Asymmetric Synthetic Strategies of (R)-(–)-Baclofen: An Antispastic Drug

Dedicated to Dr. Nitin W. Fadnavis, Natural Products Chemistry Division, IICT, Hyderabad on the occasion of his 63rd birthday

Abstract

Baclofen is an antispastic drug used as a muscle relaxant in the treatment of the paroxysmal pain of trigeminal neuralgia, spasticity of the spinal cord and cerebral origin. Baclofen resides biological activity exclusively in its (R)-(–)-enantiomer. In this review, various asymmetric synthetic strategies for (R)-(–)-baclofen are described.

1 Introduction

2 Resolution Synthetic Approaches

2.1 Chemical Resolution

2.2 Biocatalytic Resolution

3 Asymmetric Desymmetrization

3.1 Catalytic Enantioselective Desymmetrization

3.2 Enzymatic Desymmetrization

4 Chiral Auxiliary Induced Asymmetric Synthesis

4.1 Asymmetric Michael Addition

4.2 Asymmetric Aldol Addition

4.3 Asymmetric Nucleophilic Substitution

5 Asymmetric Reduction

5.1 Catalytic Asymmetric Hydrogenation

5.2 Bioreduction

6 Catalytic Asymmetric Conjugate Addition

7 Conclusion

Key words

asymmetric synthesis - total synthesis - amino acids - chiral resolution - baclofen - synthetic methods - biocatalysis

1

Introduction

Baclofen [γ-amino-β-(4-chlorophenyl)butyric acid, 1, Figure [1]] was first designed as a drug for treating epilepsy by Heinrich Keberle in 1962.[1] The effect of baclofen on epilepsy was disappointing, but it was found that spasticity was decreased in certain people. In 1992, it was approved and marketed under the trade name of Lioresal^® for the treatment of spasticity. The molecular weight of baclofen is 213.66 g/mol; it is a white odorless crystalline powder and slightly soluble in water.

Dr. Perla Rameshwas born in a small village Obulapoor, Siddipet District­, Telangana, India. He graduated from Osmania University, Hyderabad­ in 2006. After obtaining his M.Sc. in 2008 from Kakatiya University, he joined the group of Dr. Nitin W. Fadnavis at the Indian Institute­ of Chemical Technology, Hyderabad, India, where he carried out his doctoral studies in the field of synthetic organic chemistry and biotransformation. His research interests include the total synthesis of bioactive natural products and pharmaceutical drugs and development of new reactions.

Baclofen (1), a strongly lipophilic γ-aminobutyric acid (GABA) analogue, plays an important role as an inhibitory neurotransmitter in the central nervous system.[2] It helps to reduce the excitatory effect of active compounds such as benzodiazepine, barbiturates, etc.[3] A deficiency of GABA is associated with diseases that exhibit neuromuscular dysfunctions, including Parkinson’s disease, Huntington’s disease and epilepsy.[4] Baclofen is widely used as a muscle relaxant in the treatment of the paroxysmal pain of trigeminal neuralgia[5] as well as spasticity of spinal cord and cerebral origin.[6] Pharmacological studies suggest that the biological activity of baclofen resides exclusively in the (–)-enantiomer only,[7] therefore, access to (–)-baclofen in an enantiomerically pure form is of great importance. The absolute configuration of (–)-baclofen was assigned as R configuration on the basis of X-ray crystallography analysis.[8]

Figure 1 Structure of baclofen (1)

2

Resolution Synthetic Approaches

2.1

Chemical Resolution

In 1997, Caira and co-workers reported the large-scale production of (R)-baclofen [(R)-1] using a chemical resolution method (Scheme [1]).[9] This method involved direct resolution of racemic 3-(4-chlorophenyl)glutaramic acid (rac-2) by diastereomeric salt formation with (S)-(–)-α-phenylethylamine. The reaction of rac-2 with (S)-α-phenylethylamine in methanol readily gave diastereomeric (S)-α-phenylethylamine salts, which were separated by crystallization. The structures of the diastereomeric salts were established by X-ray diffraction analysis. The optically pure salt was treated with aqueous NaOH then neutralized with dilute HCl to afford (R)-2, which was converted into selective GABA receptor agonist (R)-baclofen [(R)-1] by Hofmann reaction in 57% yield with 99.8% ee.

Scheme 1 Chemical resolution by (S)-(–)-α-phenylethylamine

Muñoz-Torrero, Sánchez, and Camps[10] reported the resolution of racemic γ-nitro acid rac-4 using (R)-N-phenylpantolactam (5) as a chiral auxiliary (Scheme [2]); rac-4 was obtained from 3 via a three-step sequence (esterification, Michael addition with nitromethane, and ester hydrolysis). The esterification of rac-4 with (R)-N-phenylpantolactam (5) gave a 1:1 mixture of two diastereomers, which was subjected to column chromatography to obtain 6 in 22% yield and >98:2 dr. On the other hand, compound 6 was also synthesized in 17% yield with 96:4 dr (after column chromatography) by the Michael addition of nitromethane to chiral auxiliary compound 7. Hydrolysis of compound 6 in the presence of LiOH furnished (R)-4 in 84% yield with >99% ee with the recovery of (R)-N-phenylpantolactam (5) in 91% yield. Reduction of the nitro group in (R)-4 catalyzed by Raney nickel and then acid hydrolysis completed the synthetic sequence to give (R)-baclofen [(R)-1] in 91% yield. Similarly, reduction followed by acid hydrolysis of compound 6 provided (R)-baclofen [(R)-1] via the formation of chiral intermediate (R)-8. (S)-Baclofen was also synthesized by using (S)-5 as a chiral auxiliary.

