(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in the enantioselective preparation of α-aryloxypropanoic acid herbicides and α-chlorocarboxylic acids

rac-α-Chlorocarboxylic acids, rac-9a–e, were formally deracemized by reaction of the corresponding acyl chlorides with the chiral auxiliaries (R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, (R)- and (S)-4, followed by mild alkaline hydrolysis. The highest o.p. (99%) was obtained in the case of (S)-α-chloropropanoic acid, a known precursor for the synthesis of (R)-α-aryloxypropanoic acid herbicides such as dichlorprop-P, (R)-3a, or mecoprop-P, (R)-3b, which, together with their enantiomers, were also obtained in moderate e.e.s by dynamic kinetic resolution from (αRS,3S)-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-bromopropanoate, (αRS,3S)-6, by reaction with the corresponding phenoxide followed by mild acid hydrolysis.     

First stereocontrolled acetylation of a hydroxypropargylpiperidone by lipase CALB

Hydroxypropargylpiperidones rac-1–3 were efficiently obtained by a one-pot three-component coupling reaction; enantioenriched propargylpiperidones were then obtained by a kinetic resolution process using the lipase from Candida antarctica. Lipase CALB has been shown to efficiently catalyse the stereocontrolled acetylation of hydroxypropargylpiperidones rac-3 by promoting stereodiscrimination at the carbinolic centre. The enzymatic catalytic processes allow the separation of the (S,R)- and (S,S)-3 diastereoisomers into the corresponding acetates produced as a (R,S)- and (R,R)-6 diastereoisomeric pair. The CALB was able to discriminate the stereogenic centre of the secondary (R)-enantiomer of rac-3 according to the Kaslauzkas rule. The remote stereogenic centre was not discriminated by the lipase. The functionalised enantioenriched diastereoisomers obtained are important building blocks in organic synthesis.     

Lipase mediated enantiomer and diastereomer separation of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols

Separation of diastereomeric and enantiomeric mixtures of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols rac-3a and meso-3a, and rac-3b and meso-3b—resulting from the reactions of pyrocatechol 1a and resorcinol 1b with cyclohexene oxide 2—were performed using acetylation catalyzed by the highly stereoselective Candida antarctica lipase B (Novozym 435). The absolute configurations of the resulting diols (S,S,S,S)-3a,b, monoacetates (R,R,S,S)-4a,b and diacetates (R,R,R,R)-5a,b were assigned on the basis of the steric analogy to the acetylation of racemic trans-2-phenoxycyclohexanol rac-6 with the same enzyme resulting in the known acetate (−)-(R,R)-7.     

Synthesis of chiral ligands containing the N-(S)-α-phenylethyl group and their evaluation as activators in the enantioselective addition of Et2Zn to benzaldehyde

The synthesis of chiral ligands 4–18 derived from N-[(S)-α-phenylethyl]-trans-β-aminocyclohexanols (S,S,S)-1a and (R,R,S)-2 is described. Addition of diethylzinc to benzaldehyde catalyzed by ligands 4–18 (6 mol %) proceeds in fair to good yield (45–86%), and low to good enantioselectivities (1–76% ee). Highest enantioselectivities were induced by ligands (S,S,S)-4 and (S,S,S,S,R,R)-18 (76% and 68% ee, respectively). The configuration of the major enantiomer of carbinol 3 is (R) in both cases.     

Simultaneous enzymatic synthesis of (S)-3-fluoroalanine and (R)-3-fluorolactic acid

A coupled enzymatic system for the simultaneous synthesis of (S)-3-fluoroalanine (1a) and (R)-3-fluorolactic acid (3) with l-alanine dehydrogenase (l-AlaDH) from Bacillus subtilis and rabbit muscle l-lactate dehydrogenase (l-LDH) using rac-1 and NAD⁺ is described. Analysis of isolated products of the laboratory preparative scale process revealed 1a in 60% yield and 88% ee and 3 in 80% yield and over 99% ee. The compounds 1a and 3 represent chiral building blocks for the synthesis of several products with pharmacological activity.     

Heterocycles 35. CaL-B mediated synthesis of enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates

Herein we present the lipase catalyzed synthesis of four new enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates and their butanoates by enzymatic enantioselective acylation of the racemic alcohols rac-1a–d and by ethanolysis of the corresponding racemic esters rac-2a–d mediated by lipase B from Candida antarctica (CaL-B) in organic solvents. In terms of stereoselectivity and activity, both procedures, the acylation and alcoholysis, are successful (50% conversion, E ≫ 200). The absolute configuration of the resolution products was determined by a detailed ¹H NMR study of the Mosher’s derivatives of (S)-1a.     

