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The first asymmetric synthesis of ethyl 4-aryl-3-azido-2-hydroxy-2-methyl-4-oxobutanoates via a cinchona organocatalyst induced aldol addition of α-azido ketones to ethyl pyruvate has been developed. The coupling reaction under optimized conditions was carried out to furnish tetrafunctionalized synthons with enantioselectivities of up to 91:9 and enriched diastereoselectivities of up to 95:5 (syn:anti).

A proline–calix[4]arene thiourea host–guest complex catalyzed intermolecular aldol reaction of aromatic aldehydes with cyclohexanone has been developed. The anti-configured products were obtained in good yields and with high enantioselectivities. The reaction is proposed to work via a modified Houk–List model, where the carboxylate part of the proline constitutes as a supramolecular system with the thiourea. The outcome of the study indicates the influence of the calix[4]arene thiourea on both the reactivity and selectivity in a non-polar reaction medium, even in the presence of water at moderate temperatures.

In this study, the production of enantiopure benzoin from rac-benzoin acetate was achieved by lipase catalyzed kinetic resolution combined with deracemization using Rhizopus oryzae (CBS111718). The growth cells were pretreated with 20 kHz and 30 kHz ultrasound irradiation and mechanical homogenization. Approximately 100% conversion and 96% enantiomeric excess of the product (S-benzoin) were obtained by applying 20 kHz ultrasound irradiation at pH 6. The deracemization process involves new and important processes that allow for the transformation of a racemate into a single stereoisomeric product in 100% theoretical yields. Moreover, the application of ultrasound increases the conversion rate by reducing mass transfer limitation.

alpha-Hydroxy ketones are important precursors for biologically active compounds, especially benzoins have important applications in chemistry and pharmacy. In this study enantioselective synthesis of benzoin was studied in supercritical carbon dioxide (SCCO2). Response surface methodology (RSM) was used to investigate the effects of temperature (T), pressure (P) and pH on enantiomeric excess of chiral benzoin using Candida cylindracea lipase in SCCO2. A 2(3) factorial design was performed to optimize the chiral benzoin synthesis. The optimum conditions were found as 40 degrees C, 79 bar, pH 6.4 and at these conditions enantiomeric excess (ee) was obtained as 62% (R-benzoin). At the optimum conditions, bases such as DMAP (4-dimethylaminopyridine) and triethylamine were added to reaction medium to increase kinetic resolution. The addition of DMAP considerably enhanced the enantiomeric excess (80% S-benzoin), while triethylamine had negative effect on ee. (C) 2008 Elsevier B.V. All rights reserved.

Aspergillus oryzae OUT5048 and Fusarium roseum OUT4019 were found to be effective biocatalysts in the reduction of benzils to optically active benzoins. Easily available symmetrical benzil derivatives were reduced to the corresponding benzoins [(S)-2-hydroxy-1,2-diphenylethanones] by A. oryzae OUT5048 with tip to 94% ee and by F roseum OUT4019 with up to 98% ee, respectively. In this Work. first general method for whole-cell-mediated selective reduction of benzils to benzoins is reported. It is also shown that this method is applicable for benzils with both electron-withdrawing and electron-donating groups. (c) 2008 Elsevier B.V. All rights reserved.

Enzymes are biodegradable and renewable resources that utilize water as the reaction solvent. Reactions catalyzed by enzymes are among the most effective, selective, and ‘green’ processes available today. The advantages of using biocatalysts include their high degree of regio- and stereo-specificity, versatility, and high reaction rates under mild reaction conditions. Enzyme catalyzed enantioselective C–C bond formation reactions are rather important aspects of synthetic organic chemistry. Thiamine pyrophosphate (TPP) dependent enzymes, especially, have an important role in the stereoselective formation of C–C bonds. This review covers the recent advances in enzyme catalyzed asymmetric C–C bond formation using the most pronounced thiamine pyrophosphate dependent enzymes: acetohydroxyacid synthase, benzaldehyde lyase, benzoylformate decarboxylase, pyruvate decarboxylase, and phenylpyruvate decarboxylase. These enzymes are all capable of acyloin-type condensation reactions in water under mild conditions, in turn leading to chiral α-hydroxy ketones, which are versatile building blocks for the pharmaceutical and chemical industries.