Scheme 2 Resolution using (R)-N-phenylpantolactam

In 2015, Linzaga-Elizalde and co-workers[11] described the synthesis of optically pure pyrrolidinone intermediate (R)-8 by using chemical resolution method as a key step (Scheme [3]). Condensation of aldehyde 10 with dimethyl malonate (9) in the presence of piperidine base afforded the diester 11, which on Michael addition with nitromethane yielded nitro diester 12. Catalytic hydrogenation of 12 in the presence of Raney nickel yielded 13 which on hydrolysis of the ester group followed by decarboxylation provided the desired rac-8. The racemic compound rac-8 was coupled with optically pure 14 to give a mixture of diastereomers, which was separated by using column chromatography. Removal of the chiral naproxen auxiliary from the diastereomerically pure imide 15, provided optically pure (R)-8 in 79% yield, which on acid hydrolysis yielded (R)-baclofen [(R)-1].

Scheme 3 Resolution using (S)-naproxen

2.2

Biocatalytic Resolution

Biocatalysts are widely used in organic synthesis and the pharmaceutical industry as environmentally friendly catalysts for the synthesis of optically pure chiral intermediates under mild reaction conditions.[12]

Scheme 4 Rhodococcus sp. AJ270 catalyzed resolution

Microbial hydrolysis of 2-arylpent-4-enenitriles 16 was investigated by Wang and Zhao using Rhodococcus sp. AJ270 nitrile hydratase amidase as a biocatalyst (Scheme [4]).[13] Thus the reactions were performed under milder and environmentally friendly conditions. Excellent enantioselectivity was observed with 2-(4-chlorophenyl)pent-4-enenitrile (16, 0.5 mmol), in the presence of Rhodococcus sp. AJ270, in 0.1 M phosphate buffer solution (pH 7) at 30 °C. After a reaction time of 6 days, amide (R)-17 and acid (S)-18 were obtained with 99% ee (44% yield) and 99% ee (50% yield), respectively. A further increase of substrate concentration to 1 mmol actually decreased the enantioselectivity and prolonged the reaction time. The chiral amide 17 was reduced with LiAlH₄ to afford the corresponding amine 19, which was then oxidized to (R)-baclofen [(R)-1] using OsO₄ and Jones’ reagent.

The enzymatic resolution of racemic methyl 3-(4-chlorophenyl)-4-nitrobutanoate (21) by ester hydrolysis, in 0.1 M phosphate buffer solution at pH 7.4, using α-chymotrypsin was described by Felluga and co-workers (Scheme [5]).[14] When the reaction was stopped at 53% conversion, the unreacted ester (R)-21 was isolated with 99.9% ee (42% yield) and (S)-acid with 96% ee in 43% yield (enantioselectivity >200). (R)-Baclofen [(R)-1] was obtained by hydrolysis of the optically pure γ-nitro ester (R)-21 followed by the reduction of the nitro group on Raney nickel.

Scheme 5 α-Chymotrypsin-catalyzed resolution

The hydrolysis of racemic butyl 4-amino-3-(4-chlorophenyl)butanoate (rac-22a), catalyzed by the same protease (α-chymotrypsin) was also described by Veinberg and co-workers (Scheme [6]).[15] The reaction was carried out in phosphate buffer (pH 6–7) or phosphate buffer/dioxane ratio (10:1) or phosphate buffer/acetone ratio (10:2). Good enantioselectivity was reported for this reaction with the formation of pyrrolidinone (S)-8 (98% ee), and the recovery of unreacted ester (R)-22a in 97% ee from racemic 22a. Acid hydrolysis of the ester group in (R)-22a gave (R)-baclofen [(R)-1].

3

Asymmetric Desymmetrization

Enantioselective desymmetrization of prochiral and meso compounds is the most important strategy to produce an optically pure single enantiomer in 100% theoretical yield and 100% optical purity. For this reason, asymmetric desymmetrization constitutes the most important alternative to kinetic resolution methods for the synthesis of optically pure compounds.[16]

Scheme 6 Protease-catalyzed resolution

Scheme 7 Desymmetrization of a meso-cyclic anhydride with a modified cinchona alkaloid

