A practical synthesis of enantiopure N-carbobenzyloxy-N′-phthaloyl-cis-1,2-cyclohexanediamine by asymmetric reductive amination and the Curtius rearrangement

Enantiomerically pure N -carbobenzyloxy- N ′-phthaloyl- cis -1,2-cyclohexanediamine was synthesized by the asymmetric reduction of a β-enamino ester formed from benzyl 2-oxocyclohexanecarboxylate and ( R )-phenylethylamine, followed by hydrogenolysis, phthaloylation, and the Curtius rearrangement. (1 S ,2 R )-2-Aminocyclohexanecarboxylic acid C 7 H 13 NO 2 Ee = >99% [ α ] D 29 = + 20.2 ( c 0.25, H 2 O) Source of chirality: asymmetric synthesis Absolute configuration: (1 S ,2 R ) (1 S ,2 R )-2-Phthalimidocyclohexanecarboxylic acid C 15 H 15 NO 4 Ee = >99% [ α ] D 28 = + 98.3 ( c 1.00, MeOH) Source of chirality: asymmetric synthesis Absolute configuration: (1 S ,2 R ) (1 S ,2 R )-1-( N -Benzyloxycarbonylamino)-2-phthalimidocyclohexane C 22 H 22 N 2 O 4 Ee = >99% [ α ] D 29 = + 92.1 ( c 0.10, MeOH) Source of chirality: asymmetric synthesis Absolute configuration: (1 S ,2 R ) (1 S ,2 R )-1-( N -Benzyloxycarbonylamino)-2-acetamidecyclohexane C 16 H 22 N 2 O 3 Ee = >99% [ α ] D 29 = + 33.6 ( c 0.10, MeOH) Source of chirality: asymmetric synthesis Absolute configuration: (1 S ,2 R ) 1 Introduction Asymmetrically N -substituted cis -1,2-cylohexanediamines are important chiral building blocks for conformationally preorganized peptide nucleic acids 1 and for biologically active small molecules such as NOC-797 1 as an antipruritic agent, 2 MEN-11467 2 as a tachykinin NK 1 antagonist, 3 and MEN-13918 3 as a tachykinin NK 2 antagonist 4 ( Fig. 1 ). These chiral cis -1,2-cyclohexanediamines have been synthesized 1 from chiral trans -2-azidocyclohexanol, 5 which was prepared by lipase-mediated enzymatic hydrolysis of the corresponding racemic esters. 6 Recently, enantioselective desymmetrization of meso -1,2-cyclohexanediamine derivatives has been reported. 7 Due to their unique conformational properties, the use of chiral cis -1,2-cyclohexanediamines is expected to increase in various research fields, especially in medicinal chemistry. Therefore, a more efficient method for their preparation should be developed. We planned the synthesis of enantiomerically pure N -protected cis -1,2-cylohexanediamines 4 from cis -2-amino-1-cyclohexanecarboxylic acid 5 by the Curtius rearrangement because 5 was readily prepared on a large scale by Palmieri’s asymmetric reduction 8 of β-enamino ester 6 ( Scheme 1 ). 9 2 Results and discussion We started the synthesis of 4 by transesterification of commercially available ethyl 2-oxocyclohexanecarboxylate 7 with benzyl alcohol in refluxing toluene without any catalyst 10 to afford 8 in 83% yield ( Scheme 2 ). Asymmetric reductive amination of 8 was performed by Xu’s protocol. 