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(R)-(+) and (S)-(−)-1-phenylethylamine have been shown to promote highly diastereoselective and complementary enantioselective formal [3 + 2]carbocyclization reactions between 2,3-butanedione and conjugated nitroalkenes with formation of enantiomerically rich 2-hydroxy-3-nitrocyclopentanone derivatives. The reactions were carried out both in solvent and under solvent-free conditions. The absolute configurations of the products were assigned by X-ray and circular dichroism spectra analyses. Chirality 24:1005–1012, 2012. © 2012 Wiley Periodicals, Inc.

The distinctive nucleus of kainoid amino acids, (2S,3R)-(+)-2-carboxypyrrolidine-3-acetic acid 6, was synthesized by a chemoenzymatic process, exploiting the diastereomeric cis/trans methyl pyroglutamate derivatives 10a, 10b, 10c/11a, 11b, 11c as key intermediates. These mixtures, when subjected to a kinetic resolution mediated by α-chymotrypsin, reacted diastereo-, regio-, and enantioselectively to give the trans derivatives (+)-10a, 10b, 10c possessing the correct (2S,3R) configuration. Subsequently, the desired product (2S,3R)-(+)-6 could be obtained after well-established transformations. Chirality, 2012. © 2011 Wiley Periodicals, Inc.

Esterase from Horse Liver (HLAP) was able to hydrolyze a series of linear and cyclic β,β-dialkyl-γ-nitroesters, in spite of the well-known reluctance of hydrolytic enzymes to recognize and transform hindered substrates, such as those possessing a stereogenic quaternary carbon atom next to the reaction site. The resulting optically active γ-nitroesters gave access to optically active β,β-disubstituted γ-aminoacids as well as α,α-disubstituted succinic acids, both being biologically relevant compounds.

Both enantiomerically pure antipodes of GABA analogues were prepared as hydrochloride salts, by enzymatic kinetic resolution of their precursors ethyl 2-(nitromethyl)alkanoates. These latter compounds can be easily transformed into enantiomerically pure 2-alkylsuccinic acids by a Nef reaction followed by oxidation. Interestingly, this reaction was particularly easy for the neopentyl derivative ( S )-(+)- 7d , which underwent conversion into its corresponding succinic acid derivative ( S )-(−)- 8d in buffered solution. The absolute configurations of the main compounds of interest involved are given, together with their CD spectra.

A new, five-step route to ( Z)-pulchellalactam, a CD45 protein tyrosine phosphatase inhibitor, is presented. Key steps are the copper(I) chloride-bipyridyl catalyzed atom-transfer radical cyclization- of an appropriate allyl α,α-dichloroacetate and the subsequent dehydrochlorination/prototropic rearrangement of the resulting dichlorolactone.

(R)-(+)-Paraconic acid 4 , (S)-(−)-terebic acid 6 and their corresponding methyl and ethyl esters having ee’s ranging from 60% to 92% were obtained by enzymatic resolution of their racemates. The enzymatic resolution of racemic ethyl γ-methylparaconates 14a and 14b allowed the isolation of the unreacted ester (2R,3R)-(+)-14a and that of the lactonic acid (2S,3R)-(−)-5b with 80% and 93% ee, respectively, the former by the use of Horse liver acetone powder (HLAP), the latter using α-chymotrypsin (α-CT). The enantiomeric ethyl (2S,3S)-(−)-14a and (2S,3R)-(−)-14b , both with >99% ee, were obtained by baker’s yeast reduction of diethyl acetylsuccinate.

The structure of enamines derived from 1-phenylsulfonyl-2-propanone was studied and their nucleophilic reactivity towards electrophiles was investigated as far as the equilibrium between the more and less substituted tautomers and the asymmetric induction on the products by a chiral amine moiety are concerned.

