Chemoenzymatic preparation of optically active trans-cyclohexane-1,2- diamine derivatives: An efficient synthesis of the analgesic U-(-)-50,488

Article abstract of DOI:10.1002/chem.200400607

Stereoespecific syntheses of (±)-trans-N,N-cyclohexane-1,2-diamines ((±)-4a-g) were carried out from the corresponding (±)-trans-N,N- dialkylaminocyclohexanols by successive treatment with mesyl chloride and aqueous ammonia. The stereochemical outcome indicates the formation of a meso-aziridinium ion intermediate, Kinetic resolutions of diamines (±)-4 were efficiently accomplished in aminolysis reactions catalyzed by lipase B from Candida antarctica with ethyl acetate as the solvent and acyl donor. Acetamides and the remaining diamines, isolated as the benzyloxycarbonyl derivatives, were obtained with very high ee values (92-99%), One of the carbamates was used as a precursor of the analgesic U-(-)-50,488.

Full text of DOI:10.1002/chem.200400607

FULL PAPER
Chemoenzymatic Preparation of Optically Active trans-Cyclohexane-1,2-
diamine Derivatives: An Efficient Synthesis of the Analgesic U-(À)-50,488
Javier Gonzµlez-Sabín, Vicente Gotor,* and Francisca Rebolledo*[a]
Abstract: Stereoespecific syntheses
of
(Æ)-trans-N,N-cyclohexane-1,2-di-
netic resolutions of diamines (Æ)-4
were efficiently accomplished in ami-
nolysis reactions catalyzed by lipase B
from Candida antarctica with ethyl ace-
tate as the solvent and acyl donor.
Acetamides and the remaining dia-
mines, isolated as the benzyloxycarbon-
yl derivatives, were obtained with very
high ee values (92–99%). One of the
carbamates was used as a precursor of
the analgesic U-(À)-50,488.
amines ((Æ)-4a–g) were carried out
from the corresponding (Æ)-trans-N,N-
dialkylaminocyclohexanols by succes-
sive treatment with mesyl chloride and
aqueous ammonia. The stereochemical
outcome indicates the formation of a
meso-aziridinium ion intermediate. Ki-
Keywords: asymmetric synthesis ·
chemoenzymatic synthesis
·
di-
amines · kinetic resolution · lipases
Introduction
Optically active trans-cyclohexane-1,2-diamine derivatives
are an important class of compounds due to their use as
chiral reagents, scaffolds, and ligands for asymmetric cataly-
sis.[1] Moreover, the cyclohexane-1,2-diamine unit can be
found in various compounds displaying a broad spectrum of
biological activity.[1b,2] For example, compound U-50,488[3]
(1) and other structural analogues[4] (such as 2 and 3;
Scheme 1) have been reported to be highly selective k-
opioid agonists, free from the adverse side effects of m-
opioid agonists like morphine.[5] As for the majority of phar-
macologically active compounds, their properties are related
to the configuration of their stereogenic centers. Thus,
(1S,2S)-(À)-1 exhibits greater k agonist activity than its
enantiomer, and the cis diastereomer of U-50,488 has practi-
cally no affinity for k receptors.[6]
The wide ranging applicability of cyclohexane-1,2-diamine
derivatives in various areas of chemistry makes the design
of efficient methods for their preparation of great interest.
Whereas the synthesis of nonracemic N,N’-disubstituted
trans-cyclohexane-1,2-diamines can be readily achieved from
the commercial but expensive (1R,2R)- or (1S,2S)-cyclohex-
ane-1,2-diamine,[7] the methods for obtaining the corre-
Scheme 1. Selected k-opioid analgesics.