11 That is, compound 6 was prepared in situ from ( R )-phenylethylamine and 8 in the presence of isobutyric acid, and the resulting β-enamino ester 6 was reduced with sodium borohydride–isobutyric acid at 0 °C in toluene to afford, in 87% yield, a mixture 12 of two cis -diastereomers including amine 9 as a major stereoisomer. Its diastereomeric excess (82% de) was determined by 1 H NMR analysis referring to NMR spectra of all four diastereoisomers of the corresponding ethyl ester. 11 Hydrogenolysis of two benzylic groups of the thus-obtained cis -diastereomers with Perlman’s catalyst followed by recrystallization with acetone–water gave enantiomerically pure 5 in 73% yield. The enantiomeric purity of 5 was checked by comparison with reported specific rotation 13 and chiral HPLC analysis of N -Cbz derivative of 5 . Next, suitable protection of the amino group of 5 and the following Curtius rearrangement 14 were investigated. β-Amino acid 5 was protected with the Boc group, and the Curtius rearrangement of N -Boc derivative 10 with diphenylphosphoryl azide (DPPA) 15 in refluxing toluene gave cyclic urea 11 in 85% yield ( Scheme 3 ). 16 The phthalimide group was then chosen as a protecting group for β-amino acid 5 . Reaction of 5 with phthalic anhydride 17 and recrystallization from hexane–ethyl acetate gave 12 in 75% yield, and the enantiomeric purity of 12 was confirmed by chiral HPLC analysis (>99% ee). The Curtius rearrangement of 12 with DPPA followed by hydrolysis of the corresponding isocyanate gave 13 as a mixture of two diastereomers in 63% yield ( Scheme 4 ). Further derivatization (e.g., N -acetylation) of 13 , however, did not proceed. We next tried to trap the intermediate isocyanate group with alcohol to form a carbamate ( Scheme 5 ). Carboxylic acid 12 was converted to the corresponding acyl chloride, and it was reacted with sodium azide to form acyl azide 14 . It was found that the Curtius rearrangement of 14 18 proceeded in refluxing toluene to afford the corresponding isocyanate, and isocyanate was allowed to react with benzyl alcohol 19 to afford N -Cbz derivative 15 20 in 78% yield for three steps from 12 . Orthogonal reactivity between N -Cbz and N -phthaloyl group was demonstrated by deprotection of the phthaloyl group with hydrazine in refluxing methanol, followed by acetylation to give the N -acetylated product 16 20 in 84% yield. 3 Conclusion In conclusion, enantiomerically pure N -carbobenzyloxy- N ′-phthaloyl- cis -1,2-cyclohexanediamine 15 was synthesized by a diasetereoselective reduction of a β-enamino ester employing inexpensive chiral phenylethylamine as a chiral auxiliary. The appropriately N -protected compound 15 would be useful for preparing a chiral unit composed of cis -cyclohexanediamine. 4 Experimental 4.1 General methods All melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected. Infrared (IR) spectra were recorded on a Shimadzu FTIR-8100. 