The application of a computational approach, based on molecular dynamics (MD) simulations and quantum mechanical-free energy (QM-FE) calculations, to explain the different substrate specificity and enantioselectivity of -chy- motrypsin (-CT) in the hydrolysis of methyl cis -a ndtrans-5-oxo-2-pentylpirrolidine-3-carboxylates is described. By applying a combination of molecular mechanics energy derived from MD simulations in explicit solvent, and solvation free energy derived from a continuum solvation model, we have calculated reasonable absolute free energies of binding (Gbind) for each -CT/enantiomer complex formation, and elucidated the balanced nature of the factors contributing to Gbind. Furthermore, our calculations based on QM-FE techniques have yielded an insight into the major issues affecting the observed enantioselectivity in the hydrolysis of substrate ester bonds by -chymotrypsin. © 2003 Elsevier Ltd. All rights reserved.

Enantiomerically pure methyl esters of (+)-(2R,3S)- and (−)-(2S,3R)-5-oxo-2-pentylpyrrolidine-3-carboxylic acid with 99% and 98% ee were obtained by enzymatic resolution of the corresponding racemic mixture using α-chymotrypsin and pig-liver acetone powder, respectively. Their absolute configurations were established by chemical methods, i.e., conversion of the trans-γ-lactam moiety to the corresponding γ-lactone of known configuration. The favorable interactions between the trans-γ-lactam and α-chymotrypsin were rationalized by molecular-mechanics calculations, which suggest a different situation for the cis-diastereoisomer.

In our previous work, racemic β-carbomethoxy-γ-lactams were subjected to enzymatic hydrolysis in the presence of α-chymotrypsin. The hydrolysis of three N -substituted lactams proved to be highly enantioselective, whereas an unsubstituted lactam was recovered in racemic form. Thus, in this paper we applied several molecular modeling protocols to explain the substrate specificity and the enantioselectivity of this enzyme. The adopted procedures involved accurate docking experiments of both enantiomers of each lactam to the protein active site, whose 3-D structure was obtained from X-ray crystallographic data, followed by extensive conformational and energetic analysis of the computer-generated complexes. The results obtained fully account for the experimental evidences on the enantioselective hydrolysis of these interesting, potential drugs by α-chymotrypsin.

A series of yeasts were used in the bioreductions of aliphatic and aromatic gamma- and delta -ketoacids and esters to investigate the preparation of enantiomerically pure gamma- and delta -lactones through the intermediacy of their corresponding gamma- and delta -hydroxyacids and esters. Bioreduction of ethyl 4-oxononanoate 2a with Pichia etchellsii afforded the gamma -nonanolide (+)-5a with 99% e.e., while Pichia minuta proved to be the best choice for the bioreduction of ethyl 2-oxocyclohexylacetate 2e, which afforded cis-(-)-5e and trans-(-)-5e with 98 and 99% e.e., respectively. Reduction of 3-(2-oxocyclohexyl)propionic acid 3e with Pichia glucozyma gave predominantly the corresponding delta -lactone trans-(-)-6e with 94% e.e., whose absolute configuration was determined by means of CD spectroscopy.

The possibility of using enzymes for the kinetic resolution of an α-methylene-γ-lactone was explored. The probe molecule, ethyl 2-methyl-4-methylene-tetrahydro-5-oxo-2-furancarboxylate was successfully resolved with Porcine pancreatic lipase and Candida rugosa lipase, in the presence of a cosolvent, leading to both enantiomers of the corresponding acid with high enantiomeric excesses.

The synthesis of Z- and E-arylhydrazones by 1,4-conjugate addition of glycine, L-alanine and L-tyrosine ethyl esters to phenylazostilbene 1, p-nitrophenylazostilbene 2 and p-nitrophenylazocyclohexene 3 is described. Optically active N-functionalized 2-aminocyclohexanones 22–26 are obtained by TiCl3 catalysed hydrolysis of the corresponding hydrazones. However, they have been shown to be unstable, as they undergo easy oxidation by air. X-Ray analysis of the phenylhydrazone 8a in the Z configuration is also reported.

The one-pot three-component reaction between diacetyl compounds (I), β-nitrostyrene (II), and L-proline (III) in isopropanol at room temperature affords the regioisomeric cycloadducts (IV) and (V).

Direct L-proline-catalyzed reaction of diazadienes (I) with benzylic aldehydes provides access towards title dihydropyridazines (III) in moderate enantioselectivity.

