Synthesis of Stereoisomers of 3-Aminocyclohexanecarboxylic Acid and cis-3-Aminocyclohexene-5-carboxylic Acid

Chinese Journal of Chemistry, 2006, 24, 795—799 Full Paper

* E-mail: [email protected]; Tel.: 0086-28-85229689; Fax: 0086-28-85223978 Received August 29, 2005; revised November 10, 2005; accepted February 15, 2006. Project supported by the National Natural Science Foundation of China (Nos. 20172050, 20025205).

© 2006 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of Stereoisomers of 3-Aminocyclohexanecarboxylic Acid and cis-3-Aminocyclohexene-5-carboxylic Acid

HU, Yua,b(胡昱) YU, Sheng-Liang a(余盛良) YANG, Yu-Jina,b(杨玉金) ZHU, Jin*a(朱槿) DENG, Jin-Gen*a(邓金根)

a Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province at Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China

bGraduate School of Chinese Academy of Sciences, Beijing 100039, China

A practical synthesis of stereoisomers of 3-aminocyclohexanecarboxylic acid and cis-3-aminocyclohexene-5- carboxylic acid was achieved from cyclohexene-4-carboxylic acid via a key resolving approach with chiral 1-phenylethylamine.

Keywords resolution, enantiopure γ-aminobutyric acid, 3-aminocyclohexanecarboxylic acid, 3-aminocyclohex-ene-5-carboxylic acid

Introduction

The biological functions of proteins are based on the property of the peptide chain to fold into definite three- dimensional structures.1 Different secondary structural motifs such as helices, sheets and turns are found in many biomacromolecules. The research of γ-peptide is beneficial to the aspects of our understanding of life and potential applications to life sciences.2,3 Moreover, self-assembling peptide nanotube with γ-amino acid has structural and functional properties that may be suitable for various applications to biology and material sci-ences.4 In another respect, the importance of the inhibi-tory neurotransmitter, γ-aminobutyric acid (GABA) 1, to certain neurological and psychiatric disorders has be-come generally accepted.5,6 As the analogues of GABA, 3-aminocyclohexanecarboxylic acid (ACHC) 2 and 3-aminocyclohexene-5-carboxylic acid (ACHEC) 3 were inhibitor of GABA uptake7,8 or time-depend inac-tivator of GABA aminotransferase.8,9 Only enantiopure cis-ACHC isomers were previously prepared from 3-aminobenzoic acid4 and cyclohexene-4-carboxylic acid,7,10 respectively. However, to the best of our knowledge, the synthesis of four enantiomers of ACHEC7-9 and enantiopure trans-ACHC isomers has not been reported. Herein we present a practical synthe-sis of enantiopure cis- and trans-ACHC isomers, as well as cis-ACHEC isomers, from the same starting

material, cyclohexene-4-carboxylic acid 4, via a key resolving approach.

Results and discussion

Cis- and trans-3-azidocyclohexene-5-carboxylic acid 7, the key intermediates for preparation of cis- and trans-ACHC 2, can be derived from 3-hydroxycyclo-hexene-5-carboxylic acid lactone 5 via diastereoselec-tive azidation in the presence or absence of palladium(0) catalyst (Scheme 1).10 Initially, to get four enantiomers of ACHC, enantiopure lactone, R,R-5, was obtained from the enantiopure cyclohexene-4-carboxylic acid, R-4,11-13 which was effectively resolved with chiral L-1-phenylethylamine in 34% yield and 97.6% enanti-oselectivity.14 Unfortunately, the azidation of R,R-5 in the presence of palladium(0) catalyst nearly gave race-mate of cis-azidocarboxylic acid rac-7. Meanwhile, the direct substitution with NaN3 only afforded 3S,5R-7 with 42.4% enantioselectivity.11

The racemization during the azidation catalyzed by Pd(0) complex is due to the formation of symmetric π-allyl-palladium intermediate 6 and the facile 1,3-rearrangement of the product (Scheme 1, path a and b). The direct substitution with NaN3 only gave 42.4% ee product, of which trans-azidocarboxylic acid was the only product. The partial loss of enantiomeric purity may be related to the SN2 and SN2' substitution10,11 dur-ing the azidation process (Scheme 1, path c and d), be-cause the configuration of stereochemical course of SN2' type azidation is opposite to that of SN2 type azidation.