1 H NMR spectra were recorded on a JEOL JNM EX270 (270 MHz) or a JEOL JNM GSX500 (500 MHz) spectrometer; chemical shifts ( δ ) are reported in parts per million relative to tetramethylsilane. Splitting patterns are designated as s, singlet; d, doublet; t, triplet; m, multiplet. 13 C NMR spectra were recorded on a JEOL JNM GSX500 (500 MHz) spectrometer with complete proton decoupling. Chemical shifts are reported in parts per million relative to tetramethylsilane with the solvent resonance as the internal standard (CDCl 3 ; δ 77.0 ppm). High resolution mass spectra (HRMS) were recorded on a JEOL JMS-SX-102A mass spectrometer. Analytical TLC was performed on Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm). Silica gel column chromatography was carried out on silica gel 60 N (Kanto Kagaku Co., Ltd., spherical, neutral, 63–210 μm). Optical rotations were measured on a Horiba SEPA300 polarimeter. Elemental analyses were carried out on a Yanaco CHN Corder MT-5. High resolution mass spectra (HRMS) were recorded on a JEOL JMS-SX-102A mass spectrometer. 4.2 Benzyl 2-oxocyclohexanecarboxylate 8 21 A solution of ethyl 2-oxocyclohexanecarboxylate ( 7 , 5.01 g, 29.4 mmol) and benzyl alcohol (3.85 g, 35.6 mmol) in toluene (44 mL) was stirred at 120 °C (oil bath temp) for three days. After evaporation of toluene, the residue was purified by column chromatography on silica gel (hexane–ether = 10:1) to afford 8 (5.64 g, 24.3 mmol, 83%) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 , a mixture of keto and enol forms (keto/enol = 1:3)) δ : 1.56–1.70 (4H, m, enol), 1.74–1.88 (2H, m, keto), 1.91–1.99 (1H, m, keto), 2.08–2.20 (2H, m, keto), 2.26 (4H, m, enol), 2.30–2.38 (1H, m, keto), 2.45–2.52 (1H, m, keto), 3.42 (1H, ddd, J = 10.0, 5.5, 1.0 Hz, keto), 5.16 (1H, d, J = 12.5 Hz, keto), 5.19 (2H, s, enol), 5.21 (1H, d, J = 12.0 Hz, keto), 7.29–7.44 (5H, m), 12.1 (1H, s, enol OH); 13 C NMR (126 MHz, CDCl 3 ) δ : 21.8, 22.3, 22.3, 23.3, 27.0, 29.1, 29.9, 41.5, 57.2, 65.6, 66.7, 97.6, 127.8, 128.0, 128.1, 128.1, 128.2, 128.3, 128.5, 128.5, 129.6, 132.9, 135.6, 136.1, 169.8, 172.3, 172.5, 205.8. 4.3 Benzyl (1 S ,2 R )-2-{[(1′ R )-1′-phenylethyl]amino}cyclohexanecarboxylate 9 8c A solution of 8 (4.79 g, 20.6 mmol), ( R )-phenylethylamine (2.57 mmol, 21.2 mmol), and isobutyric acid (1.9 mL, 20.5 mmol) in toluene (21 mL) was refluxed for 2 h with azeotropic removal of water. This solution was cooled to room temperature, and added to the reducing medium prepared as follows. To isobutyric acid (57.3 mL, 618 mmol) was added sodium borohydride (2.34 g, 61.9 mmol) portion wise under nitrogen at 0–10 °C. The mixture was stirred at 20 °C for 0.5 h and then cooled to 0 °C. The above-mentioned enamine solution in toluene was added dropwise at 0 °C, and the mixture was stirred for 2 h at 0 °C. The reaction was quenched with water, and the mixture was basified with 10% NaOH solution (pH 9–10). The resulting mixture was extracted with ether, and combined organic