3.1

Catalytic Enantioselective Desymmetrization

In 2000–2001, Deng and co-workers developed an asymmetric methanolysis of cyclic anhydrides using modified cinchona alkaloids as chiral Lewis base catalysts.[17] Taking advantage of this method, the asymmetric synthesis of (R)-baclofen [(R)-1] using (DHQD)₂AQN-catalyzed enantioselective meso-cyclic anhydride 24 desymmetrization as a key step was accomplished by Zhang and co-workers in 2009 (Scheme [7]).[18] The meso-cyclic anhydride 24 was prepared from 23 by treatment with acetic anhydride. The asymmetric methanolysis of meso-cyclic anhydride 24 using (DHQD)₂AQN catalyst (10 mol%) provided hemiester (S)-25 in 76% yield with 95% ee. It is proposed that the anhydride fits into a U-shaped conformation of the (DHQD)₂AQN­ catalyst[19] as shown in the transition state. The chiral amine of the catalyst activates the methanol nucleo­phile via hydrogen bonding. Then the activated methanol nucleophile attacks the nearest carbonyl group of the anhydride to produce the desired product 25 with absolute S-configuration. Ammonolysis of monoester (S)-25 with aqueous ammonia yielded amide (R)-2, which was then treated with [bis(trifluoroacetoxy)iodo]benzene (PIFA) and hydrochloric acid to provide (R)-baclofen [(R)-1] in 60% yield. Similarly, (S)-baclofen was also prepared from (S)-25 by Curtius rearrangement followed by acid hydrolysis.

Scheme 8 Enantioselective desymmetrization using a chloramphenicol-base-derived thiourea organocatalyst

In 2016, Chen and co-workers[20] also described deracemization of meso-cyclic anhydrides using newly synthesized chloramphenicol-base-derived thiourea organocatalysts. The best result for deracemization of meso-cyclic anhydride 24 was achieved giving (R)-25 with 80% ee and 98% yield using 10 mol% of A as the catalyst. The enantiopurity of (R)-25 was increased to 95% ee after recrystallization (n-hexane/EtOAc, 20:1). The tertiary amino group of the catalyst activates the alcohol by hydrogen bonding, while the thiourea group activates the anhydride by double hydrogen bonding as shown in the transition state. Quantum chemical calculations provided the theoretical explanation for the enantioselectivity of the catalyst and stability of the transition states.[21] The hemiester (R)-25 was then converted into (R)-baclofen [(R)-1] using Curtius rearrangement followed by acid hydrolysis in 80% yield over two steps (Scheme [8]).

3.2

Enzymatic Desymmetrization

Chenevert and Desjardins[22] have employed two different enantioselective enzymatic desymmetrization approaches for the synthesis (R)-baclofen: 1. hydrolysis of a meso-ester using α-chymotrypsin, and 2. acylation of the meso-alcohol by a transesterification reaction using PPL. The α-chymotrypsin-catalyzed ester hydrolysis of symmetrical dimethyl 3-(4-chlorophenyl)pentanedioate (26) afforded the desymmetrized monoester (R)-25 in 85% yield with 98% ee. Curtius rearrangement of (R)-25 followed by acid hydrolysis provided the target molecule (R)-1 through the formation of isocyanate 27 (Scheme [9]).

Scheme 9 α-Chymotrypsin-catalyzed desymmetrization

They also desymmetrized 2-(4-chlorophenyl)propane-l,3-diol (28) through PPL-catalyzed transesterification (Scheme [10]). The transesterification process led to the monoacetate of (S)-configuration 29, which was isolated in 93% yield with 96% ee. Mesylation of the free alcohol in hemiester 29 using MsCl followed by nucleophilic substitution with cyanide provided 30. Removal of the acetyl group from 30, O-mesylation, followed by displacement of the mesylate group with azide furnished the cyano azide 31. Finally, azide group reduction followed by acid hydrolysis of the cyanide group yielded (R)-baclofen [(R)-1].

Scheme 10 PPL-catalyzed desymmetrization

Furstoss and co-workers[23] reported a seven-step synthesis of (R)-baclofen using a microbiologically mediated Baeyer–Villiger oxidation as a key step (Scheme [11]). The prochiral intermediate 33 was prepared from commercially available 4-chlorostyrene (32) in two steps.[24] The stereoselective oxidation of prochiral ketone 33 in the presence of the fungus Cunninghamella echinulata NRLL 3655 provided (R)-chlorobenzyl lactone 34 in 30% yield with 99% ee. Lactone opening of 34 with Me₃SiI and EtOH followed by reaction with NaN₃ gave azido ester 35. Hydrolysis of the ester group in 35 followed by reduction of the azide group provided the target molecule (R)-1.

Scheme 11 Cunninghamella echinulata NRLL 3655 catalyzed desymmetrization

Wang and co-workers[25] reported the microbial desymmetrization of 3-arylglutaronitriles. The enantioselective hydrolysis of prochiral intermediate 36 catalyzed by Rhodococcus sp. AJ270 in aqueous buffer at 30 °C provided (S)-37 in 37% yield with low enantiomeric excess (26%). However, in the presence of acetone as an additive the enantiomeric excess increased to 63%. In 2014, the desymmetrization of the 3-substituted glutaronitriles was attempted in the presence of several nitrilases from diverse sources by Wu, Zhu, and co-workers.[26] Among them, AtNIT3 nitrilase produced (R)-37, whereas BjNIT6402 and HsNIT nitrilases generated the opposite enantiomer (S)-37 with high conversion and ee values. Finally, HsNIT nitrilase afforded the monoacid (S)-37 in 80% yield with 99% ee. Curtius rearrangement of (R)-37 and subsequent acid hydrolysis yielded (R)-baclofen [(R)-1] (Scheme [12]).

