The only other examples of bromoconduritol inhibition reported so far are a cytosolic jff-D-glucosidase from calf liver and the lysosomal ff-D-glu-cosidase from calf spleen. In spite of the 6500-fold difference in their reactivity with conduritol B epoxide (see Table XI), both enzymes are rapidly inactivated by bromoconduritol F, with kj(max)/Kj 10 M min for the cytosolic enzyme and lq(max)/Ki 3.2 10 for the crude and 3.9 10 M min for the purified lysosomal enzyme. It should be noted that purification of the lysosomal jS-D-glucosidase had effects on the reactivity with bromoconduritol F similar to those it had on the reactivity with conduritol B epoxide (see Table XI). 

Labeling experiments with conduritol epoxides have permitted determination of the amino acid sequence around the essential aspartate (glutamate) with the following results. 

Analogs of conduritols from toluene cA-dihydrodiol by reaction with singlet oxygen followed by scission with thiourea (Figure 8.7d) (Carless et al. 1989). 

FIGURE 8.7 Examples of chemical syntheses based on cyclohexadiene cis dihydrodiols (a) pinitol, (b) condnramine A, (c) (-)-laminitol, and (d) conduritol analogs. (From Neilson, A.H. and Allard, A.-S. The Handbook of Environmental Chemistry, Springer, 1998. With permission.)... 

In laboratory synthesis, these catalysts have been utilized primarily to form both common and large rings by coupling two terminal alkenes.295 For example, catalyst H has been used to synthesize the highly oxygenated cyclohexenes known as conduritols. 

Condensation of p-acetylben-zenediazonium bromide with acrylic acid, 51, 1 Conduritol-D, 50, 27 Conjugate addition of Grignard reagents, 50, 41 CONTROLLED POTENTIAL ELECTROLYTIC REDUCTION 1,1-BIS (BROMOMETHYL)CYCLOPROPANE,... 

Reduction of 166 with NaBH4/CeCl3 in aqueous MeOH afforded the protected, chiral derivative 169 of Conduritol-D in 73 % yield. Conduritol-D (170) was formed nearly quantitatively upon acid hydrolysis of 169. Treatment with Ac20/pyridine gave the crystalline tetracetate 171. Reduction of 165 with diisobutylaluminium hydride (DIBAL) in toluene (-80 °C, 6 h) gave 172, another chiral derivative of Conduritol-D, in 97 % yield. Alternatively, 167 was reduced with LiAlH4 (THF, -90 °C, 6 h) into 173 (95 %). Deprotection of 167 with tetrabutylammonium fluoride... 

The stoichiometric approach has been successfully used as the key step for the synthesis of biologically active compounds, to obtain enantioenriched allylic alcohols, as illustrated by the synthesis of conduritols derivatives 84 or the aggregation pheromone of the Douglas-fir beetle 85 , as well as enantioenriched oxiranes, intermediates for the synthesis of (—)-isomenthone 86 ° (Scheme 34). 

L. Premkumar, A. R. Sawkar, S. Boldin-Adamsky, L. Toker, I. Sihnan, J. W. Kelly, A. H. Futerman, and J. L. Sussman, X-ray structure of human acid-p-glucosidase covalently bound to conduritol-B-epoxide,./. Biol. Chem., 25 (2005) 23815-23819. 

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