Enantioselective enzymatic hydrolysis of benzoyl-benzoin catalyzed by Candida cylindracea (CCL) lipase was carried out in SCCO 2 . It was found that CCL lipase enantioselectively hydrolyzed the ( R )-benzoin. The enantiomeric excess of product (ee p ) was maximized at 35 °C near the critical region 90 bar and obtained 61.3% at a 50% conversion. CCL did not catalyze the reaction in an atmospherical condition.

The chemoenzymatic synthesis of both of the enantiomers of pharmacologically interesting compounds such as 4,5,6,7-tetrahydro-4-oxo-benzofuran-5-yl acetate (2a), 4,5,6,7-tetrahydro-4-oxo-6,6-dimethylbenzofuran-5-yl acetate (2b), and their hydroxy derivatives 3a, 3b, 1-benzyl-4,5,6,7-tetrahydro-4-oxo-1(H)-indol-5-yl acetate (5), starting from 6,7-dihydrobenzofuran-4(5H)-one (1a), 6,7-dihydro-6,6-dimethylbenzofuran-4(5H)-one (1b), and 1-benzyl-6,7-dihydro-1H-indol-4(5H)-one (4) are reported. Manganese(III) acetate-mediated acetoxylation followed by the enzyme-mediated kinetic resolution of α′-acetoxy enone provides acetoxy and hydroxy derivatives in good yields and high enantiomeric excesses.

Novel norephedrine-based chiral ligands with multiple stereogenic centers were conveniently prepared from norephedrine and N-substituted pyrrole. These novel chiral ligands were used to catalyze the enantioselective addition of diethylzinc to aldehydes and to chalcone in high yields and with good to high enantioselectivities. The absolute configuration of products was found to be affected by the stereogenic centers on the norephedrine part of the novel chiral ligands.

Starting from simple aromatic aldehydes and acetylfuran, (E)-1-(furan-2-yl)-3-arylprop-2-en-1-ones (2) were synthesized in high yields. Cyclopropanation of the CC bond with trimethylsulfoxonium iodide (Me3SO+I−) furnished (furan-2-yl)(2-arylcyclopropyl)methanones 3 in 90–97% yields. Selective conversion of cyclopropyl ketones to their (E)- and (Z)-oxime ethers 5 and oxazaborolidine-catalyzed stereoselective reduction of the CN bond followed by separation of the formed diastereoisomers, furnished (2-arylcyclopropyl)(furan-2-yl)methanamines 6 in optically pure form and high yield. Oxidation of the furan ring of (S,S,S)-, (S,R,R)-, (R,S,S)-, and (R,R,R)-6a afforded the four stereoisomers of α-(2-phenylcyclopropyl) glycine (1a).

4-Oxo-3,4-dihydro-2-chromen-3-yl acetate is synthesized using manganese(III)acetate starting from 2,3-dihydro-4H-chromen-4-one. K2CO3 mediated hydrolysis of 4-oxo-3,4-dihdro-2-chromen-3-yl acetate furnished 3-hydroxy-2,3-dihydro-4H-chromen-4-one in high yield.The enantioselective hydrolysis of (±)-4-oxo-3,4-dihydro-2-chromen-3-yl acetate in various organic solvent-phosphate buffer (pH7) systems and enantioselective transesterification of (±)-3-hydroxy-2,3-dihydro-4H-chromen-4-one in organic solvents was investigated by screening a range of lipases. The lipase Amano PS, PPL, PLE and CCL-catalyzed asymmetric ester hydrolysis and transesterification afforded the enantiomers of 3-hydroxy-2,3-dihydro-4H-chromen-4-one and 4-oxo-3,4-dihydro-2-chromen-3-yl acetate with high enantiomeric excess (up to 97% ee) and in good yields.