Scheme 12 Nitrilase-catalyzed desymmetrization

4

Chiral Auxiliary Induced Asymmetric Synthesis

4.1

Asymmetric Michael Addition

Several synthetic routes to (R)-baclofen using chiral auxiliary induced diastereoselective conjugate addition have been reported. One contribution, a chiral auxiliary induced enantioselective synthesis approach by the Licandro group,[27a] utilized the diastereoselective Michael addition of Fischer-type amino carbene 39 to (E)-4-chloro-β-nitrostyrene (40) to give 41 as a mixture of diastereomers in 90% yield and 76% de (Scheme [13]).

Scheme 13 Diastereoselective Michael addition of Fischer-type amino carbene

The Licandro group[27b] proposed that the presence of an electronic interaction between the negatively charged Cr(CO)₅ ^– group and the chlorine group of the nitrostyrene on the Re face of the proposed transition state leads to the formation of the desired S,S,R-diastereomer as the major product. The optically pure S,S,R-isomer 41 was then isolated in 77% yield using silica gel column chromatography. Compound 41 was completely transformed into amide 42 using the oxidizing agent CAN; compound 42 on reduction followed by hydrolysis afforded (R)-baclofen [(R)-1].

Kuo and Wong[28] reported that the tetramethylguanidine (TMG)-catalyzed diastereoselective conjugate addition of nitromethane to chiral α,β-unsaturated oxazolidinone 43 provided 44 with 93:7 dr (Scheme [14]). The purity of compound 44 could be increased to 99% de (78% yield) by crystallization from ethyl acetate. Removal of the chiral auxiliary group followed by reduction provided (R)-baclofen [(R)-1] in 65% yield with 99% ee.

Scheme 14 TMG-catalyzed diastereoselective conjugate addition

Oba, Nishiyama, and co-workers[29] reported the synthesis of non-proteinogenic amino acids via Michael addition to an α,β-unsaturated orthopyroglutamate derivative. Compound 46 was synthesized by Michael addition of Gilman reagent (4-ClC₆H₄)₂CuMgBr to unsaturated pyroglutamate derivative 45 in 68% yield (Scheme [15]). Methanolysis of the orthoester function followed by concomitant Boc group deprotection with HCl in methanol yielded 47 in 75% yield. Benzyl protection of the lactam nitrogen followed by LiOH-promoted ester hydrolysis provided the desired pyroglutamic acid 48, which could be converted into (R)-baclofen [(R)-1] as described by Chang and co-workers.[30] [31]

Scheme 15 Michael addition to unsaturated orthopyroglutamate

4.2

Asymmetric Aldol Addition

Nair and co-workers[32] reported the synthesis of (R)-baclofen [(R)-1] using a diastereoselective aldol reaction (Scheme [16]). Acetate aldol addition using the titanium enolate of (S)-1-(5-isopropyl-3-phenyl-2-thioxoimidazolidin-1-yl)ethan-1-one (49) with 4-chlorobenzaldehyde (10) at –78 °C in CH₂Cl₂ provided compound 50 in 69% yield with 98:2 dr. The titanium enolate was formed when N-acylated imidazolidine-2-thione 49 reacted with 2 equivalents of TiCl_4­ and 1 equivalent of DIPEA. The aldehyde approaches the titanium enolate from the sterically less hindered face (bottom face) to form a highly favored chelated transition state and provide the syn-acetate aldol adduct as the major diastereomer. The chiral auxiliary of aldol adduct 50 was removed by treatment with K₂CO₃ in EtOH to obtain compound 51. Bromination of 51 afforded the β-bromo ester 52, which was then converted by reaction with TMSCN/TBAF into the corresponding β-cyano ester 53a. Subsequent reduction followed by acid hydrolysis provided (R)-baclofen [(R)-1] with high enantiopurity.

Scheme 16 Asymmetric aldol addition

4.3

Asymmetric Nucleophilic Substitution

Schoenfelder and co-workers[33] reported the enantioselective synthesis of (R)-baclofen [(R)-1] (Scheme [17]). The chiral imide 54 was coupled with tert-butyl bromoacetate in an Evans asymmetric alkylation reaction to give the alkylated product 55 in 82% yield and 95:5 dr. Deprotonation of 54 by means of sodium hexamethyldisilazanide results in the Z-enolate transition state. Chelation of the auxiliary carbonyl group to the sodium restricts the confirmation so that the isopropyl group shields the top face of the enolate. Therefore, the tert-butyl bromoacetate electrophile approaches from the bottom face with high diastereoselectivity.[34] Removal of the oxazolidinone chiral auxiliary from 55 under mild basic conditions followed by selective ester reduction in the presence of BH₃·DMS yielded the desired lactone product 34. The lactone 34 was transformed into the azide ester 35 using lactone opening with HBr/EtOH followed by halogen displacement with NaN₃. Finally, the reduction of azide group and acid hydrolysis yielded the target molecule through the formation of lactam (R)-8.

