trans-Cyclohexane Analogues of Phenylalanine
161.26, 171.67 ppm. C16H17NO4: calcd. C 66.89, H 5.96, N 4.88; day). The catalyst was filtered off and the solvent evaporated to
FULL PAPER
found C 66.70, H 5.94, N 4.85.
give rac-3b as a white solid (306 mg, 0.89 mmol, 89% yield). M.p.
73 °C (CH2Cl2/hexane). Rf (hexane/EtOAc, 8:2) ϭ 0.57. IR (nujol):
ν˜ ϭ 2237.03, 1739.48 cmϪ1. 1H NMR (CDCl3, 300 MHz): δ ϭ 1.15
(t, J ϭ 7.3 Hz, 3 H), 1.23 (s, 3 H), 1.35 (s, 3 H), 1.72Ϫ1.99 (m, 7
H), 2.22Ϫ2.29 (m, 1 H), 3.05 (dd, J ϭ 3.3, J ϭ 12.6 Hz, 1 H),
3.97Ϫ4.16 (m, 2 H), 7.20Ϫ7.30 (m, 3 H), 7.33Ϫ7.36 (m, 2 H) ppm.
13C NMR (CDCl3, 75 MHz): δ ϭ 13.96, 21.85, 23.09, 24.92, 25.43,
29.15, 35.21, 48.57, 52.72, 61.37, 80.34, 118.00, 127.73, 128.36,
128.43, 139.76, 167.56, 171.50 ppm. C20H25NO4: calcd. C 69.95, H
7.34, N 4.08; found C 69.72, H 7.30, N 4.09.
Methyl trans-1-Cyano-6-phenyl-3-cyclohexenecarboxylate (rac-2a):
Under an inert atmosphere, 5 mL of a 1 solution of AlEtCl2 in
CH2Cl2 (5 mmol) was added to a solution of methyl (E)-2-cyano-
cinnamate (935 mg, 5 mmol) in dry CH2Cl2 (10 mL). The reaction
mixture was stirred at room temperature for 1 h, the solution was
cooled to 0 °C and a solution of 1,3-butadiene (1.35 g, 2.18 mL,
25 mmol) in dry CH2Cl2 (2 mL) was added. The reaction mixture
was stirred for 72 h at 0 °C and was then quenched by the addition
of Na2CO3·10H2O. The filtrate was evaporated to give a yellow oil,
which was purified by column chromatography. The cycloadduct
rac-2a was obtained as a colourless oil (929 mg, 3.85 mmol, 77%
yield). Rf (hexane/EtOAc, 8:2) ϭ 0.36. IR (neat): ν˜ ϭ 3033.49,
2243.78, 1742.38, 1657.52 cmϪ1. 1H NMR (CDCl3, 300 MHz): δ ϭ
2.30Ϫ2.38 (m, 1 H), 2.51Ϫ2.61 (m, 1 H), 2.63Ϫ2.76 (m, 1 H),
2.85Ϫ2.92 (m, 1 H), 3.16 (dd, J ϭ 5.0, J ϭ 11.6 Hz, 1 H), 3.36 (s,
3 H), 5.65Ϫ5.70 (m, 1 H), 5.85Ϫ5.89 (m, 1 H), 7.17Ϫ7.30 (m, 5 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 29.77, 34.98, 45.69, 49.39,
52.99, 118.07, 121.61, 127.23, 127.91, 128.00, 128.55, 138.78,
168.92 ppm.
trans-1-Cyano-2-phenylcyclohexanecarboxylic Acid (rac-4): Methyl
ester rac-2a (973 mg, 4 mmol) was heated under reflux with 10%
KOH/EtOH (50 mL) for 15 h. The solvent was evaporated to dry-
ness and the residue was taken up in water (25 mL) and washed
with CH2Cl2 (3 ϫ 25 mL). The aqueous layer was acidified by ad-
dition of 12 HCl and the product extracted with CH2Cl2 (3 ϫ
25 mL). The combined organic layers were dried and the solvent
removed to give pure acid rac-4 as a white solid (770 mg,
3.36 mmol, 84% yield). M.p. 170Ϫ171 °C (CH2Cl2/hexane). IR (nu-
jol): ν˜ ϭ 3140.52, 2257.28, 1747.20 cmϪ1 1H NMR (CDCl3,
.