The selective conversion of 1-(2-furyl)-2-hydroxyethan-1-one and ethyl 2-(2-furyl)-2-oxo acetate into (E)- and (Z)-oximes and oxime ethers followed by oxazaborolidine-catalyzed enantioselective reduction using different amino alcohols furnished both enantiomers of the important chiral building block 2-amino-2-(2-furyl)ethan-1-ol with an ee of up to 96%.

A combination of a thiourea tagged calixarene and L-proline is disclosed as catalyst for the aldol condensation of cyclohexanone and aromatic aldehydes.

A proline–thiourea host–guest complex is described as a self-assembled organocatalyst for the enantioselective Michael addition of aldehydes to nitroolefins and for the asymmetric α-aminoxylation of both aldehydes and ketones. The Michael adducts were obtained in good yields of up to 80%, high diastereoselectivities of up to 5:95, and high enantiomeric excesses of up to 98%. The optically active aminoxy alcohols were synthesized in 60–85% yields with 94–99% enantiomeric excesses after reduction of the α-oxidation products using NaBH 4 .

The selective conversion of 2,2,2-trifluoro-1-furan-2-yl-ethanone into ( E )- and ( Z )-oximes and oxime ethers and subsequent oxazaborolidine-catalyzed enantioselective reduction using different amino alcohols furnished both enantiomers of the important chiral building block 2,2,2-trifluoro-1-furan-2-yl-ethylamine with e.e. of up to 88%. Oxidation of the furan ring afforded both enantiomers of 3,3,3-trifluoroalanine in 91–93% yields.

Chiral 2-hydroxypropanone derivatives 5a−v, 8a−d, and 10a, b were formed by benzoylformate decarboxylase (BFD) catalyzed C−C bond formation. A donor aldehyde and acetaldehyde as an acceptor were carboligated in aqueous buffer solution with remarkable ease in high chemical yield and good to high optical purity. The substrate range of this thiamin diphosphate dependent enzyme was examined to employ this benzoin condensation type reaction in stereoselective synthesis. The observed dependence of the enantiomeric excess on the substitution pattern could be exploited to design substrates resulting in high selectivity. Best substrates with regard to optical purity were meta-substituted benzaldehyde derivatives. To enable a general and convenient applicability of the BFD-catalyzed C−C bond formation, analytical batch experiments were scaled up to give (S)-2-hydroxy ketones in good to high yields on a preparative scale. Further, the solubility of some of the organic substrates in aqueous solution was increased by the use of cyclodextrin or buffer/DMSO mixtures.

Mn(OAc)3 oxidation of aromatic ketones afforded the α-acetoxy ketones in good yield. Selective hydrolysis of the acetoxy ketones by the fungus Rhizopus oryzae yields (R)-hydroxy ketones in high enantiomeric excess.

d - and l -α-(2-carboxycycloprop-1-yl)glycines were synthesized from trans -1,3-di(2-furyl)propenone. Conversion of the double bond to a cyclopropane is followed by the formation of an oxime ether. Enantioselective reduction of the oxime ether, separation of diastereomers and oxidation of the furane rings gave enantiomerically pure d - and l -CCG I and CCG II. The structure of oxime 7b was determined by X-ray crystal structure analysis. The key step is the oxazaborolidine catalyzed enantioselective conversion of oxime ethers to amines.

New catalysts have been prepared from (S)- and (R)- proline and the asymmetric borane reduction of prochiral ketones using these catalysts has been studied. The secondary alcohols were obtained in 76–95% yield with 57– 96% enantiomeric excesses.

Application of the SAMP-/RAMP-hydrazone method offers an efficient and flexible access to compounds with a quaternary stereogenic center. Examples bearing silyl, thio, phenyl, aldo, keto, ester, and alkyl functionalities are described. The 2-phenylaldehydes and -ketones and the β-keto esters 4 were obtained in good overall yields and with variable enantiomeric excesses. The synthesis of the thiolated 2-formyl and 3-formyl carboxylic esters 12 was achieved in high overall yields and with high enantiomeric excesses. The silylated carboxylic ester and acids 16 were produced in moderate to high overall yields and with moderate to excellent enantiomeric excesses, depending on the electrophile used for the quaternization. The absolute configurations of the compounds 12 and 16 were determined by X-ray structure analyses, and the mechanism of the quaternization is postulated.