extracts were dried with anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane–ethyl acetate = 10:1 to 5:1) to afford a mixture of 9 and diastereomers (5.95 g, 86%, 82% de by 1 H NMR analysis) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 , major isomer) δ : 1.17 (3H, d, J = 6.7 Hz), 1.20–1.32 (2H, m), 1.40–1.68 (5H, m), 1.84–1.93 (1H, m), 2.79 (1H, dt, J = 7.3, 3.7 Hz), 2.86 (1H, dt, J = 7.9, 3.7 Hz), 3.78 (1H, q, J = 6.7 Hz), 5.16 (2H, s), 7.13–7.43 (10H, m); 1 H NMR (500 MHz, CDCl 3 , minor isomer) δ : 1.27 (3H, d, J = 6.7 Hz), 2,57 (1H, dt, J = 9.2, 3.7 Hz), 3.85 (1H, t, J = 6.7 Hz), 4.97 (1H, d, J = 12.8 Hz, one of OCH 2 Ph); 13 C NMR (68 MHz, CDCl 3 , major isomer) δ : 22.6, 23.2, 24.4, 25.3, 29.7, 44.7, 53.3, 54.9, 65.8, 126.5, 126.6, 128.0, 128.2, 128.5, 136.2, 146.4, 174.2; 13 C NMR (68 MHz, CDCl 3 , minor isomer) δ : 21.4, 23.9, 24.7, 25.4, 27.6, 46.5, 51.7, 54.2, 65.8, 126.6, 126.7, 128.0, 128.1, 128.4, 136.2, 145.9, 174.3. 4.4 (1 S ,2 R )-2-Aminocyclohexanecarboxylic acid 5 8c A mixture of 9 and a diastereomer (2.01 g, 5.96 mmol) and 20% Pd(OH) 2 /C (210 mg, 0.30 mmol) in MeOH (8 mL) was heated at 50 °C under a H 2 atmosphere (50 atm) for 24 h. Then, the mixture was filtered through a Celite pad, and the filtrate was concentrated in vacuo to afford a crude product. The crude product was recrystallized twice from H 2 O and acetone to afford 5 (458 mg, 3.20 mmol, 54%, not optimized) as colorless needles. 1 H NMR (270 MHz, D 2 O) δ : 1.18–1.42 (3H, m), 1.42–1.60 (2H, m), 1.60–1.72 (2H, m), 1.72–1.90 (1H, m), 2.51 (1H, dt, J = 6.8, 4.1 Hz), 3.33 (1H, td, J = 6.2, 4.3 Hz); 13 C NMR (68 MHz, CD 3 OD) δ : 23.9, 24.0, 28.0, 28.8, 44.5, 51.8, 180.1; mp 215–220 °C (dec) (lit. 217–220 °C, 13 220–223 °C 8c ); [ α ] D 29 = + 20.2 ( c 0.25, H 2 O) (lit. 13 [ α ] D 24 = + 20.0 ( c 0.25, H 2 O)). HPLC analysis of N -Cbz derivative of thus-obtained 5 by using chiralcel ODH (hexane/ i -PrOH/HCO 2 H = 95:5:1, 0.5 mL/min, 254 nm) indicated that only the (1 S ,2 R )-enantiomer was included ((1 S ,2 R )-enantiomer: 13.8 min, (1 R ,2 S )-enantiomer: 15.3 min). 4.5 (1 S ,2 R )-2-Phthalimidocyclohexanecarboxylic acid 12 A mixture of 5 (325.6 mg, 2.27 mmol) and powdered phthalic anhydride (371 mg, 2.50 mmol) was heated at 150 °C for 2 h. The mixture was purified by column chromatography on silica gel (hexane–ethyl acetate = 3:1 to 1:1) gave 12 (552 mg, 89%) and recrystallization with hexane (30 mL) and ethyl acetate (3 mL) gave 12 (465 mg, 1.70 mmol, 75%) as colorless cubic crystals. 1 H NMR (500 MHz, CDCl 3 ) δ : 1.34–1.45 (1H, m), 1.53–1.59 (1H, m), 1.63–1.72 (1H, m), 1.77–1.84 (1H, m), 1.91–2.02 (2H, m), 2.13–2.19 (1H, m), 2.83 (1H, qd, J = 9.3, 3.4 Hz), 3.16 (1H, td, J = 4.6, 3.2 Hz), 4.34 (1H, ddd, J = 12.5, 5.1, 3.4 Hz), 7.66 (2H, dd, J = 5.4, 2.9 Hz), 7.77 (2H, dd, J = 5.4, 2.9 Hz); 13 C NMR (127 MHz, CDCl 3 ) δ : 21.1, 25.9, 25.9, 27.4, 42.8, 52.7, 123.1, 131.9, 133.8, 168.6, 178.0; IR (CHCl 3 , cm −1 ) 3020, 1709; mp 159–160 °C; [ α ] D 28 = + 98.3 ( c 1.00, MeOH); Anal. Calcd for C 15 H 15 NO 4 : C, 65.92; H, 5.53; N, 5.13. Found: C, 65.93; H, 5.56; N, 5.15. 