An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation

A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.     

Catalytic asymmetric hydrogenation of 2,3,5-trisubstituted pyrroles

Catalytic asymmetric hydrogenation of N-Boc-protected pyrroles proceeded with high enantioselectivity by using a ruthenium catalyst modified with a trans-chelating chiral bisphosphine PhTRAP. The ruthenium catalyst prepared from Ru(eta3-methallyl)2(cod) and (S,S)-(R,R)-PhTRAP in the presence of triethylamine was the most enantioselective for the asymmetric hydrogenation of methyl pyrrole-2-carboxylate, giving the desired (S)-proline derivative with 79% ee in 92% yield. Moreover, 2,3,5-trisubstituted pyrroles bearing a large substituent at the 5-position were hydrogenated with 93-99.7% ee. The asymmetric reduction of 4,5-dimethylpyrrole-2-carboxylate gave only all-cis isomer and created three chiral centers with high degree of stereocontrol in a single process. This is the first highly enantioselective reduction of pyrroles.     

Highly enantioselective sequential hydrogenation of ethyl 2-oxo-4-arylbut-3-enoate to ethyl 2-hydroxy-4-arylbutyrate

The hydrogenation of (E)-ethyl 2-oxo-4-arylbut-3-enoate with [NH2Me2](+)[{RuCl [(S)-SunPhos]}2(mu-Cl3)] gave ethyl 2-hydroxy-4-arylbutyrate with 94-96% ee. Further investigation has proved that the hydrogenation proceeded via a sequential hydrogenation of CO and CC bonds, which is sensitive to the reaction temperature. Hydrolysis of ethyl 2-hydroxy-4-phenylbutyrate (ee 93%) provided the 2-hydroxy-4-phenylbutyric acid with 81% yield at 99% ee after a single recrystallization from 1,2-dichloroethylene.     

Rhodium-catalyzed asymmetric hydrogenation of olefins with PhthalaPhos, a new class of chiral supramolecular ligands

A library of 19 binol-derived chiral monophosphites that contain a phthalic acid diamide group (PhthalaPhos) has been designed and synthesized in four steps. These new ligands were screened in the rhodium-catalyzed enantioselective hydrogenation of prochiral dehydroamino esters and enamides. Several members of the library showed excellent enantioselectivity with methyl 2-acetamido acrylate (6 ligands gave >97% ee), methyl (Z)-2-acetamido cinnamate (6 ligands gave >94% ee), and N-(1-phenylvinyl)acetamide (9 ligands gave >95% ee), whilst only a few representatives afforded high enantioselectivities for challenging and industrially relevant substrates N-(3,4-dihydronaphthalen-1-yl)-acetamide (96% ee in one case) and methyl (E)-2-(acetamidomethyl)-3-phenylacrylate (99% ee in one case). In most cases, the new ligands were more active and more stereoselective than their structurally related monodentate phosphites (which are devoid of functional groups that are capable of hydrogen-bonding interactions). Control experiments and kinetic studies were carried out that allowed us to demonstrate that hydrogen-bonding interactions involving the diamide group of the PhthalaPhos ligands strongly contribute to their outstanding catalytic properties. Computational studies carried out on a rhodium precatalyst and on a conceivable intermediate in the hydrogenation catalytic cycle shed some light on the role played by hydrogen bonding, which is likely to act in a substrate-orientation effect.     

New synthetic route to the important (S)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-methylthiophene-3-carboxylic acid intermediate for the synthesis of a novel glucokinase activator

To obtain an efficient and practical route to a novel glucokinase activator, we investigated a novel synthetic method for the preparation of its key intermediate (S)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-methylthiophene-3-carboxylic acid through the asymmetric transfer hydrogenation of a pyrroline derivative. The hydrogenation of this pyrroline derivative using the iridium (III)-prolinamide complex Cp*IrCl[(R)-PA] at atmospheric pressure provided an initial intermediate in approximately 50% ee. Further purification via recrystallization provided the desired key intermediate in an excellent enantiopurity, which was applicable to practical use.     