300 MHz): δ ϭ 1.41Ϫ1.56 (m, 1 H), 1.71Ϫ2.15 (m, 6 H), 2.21Ϫ2.29
(m, 1 H), 3.05 (dd, J ϭ 3.3, J ϭ 12.9 Hz, 1 H), 7.25Ϫ7.33 (m, 5
H), 9.02 (br. s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 21.85,
25.38, 28.87, 34.94, 48.43, 53.52, 117.55, 127.95, 128.04, 128.59,
139.52, 173.90 ppm. C14H15NO2: calcd. C 73.34, H 6.59, N 6.11;
found C 73.15, H 6.14, N 6.07.
(1-Carboxyethyl-1-methyl)ethyl trans-1-Cyano-6-phenyl-3-cyclohex-
enecarboxylate (rac-2b): Under an inert atmosphere, 1 mL of a 1
solution of TiCl4 in CH2Cl2 (1 mmol) was added to a solution of
(1-carboxyethyl-1-methyl)ethyl (E)-2-cyanocinnamate (287 mg,
1 mmol) in dry CH2Cl2 (10 mL). The reaction mixture was stirred
at room temperature for 1 h, the solution was cooled to 0 °C and
a solution of 1,3-butadiene (540 mg, 0.87 mL, 10 mmol) in dry
CH2Cl2 (1 mL) was added. The reaction mixture was stirred for
Methyl trans-1-Cyano-2-phenylcyclohexylcarbamate (rac-5): PCl5
(0.21 g, 1 mmol) was added to a solution of carboxylic acid rac-4
(229 mg, 1 mmol) in dry Et2O (10 mL). The reaction mixture was
stirred at room temperature for 90 min. The solvent and most of
the PCl5 was removed under reduced pressure. In order to complete
the removal of the residual PCl5, toluene was added and then re-
moved under reduced pressure (3 ϫ 5 mL). The acid chloride was
dissolved in acetone (3 mL) and a solution of NaN3 (114 mg,
1.75 mmol) in water (1 mL) was added. The reaction mixture was
stirred at room temperature for 90 min. The solvent was removed
and the residue was extracted with toluene. The organic solution
was dried over MgSO4 and, after filtration, MeOH (4 mL) was ad-
ded. The reaction mixture was stirred at 80 °C for 2 h and the
solvent was removed under reduced pressure to afford a white solid
(212 mg, 0.82 mmol, 82% yield). M.p. 145Ϫ6 °C (CH2Cl2/hexane).
Rf (hexane/EtOAc, 8:2) ϭ 0.18. IR (nujol): ν˜ ϭ 3346.50, 2237.30,
72 h at
0 °C and was then quenched by the addition of
Na2CO3·10H2O. The filtrate was evaporated to give a yellow oil,
which was purified by column chromatography. The cycloadduct
rac-2b was obtained as a white solid (264 mg, 0.78 mmol, 78%
yield). M.p. 85 °C (EtOAc/hexane). Rf (hexane/EtOAc, 8:2) ϭ 0.58.
IR (nujol): ν˜ ϭ 2240.89, 1736.59, 1655.59 cmϪ1. 1H NMR (CDCl3,
300 MHz): δ ϭ 1.08 (s, 3 H), 1.14 (t, J ϭ 7.00 Hz, 3 H), 1.28 (s, 3
H), 2.33Ϫ2.42 (m, 1 H), 2.62Ϫ2.74 (m, 1 H), 2.81Ϫ2.89 (m, 1 H),
3.22 (dd, J ϭ 5.5, J ϭ 11.8 Hz, 1 H), 3.95Ϫ4.15 (m, 2 H),
5.70Ϫ5.76 (m, 1 H), 5.89Ϫ5.94 (m, 1 H), 7.23Ϫ7.30 (m, 3 H),
7.37Ϫ7.40 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 13.79,
22.72, 24.46, 30.55, 35.27, 45.21, 48.71, 61.18, 80.21, 117.98,
121.55, 127.33, 127.76, 128.20, 128.35, 129.09, 129.38, 138.89,
167.01, 171.16 ppm. C20H23NO4: calcd. C 70.36, H 6.79, N 4.10;
found C 70.34, H 6.58, N 4.20.