Thus, the enantiopure lactone R,R-5 was hydrolyzed to yield unsaturated hydroxyl ester R,R-8 with sodium

796 Chin. J. Chem., 2006, Vol. 24, No. 6 HU et al.


Scheme 1

carbonate in methanol (Scheme 2).11 After hydrogena-tion of double bond and sequential tosylation, para-toluenesulfonate 1R,3S-9 was obtained. Then, SN2 substitution of 1R,3S-9 with NaN3 gave methyl R,R-3-azidocyclohexanecarboxylate 10. The enantio-pure isomer of R,R-2 was synthesized by the removal of the methyl ester and sequentially catalytic reduction of azido group of R,R-10 in 29% overall yield from R,R-8. Meanwhile, enantiopure isomer of trans-ACHC, S,S-2 was obtained via similar procedure in 27% overall yield from S,S-8.

Scheme 2

Furthermore, resolution of azido acid 7, unsaturated amino acid 3 and protected amino acid 117 with chiral amines was aimed. The resolution of the acids cis-3 and 7, as well as the stereoisomer trans-3, 7 and 11, was unsuccessful with the available chiral amines, such as chiral 1-phenylethylamine and threo-S,S-2-amino-1-(p- nitrophenyl)-1,3-propanediol. Fortunately, the protected amino acid, cis-Boc-ACHEC 11, could be successfully resolved with chiral 1-phenylethylamine as resolving agent (Scheme 3). Unsaturated amino acid, cis-3 was synthesized via a selective hydrogenation of cis-azido

acid 7, which was prepared according to literature pro-cedure,10 catalyzed by Lindlar catalyst with 86% yield.8 After Boc-protection of cis-3, racemic cis-11 was af-forded and then enantiopure R,R-11 and S,S-11 were prepared by the resolution with D-1-phenylethylamine in 57% yield with 100% ee and L-1-phenylethylamine in 55% yield with 99.7% ee, respectively. Two enanti-omers of cis-ACHEC 3 were concisely obtained by re-moving the Boc group of R,R-11 and S,S-11, respec-tively. Meanwhile, catalytic hydrogenation of R,R-11 and S,S-11 followed by removal of the Boc group with HCl gave both enantiomers of cis-ACHC 2, respectively. Interestingly, in one route, both optically pure isomers of cis-ACHC 2 and cis-ACHEC 3 can be synthesized via the key resolving approach with chiral 1-phenyl-ethylamine.

In summary, four stereoisomers of ACHC and the enantiomers of cis-ACHEC were demonstrated to be synthesizable from the same starting material, cyclo-hexene-4-carboxylic acid via the key resolving approach with chiral 1-phenylethylamine. To the best of our knowledge, enantiopure enantiomers of trans-ACHC and cis-ACHEC were successfully prepared for the first time. Thus, this work may contribute to the develop-ment of new inhibitor of GABA uptake and time-depend inactivator of GABA aminotransferase,7-9 and the investigation of γ-peptides.3,15 Also, the self-assembling of the cyclic γ-peptides is under study in our laboratory.16

Experimental

General

TLC was performed on glass-backed silica plates. 1H and 13C NMR spectra were recorded on a Bruker 300 MHz spectrometer, and chemical shifts were reported down field from tetramethylsilane with the solvent resonance as the internal standard. HPLC analysis was conducted

Enantiopure γ-aminobutyric acid Chin. J. Chem., 2006 Vol. 24 No. 6 797


Scheme 3

on Waters-Breeze (2487 dual absorbance detector and 1525 binary HPLC pump) using chiral columns. Chiralpak OD and OJ columns were purchased from Daicel Chemical Industries, Ltd. Optical rotations were measured on a Perkin Elmer 341 polarimeter at 589 nm. Infrared spectra were recorded on a Nicolet MX-1 FT IR spectrometer as KBr pellets or liquid film. Melting points were determined in open capillaries and uncor-rected. Commercial grade solvents were dried and puri-fied by standard procedures.

