Stereoselective reduction of 2-butenolides to chiral butanolides by reductases from cultured cells of Glycine max

The stereoselective reduction of 2-butenolides by two reductases, p51 and p83, from cultured plant cells of Glycine max was investigated. The reduction of 2-methyl-2-butenolide by p51 reductase produced (R)-2-methylbutanolide, whereas the reduction by p83 reductase gave (S)-2-methylbutanolide. Both reductases reduced 3-methyl-2-butenolide to (R)-3-methylbutanolide. The reduction of 2,3-dimethyl-2-butenolide by p51 reductase gave (2R,3R)-2,3-dimethylbutanolide, whereas the reduction by p83 reductase produced (2S,3R)-2,3-dimethylbutanolide. The reduction of 4-alkyl-2-butenolides with these reductases was accompanied by resolution of chiral centers affording (R)-4-alkylbutanolides.     

Synthesis and spectroscopic characterization of enantiopure protected trans-4-amino-1-oxyl-2,2,6,6-tetramethyl piperidine-3-carboxylic acid (trans β-TOAC)

Enantiomerically pure (3R,4S) and (3S,4R) protected 4-amino-1-oxyl-2,2,6,6-tetramethylpiperidine-3-carboxylic acids were synthesized by reduction of the enamines resulting from the condensation of 3-carboxymethyl-1-oxyl-2,2,6,6-tetramethyl-4-piperidone with (R) or (S)-α-methylbenzylamine. While NaBH₃CN/CH₃COOH reduction gave predominantly a mixture of the two possible cis-diastereomers, the use of NaBH₄/(CH₃)₂CHCOOH resulted in a mixture of only one trans- and one cis-diastereomer. Removal of the chiral auxiliary from the separated diastereoisomers by hydrogenolysis and regeneration of the nitroxide radical gave the desired β-amino esters. The ESR spectrum of the (3R,4S)-enantiomer is also reported.     

Stereospecific microbial reduction of ethyl 1-benzyl-3-oxo-piperidine-4-carboxylate

Microbial reduction of ethyl 1-benzyl-3-oxo-piperidine-4-carboxylate by the majority of evaluated microorganisms gave the ethyl cis-(3R,4R)-1-benzyl-3R-hydroxy-piperidine-4R-carboxylate as the major product in high diastereo- and enantioselectivities. The 3R,4R-hydroxy ester was produced in 97.4% diastereomeric excess (de) and 99.8% enantiomeric excess (ee) by Candida parapsilosis SC16347, while 99.5% de and 98.2% ee were obtained from reduction by Pichia methanolica SC16415. A few of the evaluated microorganisms gave 10–40% of the ethyl trans-(3R,4S)-1-benzyl-3R-hydroxy-piperidine-4S-carboxylate as the minor product.     

Organocatalytic asymmetric synthesis of quinine and quinidine

Quinine and quinidine were synthesized by a highly enantio- and stereoselective approach starting from a proline-catalyzed asymmetric cycloaldolization of benzyl bis(2-formylethyl)carbamate which gave a 70:30 mixture of (3R,4R)-N-Cbz-3-hydroxymethyl-4-hydroxypiperidine (96% ee) and its 4S-epimer (92% ee) in 94% yield after in situ NaBH₄ reduction.     

Novel and enantioselective syntheses of (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid: a synthon for sitagliptin and its derivatives

A new synthetic strategy for (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid, a building block in the preparation of sitagliptin and its derivatives, was developed. Pd(OAc)₂ catalyzed coupling of 2,4,5-trifluoro-1-iodobenzene with allyl alcohol gave 3-(2,4,5-trifluorophenyl)propanal in a yield of 95%. l-Proline catalyzed reaction of the 3-phenylpropanal (in only 1.2 molar equiv) with nitrosobenzene followed by reduction with NaBH₄ and Pd/C catalyzed hydrogenation gave (R)-3-(2,4,5-trifluorophenyl)propane-1,2-diol with >99% ee and 65% yield. Selective tosylation of primary hydroxyl group of the 1,2-propandiol unit followed by cyanide displacement afforded (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanenitrile (80%). The nitrile was converted to the title β-hydroxy acid under basic hydrolysis in a yield of 90%. Thus, (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid was prepared enantioselectively from the starting material in four steps and 45% overall yield. The reaction sequence was repeated with d-proline as the catalyst to give (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid in 45% overall yield and >99% enantiomeric excess.     