1
1726.16 cmϪ1. H NMR (CDCl3, 300 MHz): δ ϭ 1.36Ϫ1.49 (m, 1
H), 1.57Ϫ1.69 (m, 1 H), 1.73Ϫ1.95 (m, 4 H), 2.06Ϫ2.21 (m, 1 H),
2.71 (dd, J ϭ 3.1, J ϭ 12.7 Hz, 1 H), 3.01Ϫ3.10 (m, 1 H), 3.58 (s,
3 H), 4.84 (br. s, 1 H), 7.31Ϫ7.44 (m, 5 H) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 22.72, 25.48, 30.17, 36.77, 51.50, 52.27, 57.14,
118.53, 128.37, 128.48, 129.27, 138.35, 154.76 ppm. C15H18N2O2:
calcd. C 69.74, H 7.02, N 10.84; found C 69.89, H 6.99, N 11.01.
Methyl trans-1-Cyano-2-phenylcyclohexanecarboxylate (rac-3a): A
solution of rac-2a (1.206 g, 5 mmol) in EtOH (40 mL) was hydro-
genated at room temperature in the presence of 10% palladium/
carbon (300 mg) until completion of the reaction (1 day). The cata-
lyst was filtered off and the solvent evaporated to afford rac-3a as
a white solid in quantitative yield. M.p. 70 °C (CH2Cl2/hexane). Rf
(hexane/EtOAc, 8:2) ϭ 0.38. IR (nujol): ν˜ ϭ 2241.85, 1734.66
Hydrolysis of Methyl trans-1-Cyano-2-phenylcyclohexylcarbamate:
A suspension of cyano-carbamate rac-5 (0.5 mmol, 129 mg) in 12
HCl (10 mL) was heated under reflux for 3 d. The solvent was
removed under vacuum and the residue partitioned between H2O
and Et2O. The phases were separated and the aqueous layer was
washed with Et2O (3 ϫ 5 mL) and the solvents evaporated to dry-
ness to afford the amino acid hydrochloride rac-6 and the hydro-
chloride of trans-1-cyano-2-phenylcyclohexylamine in a 65:35 mix-
cmϪ1 1H NMR (CDCl3, 300 MHz): δ ϭ 1.40Ϫ1.56 (m, 1 H),
.
1.70Ϫ2.22 (m, 7 H), 3.05 (dd, J ϭ 3.3, J ϭ 12.9 Hz, 1 H), 3.51 (s,
3 H), 7.24Ϫ7.30 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
21.83, 25.43, 28.67, 34.81, 49.07, 52.98, 53.28, 118.00, 127.86,
127.94, 128.49, 139.77, 169.38 ppm. C15H17NO2: calcd. C 74.05, H
7.04, N 5.76; found C 74.23, H 7.01, N 5.78.
1
(1-Carboxyethyl-1-methyl)ethyl trans-1-Cyano-2-phenylcyclohexane-
ture. The H and 13C NMR spectroscopic data of trans-c6Phe hy-
carboxylate (rac-3b): A solution of rac-2b (341 mg, 1 mmol) in EtOH drochloride were identical to those obtained by the alternative
(10 mL) was hydrogenated at room temperature in the presence of
10% palladium/carbon (85 mg) until completion of the reaction (1
Strecker synthetic pathway. Spectroscopic data for the hydrochlo-
ride of trans-1-cyano-2-phenylcyclohexylamine: 1H NMR (D2O,
Eur. J. Org. Chem. 2004, 3898Ϫ3908
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3905