4.6 (1 S ,2 R )-1-( N -Benzyloxycarbonylamino)-2-phthalimidocyclohexane 15 To a stirred solution of 12 (100 mg, 0.367 mmol) and dimethylformamide (3 drops) in dry CH 2 Cl 2 (6 mL) was added thionyl chloride (0.27 mL, 3.70 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 h. After evaporation of the volatiles, dry acetone (5 mL) was added to the residue. To this solution was added a saturated aqueous solution of NaN 3 (1 mL) at 0 °C, and the mixture was stirred for 10 min. An excess amount of H 2 O was added to the reaction mixture, and the precipitated solid was collected by filtration, and dried in vacuo to give crude acyl azide 14 (102.9 mg). A mixture of thus-obtained acyl azide 14 (102.9 mg) in dry toluene (3 mL) was refluxed for 1 h. After confirming the disappearance of acyl azide by TLC analysis, benzyl alcohol (0.19 mL, 1.84 mmol) was added and the mixture was refluxed for 27 h. After the addition of H 2 O, the mixture was extracted with ethyl acetate, and combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (benzene-ethyl acetate) to afford 15 (108.8 mg, 0.288 mmol, 78%) as a white solid. 1 H NMR (500 MHz, CDCl 3 ) δ : 1.33–1.53 (2H, m), 1.53–1.73 (3H, m), 1.84–2.13 (2H, m), 2.69 (1H, qd, J = 13.1, 3.3 Hz), 4.03–4.08 (0.1H, br s), 4.11 (0.9H, d, J = 3.4 Hz), 4.24–4.32 (0.1H, br s), 4.36 (0.9H, dt, J = 13.4, 3.7 Hz), 4.73–4.86 (0.1H, br s), 4.96 (0.9H, d, J = 12.5 Hz), 5.02 (0.9H, d, J = 12.5 Hz), 5.65–5.75 (0.1H, br s), 5.98 (0.9H, d, J = 6.8 Hz), 7.07–7.34 (5H, m plus br s), 7.68 (2H, dd, J = 5.2, 3.1 Hz), 7.68 (2H, dd, J = 3.1, 5.1 Hz), 7.79 (2H, dd, J = 3.2, 5.2 Hz); 13 C NMR (127 MHz, CDCl 3 ) δ : 19.4, 24.3, 25.7, 30.2, 51.1, 52.8, 66.2, 123.2, 127.7, 127.7, 128.3, 131.6, 133.9, 136.7, 156.0, 168.9; IR (CHCl 3 , cm −1 ) 1709, 1518; mp 114.0–115.0 °C; [ α ] D 29 = + 92.14 ( c 0.10, MeOH); HRMS (EI) calcd for C 22 H 22 N 2 O 4 : 378.15796; found, 378.15866. 4.7 (1 S ,2 R )-1-( N -Benzyloxycarbonylamino)-2-acetamidecyclohexane 16 A mixture of 15 (82.4 mg, 0.218 mmol) and 1 M solution of hydrazine in MeOH (2.5 mL) and in MeOH (10 mL) was refluxed for 10 h. After evaporation of the solvent, ethyl acetate was added to the residue, and the mixture was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. To the residue obtained pyridine (0.9 mL) and acetic anhydride (3 mL) were added and the mixture was stirred at room temperature for 2 h. After evaporation of volatiles, ethyl acetate and saturated aqueous NaHCO 3 were added. The organic layer was separated, and washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography on silica gel (CHCl 3 /MeOH = 9:1) to afford 16 (54.8 mg, 0.189 mmol, 87%) as a colorless solid. 