sponding N,N-disubstituted derivatives involve several addi-
tional steps: initial monoprotection of the diamine—a step
which often takes place with moderate to low yield—and
eventual removal of the protecting group.[8]
Here we wish to report a very simple and efficient
method for preparing optically active N,N-disubstituted cy-
clohexane-1,2-diamines by using cyclohexene oxide as the
starting material. Two key steps are involved in this method,
namely, stereospecific transformation of (Æ)-trans-2-(N,N-
dialkylamino)cyclohexanols into (Æ)-trans-1,2-diamines and
subsequent enzymatic resolution. Some of these diamines
were chosen for their importance as precursors of pharma-
cologically active compounds. This is the case, for instance,
with 4a, a chemically versatile intermediate for the synthesis
of analogues of 1. Diamines 4d and 4e bear additional me-
thoxycarbonyl and formamide functions, respectively, there-
[a] J. Gonzµlez-Sabín, Prof. V. Gotor, Dr. F. Rebolledo
Departamento de Química Orgµnica e Inorgµnica
Facultad de Química, Universidad de Oviedo, Oviedo (Spain)
Fax : (+34)9851-03448
E-mail: vgs@fq.uniovi.es
frv@fq.uniovi.es
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DOI: 10.1002/chem.200400607
Chem. Eur. J. 2004, 10, 5788 – 5794

5788 – 5794
by allowing their transformation into other interesting com-
pounds such as diamino acids or polyamines. Moreover, di-
amine 4g bears a benzyl group, which could be easily re-
moved to render the corresponding monomethylate deriva-
tive, a difficult task to accomplish from the unsubstituted cy-
clohexane-1,2-diamine.
Reactions were stereospecific in all cases. Thus, the trans
configuration for diamines (Æ)-4a and (Æ)-4g was estab-
3
3
lished by the value of the coupling constants J1,2, J1,6ax, or
1
3J2,3ax in their respective H NMR spectra being greater than
10 Hz (Table 1, entries 1 and 2). The trans configuration for
1
Table 1. Selected coupling constants [Hz] measured in the H NMR spec-
tra of (Æ)-4, (Æ)-6, or (Æ)-7.[a]
Results and Discussion
Syntheses of racemic diamines (Æ)-4 were achieved by ap-
plying the methodology previously described for acyclic di-
amines.[9] Reaction of cyclohexene oxide with a secondary
amine provides the corresponding (Æ)-trans-2-aminocyclo-
hexanol 5 in quantitative yield.[10] One-pot reaction of the b-
amino alcohols with mesyl chloride and subsequently with
aqueous ammonia yielded the (Æ)-trans-cyclohexane-1,2-di-
amines (Æ)-4 in 70–90% overall yields (Scheme 2).
Entry Compound Solvent
3J1,2 3J1,6ax 3J1,6eq 3J2,3ax 3J2,3eq
1
2
3
4
5
6
7
8
(Æ)-4a
(Æ)-4g
(Æ)-6a[b]
(Æ)-6b[b]
(Æ)-6d
(Æ)-6e
(Æ)-6 f
(Æ)-7c
CDCl3
CDCl3
CDCl3
CDCl3
10.3
10.3
3.0
10.3 10.3
10.4 10.4
10.8 10.8
4.3
3.9
3.0
3.9
4.3
3.9
4.7
CDCl3 +D2O 10.6 10.6
CD3OD 10.3 10.3
CDCl3 +D2O 10.6 10.6
CDCl3 +D2O 10.2 10.2
[a] Cbz=benzyloxycarbonyl. [b] J values were measured after decoupling
of the NH signal.
the other diamines was established by analysis of the
1H NMR spectra of their corresponding acetamide or carba-
mate derivatives (Table 1, entries 4–8). In all cases, the large
J values are indicative of a trans-diaxial arrangement be-
tween H-1 and H-2, and H-1 and H-6ax. This trans configu-
ration indicates that the reaction proceeds through a meso-
Scheme 2. Preparation of racemic diamines (Æ)-4a–g. Ms=mesyl=meth-
ane sulfonate.
Scheme 3. The conversion of (Æ)-trans-2-aminocyclohexanols 5 into race-
mic diamines (Æ)-4a–g proceeds through a meso-aziridinium ion inter-
mediate (Az).