Enantioselective hydrolysis of the methyl ester of racemic paraconic acid C75 (I) is accomplished by means of acylase I from Aspergillus to afford after recrystallization enantiopure acid (II).

Three linear α-ketoenamines were allowed to react with a series of cyclic and acyclic nitroolefins, to yield aminocyclopentene derivatives with high diastereoselectivity. The corresponding polysubstituted nitrocyclopentanones were obtained by hydrolysis, which also proceeded with a high degree of diastereoselectivity when the system was prochiral.

The title compound reacted with nitroolefins to give either cyclobutanes or pyrrolizidine derivatives, depending on whether it acted as an enamine or as a 1,3-dipole.

The synthesis of Z- and E-arylhydrazones by 1,4-conjugate addition of glycine, L-alanine and L-tyrosine ethyl esters to phenylazostilbene 1, p-nitrophenylazostilbene 2 and p-nitrophenylazocyclohexene 3 is described. Optically active N-functionalized 2-aminocyclohexanones 22–26 are obtained by TiCl3 catalysed hydrolysis of the corresponding hydrazones. However, they have been shown to be unstable, as they undergo easy oxidation by air. X-Ray analysis of the phenylhydrazone 8a in the Z configuration is also reported.

The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and i-proline alkyl esters with several nitroolefins was investigated. Cyclic and acyclic nitroolefins add to the anti form of the ylide in a highly diastereoselective but poorly regioselective manner to give pyrrolizidine derivatives. In a few cases, the stereochemical results strongly support a stepwise mechanism.

Trisubstituted 1,4,5,6,-tetrahydro-7H-indolones are obtained in a one-pot synthesis from conjugated nitroolefins and α-ketoenamines derived from α-amino esters and cyclohexane-1,2-dione. In some cases bicyclo[3.2.1]octan-8-one and 1,2-oxazine N-oxide derivatives are isolated.

Baker's yeast reduction of 3-(2-nitroethyl)-tetrahydro-4H-pyran-4-one 10 and 3-(2-nitroethyl)-tetrahydro-4H-thiopyran-4-one 11 gave the corresponding optically active cis alcohols with good diastereo- and enantioselectivity. The unreacted optically active ketones were also isolated.

The reactivity of the title dienamine towards conjugated nitroolefins has been investigated. With 1-nitrocyclopentene carbocyclic products largely predominated, whereas with 1-nitrocyclohexene only Michael-type products were formed. The behaviour of β-nitrostyrene was found to be dependent on the reaction conditions used.

Enantiomerically pure condensed δ-lactones have been prepared from the corresponding δ-ketoesters by the use of Saccharomyces cerevisiae . The reactions were not only highly enantioselective but also highly diastereoselective, provided the baker's yeast was preincubated at 50°C for 30 min. Interestingly, and contrary to what is usually found, the use of nutrients inhibited the bioreductions. The relative configurational assignments have been made by means of NMR, while the absolute configurations and conformations of the lactone rings were attributed by means of CD studies.

Enantiomerically pure tetrahydro-5-oxo-2-furancarboxylic esters can be prepared either by enzymatic resolution of the racemic γ-lactones themselves or by bioreduction with baker's yeast of dialkyl 2-oxoglutarates and subsequent cyclization of the resulting dialkyl 2-hydroxyglutarates. The best results were obtained by the former route, by which the desired compounds were isolated in high enantiomeric excess. Bioreductions were less satisfactory. In fact the hydroxyester intermediates were initially formed as racemic mixtures and their final enantiomeric enrichment was reached by asymmetric destruction, occurring in the bioreaction medium, however at the same time large amounts of alkyl 4-hydroxybutanoates were formed as side products.

Enantiomerically pure 4-methyl-tetrahydro-5-oxo-2-furancarboxylic acids and esters are prepared by enzymatic resolution of the chiral racemic esters. Their stereochemistry as well as their absolute configurations have been established by chemical correlation. The influence of the alkoxycarbonyl group at C-2 and that of the methyl group at C-4 on the sign of the Cotton effect in their CD spectra have been investigated. Formation of enantiomerically pure hydroxydiesters, precursors of the above-mentioned γ-lactones, by baker’s yeast reduction of the corresponding ketodiesters was unsatisfactory.