Scheme 17 Evans asymmetric alkylation

An efficient and short asymmetric synthesis of (R)-baclofen [(R)-1] has been described by Enders and Niemeier (Scheme [18]).[35] The α-alkylation of 56 with methyl bromo­acetate in the presence of the strong base lithium diisopropylamide (LDA) afforded 57 with 96% de (84% yield). Deprotonation of SAMP-hydrazone 56 with strong base LDA produces an azaenolate with E _C-C, Z _C-N geometry, and lithium cation chelated by the oxygen and nitrogen atoms as shown in the transition state.[36] The steric repulsions between the pyrrolidine ring of the SAMP-hydrazone and the methyl bromoacetate hinder the attack of the methyl bromoacetate from the top face. Thus, the methyl bromoacetate attacks from the bottom face, where the steric repulsions do not exist.[37] The aldehyde hydrazone 57 was converted into nitrile product (R)-53b by oxidation in the presence of magnesium monoperoxyphthalate hexahydrate (MMPP). At this stage, the reaction conditions for the selective reduction of the nitrile group were optimized. The nitrile ester (R)-53b was converted into γ-lactam (R)-8 using NaBH₄ as the reducing agent in methanol at –20 °C. Finally, the lactam (R)-8 was hydrolyzed to give (R)-baclofen [(R)-1].

Scheme 18 Chiral auxiliary induced nucleophilic substitution

5

Asymmetric Reduction

5.1

Catalytic Asymmetric Hydrogenation

In 2003, Sudalai and co-workers[38] reported a ruthenium-catalyzed asymmetric hydrogenation in the synthesis of (R)-baclofen [(R)-1]. Compound 59 was prepared from 4-chloroacetophenone (58) in 78% yield (E/Z 70:30) using Zn-mediated Reformatsky reaction of ethyl bromoacetate followed by acid-catalyzed dehydration. The allylic bromination of 59 gave γ-bromo α,β-unsaturated ester 60, which was subjected to S_N2 reaction with NaN₃ to obtain allylic azide 61. Enantioselective hydrogenation of prochiral compound 61 in the presence of Ru(II)–(S)-BINAP in MeOH under H₂ (~13 atm) at 50 °C afforded the chiral compound 35 in 68% yield with 68% ee. Compound 35 was converted into (R)-1 with low ee (67%) in two steps (Scheme [19]).

Scheme 19 Ru(II)–BINAP catalyzed asymmetric hydrogenation

On the other hand, the highly enantioselective hydrogenation of β-keto ester 62 was carried out in the presence of Ru(II)–(S)-BINAP catalyst in MeOH under H₂ (54 atm) to give (R)-hydroxy ester 51 in 95% yield with high enantioselectivity (96% ee) (Scheme [20]). The oxygen atoms in the β-keto ester coordinated to the ruthenium center of the Ru–(S)-BINAP catalyst. Due to steric repulsions between the phenyl ring of (S)-BINAP and the 4-chlorophenyl group of the β-keto ester, the transition state on the right side is disfavored. The hydride ion is transferred from the ruthenium catalyst to the keto group through the favored transition state and provides the desired product 51 with absolute R configuration.[39] The chiral β-hydroxy ester 51 was converted into (R)-baclofen [(R)-1] in four steps by a similar method to that shown in Scheme [16].

Scheme 20 Ruthenium(II)–BINAP catalyzed asymmetric hydrogenation

Scheme 21 Cobalt-catalyzed asymmetric reductive cyclization

Paraskar and Sudalai reported[40] the synthesis of (R)-baclofen [(R)-1] via enantioselective reduction of α,β-unsaturated ester 61 using a cobalt–semicorrin complex.[41] 4-Chlorophenylboronic acid (63) and ethyl crotonate (64) are commercial products that were used as starting materials for the preparation of key precursor ethyl (Z)-4-azido-3-(4-chlorophenyl)but-2-enoate (61) in a three-step sequence (Scheme [21]). Arylation of ethyl crotonate with boronic acid 63 in the presence of palladium(II) acetate catalyst provided α,β-unsaturated ester 59, which on allylic bromination followed by S_N2 reaction with NaN₃ yielded compound 61. A set of chiral ligands was screened for the reductive cyclization of azido-substituted unsaturated esters in the presence of CoCl₂ and NaBH₄. The chiral ligand B (1.1 mol%) was found to be the best ligand, giving lactam (R)-8 in 82% yield with 89% ee. Finally, acid hydrolysis of (R)-8 afforded the hydrochloride salt of (R)-baclofen [(R)-1] in 73% yield with 88% ee.

The asymmetric hydrogenation of γ-phthalimido-α,β-unsaturated esters in the presence of a rhodium catalyst was reported by Zheng and co-workers in 2007.[42] The prochiral substrate 65 was prepared from commercially available 4-chloroacetophenone (58) via a three-step sequence: 1. olefination of ketone 58, 2. allylic bromination, and 3. nucleophilic substitution with phthalimide. Optimization of the reaction conditions using [Rh(COD)₂]BF₄ as a catalyst revealed that (S _C,R _Fc,R _P)-C and dichloromethane were the best ligand and solvent, respectively. Under the optimized reaction conditions, substrate 65 was transformed into the desired chiral compound 66 in 91% yield with 99% ee after a single crystallization, which was then hydrolyzed with 6 N HCl under reflux to give the HCl salt of (R)-baclofen [(R)-1] in quantitative yield (Scheme [22]).

Scheme 22 Rhodium-catalyzed asymmetric hydrogenation

In 2008, Zheng and co-workers reported the asymmetric hydrogenation of 65 using Cu(OAc)₂·H₂O as the catalyst and (R)- or (S)-BINAP as the ligand (Scheme [23]),[43] together with PMHS as the hydride source and t-BuOH as an additive. Using this methodology the desired chiral compound 66 was obtained in 92% yield with 94% ee (98% ee after recrystallization).