Abstract in Spanish: Se ha llevado a cabo la síntesis este-
reoespecífica de diversas (Æ)-trans-N,N-cyclohexano-1,2-dia-
minas ((Æ)-4a–g) a partir de los correspondientes (Æ)-trans-
N,N-dialquilaminociclohexanoles,mediante el tratamiento su-
cesivo con cloruro de mesilo y amoníaco acuoso. La estereo-
química de los productos sugiere la formación de un ion
meso-aziridinio intermedio. La resolución cinØtica de las dia-
minas (Æ)-4 ha sido realizada eficazmente mediante reaccio-
nes de aminólisis catalizadas por la lipasa-B de Candida an-
tarctica,utilizando acetato de etilo como disolvente y como
dador de acilo. Las acetamidas producidas y las diaminas,
aisladas como sus derivados carbamatos,se obtuvieron con
altos excesos enantiomØricos (92–99%). Uno de los carbama-
tos se ha empleado como precursor del analgØsico U-(À)-
50,488.
aziridinium ion[11] intermediate (Az, Scheme 3), which is
stereospecifically opened by the ammonia present in the re-
action medium. Additional proof supports the notion that
trans-diamines are only formed through the meso-aziridini-
um ion: when enantiopure amino alcohol (1R,2R)-5g[10b]
was submitted to the same reaction conditions, a complete
loss of optical activity took place and racemic trans-diamine
(Æ)-4g was isolated. This result also demonstrates that opti-
cally active trans-2-N,N-dialkylaminocyclohexanols cannot
be used as precursors of their analogous optically active di-
amines.
Enzymatic resolution of diamines (Æ)-4 was carried out
by using lipase B from Candida antarctica (CAL-B) as a cat-
alyst. So far, CAL-B (Novozyme SP-435) has proven to be
Chem. Eur. J. 2004, 10, 5788 – 5794
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V. Gotor, F. Rebolledo, and J. Gonzµlez-Sabín
FULL PAPER
the most effective catalyst for the aminolysis reaction in or-
ganic solvents.[12] In particular, this enzyme has shown great
efficiency in catalyzing the kinetic sequential resolution of
(Æ)-trans-cyclohexane-1,2-diamine, thereby resulting in a
useful route for the preparation of optically active symmet-
rically N,N’-disubstituted derivatives.[13]
primary amino group of the diamine was catalyzed by the
vicinal tertiary amino group. The use of an additional base
such as sodium carbonate led to the formation of a mixture
of mono- and di-Cbz derivatives, with the di-Cbz derivative
being the major compound.
As can be seen in Table 2, yields of both remaining sub-
strate and product were high, especially in the reaction of
diamine (Æ)-4g. The high enantioselectivities observed in
all cases allowed us to obtain the acetamides (1R,2R)-6 with
very high ee values. The remaining diamines (1S,2S)-4, in
most cases isolated as their carbamates, were also mostly ob-
tained with very high ee values at conversions (C) near to
50%. Although only moderate enantiomeric excess was ob-
served for the remaining substrates of the reactions of (Æ)-
4d,e,g (C<50%, see Table 2), longer reactions times (13,
14, and 9 h, respectively) allowed us to isolate (1S,2S)-7d,
(1S,2S)-7e, and (1S,2S)-4g with ee>99%, albeit lower
yields. In addition, free diamines (1S,2S)-4a–f (ee: 93–99%)
were obtained in very high yields after removal of the Cbz
group (H2, 10% Pd/C).
We performed the CAL-B-catalyzed resolution of dia-
mines (Æ)-4 under the simplest of reaction conditions, that
is, by using ethyl acetate as the acyl donor and solvent. The
results presented in Table 2 show that lipase is a very effi-
cient catalyst, and all reactions proceeded with very high
values of enantiomer selectivity.[14] In the enzymatic reaction
of (Æ)-4g, the resulting mixture formed by the acetamide
(1R,2R)-6g and the diamine (1S,2S)-4g was easily separated
by flash chromatography. In the other cases, the isolation of
both diamine and acetamide was facilitated by the reaction
mixtures being previously treated with benzylchloroformate.