Enantioselective synthesis of axially chiral 1-(1-naphthyl)isoquinolines and 2-(1-naphthyl)pyridines through sulfoxide ligand coupling reactions

Racemic 1-(1′-isoquinolinyl)-2-naphthalenemethanol rac-12 was prepared through a ligand coupling reaction of racemic 1-(tert-butylsulfinyl)isoquinoline rac-7 with the 1-naphthyl Grignard reagent 10. Resolution of rac-12 was achieved through chromatographic separation of the Noe-lactol derivatives 14 and 15, providing (R)-(−)-12 of >99% ee and (S)-(+)-12 of 90% ee. The ligand coupling reaction of optically enriched sulfoxide (S)-(−)-7 (62% ee) with Grignard reagent 10 furnished rac-12, with the absence of stereoinduction resulting from competing rapid racemisation of the sulfoxide 7. Reaction of optically enriched (S)-(−)-7 with 2-methoxy-1-naphthylmagnesium bromide was also accompanied by racemisation of the sulfoxide 7, and furnished optically active (+)-1-(2′-methoxy-1′-naphthyl)isoquinoline (+)-3b in low enantiomeric purity (14% ee). The absolute configuration of (+)-3b was assigned as R using circular dichroism spectroscopy, correcting an earlier assignment based on the Bijvoet method, but in the absence of heavy atoms. Optically active 2-pyridyl sulfoxides were found not to undergo racemisation analogous to the 1-isoquinolinyl sulfoxide 7, with the ligand coupling reactions of (R)-(+)- and (S)-(−)-2-[(4′-methylphenyl)sulfinyl]-3-methylpyridines, (R)-(+)-17 and (S)-(−)-17, with 2-methoxy-1-naphthylmagnesium bromide providing (−)- and (+)-2-(2′-methoxy-1′-naphthyl)-3-methylpyridines, (−)-18 and (+)-18, in 53 and 60% ee, respectively. The free energy barriers to internal rotation in 3b and 18 have been determined, and the isoquinoline (R)-(−)-12 examined as a ligand in the enantioselectively catalysed addition of diethylzinc to benzaldehyde; (R)-(−)-12 was also converted to (R)-(−)-N,N-dimethyl-1-(1′-isoquinolinyl)-2-naphthalenemethanamine (R)-(−)-19, and this examined as a ligand in the enantioselective Pd-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate.     

Parallel kinetic resolution of propargyl ketols: formal synthesis of (+)-bakkenolide A

We describe an intriguing new example of a parallel kinetic resolution; an asymmetric cyclization-carbonylation of propargyl ketols catalyzed by palladium(II) with chiral bisoxazoline (box) ligands. The 2S,3S enantiomer of (±)-6 was preferentially converted to 13 (45-49% yields, 37-46% ee), and the 2R,3R enantiomer of (±)-6 was preferentially converted to 14 (21-23% yields, 92-97% ee). As an application of this reaction, formal synthesis of (+)-bakkenolide A was achieved.     

Natural product synthesis from (8aR)- and (8aS)-bicyclofarnesols: synthesis of (+)-wiedendiol A, (+)-norsesterterpene diene ester and (−)-subersic acid

Both enantiomers (8aR)-7 and (8aS)-7 of bicyclofarnesol were synthesized from the enzymatic resolution products (1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-5 (98% ee) and acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aS)-6 (>99% ee), respectively. The formal synthesis of (+)-wiedendiol 1 was achieved via a coupling reaction of an ate complex derived from 1,2,4-trimethoxybenzene with allyl bromide (8aS)-8 derived from (8aS)-7. The total synthesis of (+)-norsesterterpene diene ester 2 was achieved, based on the synthesis of (13E,10S)-α,β-unsaturated aldehyde 12, derived from (8aS)-7, followed by the selective construction of the (3E,5E)-diene moiety including a C(2)-stereogenic centre in (+)-2. The total synthesis of (−)-subersic acid 3 was carried out based on a Stille coupling between allyl trifluoroacetate congener 25c, derived from (8aR)-7, corresponding to the diterpene part, and aryl stannane congener 26 in the presence of Pd catalyst and CuI as an additive.     