Scheme 23 Copper-catalyzed asymmetric 1,4-reduction

Mita, Higuchi, and Sato[44] reported the carboxylation of allylic alcohols in the presence of a catalytic amount of PdCl₂ under a CO₂ atmosphere. Intermediate 68, prepared in 73% yield from 67 using optimal reaction conditions, was converted into butenolide 69, which on asymmetric reduction using Stryker’s reagent in the presence of (R)-DTBM-SEGPHOS­ afforded the key chiral intermediate 34 of (R)-baclofen [(R)-1] in quantitative yield with 99% ee (Scheme [24]).

Scheme 24 Asymmetric reduction using Stryker’s reagent

5.2

Bioreduction

In 2015, the tryptophan 116 mutant of Old Yellow Enzyme­ 1 (OYE1-W116L)-mediated bioreduction of (Z)-3-aryl-3-cyanoacrylates was reported by Brenna and co-workers.[45] The prochiral intermediate 71 was prepared by the condensation of arylacetonitrile 70 with glyoxylic acid in the presence of K₂CO₃ in methanol[46] followed by esterification with MeI. The bioreduction of 71 in the presence of OYE1-W116L yielded (R)-53b with 90% ee. Finally, reduction of the nitrile group in the presence of NiCl₂·6H₂O and NaBH₄ followed by acid hydrolysis provided the target molecule (R)-1 (Scheme [25]).

Scheme 25 OYE1-W116L catalyzed bioreduction

On the other hand, Fryszkowska, Stephens, and co-workers described the bioreduction of potassium 3-(4-chlorophenyl)-3-cyanoacrylate (72) with reductase [Clostridium­ sporogenes (DSM 795) or Ruminococcus productus (DSM3507) or Acetobacterium woodii (DSM 1030)] from anaerobic bacteria to provide optically pure (S)-3-(4-chlorophenyl)-3-cyanopropanoic acid (73) in quantitative yields with high enantiomeric excess.[47] After methylation, the ester (S)-53b was obtained in 83% yield with 95% ee from starting material 72. Enantiomerically pure compound (S)-53b (≥99% ee, 90% yield) was obtained after a single recrystallization, which was used in the synthesis of (S)-baclofen [(S)-1] (Scheme [26]).

Scheme 26 Biocatalytic reduction

6

Catalytic Asymmetric Conjugate Addition

Wang and co-workers[48] and Liang, Ye, and co-workers[49a] independently published the organocatalytic asymmetric conjugate addition of nitromethane to α,β-unsaturated aldehydes using (R)- or (S)-2-[diphenyl(trimethylsil­oxy)methyl]pyrrolidine as the catalyst (Scheme [27]). Wang and co-workers reported that the highly enantioselective Michael addition of nitromethane to unsaturated aldehyde 74 in the presence of proline derivative D (20 mol%) as the catalyst and benzoic acid (20 mol%) as an additive in ethanol at 0 °C provided the corresponding Michael adduct 75 in 73% yield with high 96% ee. The benzoic acid additive can effectively increase the rate of the reaction as well as the amount of product.[49b] Similarly, Liang, Ye, and co-workers in 2008 reported that when the reaction was carried out in the presence of D (10 mol%) as the catalyst and lithium acetate (10 mol%) as an additive in CH₂Cl₂/MeOH (1:9) at room temperature, product 75 was obtained in 62% yield with 91% ee. When lithium acetate was used as the additive, the nucleophilicity of deprotonated nitromethane increased and it also accelerated the formation of the iminium ion. The observed stereochemistry is explained through the formation of enamine transition state, which could be formed from the catalyst D with the unsaturated aldehyde 74. The nitromethane nucleophile approaches the planar iminium ion from the Re face (above the plane) due to the steric hindrance of Ph and OTMS bulky groups at the chiral center of the pyrrolidine ring in catalyst D and leads the observed stereochemistry.[49c] The enantiomerically pure aldehyde 75 was further oxidized to γ-nitro acid (R)-4 by reaction with NaClO₂. Finally, catalytic hydrogenolysis of the nitro group in the presence of Raney nickel provided (R)-baclofen [(R)-1]. Similarly, Jørgensen and co-workers[50] and Hayashi and co-workers[51] employed ent-D as a catalyst in the synthesis of (S)-baclofen [(S)-1] via the asymmetric conjugate addition of nitromethane to aldehyde 74.

Scheme 27 Proline derivative catalyzed enantioselective Michael addition

In 2016, Šebesta and co-workers[52a] developed new chiral squaramide derivatives and employed them in the synthesis of GABAergic drugs using asymmetric Michael addition as the key step (Scheme [28]). The asymmetric conjugate addition of nitromethane to aldehyde 74 in the presence of organocatalyst E (5 mol%) provided 75 in 64% yield with 92% ee. The enantioselectivity is explained through the formation of an enamine transition state as shown in Scheme [28].[52a] Finally, compound 75 was converted into (R)-baclofen [(R)-1] in a three-step sequence: 1. oxidation, 2. reduction, and 3. acid hydrolysis.