Flexible protected 1,3,4-trihydroxy-2-butanone is synthesized in high enantiomeric excesses by using asymmetric homo- and cross- acyloin coupling of aliphatic aldehydes catalyzed by benzaldehyde lyase.

Sodium periodate is a better reagent than sodium bismuthate, manganese dioxide, or lead tetraacetate for the cleavage of unsaturated α-ketols and affords η1-oxo-α,β-unsaturated acids in good yield. The combination of this cleavage reaction and a rhodium(I)-mediated decarbonylation of η1-oxo-α,β-unsaturated esters derived from polycyclic systems provided an enantioselective synthesis of cyclic systems bearing contiguous quaternary centers where one of the centers possessed gem-dimethyl groups

Mn(OAc)3 oxidation of aromatic ketones afforded the α-acetoxy ketones in good yield. Selective hydrolysis of the acetoxy ketones by the fungus Rhizopus oryzae yields (R)-hydroxy ketones in high enantiomeric excess.

A proline–thiourea self-assembled organocatalyst is described as a good catalyst for the enantioselective nitro-Michael addition of aldehydes to nitroalkenes. The reaction is efficient with 5% of the thiourea, to give moderate to good enantioselectivity (up to 76% ee). High syn-selectivity was obtained with both branched and unbranched aliphatic aldehydes. This is the first example of self-assembly of organocatalysts with an achiral additive in a Michael addition wherein aldehydes are utilized as donors.

A proline-thiourea self-assembled organocatalyst is described as a good catalyst for the enantioselective nitro-Michael addition of aldehydes to nitroalkenes The reaction is efficient with 5% of the thiourea, to give moderate to good enantioselectivity (up to 76% ee) High syn-selectivity was obtained with both branched and unbranched aliphatic aldehydes This is the first example of self-assembly of organocatalysts with an achiral additive in a Michael addition wherein aldehydes are utilized as donors. (c) 2009 Elsevier Ltd All rights reserved

Proline–thiourea host–guest complex-catalyzed direct enantioselectivealdol reactions have been developed, in which the catalytic activities were evaluated in the direct asymmetricaldol reactions of various aromatic aldehydes and cyclohexanone.

Proline-thiourea host-guest complex-catalyzed direct enantioselective aldol reactions have been developed, in which the catalytic activities were evaluated in the direct asymmetric aldol reactions of various aromatic aldehydes and cyclohexanone.

Previously reported experimental results indicate that photooxygenation of homochiral N-(hydroxyalkyl)-2-methylpyrroles with singlet oxygen yields transrather than cis-bicyclic lactams as the major product. In this study, the origin of selectivity in this reaction has been investigated with computational methods. Relative stabilities of homochiral N-(hydroxyalkyl)-2-methylpyrrole conformers and their effect on pi-facial selectivity of O-1(2) were extensively studied. Stepwise and concerted reaction mechanisms, starting from the endoperoxide intermediates, were proposed and modeled in vacuum using the UB3LYP method with the 6-31+G** basis set. Solvent calculations were carried out in CH2Cl2, by means of the integral equation formalism-polarizable continuum model (IEF-PCM) at the UB3LYP/6-31+G** level of theory. Free energies of activation leading to both diastereomers were analyzed in an effort to explain the stereoselectivity and product distribution. Steric interactions among the pyrrole substituents were shown to lead to a rotational barrier higher than 10 kcal/mol. Hence, hindered internal rotation is suggested to cause one pyrrole conformer to be substantially overpopulated. This in turn has a major effect on pi-facial selectivity of O-1(2), thereby favoring one endoperoxide over the other and leading to the diastereoselective synthesis of trans-pyrrolooxazolones. The importance of hindered internal rotors, for an accurate calculation of the frequency factors of a chemical reaction, has already been mentioned in the literature many times; however, in this work hindered internal rotors also seem to dictate the diastereoselective outcome of the reaction.