Methyl 1R,3S- and 1S,3R-3-tosyloxycyclohexanecar-boxylate 9

A suspension of methyl R,R-3-hydroxycycloexene- 5-carboxylate,11 R,R-8 (1.42 g, 9 mmol) and Pd/C (10%, 150 mg) in MeOH (35 mL) was stirred at room tem-perature for 3 d under a hydrogen atmosphere. After filtration through a pad of celite, the solvent was evapo-rated to yellow oil (1.18 g, 83%). To a solution of the saturated ester and pyridine (10 mL) in CH2Cl2 (20 mL) was added TsCl (2.3 g, 12 mmol) in CH2Cl2 (10 mL) at 0 . The ℃ reaction mixture was stirred at 50 for 6 h℃ and concentrated under vacuum. The residue was dis-solved in EtOAc and then stirred for 2 h, filtered. The filtrate was acidified to pH 2 and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water and brine, and dried. After removal of the solvent, the residue was purified by column chromatog-raphy on silica gel (1∶10 VEtOAc/Vpetroleum ether) to pro-vide methyl 1R,3S-3-tosyloxycyclohexanecarboxylate, 1R,3S-9 (1.3 g, 56%) as a white solid. m.p. 83.3—84.0

; ℃ [α]25D －38.6 (c 0.61, CHCl3);

1H NMR (300 MHz,

CDCl3) δ: 7.79 (d, J＝8.0 Hz, 2H), 7.33 (d, J＝8.0 Hz, 2H), 4.44—4.36 (m, 1H), 3.65 (s, 3H), 2.44 (s, 3H), 2.32—2.30 (m, 1H), 2.22—2.17 (m, 1H), 1.87—1.84 (m, 3H), 1.68—1.56 (m, 1H), 1.31—1.24 (m, 3H); 13C NMR (75 MHz, CDCl3) δ: 174.26, 144.56, 134.34, 129.78, 127.55, 80.25, 51.82, 41.47, 34.56, 31.99, 27.43, 23.05, 21.61; IR (KBr) ν: 2944, 1729 cm－1; HRMS calcd for C15H20O5S＋Na 335.0924, found 335.0922.

1S,3R-9 (44%) was obtained via the similar process of 1R,3S-9 with identical 1H NMR spectrum from S,S-8. m.p. 83.4—84.2 ℃ and [α]25

D 38.6 (c 0.59, CHCl3).

Methyl R,R- and S,S-3-azidocyclohexanecarboxylate 10

A solution of methyl 1R,3S-3-tosyloxycyclohexane-carboxylate, 1R,3S-9 (592 mg, 1.9 mmol) and sodium azide (130 mg, 2 mmol) in DMF (15 mL) was stirred at 80 for 15 h. ℃ Then water was added and the mixture was extracted with Et2O (3×15 mL). The combined organic layers were washed with water and brine, and dried. After removal of the solvent, the residue was pu-rified by column chromatography on silica gel (1∶15 VEtOAc/Vpetroleum ether) to provide methyl R,R-3-azido-cyclohexanecarboxylate, R,R-10 (250 mg, 72%) as col-orless oil. [α]25

D －39.2 (c 1.30, CHCl3); 1H NMR (300

MHz, CDCl3): δ 3.89—3.87 (m, 1H), 3.67 (s, 3H), 2.70—2.65 (m, 1H), 1.88—1.79 (m, 3H), 1.66—1.54 (m, 5H); 13C NMR (75 MHz, CDCl3) δ: 175.56, 56.99, 51.71, 38.01, 32.23, 29.53, 27.84, 20.26; IR (liquid film) ν: 2110, 1737 cm－1; HRMS calcd for C8H13N3O2N2 156.1019, found 156.1007.

S,S-10 (73%) was obtained via similar process of

798 Chin. J. Chem., 2006, Vol. 24, No. 6 HU et al.


R,R-10 with identical 1H NMR spectrum from 1S,3R-9. [α]25

D 40.6 (c 1.12, CHCl3).

