Chemoenzymatic synthesis of both enantiomers of 3-hydroxy- and 3-amino-3-phenylpropanoic acid

Ethyl (S)-3-hydroxy-3-phenylpropionate (S)-2 was obtained by the asymmetric reduction of ethyl 3-phenyl-3-oxopropionate 1 with the yeast Saccharomyces cerevisiae (ATCC 9080). The kinetic resolution of racemic ethyl 2-acetoxy-3-phenyl-propionate rac-3 with the same microorganism, gave after hydrolysis ethyl (R)- and (S)-3-hydroxy-3-phenylpropionates (R)-2 and (S)-2 which were converted by a straightforward series of reactions to the enantiomers of 3-amino-3-phenyl-propionic acids (S)-6 and (R)-6. The asymmetric reduction and hydrolytic kinetic resolution were also tested with several other whole cell systems under a variety of conditions.     

Enantioselective hydrolysis of (RS)-2-fluoroarylacetonitriles using nitrilase from Arabidopsis thaliana

The enzymatic resolution of 2-fluoroarylacetonitriles (RS)-3 using nitrilase from the plant Arabidopsis thaliana is described. Racemic 2-fluoronitriles 3 are easily accessible from O-silylated aromatic cyanohydrins 2 by reaction with DAST. The nitriles (RS)-3 were hydrolysed with the nitrilase as a catalyst, not to the expected 2-fluoroarylacetic acids but to the corresponding (R)-2-fluoroarylacetamides (R)-5 as the main products. After optimization of reaction conditions (pH 9, 7°C), the enantiomeric excesses of (R)-5a,c and f (R=H, 3-Me, 3-OMe) could be improved to >99% by one recrystallization. The acid catalysed hydrolysis of (R)-5a,5c and 5f afforded the corresponding (R)-2-fluoroarylacetic acids (R)-4a,4c and 4f without racemization.     

Efficient and practical synthesis of both enantiomers of 6-silyloxy-3-pyranone derivatives

Lipase catalyzed kinetic resolution of racemic cis-6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-ol (rac)-1 was achieved in high enantiomeric excess. Transesterification of (rac)-1 with vinylacetate in ^tBuOMe yielded the alcohol (3S,6R)-1 in 99.0% ee, whereas (3R,6S)-1 was obtained, in 99.0% ee, by the lipase catalyzed ester hydrolysis of acetate (3R,6S)-2, which was obtained along with the transesterification. Both (3S,6R)-1 and (3R,6S)-1 were subjected to oxidation to provide the corresponding 6-silyloxy-3-pyranone (6R)-3 and (6S)-3, respectively. Application to the synthesis of 7, which is the key intermediate of asymmetric synthesis of pseudomonic acid A 9 is also described.     

Homochiral (R)- and (S)-1-heteroaryl- and 1-aryl-2-propanols via microbial redox

Preparation of various heteroaryl propanols 2a–g and of the corresponding propanones 3a–g as starting materials for microbial redox is described. The kinetic resolution of the racemic propanols 2a–g is obtained via oxidation with Pseudomonas paucimobilis and Bacillus stearothermophilus [(R)-alcohols, ee 74–100%]. Similar results are achieved with 3-(2-hydroxypropyl)trifluoromethylbenzene 7 (44%, ee 100% of the (R)-alcohol 6). The reduction of the propanones 3a–d and 3g with baker's yeast and other fungi gives the (S)-alcohols (ee 100%). The pure (S)-alcohols are also obtained by reduction of 1-[3-(trifluoromethyl)phenyl]-2-propanone 7. 1-[(4,4-Dimethyl)-2-(Δ²)oxazolinyl]-2-propanone 3e and 1[2-(Δ²)-thiazolinyl)-2-propanone 3f are not reduced. The heterocyclic rings of (S)-5-(2-hydroxypropyl)-3-methylisoxazole 2d and of (S)-2-(2-hydroxypropyl)-4-methylthiazole 2g are deblocked to the homochiral enamino ketone 8 (78%) and to the protected β-hydroxy aldehyde 9 (73%), respectively. The (R)-3-(2-hydroxypropyl)trifluoromethylbenzene 6 is transfomed into the homochiral precursor of (S)-fenfluramine 10 (overall yield 65%).     