The formation of enantiopure δ-lactones condensed with alicyclic rings has been achieved either by reduction with baker's yeast of the corresponding δ-keto esters and δ-keto acids or by enzymic resolution of the former compounds. The absolute configurations of the lactones were determined by means of CD spectroscopy, using the correlation method.

Three α-methylene-γ-carbomethoxy-γ-butyrolactams (methyl α-methylene-pyroglutamates) 11, 12 and 13, differing in the substitution at the heterocyclic nitrogen, as well as the structurally related γ-lactones 14 and 15 were synthesised and resolved enzymatically by hydrolysis of their ester function, mediated by commercially available hydrolytic enzymes. In particular, the α-chymotrypsin proved to be active to all the substrates examined, displaying a different degree of activity and enantioselectivity, this latter increasing significantly towards the substrate with an aromatic substituent at the nitrogen.

Enantioselective hydrolysis of methyl ester of (±)-C75 was successfully accomplished by means of Acylase I from Aspergillus to afford (2R,3S)-(+)-C75 with 96% e.e. The unreacted methyl ester was recovered with >99% e.e. This latter compound was either chemically or enzymatically hydrolyzed to furnish (2S,3R)-(–)-C75 with >99% e.e.

The reaction of 2,3-butanedione, ethyl pyruvate and phenylglyoxal with β-nitrostyrene and L-proline in isopropanol at room temperature gives substituted pyrrolizidines, as a result of one-pot three component reaction.On the contrary, a spiropyrrolizidine is formed from 1,2-cyclohexanedioneonly when the reaction is carried out in refluxing isopropanol, whereas at room temperature, incorporation of the amine component into the products is not observed and bicyclo[3.2.1]octanones are formed, as a result of atandem Michael-Henry reaction. In this latter case L-proline acts as an organocatalyst, although with modest enantioselectivity. Thestereochemistry of the products is given and the mechanism of formation of products is postulated, on the basis of stereochemical arguments.

Chiral non-racemic 1,4-dihydropyridazines were prepared by the reaction of 1,2-diaza-1,3-dienes with arylacetaldehydes under organocatalytic conditions. l -Proline and (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine coupled with trifluoroacetic acid were used as organocatalysts. Enantiomeric excesses ranged from 25% to 78%.

The cis - and trans -4-benzylparaconic acids and their ethyl esters were synthesized with high enantiomeric excess by hydrolysis of the corresponding diastereomeric lactonic esters using α-chymotrypsin. Thus, at low conversion values, cis - and trans -4-benzyl-5-oxo-3-tetrahydrofurancarboxylic acids were separately isolated with 99% ee and 92% ee, respectively. Both ethyl ester diastereomers were also obtained in enantiopure form. The absolute configuration of the trans -lactonic acid was assigned by 1 H NMR analysis of its ester derivatives with both enantiomers of 1-(9-anthryl)-2,2,2-trifluoroethanol, while that of the cis -lactonic acid was assigned by means of X-ray analysis of a crystalline derivative. The circular dichroism curves of the products obtained are also reported.

The preparation of the 3,4-dialkyl-substituted maleic anhydride nucleus, through the functional rearrangement of dichloro γ-lactams, allowed the comparison of various N-substituents in the functional rearrangement step. The 2-pyridyl group proved to be the most appropriate N-substituent for the hydrolysis of the 5-methoxy-1,5-dihydro-2H-pyrrol-2-one intermediate into the 5-hydroxy adduct, and for the hydrolysis of the maleimide nucleus into the maleic anhydride. The oxidation of the 5-hydroxy-1,5-dihydro-2H-pyrrol-2-one into the corresponding maleimide was achieved with manganese(IV) oxide.

The synthesis of γ-phenyl and γ-( n -pyridyl)paraconates was accomplished by chemical reduction of their respective ketodiester precursors followed by cyclisation of the resulting hydroxy diester intermediates. The cis - and trans -lactones thus obtained were separated and separately subjected to enzymatic hydrolysis with HLAP. The cis -lactonic esters had enantiomeric excesses ranging from 94% to 99%, while for the trans -isomers the ee’s ranged from 80% to 93%. The same ketodiester precursors were subjected to reduction with a series of yeasts. The absolute configuration of trans -(−)-2-pyridyl paraconic acid was assigned by means of X-ray analysis of its hydrobromide salt, while the absolute configurations of the other lactones were determined via analysis of their respective CD curves.