A stereoconvergent synthesis of (+)-4-demethoxydaunomycin

Sharpless kinetic asymmetric epoxidation on (±)-2-(l-hydroxyethyl)-5,8-dimethoxy-3,4-dihydronaphthalene (8) followed by LAH reduction gave R-2-(S-l-hydroxyethyl)-2hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene and the undesired antipode. The former was converted to R-(-)-2-acetyl-2 hydroxy-5,8-dimethoxy-l,2,3,4-tetrahydronapthalen[R-(-)-5],while the latter was epimerized and recycled. R-(-)-5 has been exploited for the synthesis of(+)-4-demethoxydaunomycin     

Non-enzymatic diastereoselective asymmetric desymmetrization of 2-benzylserinols giving optically active 4-benzyl-4-hydroxymethyl-2-oxazolidinones: asymmetric syntheses of α-(hydroxymethyl)phenylalanine,N-Boc-α-methylphenylalanine,cericlamine and BIRT-377

A reaction of (S)-2-benzyl-2-(α-methylbenzyl)amino-1,3-propanediol (S)-4a and 2-chloroethyl chloroformate, and the subsequent addition of DBU gave (4R,αS)-4-benzyl-4-hydroxymethyl-3-(α-methylbenzyl)-2-oxazolidinone (4R)-5a (92% de) via a diastereoselective asymmetric desymmetrization process. Debenzylation of (4R)-5a using trifluoromethanesulfonic acid and anisole in MeNO₂ gave (R)-4-benzyl-4-hydroxymethyl-2-oxazolidinone (R)-15a, which was converted into (R)-(α-hydroxymethyl)phenylalanine (7) in two steps. N-Boc-α-methylphenylalanine (8), cericlami0ne (9) and BIRT-377 (10) were also synthesized using these asymmetric desymmetrization and debenzylation.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

A chiral cyclohex-2-enone carrying a hexofuranosyl substituent which directs highly stereoselective 1,4-conjugate additions

The reaction of (Z)-3-deoxy-3-C-[(hydroxymethyl)methylene]-1,2:5,6-di-O-isopropylidene-α-D-ribo-hexo-furanose, prepared from D-glucose, with 1,1-dimethoxycyclohexane in the presence of propanoic acid at 135°C, then at 200°C, provided two Claisen rearrangement products, namely (2R,3R,4S,5S)-2,3-(isopropylidene)dioxy-5-[(1R)-1,2-(isopropylidene)dioxyethyl]-4-[(1S)- and (1R)-2-oxocyclohexyl]-4-vinyltetrahydrofuran in a ratio of 3.3:1. L-Selectride^® reduction of the major product gave the corresponding (S)-cyclohexanol exclusively. In contrast, the Claisen rearrangement of the aforementioned allylic alcohol with 3,3-dimethoxycyclohexene proceeded with complete stereoselectivity to provide the corresponding 4-[(1S)-2-oxocyclohex-3-enyl]-4-vinyltetrahydrofuran exclusively. The 1,4-conjugate additions to the thus formed cyclohexenone derivative with dimethyl and divinylcuprates proceeded with complete π-facial selection to provide the 3-methylated and 3-vinylated cyclohexanone derivatives, both in high yields.     

Enantiodivergent syntheses of cycloheptenone intermediates for guaiane sesquiterpenes

The syntheses of enantiomeric 6-isopropenyl-3-methyl-2-cycloheptenones 16 and 22 have been effected starting from (R)-(−)-carvone. In the synthesis of 16, (R)-(−)-carvone was reduced and the resulting dihydrocarvone transformed regioselectively into silyl enol ethers. Cyclopropanation with dibromocarbene and in situ rearrangement gave an α-bromo-cycloheptenone which was reduced to the (R)-(+)-cycloheptenone 16. In the synthesis of 22, (R)-(−)-carvone was cyclopropanated with a sulfur ylide, followed by reduction with LiAlH₄ and acid-catalyzed cyclopropylcarbinyl rearrangement to afford a cycloheptenol. Oxidation and double bond conjugation led to the (S)-(−)-cycloheptenone 22 in a partially racemized form. Four cycloheptenones have been obtained and are suitable intermediates for the enantiodivergent syntheses of guaiane sesquiterpenes.     