Studies on AI-77s,microbial products with gastroprotective activity. Structures and the chemical nature of AI-77s

The structures and the chemical nature of a novel gastroprotective substance AI-77-B (1) and its analogues AI-77-C (2), D (3), F (4) and G (5), which are produced by Bacillus pumilus AI-77, are described. The structure of 1 was confirmed to be 6-[[1(S)-(3(S), 4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-4(S),5(S)-dihydroxy-6-oxo-3(S)-aminohexanoic acid by X-ray in combination with chemical studies and the structures of 2, 3, 4 and 5 were determined by chemical syntheses from 1 and spectral analyses.     

Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Efficient preparations of (R)-(−)-apomorphine (R)-1 and (R)-(−)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.     

On the mechanism and diastereoselectivity of 2,3-dihydrobenzofuran formation from sulfinylbenzoquinones and 2-trimethylsilyloxyfuran

A mechanistic study of the reactions between 2-trimethylsilyloxyfuran 1 and (SS)-2-(arylsulfinyl)-1,4-benzoquinones 2a and 2b, giving rise to the diastereoselective formation of [3aS,8bS,SS]-3a,8b-dihydro-7-hydroxy-8-(arylsulfinyl)furo[3,2-b]benzofuran-2(3H)-ones 3a and 3b, is reported. The detection and ¹H NMR characterization of several precursors of 3a and 3b accounts for a Michael-type initial reaction which dictates the final diastereoselection of the process. A significant improvement of the stereoselectivity (up to 96% de) in the formation of the tert-butylsulfinyl substituted derivative 3c was achieved by using 2-(tert-butylsulfinyl)-1,4-benzoquinone 2c as the starting quinone.     

Studies on two different diastereoselective reaction pathways from a serinol derivative to 4-hydroxymethyl-2-oxazolidinones using 2-chloroethyl chloroformate and N,N′-disuccinimidyl carbonate

Two reaction pathways and their diastereoselectivity-determining steps of the asymmetric desymmetrization of (R)-2-(α-methylbenzyl)amino-1,3-propanediol 1 with 2-chloroethyl chloroformate (CCF) and with N,N′-disuccinimidyl carbonate giving (4S,αR)-4-hydroxymethyl-3-α-methylbenzyl-2-oxazolidinones (4S)-3 and its (4R,αR)-diastereomer (4R)-3 were investigated. The reaction of serinol 1 and CCF to give the corresponding carbonates was not a diastereoselectivity-determining step. The carbonates gave (R)-5-(α-methylbenzyl)amino-1,3-dioxan-2-one 4 after addition of DBU, and an intramolecular acyl transfer of 4 was found to be a diastereoselectivity-determining step to give (4S)-3. Conversely, the reaction of serinol 1 and N,N′-disuccinimidyl carbonate afforded directly the opposite diastereomer (4R)-3 but not via the intermediate 4. Thus, their diastereoselectivities depended on the acylating reagent.     

(E)-Selective hydrolysis of (E,Z)-α,β-unsaturated nitriles by the recombinant nitrilase AtNIT1 from Arabidopsis thaliana

From stereoisomeric α,β-unsaturated nitriles (E,Z)-1, the recombinant nitrilase AtNIT1 from Arabidopsis thaliana hydrolyses the (E)-isomers exclusively to the corresponding (E)-carboxylic acids (E)-2 with high specificity. The (E)-selectivity can also be utilised for the preparation of the isomerically pure nitriles (Z)-1. From (E,Z)-2-hydroxycinnamonitrile (E,Z)-3, the otherwise difficult obtainable (Z)-3 was prepared in 66% isolated yield. With β,γ-unsaturated (E,Z)-3-heptenenitrile (E,Z)-4, however, (E)-selectivity was not observed. AtNIT1 exhibits not only diastereoselectivity but also regioselectivity. From a mixture of the four isomers A–D of 3-(2-cyanocyclohex-3-enyl)propenenitrile 6, exclusively isomer D ((E)-cis-6) was hydrolysed to 3-(2-cyanocyclohex-3-enyl)propenoic acid (E)-cis-7, as stated by X-ray crystal structure. Only after complete conversion of D and high enzyme concentrations, isomer C ((E)-trans-6) was hydrolysed to a small extent.     