Enantioselective deacetylation of a-(±)-botryodiplodin acetate was successfully accomplished by means of lipase PS to afford (+)-botryodiplodin and a-(+)-botryodiplodin acetate with high enantiomeric excesses. Enzyme-mediated transesterification of the acetylated molecule with n-butanol, as well as its hydrolysis in several organic solvents, are also reported. The CD spectra of (+)-botryodiplodin and a-(+)-botryodiplodin acetate are also presented.

A study of the behaviour of some electron-rich 2-methyleneindolines (1–3) with different electron-poor reagents (formation of new carbon–carbon and nitrogen–carbon bonds) has furnished interesting results from both synthetic and the mechanistic viewpoints. Enamines 1–3 have been reacted with the β-nitroenamines 4–7 (reaction CeCl3·7H2O promoted), giving the polymethine dyes 14–23. The same bases 1–3 have been nitroalkylated with the nitroolefins 8–10, furnishing the indolines 24–32, and the diastereoselectivity of the reaction has been thoroughly investigated. The most unexpected results derived from the first example of reaction of Fischer's bases with 1,2-diaza-1,3-butadienes. In fact, with 11–13, the ‘unknown’ indoline spirodihydropyrroles 33–40 were formed. Their structures were unambiguously assigned, and we determined, as an example, that of 33 by X-ray analysis.

Both enantiomers of the pharmacologically active GABA analogues 4-amino-3-phenyl and 4-amino-3-(4-chlorophenyl)butyric acid (Baclofen) with high enantiomeric excesses were synthesized by a chemoenzymatic method involving α-chymotrypsin mediated kinetic resolutions of the corresponding 3-phenyl- and 3-(4-chlorophenyl)-4-nitrobutyric acid methyl ester precursors.

Lipase PS acetylation of diastereomeric dihydro-4-hydroxymethyl-2(3H)-furanones bearing a methyl or a pentyl group at C-5 have been studied. Higher enantioselectivities were found for the cis-isomers with respect to the trans-isomers. They were also higher for the systems bearing the longer alkyl chain. Lipase PS-catalyzed hydrolyses of racemic acetates were found to follow the same trend, although the efficiency of the enzyme was lower than in the acetylation reactions. These results were supported by molecular modelling studies that correctly predicted the maximum stereoselectivity for the cis-isomer of 5-pentyl substituted lactones both in acetylation and in hydrolysis reactions.

Enantiopure cis- and trans-4-methylparaconic acids and their alkyl esters were synthesized by a procedure involving the kinetic enzymatic resolution of diastereomeric lactonic esters. Thus, ethyl cis- and trans-4-methyl-5-oxo-tetrahydrofuran-3-carboxylates were isolated, at high conversion values, with 99% ee from the hydrolyses with HLAP and a-CT, respectively. The corresponding enantiopure cis- and trans-lactonic acids were also obtained. The absolute configurations of the products were assigned by chemical correlation, by analysis of their circular dichroism spectra and by electronic structure calculations. All three methodologies lead to the same assignment for the species considered, another example of successful interplay between experiment and theory.

Michael addition of lithium enolates of γ-butyrolactone 1 and α-methyl-γ-butyrolactone 1 ′ to ( E )-1-nitropropene 2 , ( E )-β-nitrostyrene 3 and ( E )-2-nitro-1-phenylpropene 4 is described. Reactions of the lithium enolate of 1 ′ with 2 and 4 occurred with high diasteroselectivity (80 and 92% d.e., respectively). Reactions of the zinc enolate of 1 ′ with two β-nitroenamines and two methylthio-substituted 1-amino-2-nitro-1,3-dienes were also examined. Catalytic reduction of the nitroalkylated and nitroalkenylated products allowed the achievement of functionalized γ-lactams and/or cyclic hydroxamic acids.