Thus, diamines (1S,2S)-4 were transformed into the corre-
sponding Cbz derivatives (1S,2S)-7, and the resulting mix-
tures of carbamate and acetamide were also separated by
flash chromatography. A base was not required in this deri-
vatization process because benzyloxycarbonylation of the
In all cases, enantiomeric excess was determined by
HPLC with a chiral column. The configuration (1S,2S) for
Table 2. Enzymatic resolution of racemic diamines (Æ)-4.[a]
Diamine
NR1R2
t
C[b]
[%]
Remaining substrate
Product
yield
E[c]
[h]
diamine or
yield
[%]
ee
[%]
amide
ee
[%]
carbamate
[%]
(Æ)-4a
(Æ)-4b
7
8
51
50
(1S,2S)-7a
44
45
99
98
(1R,2R)-6a
(1R,2R)-6b
41
94
170
(1S,2S)-7b
(1S,2S)-7c
43
45
98
98
>200
>200
(Æ)-4c
(Æ)-4d
8
7
49
44
46
50
95
77
(1R,2R)-6c
(1R,2R)-6d
(1S,2S)-7d
(1S,2S)-7e
43
38
98
98
>200
>200
(Æ)-4e
8
44
40
78
(1R,2R)-6e
(Æ)-4 f
(Æ)-4g
6
5
50
46
(1S,2S)-7 f
(1S,2S)-4g
38
49
93
86
(1R,2R)-6 f
(1R,2R)-6g
43
45
92
82
>99
>200
[a] Reactions were carried out with CAL-B at 288C and 200 rpm. [b] Conversion: C=ees/(ees +eep). ees =substrate ee value, eep =product ee value.
[c] Enantiomeric ratio calculated according to ref. [14].
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trans-Cyclohexane-1,2-diamine Derivatives
5788 – 5794
the remaining diamine 4a was established after transforma-
tion into the analgesic 1 (see below) by comparison of the
optical rotation with the reported value for (1S,2S)-(À)-1.[15]
This means that CAL-B follows the rule of Kazlauskas
et al.,[16] with the diamine with the 1R,2R configuration
being the one preferentially transformed. Taking into ac-
count the stereochemical preference shown by CAL-B to-
wards primary amines bearing the steregenic center in the a
position,[12] as well as the structural resemblance between di-
amines reported here, we have tentatively assigned the con-
figurations (1S,2S) to the other remaining diamines 4b–g
and (1R,2R) to the corresponding acetamides 6b–g.
As a proof of the utility of these diamines, one of them,
(1S,2S)-2-(pyrrolidin-1-yl)cyclohexanamine, has been used
in the synthesis of the analgesic U-(À)-50,488.
Experimental Section
General: Candida antarctica lipase B (CAL-B, available immobilized on
polyacrylamide as Novozyme SP-435, 7300 PLUgÀ1
) was supplied by
Novo Nordisk Co. For the enzymatic reactions, ethyl acetate of spectro-
photometric grade (stored with 4 Š molecular sieves) was used. Melting
points were taken on samples in open capillary tubes and are uncorrect-
ed. IR spectra were recorded on an Infrared FT spectrophotometer as
KBr pellets (for solids) or neat (for liquids). Flash chromatography was
performed by using silica gel 60 (230–400 mesh). Chiral HPLC analyses
were performed by using Chiralcel OD and OD-RH columns (Daicel) at
20–358C. 1H, 13C NMR, and DEPT spectra were recorded in CDCl3 or
CD3OD by using AC-200 (1H, 200.13 MHz; 13C, 50.3 MHz) and AC-300
or DPX-300 (1H, 300.13 MHz; 13C, 75.5 MHz) spectrometers for routine
experiments. An AMX-400 spectrometer (1H, 400.13 MHz; 13C,
100.61 MHz) was used for the acquisition of 1H–1H and 1H–13C correla-
tion experiments. The chemical shift values (d) are given in ppm and the
coupling constants (J) are given in Hertz (Hz). Positive electrospray ioni-
zation (ESI+) was used to record mass spectra. Microanalyses were per-
formed on a Perkin–Elmer model 2400 instrument.