Highly stereoselective iminopinacol coupling of chiral aromatic imines derived from di- and tripeptides

The reduction of aromatic imines prepared from (S)-Ile-(S)-Ile-OMe, (S)-Val-(S)-Val-OMe, and (S)-Val-(S)-Val-(S)-Val-OMe with Zn-MsOH in THF gave C₂-symmetric (R,R)-diamines in high yields and stereoselectivities.     

Lipase-mediated resolution of 3-hydroxy-4-trityloxybutanenitrile: synthesis of 2-amino alcohols,oxazolidinones and GABOB

Lipase-mediated kinetic resolution of 3-hydroxy-4-trityloxybutanenitrile gave the (S)-alcohol and (R)-acetate in good yields and high enantioselectivities. The resolution using Pseudomonas cepacia lipase (Burkholderia cepacia) immobilized on modified ceramic particles (PS-C) in diisopropyl ether gave the best results. The use of base additives in this transesterification drastically reduces the reaction time without effecting the yields or enantioselectivities. Resolved 3-hydroxy-4-trityloxybutanenitrile has been utilized for the synthesis of enantiomerically pure 5-tosyloxymethyl-1,3-oxazolidine-2-one, which is an important intermediate for the preparation of β-adrenergic blocking agents and oxazolidinone based antimicrobial agents. Enantiomerically pure (R)-3-hydroxy-4-trityloxybutanenitrile and (S)-5-tosyloxymethyl-1,3-oxazolidine-2-one have been utilized in the enantioconvergent synthesis of (R)-GABOB.     

Ozonides with the tetrahydroquinoline and dehydroabietic fragments

Acid-catalyzed three-component condensation of methyl 12-aminodehydroabietate, aromatic aldehydes, and cyclopentadiene gave methyl (4R)-4-aryl-6-isopropyl-10,13a-dimethyl-3a,4,5,8,9,9a,10,11,12,13,13a,13d-dodecahydro-3H-cyclopenta[c]naphtho[1,2-f]quinoline-10-carboxylates and their (4S)-diastereomers. Ozonolysis of the double bond in their N-trifluoroacetyl derivatives synthesized from the (4R)-diastereomers afforded the corresponding ozonides with the (1S,4R,5aS,6R,11aR,12R,15aS,15dR)-configuration.     

Asymmetric synthesis of 4-formyl-1-(ω-haloalkyl)-β-lactams and their transformation to functionalized piperazines and 1,4-diazepanes

Chiral piperazine and 1,4-diazepane annulated β-lactams, prepared from the corresponding (3R,4S)-4-imidoyl-1-(ω-haloalkyl)azetidin-2-ones through reduction with sodium borohydride in ethanol, were transformed into novel methyl (R)-alkoxy-[(S)-piperazin-2-yl]acetates and methyl (R)-alkoxy-[(S)-1,4-diazepan-2-yl]acetates upon treatment with hydrogen chloride in methanol. On the other hand, bromination of (3R,4R)-1-allyl-4-formyl-β-lactams and (3R,4S)-1-allyl-4-imidoyl-β-lactams in dichloromethane, followed by sodium borohydride reduction of the resulting dibrominated azetidin-2-ones in ethanol, did not afford the envisaged bicyclic β-lactams but unexpectedly furnished (3R,4S)-1-(2-bromo-2-propenyl)azetidin-2-ones instead.     

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.     