Scheme 28 Asymmetric Michael addition using squaramide organocatalyst

Similarly, chiral squaramide F efficiently catalyzed enantioselective Michael addition of dimethyl malonate (9) to 4-chloro-β-nitrostyrene (40) to provide (R)-baclofen precursor 76a in 76% yield with 86% ee (Scheme [29]). Pápai, Soós, and co-workers reported the mechanism of bifunctional squaramide-catalyzed Michael addition of 1,3-dicarbonyl compounds to nitrostyrene.[52b] In the transition state of carbon–carbon bond formation, carbonyl groups are bonded to both NH units of the catalyst as N–H···O bonds (H-bonding). The NO₂ group of the electrophile is bonded to the protonated amine, which stabilizes the negative charge developing on this unit upon carbon–carbon bond formation. Hydrogenation of optically pure nitro diester 76a in the presence of Raney nickel afforded pyrrolidinone derivative 77a, which was then subjected to ester hydrolysis followed by decarboxylation to give final product (R)-baclofen [(R)-1] with 99% ee.

Scheme 29 Asymmetric Michael addition using squaramide organocatalyst

In 2009, Yasuoka and co-workers[53] patented a route to (R)-baclofen [(R)-1] (Scheme [30]). They utilized the method developed by Evans and Seidel[54] to construct the chiral intermediate 76b of (R)-baclofen [(R)-1] via asymmetric Michael­ addition. 4-Chloro-β-nitrostyrene (40), prepared from the condensation of 4-chlorobenzaldehyde (10) with nitromethane, reacted with diethyl malonate in the presence of bis[(R,R)-N,N′-dibenzylcyclohexane-1,2-diamine]-dibromonickel(II) catalyst G (2 mol%) in toluene at 50 °C for seven hours, affording the Michael adduct 76b in 74% yield with 94% ee. The enol form of diethyl malonate coordinates to the nickel complex and nucleophilic attack on nitrostyrene could proceed through a transition structure in which the electrostatic and reinforcing steric effects might orient the nitrostyrene molecule.[54] Therefore, the obtained addition product has R configuration. The chiral intermediate 76b was transformed into (R)-baclofen [(R)-1] via a sequence similar to the one in Scheme [29].

Scheme 30 Nickel-catalyzed Michael addition

In 2003, Takemoto and co-workers[55] developed the first chiral bifunctional thiourea organocatalyst and applied it to the asymmetric Michael addition of malonates to nitroalkenes. In this chiral bifunctional thiourea organocatalyst, the thiourea moiety acts as the Brønsted acidic part and lowers the lowest unoccupied molecular orbital (LUMO­) level of the electrophile. At the same time, the amine group of the chiral scaffold acts as the Lewis basic part and raises the highest occupied molecular orbital (HOMO­) level of the nucleophile (Figure [2]).[56] [57]

Figure 2 Amine-thiourea organocatalysts for dual activation of the substrates

Scheme 31 Enantioselective Michael addition catalyzed by thiourea bifunctional organocatalyst

Takemoto and co-workers reported the thiourea bifunctional organocatalyst H catalyzed enantioselective Michael addition of diethyl malonate to 4-chloro-β-nitrostyrene (40) to provide the Michael adduct 76b in 80% yield and 94% ee (Scheme [31]).[56] The acidic proton of diethyl malonate is deprotonated by the amino group of thiourea organocatalyst H and generates a nucleophile. Then nitrostyrene 40 interacts with the thiourea moiety through the formation of hydrogen bonding. Based on the product formation with R configuration, the malonate nucleophile would attack nitrostyrene from the Re face instead of the Si face, which might be due to steric repulsions of the cyclohexyl scaffold with the phenyl ring of the nitrostyrene. The optically pure intermediate 76b was further converted into (R)-baclofen [(R)-1].

García-García, Corma, and Leyva-Pérez[58] prepared multi-site organic-inorganic hybrid catalysts and employed them in the synthesis of GABAergic drugs. Condensation of aldehyde 10 with nitromethane followed by asymmetric Michael addition with dimethyl malonate (9) in a one-pot multicomponent transformation in the presence of urea-modified chiral cinchona alkaloid derivative I on a mesoporous siliceous material with additional pending aminopropyl groups afforded 76a in 77% yield with 70% ee (Scheme [32]). Compound 76a was converted into the corresponding baclofen intermediate (R)-8 by a one-pot procedure using palladium on carbon (2 mol%, 20 mg of 5 wt% solids) solid catalyst under hydrogen. Finally, the acid hydrolysis provided (R)-baclofen [(R)-1].

Scheme 32 Multicomponent reaction catalyzed by urea-modified chiral cinchona alkaloid solid catalyst

In 2011, Tian, Lin, and co-workers[59] synthesized a new chiral cinchona alkaloid organocatalyst J, for the asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes. By employing the bifunctional biscinchona alkaloid J as the catalyst, the conjugate addition of compound 40 with dimethyl malonate (9) proceeded well to afford the desired product 76a in 87% yield with >99% ee (after recrystallization) (Scheme [33]). A similar synthetic sequence to the one in Scheme [29] was used for the preparation of (R)-1 from 76a.