As mentioned above, optically active diamine (1S,2S)-4a
is
a
suitable precursor of the analgesic U-(À)-50,488
((1S,2S)-(À)-1, see Scheme 1). We carried out the synthesis
of this compound from the optically active carbamate
(1S,2S)-7a, isolated after benzyloxycarbonylation of the re-
maining substrate from the enzymatic aminolysis of (Æ)-4a.
Thus, reduction of 7a with LiAlH4 yielded the N-methyl de-
rivative (1S,2S)-8, which was treated with 3,4-dichloropheny-
lacetyl chloride to give (1S,2S)-1 in 88% overall yield
(Scheme 4).
General procedure for the preparation of racemic diamines (Æ)-trans-
4a–g: The appropriate secondary
amine (49 mmol) was added to a so-
lution of cyclohexene oxide (30 mmol)
in EtOH (30 mL), and the resulting
mixture was heated under reflux for
18 h. After cooling, the solvent was
evaporated and the crude (Æ)-trans-2-
aminocyclohexanol (Æ)-5a–g[10b] was
purified by flash chromatography
Scheme 4. Synthesis of analgesic U-(À)-50,488 ((1S,2S)-1). LAH=lithium aluminum hydride.
(hexane/ethyl acetate or ethyl acetate/
methanol mixtures). The purified (Æ)-
trans-2-aminocyclohexanol (25 mmol)
was dissolved in anhydrous diethyl
ether (45 mL), and triethylamine
Previously, compound U-(À)-50,488 was synthesized from
N-methylcyclohexaneaziridine.[15] The strategy consisted of
(39 mmol) was added. The solution was cooled to 08C, and mesyl chlo-
ride (29.7 mmol) was added dropwise. A white precipitate formed and
made stirring difficult. After 30 min, triethylamine (49 mmol) was added.
After the reaction mixture was allowed to warm to room temperature,
concentrated aqueous NH3 (50 mL) was added and the resulting two-
phase reaction mixture was vigorously stirred during 16 h. The layers
were separated, and the light-yellow aqueous layer was extracted with
Et2O (3”30 mL). The combined organic layers were washed with brine
(20 mL), dried with Na2SO4, and evaporated under reduced pressure to
give the crude product, which was purified by distillation or flash chro-
matography.
the opening of the aziridine ring with pyrrolidine to yield
(Æ)-8 and further fractional crystallization of the diastereo-
meric salts formed from (Æ)-8 and an optically active car-
boxylic acid. Although (1S,2S)-1 was also obtained with a
very high ee value, we believe that the chemoenzymatic syn-
thesis described herein is an interesting alternative to that
previously reported. We use diamine (Æ)-4a, which is ob-
tained from an N-dialkylated aziridinium ion (Az,
Scheme 3) generated in situ under mild conditions. In con-
trast, the opening of a N-alkylaziridine for the preparation
of diamine (Æ)-8 requires activation by an acidic agent.
Moreover, enzymatic resolution of (Æ)-4a is a very simple
method, with the compounds being easy to separate by flash
chromatography. However, a tedious series of recrystalliza-
tions were needed to prepare optically active (1S,2S)-8.
(Æ)-trans-2-(Pyrrolidin-1-yl)cyclohexanamine ((Æ)-4a): Yield: 90%; b.p.
55–568C (0.5 Torr); 1H NMR (200 MHz, CDCl3): d=1.30–1.00 (m, 4H;
(H-3, H-4, H-5, H-6)ax), 1.60–1.70 (m, 7H; H-8, H-8’, (H-3, H-4, H-
5)eq), 1.94 (brd, J6eq,6ax =10.6 Hz, 1H; H-6eq,), 2.12 (s, 2H; NH2), 2.28
(dt, J2,3eq =3.0, J1,2 =J2,3ax =10.3 Hz, 1H; H-2), 2.45–2.70 ppm (m, 5H; H-
1, 2”CH2N); 13C NMR (75.5 MHz, CDCl3): d=21.34 (CH2), 23.62 (C-8),
24.89 (CH2), 25.37 (CH2), 34.84 (CH2), 46.97 (CH2N), 52.62 (C-1),
65.07 ppm (C-2); IR (neat): n˜ =3356, 3302 cmÀ1; MS (ESI+): m/z (%):
169.1 (100) [M+H]+, 191.1 (15) [M+Na]+; elemental analysis calcd (%)
for C10H20N2: C 71.37, H 11.98, N 16.65; found: C 71.43, H 11.85, N
16.72.