R,R- and S,S-3-Aminocyclohexanecarboxylic acid 2

To a solution of methyl R,R-3-azidocyclohexanecar-boxylate, R,R-10 (250 mg, 1.4 mmol) in THF-H2O- MeOH (3∶1∶1) was added LiOH (295 mg, 7 mmol), and the reaction mixture was stirred at 40 for 3 h. ℃

After concentration, the residue was dissolved in water

and the aqueous solution was washed with Et2O (2×20 mL). Then the aqueous phase was acidified to pH 2 and extracted with CH2Cl2 (3×30 mL). The combined or-ganic layers were dried (Na2SO4), filtered, and concen-trated to colorless oil (231 mg, 100%). A suspension of the oil and Pd/C (10%, 20 mg) in MeOH (30 mL) was stirred at room temperature for 2 d under a hydrogen atmosphere. After filtration through a pad of celite, the solvent was evaporated to afford R,R-3-aminoyclo-hexanecarboxylic acid, R,R-2 (170 mg, 87%) as a white solid. m.p. 280.6—284.8 ; [α]℃

25D －17.2 (c 0.43, H2O);

1H NMR (300 MHz, D2O) δ: 3.44—3.41 (m, 1H), 2.54—2.52 (m, 1H), 2.08—2.04 (m, 1H), 1.81—1.46 (m, 7H); 13C NMR (75 MHz, D2O) δ: 183.04, 47.44, 40.43, 31.50, 28.86, 27.22, 19.97; IR (KBr) ν: 2955, 1557 cm－1; HRMS calcd for C7H13NO2-H 142.0863, found 142.0858.

S,S-2 (85%) was obtained via similar process of R,R-2 with identical 1H NMR spectrum from S,S-10. m.p. 278.0—283.1 ℃ and [α]25

D 17.3 (c 0.42, H2O).

cis-3-Aminocyclohexene-5-carboxylic acid 3

A suspension of cis-azidocarboxylic acid10 7 (23.6 g, 140 mmol) and Lindlar catalyst in MeOH (200 mL) was stirred at room temperature for 3 d under H2 atmosphere. After filtration through a pad of celite, the solvent was evaporated to produce cis-3-aminocyclohexene-5-car-boxylic acid 3 (17.1 g, 86%) as a white solid. 1H NMR (300 MHz, D2O) δ: 6.10—6.04 (m, 1H), 5.63—5.60 (m, 1H), 3.98—3.95 (m, 1H), 2.59—2.53 (m, 1H), 2.35—2.24 (m, 2H), 2.18—2.12 (m, 1H), 1.66—1.61 (m, 1H).

cis-3-Boc-aminocyclohexene-5-carboxylic acid 11

To a solution of cis-3-aminocyclohexene-5-carboxy-lic acid 3 (17.1 g, 120 mmol) and TEA (50 mL) in water (100 mL) was added Boc2O (31.4 g, 144 mmol) in di-oxane (60 mL). After stirred at room temperature for 24 h, the mixture was washed with Et2O (3×30 mL). The aqueous phase was acidified to pH 2 and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford cis-3-Boc-aminocyclohexene-5-carboxylic acid 11 (26.3 g, 91%) as a white solid. 1H NMR (300 MHz, CDCl3) δ: 9.91 (brs, 1H), 5.79—5.75 (m, 1H), 5.59—5.56 (m, 1H), 4.57—4.51 (m, 1H), 4.28—4.26 (m, 1H), 2.76—2.67 (m, 1H), 2.35—2.19 (m, 3H), 1.44 (brs, 10H).

R,R- and S,S-3-Boc-aminocyclohexene-5-carboxylic acid 11

The racemic cis-3-Boc-aminocyclohexene-5-car-

boxylic acid 11 (26.3 g, 109 mmol) was resolved by cocrystallization with D-1-phenylethylamine (10.5 g, 87 mmol) in ethylene glycol dimethyl ether. After third recrystallization, the resulting crystals were dissolved in EtOAc. The solution was acidified to pH 2 and ex-tracted with EtOAc (4×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to offord R,R-3-Boc-aminocyclohexene-5-carboxylic acid, R,R-11 (7.5 g, 57%) as a white solid. m.p. 127.0—129.4

;℃ [α]25D 4.77 (c 0.48, MeOH), 100% ee; 1H NMR (300

MHz, CDCl3) δ: 11.17 (brs, 1H), 5.78—5.74 (m, 1H), 5.58—5.55 (m, 1H), 4.62 (brs, 1H, NH), 4.25 (brs, 1H), 2.71—2.66 (m, 1H), 2.34—2.18 (m, 3H), 1.43 (brs, 10H); 13C NMR (75 MHz, CDCl3): δ 179.98, 155.48, 128.88, 127.55, 79.59, 46.97, 38.37, 31.97, 28.33, 26.99; IR (KBr) ν: 3343, 2980, 1688 cm－1; HRMS calcd for C12H19NO4-H 240.1230, found: 240.1239.