Stereoselective synthesis of 3-amino-4,5-dihydroxyaldehydes—a novel preparation of N-acetyl-l-daunosamine

A general route for the stereoselective synthesis of 3-amino-4,5-dihydroxyaldehydes, with almost any desired configuration at the three stereogenic centers, is described by applying a combination of enzymatic and chemical steps. l-Daunosamine 1, for example, the glycosidic fragment of many important anthracycline antibiotics has been prepared by this route starting from O-allyl-l-lactaldehyde (S)-6a. (R)-Hydroxynitrile lyase (HNL) catalyzed addition of HCN to (S)-6a yields the 2,3-dihydroxynitrile (2S,3S)-7a with high stereoselectivity (91% de) in 75% yield. The addition of allyl Grignard to the O-protected 2,3-dihydroxynitrile (2S,3S)-9a and subsequent hydrogenation of the imino intermediate leads to 4-amino-2,3-dihydroxy-1-heptene (4S,5S,6S)-12a, which after ozonization and deprotection gives N-acetylated l-daunosamine 14a in a total yield of 15% referring to (S)-6a. The general applicability of this chemoenzymatic multistep procedure is demonstrated in the stereoselective synthesis of the unnatural aminodeoxy sugar (2S,3S,4S)-14b, starting from isovaleraldehyde 3.     

Lipase mediated resolution of 1,3-butanediol derivatives: chiral building blocks for pheromone enantiosynthesis. Part 3

(R,S)-1,3-Butanediol 5 was kinetically resolved by enzymatic acetylation with vinyl acetate under the presence of Chirazyme™ L-2, c–f, yielding (S)-1-O-acetyl-1,3-hydroxybutane 6 and (R)-1,3-di-O-acetyl-1,3-butanediol 7 with enantiomeric excesses of 91% (E=67.3). Compounds 6 and 7 were easily transformed into the corresponding (S)-3-O-(2-methoxyethoxymethyl)-3-hydroxybutanal 10 and (R)-3-benzyloxybutanal 19, through a protection–deprotection and functional group interchange methodology. Subsequent reaction of 10 and 19 with 3-(methoxycarbonylpropionylmethylene)triphenylphosphorane afforded methyl (E,S)-8-O-(2-methoxyethoxymethyl)-4-oxo-5-nonenoate 12 and (E,R)-8-benzyloxy-4-oxo-5-nonenoate 20. The alkenes 19 and 20 were then catalytically hydrogenated to the corresponding saturated esters 13 and 21. Treatment of 13 and 21 with 1,2-ethanedithiol/F₃B·OEt₂ afforded dithioketals 14 and 22, which were respectively reduced to (S)-1,8-dihydroxy-4-nonanone ethylidenedithioketal 15 and (R)-8-O-benzyl-1,8-dihydroxy-4-nonanone ethylidenedithioketal 23. Finally, deprotection of 15 by catalytic hydrogenation under acidic conditions gave the expected (5S,7S)-(−)-7-methyl-1,6-dioxaspiro[4.5]decane 1. The (5R,7R)-(+)-1 enantiomer was analogously prepared from 23. Both compounds were formed by this procedure with an e.e. of 91%.     

Structural control in palladium(II)-catalyzed enantioselective allylic alkylation by new chiral phosphine-phosphite and pyridine-phosphite ligands

The ligands 6-[(diphenylphosphanyl)methoxy]-4,8-di-tert-butyl-2,10-dimethoxy-5,7-dioxa-6-phosphadibenzo[a,c]cycloheptene, 1, (S)-4-[(diphenylphosphanyl)methoxy]-3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4a′]dinaphthalene, (S)-2, and (S)-4-[(diphenylphosphanyl)methoxy]-2,6-bis-trimethylsilanyl-3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalene, (S)-3, (S)-2-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yloxymethyl)pyridine, (S)-4, and (S)-2-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yloxy)pyridine, (S)-5, have been easily prepared.The cationic complexes [Pd(η³-C₃H₅)(L-L′)]CF₃SO₃ (L–L′=1–(S)-5) and [Pd(η³-PhCHCHCHPh)(L–L′)]CF₃SO₃ (L–L′=(S)-2–(S)-4) were synthesized by conventional methods starting from the complexes [Pd(η³-C₃H₅)Cl]₂ and [Pd(η³-PhCHCHCHPh)Cl]₂, respectively. The behavior in solution of all the π-allyl- and π-phenylallyl-(L–L′)palladium derivatives 6–14 was studied by ¹H, ³¹P{¹H}, ¹³C{¹H} NMR and 2D-NOESY spectroscopy. As concerns the ligands (S)-4 and (S)-5, a satisfactory analysis of the structures in solution was possible only for palladium–allyl complexes [Pd(η³-C₃H₅)((S)-4)]CF₃SO₃, 11, and [Pd(η³-C₃H₅)((S)-5)]CF₃SO₃, 12, since the corresponding species [Pd(η³-PhCHCHCHPh)((S)-4)]CF₃SO₃, 13, and [Pd(η³-PhCHCHCHPh)((S)-5)]CF₃SO₃, 14, revealed low stability in solution for a long time. The new ligands (S)-2–(S)-5 were tested in the palladium-catalyzed enantioselective substitution of (1,3-diphenyl-1,2-propenyl)acetate by dimethylmalonate. The precatalyst [Pd(η³-C₃H₅)((S)-2)]CF₃SO₃ afforded the allyl substituted product in good yield (95%) and acceptable enantioselectivities (71% e.e. in the S form). A similar result was achieved with the precatalyst [Pd(η³-C₃H₅)((S)-3)]CF₃SO₃. The nucleophilic attack of the malonate occurred preferentially at allylic carbon far from the binaphthalene moiety, namely trans to the phosphite group. When the complexes containing ligands (S)-4 and (S)-5 were used as precatalysts, the product was obtained as a racemic mixture in high yield. The number of the configurational isomers of the Pd-allyl intermediates present in solution in the allylic alkylation and the relative concentrations are considered a determining factor for the enantioselectivity of the process.     