Conclusion
(Æ)-trans-2-(Piperidin-1-yl)cyclohexanamine ((Æ)-4b): Yield: 86%; b.p.
50–518C (0.5 Torr); 1H NMR (300 MHz, CDCl3): d=0.78–0.95 (m, 4H),
1.10–1.55 (m, 11H), 1.65–1.76 (m, 2H), 1.95–2.08 (m, 2H), 2.30–2.45 ppm
(m, 3H); 13C NMR (75.5 MHz, CDCl3): d=21.99 (CH2), 24.53 (CH2),
25.42 (CH2), 26.34 (2CH2), 34.66 (CH2), 49.15 (2CH2), 50.12 (CH),
70.68 ppm (CH); IR (neat): n˜ =3358 cmÀ1; MS (ESI+): m/z (%): 183.2
We have developed an efficient chemoenzymatic method
for the preparation of a variety of optically active N,N-di-
substituted trans-cyclohexane-1,2-diamines and their acet-
amide derivatives from the inexpensive cyclohexene oxide.
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V. Gotor, F. Rebolledo, and J. Gonzµlez-Sabín
FULL PAPER
(100) [M+H]+, 205.1 (5) [M+Na]+; elemental analysis calcd (%) for
C11H22N2: C 72.47, H 12.16, N 15.37; found: C 72.38, H 12.01, N 15.61.
(CH3), 24.23 (CH2), 24.70 (CH2), 32.04 (CH2), 46.95 (CH2), 52.01 (CH),
61.55 (CH), 170.28 ppm (C=O); IR (KBr): n˜ =3289, 1634 cmÀ1
; MS
(ESI+): m/z (%): 211.1 (80) [M+H]+, 233.1 (25) [M+Na]+; elemental
analysis calcd (%) for C12H22N2O: C 68.53, H 10.54, N 13.32; found: C
68.69, H 10.50, N 13.41.
(Æ)-trans-2-(Morpholin-4-yl)cyclohexanamine ((Æ)-4c): Yield: 85%; b.p.
65–668C (0.5 Torr); 1H NMR (300 MHz, CDCl3): d=0.70–1.07 (m, 4H),
1.36–1.67 (m, 5H), 1.70–1.88 (m, 2H), 2.18 (ddd, J=3.5, 5.7, 10.7 Hz,
2H), 2.37–2.50 (m, 3H), 3.38–3.54 ppm (m, 4H); 13C NMR (75.5 MHz,
CDCl3): d=22.06 (CH2), 24.36 (CH2), 25.23 (CH2), 34.51 (CH2), 48.22
(CH2), 49.84 (CH), 67.10 (CH2), 70.12 ppm (CH); IR (neat): n˜ =3373,
(1R,2R)-N-[2-(Piperidin-1-yl)cyclohexyl]acetamide ((1R,2R)-6b): Yield:
1
43%; m.p. 122–1248C; [a]2D0 =À65.4 (c=1.0 in CHCl3); 98% ee; H NMR
(300 MHz, CDCl3): d=0.95–1.62 (m, 11H), 1.70–1.88 (m, 2H), 1.92 (s,
3H; CH3), 2.10–2.32 (m, 3H), 2.40–2.60 (m, 3H), 3.51 (m (J1,6eq =3.0,
3318 cmÀ1
;
MS (ESI+): m/z (%): 185.1 (100) [M+H]+, 207.1 (7)
[M+Na]+; elemental analysis calcd (%) for C10H20N2O: C 65.18, H 10.94,
J
1,2 =J1,6ax =10.8 Hz, measured after irradiation of NH signal), 1H; H-1),
6.35 ppm (brs, 1H; NH); 13C NMR (75.5 MHz, CDCl3): d=22.90 (CH2),
23.45 (CH3), 24.48 (CH2), 24.70 (CH2), 25.53 (CH2), 26.63 (CH2), 32.61
(CH2), 48.98 (CH2), 50.63 (CH), 67.47 (CH), 170.52 ppm (C=O); IR
(KBr): n˜ =3286, 1651 cmÀ1; MS (ESI+): m/z (%): 225.2 (80) [M+H]+,
247.1 (10) [M+Na]+; elemental analysis calcd (%) for C13H24N2O: C
69.60, H 10.78, N 12.49; found: C 69.50, H 10.64, N 12.61.