Heterogeneous asymmetric reactions, 14. Epicinchona alkaloids in the enantioselective hydrogenation of ethyl pyruvate over Pt/alumina. What determines the sense of enantioselection?

The enantioselective hydrogenation of ethyl pyruvate to (R)-and (S)-ethyl lactate over Pt/Al₂O₃ catalyst was investigated using epiquinine (42% ee) and epiquinidine (22% ee) as modifiers and the results were compared with those found for quinine (85% ee) and quinidine (81% ee). The experimental results show that the sense of enantioselection is determined by the conformation of the entire alkaloid, and the structure of the intermediate is a 1∶1 complex of the pyruvate and the ‘anti open’ conformer of the cinchona alkaloid.     

Asymmetric synthesis of a selective endothelin A receptor antagonist

An asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. Asymmetric conjugate addition of aryllithium derived from 18 to the chiral oxazoline 17 followed by hydrolysis afforded 15 in 96% ee via purification as (S)-(-)-1-phenylethylamine salt. Pd(OAc)(2)/dppf (1,1'-bis(diphenylphosphino)ferrocene) catalyzed carbonylation followed by chemoselective addition of aryllithium derived from 23 which gave ketone 24. Diastereoselective reduction of the ketone with catecholborane followed by concomitant activation of the resulting alcohol and cyclization gave the late intermediate 26. Introduction of amino moiety on the pyridine ring by imidoyl rearrangement followed by deprotection and purification by crystallization furnished the enantiomerically pure target molecule 1b in 8% overall yield from 16.     

Synthesis of decalin type chiral synthons based on enzymatic function

Enzymatic monobenzoylation of (+/-)-2-hydroxy-decahydro-5,5,8a-trimethyl-1-naphthalenemethano l derivatives (1-4) using vinyl benzoate in organic solvent gave the optically active diols (1-4) and monobenzoates (16-19). The enantiomeric excess (ee) of the enzymatic reaction products were found to be in the range of 11% to 49%. On the other hand, enzymatic hydrolysis of the acetoxybenzylidene acetal (+/-)-25d, e was found to give more than 90% ee of (10aS)-25d, e in moderate yield. Finally, the 90% ee of (10aS)-25e was converted to the 90% ee of the desired (8aS)-1.     

Enzymatic resolution of 2-substituted tetrahydroquinolines. Convenient approaches to tricyclic quinoxalinediones as potent NMDA-glycine antagonists

Two approaches leading to the enantiomerically pure tricyclic quinoxalinedione class of NMDA-glycine antagonists using enzymatic resolutions are described. An intermediate, racemic methyl 1,2,3,4-tetrahydroquinoline-2-carboxylate 3, was resolved to (S)-3 in 97% ee and 47% yield (E=67) using -chymotrypsin. In an improved method, hydrolysis of another intermediate, racemic methyl 1,2,3,4-tetrahydroquinoline-2-acetate 4, with Novozym^® 435 provided the desired (S)-4 in high enantioselectivity and yield (93% ee, 50%, E=94).     

Efficient preparation of an N-aryl β-amino acid via asymmetric hydrogenation and direct asymmetric reductive amination en route to Ezetimibe

Two routes for the preparation of an N-aryl β-amino acid, an important precursor for the cholesterol-lowering drug Ezetimibe, were investigated. The first pathway proceeds via an Rh- or Ir-catalyzed asymmetric hydrogenation of N-aryl enamine giving the desired product with up to 82% ee. The other pathway involves a direct asymmetric reductive amination (DARA) of the β-keto ester which yielded the β-amino ester in high yield and 97% ee. Subsequent copper-catalyzed N-arylation gave the target compound.     

