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

Article abstract of DOI:10.1016/j.tetasy.2007.08.014

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, phthaloyla

Full text of DOI:10.1016/j.tetasy.2007.08.014

Tetrahedron: Asymmetry 18 (2007) 1906–1910
A practical synthesis of enantiopure N-carbobenzyloxy-N0-phthaloyl-
cis-1,2-cyclohexanediamine by asymmetric reductive
amination and the Curtius rearrangement
Jun-ichi Matsuo,* Masahiko Okano, Kosuke Takeuchi, Hiroyuki Tanaka
and Hiroyuki Ishibashi*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
Received 13 June 2007; accepted 10 August 2007
Abstract—Enantiomerically pure N-carbobenzyloxy-N0-phthaloyl-cis-1,2-cyclohexanediamine was synthesized by the asymmetric reduc-
tion of a b-enamino ester formed from benzyl 2-oxocyclohexanecarboxylate and (R)-phenylethylamine, followed by hydrogenolysis,
phthaloylation, and the Curtius rearrangement.
Ó 2007 Elsevier Ltd. All rights reserved.
H N
2
NH
NH
NH
1. Introduction
O
O
Me
N
O
N
N
Asymmetrically N-substituted cis-1,2-cylohexanediamines
are important chiral building blocks for conformationally
preorganized peptide nucleic acids1 and for biologically ac-
tive small molecules such as NOC-797 1 as an antipruritic
agent,2 MEN-11467 2 as a tachykinin NK1 antagonist,3
and MEN-13918 3 as a tachykinin NK2 antagonist4
(Fig. 1).
H
H
N
Me
N
O
Me
N
N
H
Cl
MEN-11467, 2
NOC-797, 1
O
O
NH
2
H
H
These chiral cis-1,2-cyclohexanediamines have been synthe-
sized1 from chiral trans-2-azidocyclohexanol,5 which
was prepared by lipase-mediated enzymatic hydrolysis of
the corresponding racemic esters.6 Recently, enantio-
selective desymmetrization of meso-1,2-cyclohexanedi-
amine derivatives has been reported.7 Due to their unique
conformational properties, the use of chiral cis-1,2-cyclo-
hexanediamines 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-pro-
tected 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 Palmi-
N
N
N
N
H
H
S
O
O
MEN-13918, 3
Figure 1. Bioactive small molecules bearing a chiral unit composed of cis-
1,2-cyclohexanediamine.
eri’s asymmetric reduction8 of b-enamino ester 6 (Scheme
1).9
2. Results and discussion
We started the synthesis of 4 by transesterification of com-
mercially available ethyl 2-oxocyclohexanecarboxylate 7
with benzyl alcohol in refluxing toluene without any cata-
lyst10 to afford 8 in 83% yield (Scheme 2). Asymmetric
*
Corresponding authors. Tel./fax: +81 76 234 4439 (J.M.); e-mail:
jimatsuo@p.kanazawa-u.ac.jp
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.08.014