A new enantioselective synthesis of furan-2-yl amines and amino acids is described, in which the key step is the oxazaborolidine-catalyzed enantioselective reduction of O-benzyl (E)- and (Z)-furan-2-yl ketone oximes to the corresponding chiral amines. The chirality of the furan-2-yl amines is fully controlled by the appropriate choice of the geometrical isomer of the O-benzyl oxime. Oxidation of the furan ring furnished amino acids in high yields.

[reaction: see text] Benzaldehyde lyase from the Pseudomonas fluorescens catalyzes the reaction of aromatic aldehydes with methoxy and dimethoxy acetaldehyde and furnishes (R)-2-hydroxy-3-methoxy-1-arylpropan-1-one and (R)-2-hydroxy-3,3-dimethoxy-1-arylpropan-1-one in high yields and enantiomeric excess via acyloin linkage. Aromatic aldehydes and benzoins are converted into enamine-carbanion-like intermediates prior to carboligation.

(R)-Benzoins and (R)-2-hydroxypropiophenone derivatives are formed on a preparative scale by benzaldehyde lyase (BAL)-catalyzed C−C bond formation from aromatic aldehydes and acetaldehyde in aqueous buffer/DMSO solution with remarkable ease in high chemical yield and high optical purity. The substrate range of this thiamin diphosphate-dependent enzyme was examined with respect to a broad applicability of this benzoin condensation-type reaction in stereoselective synthesis.

An efficient, overall enantioselective variant of the Hantzsch synthesis of 4-aryl-1,4-dihydropyridines 5 (ee = 84 - 98%), important biologically active compounds (e. g. as calcium channel blockers), is described. Key step of the new procedure is the asymmetric Michael addition of metalated chiral alkyl acetoacetate hydrazones ( S )- 2 to the Knoevenagel acceptors 4 . An accurate method to determine the enantiomeric excess of chiral dihydropyridines is also reported.

Asymmetric Michael addition of lithiated methyl ketone SAMP-hydrazones (S)-2 to 2-benzylidenemalonates and -dinitriles 3 followed by oxidative cleavage of the 1,4-adducts (SR)-4 by ozonolysis affords 2-substituted 4-oxo diesters and -dinitriles (R)-5 in good overall yields of 50–82% and high enantiomeric excesses (ee ≧ 95%). Asymmetrische Michael-Additionen via SAMP-/RAMP-Hydrazone. – Enantioselektive 1,4-Addition von Methylketonen an Knoevenagel-Akzeptoren1) Asymmetrische Michael-Addition von lithiierten Methylketon-SAMP-Hydrazonen (S)-2 an 2-Benzylidenmalonsaureester und -dinitrile 3 und anschliesende oxidative Spaltung der 1,4-Addukte (SR)-4 durch Ozonolyse liefert 2-substituierte 4-Oxodiester und -dinitrile (R)-5 in guten Gesamtausbeuten von 50–82% und hohen Enantiomerenuberschussen (ee ≧ 95%).

An efficient and highly diastereo- and enantioselective annulation of cyclic 1.3-diketones to tetrahydro-quinolinediones of type 4 and 5 in good overall yields is described. The key step is the Michael addition of the corresponding lithiated SAMP-/RAMP-hydrazones to arylidenemalonates followed by lactamization with virtually complete asymmetric induction (de,ee≧98%).

Both enantiomers of benzoins and (R)-2-hydroxy-1-phenylpropanone analogues were obtained in high yield on a preparative scale starting from aromatic aldehydes, rac-benzoins and aliphatic aldehydes via enzyme-catalysed C-C bond cleavage and C-C bond formation reactions.

A proline-thiourea host-guest complex is described as a self-assembled organocatalyst for the enantioselective Michael addition of aldehydes to nitroolefins and for the asymmetric ?-aminoxylation of both aldehydes and ketones. The Michael adducts were obtained in good yields of up to 80%, high diastereoselectivities of up to 5:95, and high enantiomeric excesses of up to 98%. The optically active aminoxy alcohols were synthesized in 60-85% yields with 94-99% enantiomeric excesses after reduction of the ?-oxidation products using NaBH4. © 2013 Elsevier Ltd. All rights reserved.