Enzymatic resolution of (±)-conduritol-B,a key intermediate for the synthesis of glycosidase inhibitors

Lipases from porcine pancreas, Candida cylindracea and Mucor miehei (adsorbed on support, Lipozyme^® IM) catalysed in t-butylmethylether the alcoholysis of rac-conduritol-B peracetate, (±)-1, by n-butanol to give enantiopure (2S,3S)-diacetoxy-(1R,4R)-dihydroxycyclohex-5-ene, (−)-3, and (1S,2R,3R,4S)-tetraacetoxy-cyclohex-5-ene, (+)-1. The enantioforms (+)- and (−)-conduritol-B, obtained after chemical hydrolysis of (−)-3 and (+)-1, respectively, may be employed to prepare both the enantiomers of conduritol-B epoxide and cyclophellitol, powerful inhibitors of glycosidases.     

Enantioselective acylation of alcohols with fluorinated β-phenyl-β-lactams in the presence of Burkholderia cepacia lipase

This paper concentrates on studies of the acylation of alcohols with 3,3-difluoro-4-phenylazetidin-2-one rac-1, trans-3-fluoro-4-phenylazetidin-2-one rac-2 and 4-phenylazetidin-2-one rac-3 in the presence of immobilized lipase PS from Burkholderia cepacia in dry tert-butyl methyl ether (TBME). Fluorine activation in the compounds studied was essential in order to split the β-lactam ring with lipase PS. The highly enantioselective ring opening of rac-1 and rac-2 with methanol (1-butanol was also studied) allowed the preparation of the (R/(3R,4R))-β-lactams as the unreacted enantiomers and (S/(2S,3S))-β-amino esters as the product enantiomers with an ee >99%. Under the same conditions, rac-3 was totally unreactive. The possibility for a competing hydrolysis caused by water in the enzyme preparations is also discussed.     

Palladium-catalyzed asymmetric allylic substitution using novel phosphino-ester (PHEST) ligands with 1,1′-binaphthyl skeleton

The asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate 1 with dimethyl malonate 2a proceeded smoothly in the presence of lithium acetate, BSA (N,O-bis(trimethylsilyl)acetamide), [Pd(η³-C₃H₅)Cl]₂, and the chiral ligand (R)-i-Pr₂N-PHEST (R)-5a to give the allylic alkylation product (R)-3a in 89% yield with 99% ee. Furthermore, the asymmetric allylic amination of 1 with potassium phthalimide 2c has been carried out using the same ligand to give the allylic amination product (S)-3c in 10% yield with 66% ee.     

Preparation of both enantiomers of β-(3,4-dihydroxybenzyl)-β-alanine, higher homologues of Dopa

β²-(3,4-Dihydroxybenzyl)-β-alanine [β²-Homo-Dopa, 1] is a novel β-amino acid homologue of Dopa, the most successful therapeutic agent in the treatment of Parkinson's disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of β-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired β-amino acids were purified by silica gel chromatography. Alternatively, enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-chain β-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary α-phenylethylamine. Finally, nearly enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-3-aminopropionic acid, rac-12, with (R)- or (S)-α-phenylethylamine, followed by catalytic hydrogenolysis.     

Stereospecific synthesis and hydrolysis of optically active diaryl(acylamino)(acyloxy)spiro-λ4-sulfanes and related cyclic diaryl(acylamino)sulfonium salts

The stereospecific synthesis of diaryl(acylamino)(acyloxy)spiro-λ⁴-sulfanes (S)-(+)-2, (R)-(+)-5, (S)-(+)-8, and their conversion into related diaryl(acylamino)sulfonium tetrafluoroborates (R)-(+)-3, (S)-(+)-6, (R)-(+)-9, respectively, is described. The enantiomers of spiro-λ⁴-sulfanes (S)-(+)-2, (R)-(+)-5 and (S)-(+)-8 were prepared by dehydration of the corresponding optically active sulfoxide–carboxylic acids (R)-(+)-1, (R)-(−)-4 and (S)-(+)-7, respectively, which were obtained from the racemic forms by diastereoisomeric salt separation with homochiral organic bases. The stereomechanism of the hydrolysis reaction of spiro-λ⁴-sulfanes and sulfonium tetrafluoroborates that depends on pH, the nature of the axial heteroatom, the size of the spiro rings and carboxyl neighbouring group participation is also discussed.     