J. Matsuo et al. / Tetrahedron: Asymmetry 18 (2007) 1906–1910
1907
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-acetyl-
ation) of 13, however, did not proceed.
NH2
NH2
O
H
N
Ph
NH
O
CO2H
OR
CO2Et
OBn
O
5
4
7
6
Scheme 1. Synthetic plan for 4.
O
O
1) DPPA, Et3N
NH2
O
O
toluene, reflux
O
O
OH
NH
O
N
N
Ph
NH2
Ph
NH
O
OH
O
O
O
O
CO2H
150 o
C
2) H2O
63%
BnOH
isobutyric acid
OBn
OEt
OBn
75% after
recrystallization
reflux, -H2O
5
toluene
reflux, 3 d
12
13
8
6
7
83%
Scheme 4. The Curtius rearrangement of 12 followed by hydrolysis of the
isocyanate formed to 13.
1) Pd(OH)2/C
NaBH4
isobutyric acid
H2 (50 atm)
50 oC, 24 h
Ph
NH
O
NH2 O
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 1418
proceeded in refluxing toluene to afford the corresponding
isocyanate, and isocyanate was allowed to react with benz-
yl alcohol19 to afford N-Cbz derivative 1520 in 78% yield
for three steps from 12. Orthogonal reactivity between N-
Cbz and N-phthaloyl group was demonstrated by depro-
tection of the phthaloyl group with hydrazine in refluxing
methanol, followed by acetylation to give the N-acetylated
product 1620 in 84% yield.
OBn
OH
toluene
0 oC, 2 h
87%
2) recryst.
54%
5
9
>99% ee
a mixture of
cis-diastereomers
(82% de)
Scheme 2. Synthesis of 5 by asymmetric reductive amination.
reductive amination of 8 was performed by Xu’s proto-
col.11 That is, compound 6 was prepared in situ from
(R)-phenylethylamine and 8 in the presence of isobutyric
acid, and the resulting b-enamino ester 6 was reduced with
sodium borohydride–isobutyric acid at 0 °C in toluene to
afford, in 87% yield, a mixture12 of two cis-diastereomers
including amine 9 as a major stereoisomer. Its diastereo-
meric excess (82% de) was determined by 1H 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 ace-
tone–water gave enantiomerically pure 5 in 73% yield.
The enantiomeric purity of 5 was checked by comparison
with reported specific rotation13 and chiral HPLC analysis
of N-Cbz derivative of 5.
3. Conclusion
In conclusion, enantiomerically pure N-carbobenzyloxy-
N0-phthaloyl-cis-1,2-cyclohexanediamine 15 was synthe-
sized by a diasetereoselective reduction of a b-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.
Next, suitable protection of the amino group of 5 and the
following Curtius rearrangement14 were investigated. b-
Amino acid 5 was protected with the Boc group, and the
Curtius rearrangement of N-Boc derivative 10 with diphen-
ylphosphoryl 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 b-amino
acid 5.
4. Experimental
4.1. General methods
All melting points were determined on a Yanagimoto mi-
cro melting point apparatus and are uncorrected. Infrared
(IR) spectra were recorded on a Shimadzu FTIR-8100. H
1
NMR spectra were recorded on a JEOL JNM EX270
(270 MHz) or a JEOL JNM GSX500 (500 MHz) spectro-
meter; chemical shifts (d) are reported in parts per million
relative to tetramethylsilane. Splitting patterns are desig-
nated as s, singlet; d, doublet; t, triplet; m, multiplet. 13C
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 (CDCl3; d 77.0 ppm). High resolution mass spec-
tra (HRMS) were recorded on a JEOL JMS-SX-102A mass
spectrometer. Analytical TLC was performed on Merck
O
Boc
Boc
NH
N
DPPA, Et N
3
NH
CO H
2
toluene, reflux
85%
10
11
Scheme 3. The Curtius rearrangement of N-Boc derivative 10.
Reaction of 5 with phthalic anhydride17 and recrystalliza-
tion from hexane–ethyl acetate gave 12 in 75% yield, and
the enantiomeric purity of 12 was confirmed by chiral

1908
J. Matsuo et al. / Tetrahedron: Asymmetry 18 (2007) 1906–1910
1) NH NH
2
2
i) toluene
reflux, 1 h
AcHN
MeOH
reflux
O
O
O
O
H
N
N
1) SOCl
2
H
N
OBn
CON
N
OBn
12
3
2) NaN
ii) BnOH
toluene
reflux
2) Ac O
2
pyridine
3
O
O
16
15
14
84%
78% for
three steps from 12
Scheme 5. The Curtius rearrangement of 14 followed by the reaction with benzyl alcohol.
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 lm). 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.
trated 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,
1
1
86%, 82% de by H NMR analysis) as a colorless oil. H
NMR (500 MHz, CDCl3, major isomer) d: 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),
1
7.13–7.43 (10H, m); H NMR (500 MHz, CDCl3, minor
isomer) d: 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 OCH2Ph); 13C NMR (68 MHz,
CDCl3, major isomer) d: 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; 13C NMR (68 MHz, CDCl3, minor isomer)
d: 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.
4.2. Benzyl 2-oxocyclohexanecarboxylate 821
A solution of ethyl 2-oxocyclohexanecarboxylate (7, 5.01 g,
29.4 mmol) and benzyl alcohol (3.85 g, 35.6 mmol) in tolu-
ene (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 col-
1
orless oil. H NMR (500 MHz, CDCl3, a mixture of keto
and enol forms (keto/enol = 1:3)) d: 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); 13C NMR
(126 MHz, CDCl3) d: 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.
4.4. (1S,2R)-2-Aminocyclohexanecarboxylic acid 58c
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 H2 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
H2O and acetone to afford 5 (458 mg, 3.20 mmol, 54%,
1
not optimized) as colorless needles. H NMR (270 MHz,
D2O) d: 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); 13C NMR
(68 MHz, CD3OD) d: 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–
4.3. Benzyl (1S,2R)-2-{[(10R)-10-phenylethyl]amino}cyclo-
hexanecarboxylate 98c
29
24
223 °C8c); ½aꢀD ¼ þ20:2 (c 0.25, H2O) (lit.13 ½aꢀD ¼ þ20:0
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 pre-
pared as follows.
(c 0.25, H2O)).
HPLC analysis of N-Cbz derivative of thus-obtained 5 by
using chiralcel ODH (hexane/i-PrOH/HCO2H = 95:5:1,
0.5 mL/min, 254 nm) indicated that only the (1S,2R)-enan-
tiomer was included ((1S,2R)-enantiomer: 13.8 min,
(1R,2S)-enantiomer: 15.3 min).
To isobutyric acid (57.3 mL, 618 mmol) was added sodium
borohydride (2.34 g, 61.9 mmol) portion wise under nitro-
gen 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 Na2SO4, filtered, and concen-
4.5. (1S,2R)-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 chro-
matography on silica gel (hexane–ethyl acetate = 3:1 to
1:1) gave 12 (552 mg, 89%) and recrystallization with hex-
ane (30 mL) and ethyl acetate (3 mL) gave 12 (465 mg,