Screening of ligands in the asymmetric metallocenethiolatocopper(I)-catalyzed allylic substitution with Grignard reagents

Screening of metallocenethiolate ligands for copper(I)-catalyzed substitution of allylic acetates with Grignard reagents has been carried out. The previously used ligand, lithium (R,S_p)-2-(1-dimethylaminoethyl)ferrocenylthiolate (4a), possessing both central and planar chirality, was the starting point for the screening. It was found that the diastereomeric ligand lithium (R,R_p)-2-(1-dimethylaminoethyl)ferrocenylthiolate (4b) exhibiting reversed planar chirality gave increased enantioselectivity in the allylic substitution, at least when cinnamyl acetate was used as a substrate. The ruthenocene-based ligand lithium (R,S_p)-2-(1-dimethylaminoethyl)ruthenocenylthiolate (4c) gave an enhanced reaction rate, but lower chiral induction. The use of disulfide bis[(R,S_p)-2-(1-dimethylaminoethyl)ferrocenyl]disulfide (7a) as a ligand precursor worked well but resulted in lower enantioselectivity.     

Synthesis of (S-(−)-wybutine,the fluorescent minor base from yeast phenylalanine transfer ribonucleic acids

The Wittig reaction of 1-benzyl-7-formylwye (12) with (R)-[2-carboxy-2-[(methoxycarbonyl)amino]ethyl]triphenylphosphonium chloride (8) followed by successive methylation and reduction gave (-)-wybutine [(S)-1a].     

Synthesis of both enantiomers of baclofen using (R)- and (S)-N-phenylpantolactam as chiral auxiliaries

Esterification of racemic 4-nitro-3-(4-chlorophenyl)butanoic acid with (R)- or (S)-N-phenylpantolactam as the chiral auxiliary allowed us to obtain the (3R,3′R)- or (3S,3′S)-nitro esters with >98:2 dr after column chromatography. Hydrolysis of the resulting diastereopure nitro esters gave the corresponding enantiopure nitro acids, which were readily converted in high yields into either (R)- or (S)-baclofen hydrochloride.     

Diastereoselective reduction of β-keto carbonyl compounds by cultured plant cells

The diastereoselective reduction of β-keto carbonyl compounds such as 2-benzamidomethyl-3-oxobutanoates and 2-methyl-2-(2-propenyl)cyclopentan-1,3-dione by cultured cells of higher plants was investigated. The reduction of the 2-benzamidomethyl-3-oxobutanoates by Parthenocissus tricuspidata diastereoselectively produced the (2R,3S)-2-benzamidomethyl-3-hydroxybutanoates, whereas the reduction by Gossypium hirsutum gave the (2S,3S)-2-benzamidomethyl-3-hydroxybutanoates. The (2R,3S)/(2S,3S) predominance in the reduction with Nicotiana tabacum, Glycine max, and Catharanthus roseus was reversed by the change in the structure of the alkoxyl group in the substrate. On the other hand, the reduction of 2-methyl-2-(2-propenyl)cyclopentan-1,3-dione by P. tricuspidata produced (2R,3S)-3-hydroxy-2-methyl-2-(2-propenyl)cyclopentan-1-one, whereas the reaction by N. tabacum, G. max, C. roseus, and G. hirsutum gave (2S,3S)-3-hydroxy-2-methyl-2-(2-propenyl)cyclopentan-1-one.     

Application of axially dissymmetric ligand recoverable with fluorous solvent as a chiral auxiliary

(Ra)-(R)₂-2,2′-Bis(1-hydroxy-1H-perfluorooctyl)biphenyl ((Ra)-(R)₂-1c), which is an axially dissymmetric ligand with two chiral centers, works as a good chiral auxiliary for asymmetric aldol reaction. Thus, the reaction of monopropanoyl ester of 1c (2) with benzaldehyde in the presence of triethylamine and titanium(IV) chloride gave (2R),(3S)- and (2R),(3R)-3-hydroxy-2-methyl-3-phenylpropanoic acid esters (3a) in an approximate ratio of 4:1 in a total high yield. This result shows that stereoselectivity at 2-position is quite high, while that at 3-position is moderate. Both isomers were easily separated by column chromatography. Methanolysis of the separated isomers gave nearly quantitative recovery of 1c by extraction with a fluorous solvent without any loss of ee, while methyl (2R),(3S)- or (2R),(3R)-3-hydroxy-2-methyl-3-phenylpropanoates were obtained by CH₂Cl₂ extraction quantitatively in >99% ee. Aldol reaction of 2 with various aldehydes gave similar results.