Scheme 33 Asymmetric conjugate addition using biscinchona alkaloid organocatalyst

Scheme 34 Primary amine thiourea bifunctional organocatalyst catalyzed asymmetric Michael addition

In 2013, Tsogoeva and co-workers[60] reported the successful asymmetric Michael addition of nitroalkanes to various α,β-unsaturated ketones catalyzed by primary amine-thiourea catalyst K, providing Michael adducts in good yields with excellent enantioselectivities. The enantioselective Michael addition of nitromethane to (E)-1-(4-chlorophenyl)-4-methylpent-1-en-3-one (78) provided the desired product 79 in 85% yield with 98% ee (Scheme [34]). The compound 78 is activated via hydrogen-bonding interactions between the thiourea two NH moieties of the catalyst and the carbonyl group of ketone 78. Furthermore, the Re-face approach of nitromethane is induced by the amine group of the catalyst K and leads to the formation of product with R-configuration. Baeyer–Villiger oxidation followed by nitro group reduction yielded the amino ester (R)-22b, which on acid hydrolysis provided the target molecule (R)-baclofen [(R)-1].

Corey and co-workers[61] used chiral quaternary ammonium salt as a catalyst L in their asymmetric synthesis of (R)-baclofen [(R)-1] (Scheme [35]). The synthesis commenced with Michael addition of nitromethane to α,β-enone 80 in the presence of cinchoninium salt L (10 mol%) at –40 °C in toluene to afford Michael adduct 81 in 89% yield with 70% ee. A single recrystallization from EtOAc/hexane mixture afforded enantiomerically pure 81 with 95% ee. Baeyer–Villiger oxidation of ketone 81 in the presence of m-CPBA in the next step afforded nitro ester 82 in 90% yield. Compound 82 was further converted into (R)-baclofen [(R)-1] via reduction followed by acid hydrolysis of the corresponding pyrrolidone (R)-8.

Scheme 35 Chiral quaternary ammonium salt catalyzed enantioselective Michael addition

The catalytic asymmetric conjugate addition of nitromethane with α,β-unsaturated thioamides was described by Kumagai, Shibasaki, and co-workers.[62] With the mesitylcopper/(R)-DTBM-Segphos precatalyst, the asymmetric addition of nitromethane to 83 gave the desired product 84 in 92% yield with high enantioselectivity, 99% ee (Scheme [36]). Thioester 85 was obtained by the reaction of thioamide 84 with MeI/TFA in wet THF.[63] Finally, thioester 85 was converted into (R)-baclofen [(R)-1] by hydrolysis and reduction.

Scheme 36 Mesitylcopper/(R)-DTBM-Segphos catalyzed asymmetric conjugate addition

Helmchen and co-workers reported[64] the asymmetric addition of arylboronic acids to N-protected 4-aminobut-2-enoic acid derivatives using a rhodium catalyst and chiral BINAP as a ligand. The starting material 87 was prepared from N-protected 2-aminoethanol 86 using IBX oxidation followed by Horner–Wadsworth–Emmons olefination. The Michael adduct 88 was obtained in quantitative yield with 89% ee by the enantioselective addition of 4-chlorophenylboronic acid (63) to unsaturated ester 87 in the presence of [Rh(acac)(C₂H₄)₂] (4.5 mol%) catalyst and (S)-BINAP ligand in dioxane/water (10:1) (Scheme [37]). The (S)-BINAP–rhodium intermediate should have an open space at the lower part of the vacant coordination site, the upper part is blocked by one of the phenyl rings of the (S)-BINAP ligand.[65a] Therefore, the unsaturated ester coordinates to rhodium with its 2Re face rather than its 2Si face. The 1,4-addition of the aryl group to the unsaturated ester leads to the formation of product with R-absolute configuration.[65b] Deprotection of the Boc group followed by ester hydrolysis provided (R)-1.

Scheme 37 Rhodium-catalyzed conjugate addition

A set of chiral dienes was screened by Feng, Lin, and co-workers[66] for the asymmetric addition of arylboronic acids to α,β-unsaturated γ-lactams in the presence of rhodium catalyst. The chiral diene M was found to be the best ligand. In the presence of rhodium/diene complex as a catalyst, the adduct 90 was obtained in 99% yield with high enantioselectivity, 97% ee (Scheme [38]). The rhodium complex of chiral ligand M recognizes the enantioface of the α,β-unsaturated γ-lactam 89 by the steric repulsions between the phen­yl group on the chiral ligand M and the carbonyl moiety of the unsaturated lactam, the coordination with the αRe face is favorable for the unsaturated lactam, which leads to the formation of product with R configuration.[67] After a single recrystallization, the enantiomeric excess of 90 increased to >99%. Deprotection of the Boc group, followed by hydrolysis completed the synthetic sequence to enantiomerically pure (R)-baclofen [(R)-1].

Scheme 38 Rhodium/diene-catalyzed 1,4-additions

7

Conclusion

In conclusion, baclofen is the only available selective agonist of the GABA_B receptor and it is used as a muscle relaxant. It is also used in the treatment of the paroxysmal pain of trigeminal neuralgia. The pharmaceutical activity of baclofen­ resides in the R-enantiomer only. This review focused on the numerous asymmetric strategies used for the synthesis of the antispastic drug (R)-baclofen.

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