Synthese et reactivite des perfluoroalkyl-3 alkylthio-3 propenoates d'ethyle: thiophenes et β-thioxoesters perfluoroalkyles

The action of thiols with perfluoroalkylated α,β,-unsaturated compounds (ethyl 3-F-alkyl propynoates 1 and ethyl 3-F-alkyl propenoates 2) was investigated and the reactivity of the adducts reported. The mono-adducts Z and E formed by the action of thiols with 1 were unambiguously identified by ¹⁹F-NMR. In addition to the expected alkenes Z and E, the reaction of 1 with ethyl mercaptoacetate led to ethyl 2-F-alkyl-4-hydroxy-3-thiophenecarboxylate 7. The cyclisation of ethyl 3-F-alkyl-3-(methoxycarbonylmethylthio) propenoate Z in basic medium afforded methyl 5-F-alkyl-3-hydroxy-2-thiophenecar-boxylate 8, whereas in similar conditions ethyl 3-F-alkyl-3-(methoxycarbonylethylthio)propenoate led to ethyl 3-F-alkyl-3-mercaptopropenoate as a first example of β-thioxoesters bearing a sulfur atom on the α-carbon of the perfluoroalkylated chain.     

Resolution of ortho- and meta-substituted 1-phenylethylamines with isopropylidene glycerol hydrogen phthalate

The hydrogen phthalate of isopropylidene glycerol 1, previously reported as an efficient resolving agent of p-substituted 1-phenylethylamines, was also found to resolve selected o- and m-isomers. In particular, the (S)-enantiomers of 1-(2-methylphenyl)ethylamine 2, 1-(3-methylphenyl)ethylamine 3, 1-(2-chlorophenyl)ethylamine 4 and 1-(3-methoxyphenyl)ethylamine 5 were obtained in good yields and very high enantiomeric excess (e.e.) by selective crystallization of the respective salts with (S)- or (R)-1. The e.e.s of the resolved substrates were determined by chiral HPLC analysis. The (S)-configuration of (−)-3 was established according to Raban's procedure. Optical rotations of non-racemic free amines 2 and 3 are reported. The success of the resolutions presented and of the precedent ones using 1 indicate that the position of the substituent on the 1-phenylethylamine framework does not affect the resolution, showing the uncommon versatility of 1 in the resolution of monosubstituted 1-phenylethylamines.     

Crystal and molecular structure of the levorotatory (1R,2S)-ephedrinium (S)-t-butylsulfinylacetate: a definitive proof of the absolute configuration of enantiomeric t-butyl methyl sulfoxides

The levorotatory enantiomer of t-butylsulfinylacetic acid 3 was obtained in the reaction of the α-carbanion of (+)-t-butyl methyl sulfoxide 1 with carbon dioxide. The same enantiopure form of the acid 3 was isolated from its diastereomerically pure levorotatory salt 5 with (−)-(1R,2S)-ephedrine. The structure of this salt was determined by X-ray analysis and the absolute configuration (S) at sulfur was ascribed to the t-butylsulfinylacetate anion. Consequently, the absolute configuration (S) was assigned to the acid (−)-3 and its precursor (+)-t-butyl methyl sulfoxide 1.     