J. Matsuo et al. / Tetrahedron: Asymmetry 18 (2007) 1906–1910
1909
1.70 mmol, 75%) as colorless cubic crystals. 1H NMR
(500 MHz, CDCl3) d: 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); 13C NMR (127 MHz, CDCl3) d: 21.1,
25.9, 25.9, 27.4, 42.8, 52.7, 123.1, 131.9, 133.8, 168.6,
Na2SO4, 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 tempera-
ture for 2 h. After evaporation of volatiles, ethyl acetate
and saturated aqueous NaHCO3 were added. The organic
layer was separated, and washed with water and brine,
dried over anhydrous Na2SO4, filtered, and concentrated.
The crude product was purified by preparative thin-layer
chromatography on silica gel (CHCl3/MeOH = 9:1) to
afford 16 (54.8 mg, 0.189 mmol, 87%) as a colorless solid.
1H NMR (500 MHz, CDCl3) d: 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); 13C NMR (67.8 MHz, CDCl3) d: 21.3, 22.6,
23.4, 28.0, 29.2, 50.1, 50.8, 66.9, 128.1, 128.5, 136.3,
178.0; IR (CHCl3, cmꢁ1) 3020, 1709; mp 159–160 °C;
28
½aꢀD ¼ þ98:3 (c 1.00, MeOH); Anal. Calcd for
C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C, 65.93;
H, 5.56; N, 5.15.
4.6. (1S,2R)-1-(N-Benzyloxycarbonylamino)-2-phthalimido-
cyclohexane 15
156.6, 170.2; IR (CHCl3, cmꢁ1) 1713, 1667; mp 163.0–
29
To a stirred solution of 12 (100 mg, 0.367 mmol) and
dimethylformamide (3 drops) in dry CH2Cl2 (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 aque-
ous solution of NaN3 (1 mL) at 0 °C, and the mixture was
stirred for 10 min. An excess amount of H2O was added to
the reaction mixture, and the precipitated solid was col-
lected by filtration, and dried in vacuo to give crude acyl
azide 14 (102.9 mg).
164.0 °C; ½aꢀD ¼ þ33:6 (c 0.10, MeOH); Anal. Calcd for
C16H22N2O3: 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.
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 alco-
hol (0.19 mL, 1.84 mmol) was added and the mixture was
refluxed for 27 h. After the addition of H2O, the mixture
was extracted with ethyl acetate, and combined organic
extracts were washed with brine, dried over anhydrous
Na2SO4, 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,
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CDCl3) d: 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); 13C NMR (127 MHz, CDCl3) d:
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 (CHCl3, cmꢁ1
1709, 1518; mp 114.0–115.0 °C; ½aꢀD ¼ þ92:14 (c 0.10,
MeOH); HRMS (EI) calcd for C22H22N2O4: 378.15796;
found, 378.15866.
)
29
4.7. (1S,2R)-1-(N-Benzyloxycarbonylamino)-2-acetamide-
cyclohexane 16
´
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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. Plieninger, H.; Castro, C. E. Chem. Ber. 1954, 87, 1760–1767.