Maria Ferretti

The epoxide hydrolase catalyzed hydrolysis of trans-3-bromo-1,2-epoxycyclohexane. A direct proof for a general base catalyzed mechanism of the enzymatic hydration.

Abstract The hydrolysis of (±)- trans -3-bromo-1,2-epoxycyclohexane in the presence of rabbit liver microsomes was investigated, and found to yield, beside c -3-bromocyclohexane- r -1, t -2-diol, 2,3-epoxycyclohexanol. It was demonstrated that the latter compound was the only product of the enzymatic reaction, whereas the diol resulted from a non enzymatic hydration in the reaction medium. These data provide the first direct proof for a general base catalysis in the enzymatic epoxide hydration, previously hypothesized on the basis of several lines of indirect evidence, and disprove alternative mechanisms involving protonation of the oxirane oxygen.

Reinvestigation of reductive butylation of aminophthalimides: new compounds with local anesthetic activity

A careful reinvestigation on reductive butylation of N-β-diethylaminoethyl aminophthalimides showed that this reaction yields the corresponding butylaminophthalimides together with the 1-hydroxy butylaminophthalimidines. The same reaction carried out on N-β-diethylaminoethyl aminophthalimides hydrochlorides gave the corresponding butylamino phthalimidines. The 1-hydroxy butylaminophthalimidines 5 and 6, tested for their local anesthetic properties, exhibited interesting activity comparable to that of Novesine, showing hence a potential therapeutic efficacy.

Regio- and stereoselectivity of the 3-membered ring opening of some 3,4-epoxytetrahydropyrans and of the corresponding epibromonium ions.

Abstract The reactions of 3,4-epoxytetrahydropyran and of its cis - and trans -2-methyl derivatives with hydrogen halides and with lithium aluminum hydride have been investigated in order to assess the influence of an O atom in the β position on the regioselectivity of the epoxide ring opening. All these reactions exhibit a high preference for nucleophilic attack at position 4, which decreases moderately only when the inductive effect of the O atom and the stereoelectronic requirements of the attack act in opposite directions. Similar trends are observed in the reactions of the 5,6-dihydro-2 H -pyrans with NBA, which occur with preferential nucleophilic attack by water at position 4 of the intermediate epibromonium ions. A remarkably high preference (96%) for electrophilic attack syn to the 2-Me group is observed in the latter type of reaction, in accordance with a previous proposal of a mechanism in which the nucleophilic step is rate determining.

Substituent effect on the diasterloselectivity of the acid hydrolysis and trichloroacetolysis of 9,10-oxides derived from trans-1, 2, 3, 4, 4a,

Abstract The mechanism of the acidic ring opening reactions of 2-aryloxiranes which are simple models of arene oxides, is still under discussion. Two different mechanisms have been suggested to rationalise the product distributions of the acid hydrolysis of the two types of conformationally restricted 2-aryloxiranes (2 and 3, and 5 and 6) : it would appear to be difficult to reconcile the two rationales. In order to gain insight into the reactions of benzo-epoxides of type 5 and 6, the 6-methoxy (5c and 6c) and the 7-bromo derivatives (5a and 6a) were synthesised and their acid hydrolysis (l :.l dioxane/water) and trichloroacetolysis in benzene were studied and compared with those of the unsubstituted compounds (5b and 6b). Contrary to expectations based on the results obtained with the epoxides of type 2 and 3, the introduction of the substituent on the aromatic moiety, in particular the strong electron-donating 6-methoxy, does not modify the complete anti diastereoselectivity observed in the acid hydrolysis of the unsubstituted epoxide 6b. In the case of the epoxides 5, on the contrary, the percentage of syn adduct increases noticeably with the ability of the aromatic moiety to stabilise the benzylic carbocationic centre. As for the trichloroacetolysis reactions, significant amounts of syn adducts are observed for both the epoxides 5 and 6 ; the syn stereoselectivity increases for both the epoxides 5 and 6 with the ability of the aryl to stabilise a benzylic carbocationic centre. A Hammett-type linear correlation was found between the diastereoselectivity and the σ+ constants for the acid hydrolysis of 5a-c and for the trichloroacetolysis reactions of 5a-c and 6a-c. The results obtained are difficult to explain on the basis of either of the mechanisms hypothesised for 2-aryloxiranes, at least as they were originally proposed.

Synthesis and proton nuclear magnetic resonance spectra of diastereoisomeric ethyl 3-hydroxy-2-methyl-3-(p-substituted phenyl)butyrates

A series of erythro- and threo-ethyl 3-hydroxy-2-methyl-3-(p-substituted phenyl)butyrates has been prepared The 1H n.m.r. spectra of these compounds and their use in assigning diastereoisomeric configurations are discussed

Enantioselectivity of the microsomal epoxide hydrolase: hydrolysis of (±)-cis-3-bromo-1,2-epoxycyclohexane

The acid-catalysed and the rabbit microsomal epoxide hydrolyse-catalysed hydrolysis of (±)-cis-3-bromo-1,2-epoxycyclohexane (1) have been investigated. Both reactions were completely regio- and stereo-specific, giving t-3-bromocyclohexane-r-1,t-2-diol (2) as the only product. Epoxide (1) was found to be a much better substrate for the epoxide hydrolyse than its trans-diastereoisomer. Under enzyme saturation conditions the hydrolysis was fairly enantioselective, as shown both by the biphasic shape of its kinetic profile and by the isolation of optically active (–)-(1R,2R,3S)-(1) and (–)(1R,2S,3R)-(2) at incomplete reaction. The absolute configurations have been deduced by correlation with (–)-(R,R)-trans-cyclohexane-1,2-diol. At about 30% conversion, the enantiomeric excesses of unchanged (1) and formed (2) were 24–30% and 56–60%, respectively, and racemic (2) was obtained after complete hydrolysis. The results have been rationalized by a competitive inhibition of (+)-(1S,2S,3R)-(1) on the hydrolysis of (–)-(1) and fit the previously proposed picture describing the substrate enantioselection carried out by the microsomal epoxide hydrolyse.

Boron trifluoride-catalysed rearrangements of some tetrasubstituted A-norcholestane epoxides. Evidence for the formation of an oxetan intermediate in a novel fragmentation reaction

3′,3′-Dimethyl-(3R)-spiro[A-norcholestane-3,2′-oxiran](1) and its 3S-isomer (2) give, on treatment with boron trifluoride–ether, acetone and A-norcholest-3(5)-ene (11). The oxetan (10). formed together with the allylic alcohol (9) during the chromatographic separation over alumina of (1) and (2), shows a similar behaviour, when submitted to the action of the same reagent. Similar treatment of 3-(1-deuterio-1-methylethyl)-3,5β-epoxy-A norcholestane (15) leads to acetone and 3-deuterio-A-norcholest-3(5)-ene (12). These results suggest a mechanism for all fragmentation reactions involving an oxetan intermediate such as (10).