Optically active cyclohexene derivative as a new antisepsis agent: an efficient synthesis of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242)

Two new synthetic methods were established for the efficient synthesis of optically active cyclohexene antisepsis agent, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [(R)-1: TAK-242)]. The first method involved recrystallization from methanol of the diastereomeric mixture (6RS,1'R)-7, obtained by esterification of carboxylic acid 3 with (S)-1-(4-nitrophenyl)ethanol [(S)-5)] to give the desired isomer (6R,1'R)-7 with 99% de in 32% yield. Subsequent catalytic hydrogenolysis and esterification gave (R)-1 with >99% ee. The second method employed enantioselective hydrolysis of acetoxymethyl ester 9a (prepared by alkylation of 3 with bromomethyl acetate) with Lipase PS-D to give the eutomeric enantiomer (R)-9a with excellent enantioselectivity (>99% ee) and high yield (48%). The desired (R)-1 was then obtained by transesterification with ethanol in the presence of concentrated sulfuric acid without loss of ee. Of these, the procedure employing enzymatic kinetic resolution using Lipase PS-D is the more efficient and practical preparation of (R)-1.     

Stereoselective biocatalytic synthesis of (S)-2-hydroxy-2-methylbutyric acid via substrate engineering by using "thio-disguised" precursors and oxynitrilase catalysis

3-Tetrahydrothiophenone (4) and 4-phenylthiobutan-2-one (7) were used as masked 2-butanone equivalents to give the corresponding cyanohydrins 5 (79 % yield, 91 % ee) and 8 (95 % yield, 96 % ee) in an enzymatic cyanohydrin reaction applying the hydroxynitrile lyase (HNL) from Hevea brasiliensis. After hydrolysis and desulphurisation the desired intermediate (S)-2-hydroxy-2-methylbutyric acid (10) was obtained with 99 % ee. Interestingly, when applying (R)-selective HNL from Prunus amygdalus again the (S)-cyanohydrin 5 was formed (62 % ee). The absolute configuration of 5 was verified by crystal structure determination of the corresponding hydrolysis derived carboxylate. The fact that both enzymes yield the same enantiomer was analysed and interpreted by molecular modelling calculations.     

Application of the asymmetric hydrogenation of enamines to the preparation of a beta-amino acid pharmacophore

(3R)-3-[N-(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid 7a has been synthesized by an asymmetric hydrogenation of enamine ester 3 using chiral ferrocenyl ligands I and II in conjunction with [Rh(COD)Cl]₂. The direct reduction of 3 provides amino ester 1b in 93% ee, which was isolated as an (S)-camphorsulfonic acid salt to upgrade the enantiomeric excess to >99%. A more concise approach was developed involving the in situ protection of 1b using di-tert-butyldicarbonate. This approach provided the desired N-Boc amino ester 7b directly from the hydrogenation with 97% ee, which was upgraded to >99% ee upon crystallization.     

Catalytic asymmetric total syntheses of quinine and quinidine

The catalytic, asymmetric syntheses of quinine and quinidine were achieved in 16 steps. The recently developed salen(Al)-catalyzed enantioselective Michael addition of methyl cyanoacetate served to set the crucial C4 stereocenter in 92% ee, and a late-stage asymmetric dihydroxylation was used to differentiate the common intermediate and access the two desired diastereomeric products with high selectivity.     

Highly enantioselective Pd-catalyzed asymmetric hydrogenation of activated imines

Pd/bisphosphines complexes are highly effective catalysts for asymmetric hydrogenation of activated imines in trifluoroethanol. The asymmetric hydrogenation of N-diphenylphosphinyl ketimines 3 with Pd(CF3CO2)/(S)-SegPhos indicated 87-99% ee, and N-tosylimines 5 could gave 88-97% ee with Pd(CF3CO2)/(S)-SynPhos as a catalyst. Cyclic N-sulfonylimines 7 and 11 were hydrogenated to afford the useful chiral sultam derivatives in 79-93% ee, which are important organic synthetic intermediates and structural units of agricultural and pharmaceutical agents.     

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.     