S,S-11 (55%) was obtained via resolving cis-11 by L-1-phenylethylamine with identical 1H NMR spectrum of R,R-11. m.p. 126.7—128.2 ℃ and [α]25

D －4.90 (c 0.49, MeOH), 99.7% ee.

1R,3S- and 1S,3R-3-Aminocyclohexanecarboxylic acid 2

A suspension of R,R-3-Boc-aminocyclohexene-5- carboxylic acid, R,R-11 (301 mg, 1.25 mmol) and Pd/C (10%, 15 mg) in MeOH (10 mL) was stirred at room temperature for 2 d under H2 atmosphere. After filtra-tion through a pad of celite, the solvent was evaporated to obtain the white solid (283 mg, 94%). Then the solid was dissolved in EtOAc (5 mL) and a solution of HCl in EtOAc (4.7 mol/L, 6 mL) was added at 0 . The mi℃ x-ture was stirred overnight at room temperature and next concentrated under vacuum, and the residue was de-salted by a Dowex 50WX8-200 ion-exchange resin (1 mol/L pyridine) to provide 1R,3S-3-aminocyclohexane-carboxylic acid, 1R,3S-2 (158 mg, 95%) as a white solid. m.p. 271.4—276.2 ; [α]℃

25D －5.64 (c 0.50, H2O); 1H

NMR (300 MHz, D2O) δ: 3.26—3.19 (m, 1H), 2.28—2.16 (m, 2H), 2.03—1.89 (m, 3H), 1.50—1.27 (m, 4H); 13C NMR (75 MHz, D2O) δ: 183.96, 49.91, 45.02, 33.55, 29.89, 28.48, 23.30; IR (KBr) ν: 2930, 1555 cm－1; HRMS calcd for C7H13NO2-H 142.0863, found 142.0859.

1S,3R-2 (91%) was obtained via similar process of 1R,3S-2 with identical 1H NMR spectrum from S,S-11. m.p. 267.3—274.5 ℃ and [α]25

D 5.46 (c 0.24, H2O).

R,R- and S,S-3-Aminocyclohexene-5-carboxylic acid 3

R,R-3-Boc-aminocyclohexene-5-carboxylic acid, R,R-11 (301 mg, 1.25 mmol) was dissolved in EtOAc (5 mL), and a solution of HCl in EtOAc (4.7 mol/L, 6 mL) was added at 0 . The mixture was stirred over℃ night at room temperature and concentrated under vacuum, and the residue was desalted by a Dowex 50WX8-200 ion- exchange resin (1 mol/L pyridine) to provide R,R-3- aminocyclohexene-5-carboxylic acid, R,R-3 (164 mg, 93%) as a white solid. m.p. 272.1—275.4 ℃; [α]25

D 3.67

Enantiopure γ-aminobutyric acid Chin. J. Chem., 2006 Vol. 24 No. 6 799


(c 0.68, H2O); 1H NMR (300 MHz, D2O) δ: 6.13—6.10 (m, 1H), 5.68—5.64 (m, 1H), 4.05—4.00 (m, 1H), 2.60—2.39 (m, 1H), 2.39—2.13 (m, 3H), 1.73—1.62 (m, 1H); 13C NMR (75 MHz, D2O) δ: 183.41, 132.87, 122.43, 47.52, 40.66, 30.08, 28.07; IR (KBr) ν: 2931, 1558 cm－1; HRMS calcd for C7H11NO2-H 140.0706, found 140.0713.

S,S-3 (92%) was obtained via similar process of R,R-3 with identical 1H NMR spectrum from S,S-11. m.p. 271.8—273.6 ℃ and [α]25

D －3.66 (c 0.25, H2O).

References

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Org. Chem. 1989, 54, 3292. 11 Trost, B. M.; Kondo, Y. Tetrahedron Lett. 1991, 13, 1613. 12 Kato, M.; Kageyama, M.; Tanaka, R.; Kuwahara, K.; Yo-

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(E0508292 YANG, X.)

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Synthesis of Stereoisomers of 3-Aminocyclohexanecarboxylic Acid and cis-3-Aminocyclohexene-5-carboxylic Acid