Syntheses and characterization of tetrakis(5-tert-butylpyrazole) Fe(II) and Mn(II) complexes. Molecular structure of Fe(Pzt-Bu)4(OTF)2

Dichlorotetrakis(5-t-butylpyrazole)iron (1), dichlorotetrakis(5-t-butylpyrazole) manganese (2), and tetrakis(5-t-butylpyrazole) iron(II) bis(trifluoromethanesulfonate) (3) were prepared and characterized. The crystal structure of 3 was determined from X-ray diffraction data. Complex 3 has a distorted octahedral structure with the two triflate ligands at mutually trans positions. Complexes 1 and 2 are mild catalysts for the selective epoxidation of styrene and norbornylene. In comparison, complex 3 is an efficient catalyst for the epoxidation of norbornylene, but promotes the oxidation of styrene predominantly to benzaldehyde.     

Synthesis of (1R,cis,αS)-cypermethrine via lipase catalyzed kinetic resolution of racemic m-phenoxybenzaldehyde cyanohydrin acetate

A technical scale preparation of optically active (1R,cis,αS)-cypermethrine 4 from racemic m-phenoxybenzaldehyde cyanohydrin acetate (RS)-1 and (1R,cis)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (1R,cis)-3 is described. Key steps of the new procedure are a lipase catalyzed enantioselective transesterification of (RS)-1 with n-butanol and direct acylation of the mixture of (R)-1 and (S)-cyanohydrin (S)-2 with (1R,cis)-3 to give enantiomerically pure (1R,cis,αS)-4. The unchanged (R)-1 is removed from (1R,cis,αS)-4 by distillation, and is racemized with triethylamine to give (RS)-1 which is returned to the process. The total yield of (1R,cis,αS)-4 referred to (RS)-1 is 80%.     

Transformations of enaminones. A simple one-pot synthesis of imidazolone derivatives

Ethyl (5-benzoyl-2-oxo-3-substituted-2,3-dihydro-1H-imidazol-1-yl)carbamates 7 were prepared by the Michael addition of diethyl azodicarboxylate (3) to (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2) followed by substitution of the dimethylamino group with primary amines 5a–n to afford a mixture of (E) and (Z) diethyl 1-(1-(substituted)amino)-3-oxo-3-phenylprop-1-en-2-yl)hydrazine-1,2-dicarboxylates (6a–n), followed by cyclization to give final products 7a–n. The intermediate 6i was isolated and characterized and transformed into 7i. All imidazolones 7a–n were synthesized in one pot reaction sequences with individual reactions being very clean.     

Practical method for crystalline-liquid resolution of chrysanthemic acids utilizing chiral 1,1′-binaphthol monoethyl ethers directed for process chemistry

We have developed an efficient practical resolution method for (1R,3R)-trans-chrysanthemic acid 1 and (1R,3S)-trans-2,2-dimethyl-3-(2,2-dichloroethenyl)cyclopropanecarboxylic acid 2, based on the preliminary results of the simpler analogues, (1R)-2,2-dichlorocyclopropanecarboxylic acid 3 and (1R)-2,2-dimethylcyclopropanecarboxylic acid 4, using a crystalline-liquid separation procedure (without column chromatography) with chiral 1,1′-binaphthol monoethyl ethers (R)-5b as the key auxiliary. Direct esterifications of 1, 2, 3, and 4 with (R)-5b gave four sets of (1R)- and (1S)-diastereomeric esters 8, 9, 6, and 7, respectively, with markedly different melting points. All of these diastereomers were easily obtained using a simple and one-step crystalline-liquid separation. The separated diastereomers 8 and 9 were easily hydrolyzed to the desired enantiopure acids 1 (>98%) and 2 (>99%), respectively, with recovery of (R)-5b (>90%).     

Asymmetric C–C bond forming reactions with chiral crown catalysts derived from d-glucose and d-galactose

New chiral monoaza-15-crown-5 derivatives anellated to methyl-4,6-O-benzylidene-α-d-glucopyranoside 2a, 2e, 2g–i and to methyl-4,6-O-benzylidene-α-d-galactopyranoside 3a, 3e, 3i have been synthesized. These crown ethers showed significant asymmetric induction as phase transfer catalysts in the Michael addition of 2-nitropropane to chalcone (87% ee), in the Darzens condensation of phenacyl chloride with benzaldehyde (71% ee) and in the self-condensation of phenacyl chloride (64% ee) to give 14. The absolute configurations of (−)-(2R,3S)-epoxy-3-(4-chlorophenyl)-1-phenyl-1-propanone 12 and (−)-4-chloro-(2R,3S)-epoxy-1,3-diphenyl-1-butanone 14 have also been determined by X-ray diffraction.