1 H NMR (500 MHz, CDCl 3 ) δ : 1.30–2.00 (8H, m), 1.95 (3H, s), 3.90 (1H, s), 4.02 (1H, s), 5.10 (2H, s), 5.28 (1H, s), 5.75–5.95 (0.2H, br s), 6.05–6.23 (0.8H, br s), 7.30–7.38 (5H, m); 13 C NMR (67.8 MHz, CDCl 3 ) δ : 21.3, 22.6, 23.4, 28.0, 29.2, 50.1, 50.8, 66.9, 128.1, 128.5, 136.3, 156.6, 170.2; IR (CHCl 3 , cm −1 ) 1713, 1667; mp 163.0–164.0 °C; [ α ] D 29 = + 33.6 ( c 0.10, MeOH); Anal. Calcd for C 16 H 22 N 2 O 3 : C, 66.18; H, 7.64; N, 9.65. Found: C, 66.24; H, 7.66; N, 9.58. Acknowledgments The authors are grateful for the financial support from the Takeda Science Foundation, and this work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. References 1 T. Govindaraju V.A. Kumar K.N. Ganesh J. Org. Chem. 69 2004 1858 1865 2 Okano, M.; Oyama, T. U.S. Patent 0176741A1, 2005. 3 C. Palma F. Nardelli S. Manzini Eur. J. Pharm. 374 1999 435 443 4 S. Meini F. Bellucci C. Catalani P. Cucchi R. Patacchini L. Rotondaro M. Altamura S. Giuliani A. Giolitti C.A. Maggi Eur. J. Pharm. 488 2004 61 69 5 (a) Review: C. Schneider Synthesis 2006 3919 3944 (b) C.A. de Parrodi E. Juaristi Synlett 2006 2699 2715 6 (a) K. Faber H. Honig P. Seufer-Wasserthal Tetrahedron Lett. 29 1988 1903 1904 (b) H. Honig P. Seufer-Wasserthal J. Chem. Soc., Perkin Trans. 1 1989 2341 2345 7 (a) O. Kitagawa K. Yotsumoto M. Kohriyama Y. Dobashi T. Taguchi Org. Lett. 6 2004 3605 3607 (b) O. Kitagawa S. Matsuo K. Yotsumoto T. Taguchi J. Org. Chem. 71 2006 2524 2527 8 (a) C. Cimarelli G. Palmieri G. Bartoli Tetrahedron: Asymmetry 5 1994 1455 1458 (b) C. Cimarelli G. Palmieri J. Org. Chem. 61 1996 5557 5563 (c) C. Cimarelli G. Palmieri E. Volpini Synth. Commun. 31 2001 2943 2953 9 (a) Compound 5 –HCl salt was prepared by the conjugate addition of enantiomerically pure lithium amides. See: S.G. Davies O. Ichihara I. Lenoir I.A.S. Walters J. Chem. Soc., Perkin Trans. 1 1994 1411 1415 (b) S.G. Davies A.D. Smith P.D. Price Tetrahedron: Asymmetry 16 2005 2833 2891 10 C. Mottet O. Hamelin G. Garavel J.-P. Deprés A.E. Greene J. Org. Chem. 64 1999 1380 1382 11 D. Xu K. Prasad O. Repič T.J. Blacklock Tetrahedron: Asymmetry 8 1997 1445 1451 12 The two cis -diastereomers were not separated by chromatography on silica gel. 13 J. Priego P. Flores C. Ortiz-Nava J. Escalante Tetrahedron: Asymmetry 15 2004 3545 3549 14 Review: P.A.S. Smith Org. React. 3 1967 337 449 15 K. Ninomiya T. Shioiri S. Yamada Tetrahedron 30 1974 2151 2157 16 For intramolecular cyclization of a NHBoc group to an isocyanate group: P.J. Dunn R. Häner H. Rapoport J. Org. Chem. 55 1990 5017 5025 17 J.C. Sheehan D.W. Chapman R.W. Roth J. Am. Chem. Soc. 74 1952 3822 3825 18 The use of isolated acyl azide 14 gave compound 15 in better yields than the combination of 12 and DPPA. 19 t -Butanol did not react with the isocyanate. 20 Enantiomeric purity was assigned by reference to compound 12 . 21 H. Plieninger C.E. Castro Chem. Ber. 87 1954 1760 1767