Palladium(0) catalyzed enantioselective rearrangement of O-allylic thiocarbamates to S-allylic thiocarbamates: asymmetric synthesis of allylic thiols

The Pd(0) catalyzed rearrangement of the O-allylic thiocarbamates rac-2a, rac-2b and rac-4 in the presence of the chiral bisphosphane 5 proceeded quantitatively and gave the S-allylic thiocarbamates 6a, 6b and 7, respectively, with 91, 92 and 97% ee, respectively, in high yields. Saponification of the S-allylic thiocarbamate 7 furnished the allylic thiol 9 with 97% ee.     

Efficient synthesis of 3,4- and 4,5-dihydroxy-2-amino-cyclohexanecarboxylic acid enantiomers

An efficient method for the synthesis of (1S,2R,4R,5S)- and (1R,2R,4R,5S)-2-amino-4,5-dihydroxycyclohexanecarboxylic acids (?)-6 and (?)-9 and (1R,2R,3S,4R)- and (1S,2R,3S,4R)-2-amino-3,4-dihydroxycyclohexanecarboxylic acids (?)-15 and (?)-18 was developed by using the OsO₄-catalyzed oxidation of Boc-protected (1S,2R)-2-aminocyclohex-4-enecarboxylic acid (+)-2 and (1R,2S)-2-aminocyclohex-3-enecarboxylic acid (+)-11. Good yields were obtained. The stereochemistry of the synthesized compounds was proven by NMR spectroscopy.     

Kinetic resolution of racemic secondary aliphatic allylic alcohols in lipase-catalyzed transesterification

Different lipases were screened as biocatalysts in the kinetic resolution process of (±)-hept-1-en-3-ol 1, (±)-5-methylhex-1-en-3-ol 2, (±)-6-methylhept-2-en-4-ol 3, (±)-6,6-dimethylhept-2-en-4-ol 4, and 1-phenylbut-3-en-2-ol 5 by enantioselective transesterification. The acylation of (±)-1 and (±)-2 catalyzed by Novozym 435 (Candida antarctica) was very effective and proceeded with good enantioselectivity. After 4–8 h of reactions the esters formed and the alcohols, which remained were obtained with high enantiomeric excess with 97–100% ee and 91–100% ee, respectively. The lipase Amano PS (Burkholderia cepacia) was the best catalyst in the asymmetric transesterification of (±)-5 affording the (R)-alcohol with 90–95% ee and the (S)-ester with 98–100% ee. Low enantioselectivities were observed in the cases of lipase-catalyzed acylation of (±)-3 and (±)-4.     

The cooperative effect of a hydroxyl and carboxyl group on the catalytic ability of novel β-homoproline derivatives on direct asymmetric aldol reactions

Novel β-homoproline derivatives, 2-hydroxy-2-(pyrrolidin-2-yl)acetic acids (R,S)- and (S,S)-1a-d, were synthesized. All of the prepared compounds were used as organocatalysts in the direct asymmetric aldol reaction of 4-nitrobenzaldehyde with several ketones. Among these catalysts, (R)-2-hydroxy-2-((S)-pyrrolidin-2-yl)acetic acid (R,S)-1a showed good catalytic ability in the formation of aldol product 13 (up to 69% ee, 95% yield), which was similar to the results catalyzed by l-proline (71% ee, 96% yield). Relatively low yields and low enantioselectivities were observed in aldol reactions catalyzed by (S,S)-1a, for example, 13 was obtained in 55% yield and 13% ee. The aldol reaction catalyzed by the methyl-protected carboxylic acid 1b and esters 1c,d produced much lower chemical yields and enantioselectivities during the formation of 13. The cooperative effect of the (R)-configured hydroxyl group and the carboxyl group was found to play an important role in inducing enantioselectivity in the aldol reaction. Relatively high diastereoselectivities (anti:syn = 85:15) and enantioselectivity (anti, 83% ee) were observed in the aldol reactions of 4-nitrobenzaldehyde with cyclohexanone, which was catalyzed by (R,S)-1a.     

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.     

Synthesis of C2-symmetric chiral crown ethers by lipase-catalyzed reactions

Kinetic resolution of a racemic mixture of C₂-symmetric 18-crown-6 diols (rac-1a) and 15-crown-5 diol (rac-1c) was achieved by lipase-catalyzed acetylation. The enantiomeric excess of the chiral crown diols (95% ee and 82% ee) was determined by ¹H NMR spectroscopy, using (R)-(+)-1-(1-naphthyl)ethylammonium hydrochloride as a shift reagent. The C₂-symmetric chiral 15-crown-5 diol (>95% ee) was also obtained by kinetic resolution of the racemic diacetate (rac-2c) using lipase-catalyzed solvolysis.