Desymmetrization of meso 1,3- and 1,4-diols with a dinuclear zinc asymmetric catalyst

A dinuclear asymmetric zinc catalyst generated by mixing a 2:1 ratio of diethylzinc and 2,6-bis[5-2-diarylhydroxy methyl-1-pyrrolidinyl]-4-methylphenol has been contrasted with enzymes for the desymmetrization of some meso diols. The best ligand has a p-biphenylyl group as the aromatic substituent defining the chiral space. A series of 2-substituted propanediols were examined. The best acyl transfer agent proved to be vinyl benzoate. Diacylation normally did not occur. The phenyl substituted substrate gave 91-95% ee which compares favorably with the best ee of 92% reported for an enzymatic desymmetrization. The methyl substituted substrate gave significantly better results with the dinuclear zinc catalyst (89% yield, 82% ee) as compared to the best enzymatic esterification (70% yield, 60% ee). One case of a 1,4-diol, cis-1,2-bis(hydroxymethyl) cyclohexane, also gave much better results with the dinuclear zinc catalysts (93% yield, 91% ee) as compared to the reported enzymatic process (44% yield, 7% ee). A model to rationalize the results is presented.     

Practical enantioselective synthesis of endothelin antagonist S-1255 by dynamic resolution of 4-methoxychromene-3-carboxylic acid intermediate

A practical multikilogram-scale synthesis of enantiomerically pure S-1255 (1), a potent and orally active ET(A) receptor antagonist, is described. Utilizing readily available starting materials and reagents, the entire sequence of reactions starting from 2,5-dihydroxyacetophenone 8 proceeded under mild conditions to give 1 in an excellent chemical yield (8 steps, 41% overall yield) and in a high enantiopurity (98% ee). The crucial step of the synthesis is a dynamic resolution of key intermediate 16. (R)-Methoxy acid (R)-16 having 97-99% ee was obtained in 83-84% yield from racemic 16 as a crystalline (1S,2R)-(+)-norephedrine or (+)-cinchonine salt by the dynamic resolution comprising concurrent crystallization and in situ racemization. A mechanism of the dynamic resolution through a ring-opened zwitterionic intermediate is discussed. In the final synthetic step, an effective carbon-carbon bond formation between the C4 carbon and the p-anisyl group was accomplished by a conjugate addition-elimination reaction of Grignard reagent 3 to (R)-16 to give 1 having 98% ee. Owing to high efficiencies of functional group transformations, carbon-carbon bond formations, and the dynamic resolution, the synthesis required no chromatographic purification and was amenable to a multikilogram-scale preparation. Several kilograms of 1 for clinical trials were successfully prepared by this process.     

A novel synthesis of (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol by sharpless asymmetric epoxidation method

Synthesis of (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol by the Sharpless asymmetric epoxidation reaction has been achieved. 2,4,5-Trifluorobenzaldehyde with methyl 2-(triphenyl-λ⁵-phosphanylidene)acetate gave methyl (E)-3-(2,4,5-trifluorophenyl)acrylate in 83% yield. The reduction of ester group with DibalH followed by Sharpless asymmetric epoxidation gave ((2R,3R)-3-(2,4,5-trifluorophenyl)oxiran-2-yl)methanol. Pd/C-catalyzed hydrogenation of epoxy alcohol furnished (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol with >90% ee and 71% yield.     

Synthesis of (S)-7-amino-5-azaspiro[2.4]heptane via highly enantioselective hydrogenation of protected ethyl 1-(2-aminoaceto)cyclopropanecarboxylates

Highly effective asymmetric hydrogenation of protected ethyl 1-(2-aminoaceto)cyclopropane carboxylates in the presence of [RuCl(benzene)(S)-SunPhos]Cl was realized, and high enantioselectivities (up to 98.7% ee) were obtained. This asymmetric hydrogenation provides a key intermediate for the enantioselective synthesis of (S)-7-amino-5-azaspiro[2.4]heptane moiety of quinolone antibacterial agents.