N 15.20; found: C 65.05, H 10.87, N 15.31.
Methyl (Æ)-trans-1-(2-aminocyclohexyl)piperidine-4-carboxylate ((Æ)-
1
4d): Yield: 70%; m.p. 168–1708C; H NMR (300 MHz, CDCl3): d=0.92–
1.15 (m, 4H), 1.45–2.05 (m, 12H), 1.70–1.88 (m, 2H), 2.15 (m, 1H), 2.41–
2.55 (m, 3H), 2.71 ppm (dt, J=3.1 and 11.7 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3): d=22.47 (CH2), 24.77 (CH2), 25.64 (CH2), 28.84
(CH2), 29.00 (CH2), 34.85 (CH2), 41.50 (CH), 44.71 (CH2), 50.45 (CH),
51.33 (CH2), 51.38 (CH3), 70.58 (CH), 175.63 ppm (C=O); IR (KBr): n˜ =
3360, 3285,1736 cmÀ1; MS (ESI+): m/z (%): 241.1 (100) [M+H]+, 263.1
(3) [M+Na]+; elemental analysis calcd (%) for C13H24N2O2: C 64.97, H
10.07, N 11.66; found: C 65.05, H 10.12, N 11.50.
(1R,2R)-N-[2-(Morpholin-4-yl)cyclohexyl]acetamide
((1R,2R)-6c):
Yield: 45%; m.p. 115–1178C; [a]2D0 =À66.5 (c=1.0 in CHCl3); 95% ee;
1H NMR (400 MHz, CDCl3): d=0.95–1.32 (m, 4H), 1.55–1.65 (m, 1H),
1.73–1.86 (m, 2H), 1.93 (s, 3H; CH3), 2.19 (dt, J=3.2, 10.7 Hz, 1H),
2.25–2.38 (m, 3H), 2.56–2.65 (m, 2H), 3.48–3.65 (m, 5H), 6.06 ppm (brs,
1H; NH); 13C NMR (75.5 MHz, CDCl3): d=22.89 (CH2), 23.05 (CH3),
24.29 (CH2), 25.00 (CH2), 32.55 (CH2), 47.94 (CH2), 49.52 (CH), 66.88
(Æ)-trans-2-(4-Formylpiperazin-1-yl)cyclohexanamine ((Æ)-4e): Yield:
80%; m.p. 168–1708C; 1H NMR (200 MHz, CDCl3): d=0.90–1.20 (m,
4H), 1.45–1.70 (m, 3H), 1.85 (m, 1H), 2.05 (dt, J=3.1 and 11.0 Hz, 1H),
2.15–2.34 (m, 2H), 2.45–2.63 (m, 3H), 2.90–3.10 (m, 2H), 3.18–3.45 (m,
4H), 7.87 ppm (s, 1H); 13C NMR (75.5 MHz, CDCl3): d=22.47 (CH2),
24.26 (CH2), 25.07 (CH2), 33.86 (CH2), 40.16 (CH2), 45.88 (CH2), 47.41
(CH2), 48.70 (CH2), 50.09 (CH), 69.67 (CH), 160.33 ppm (C=O); IR
(Nujol): n˜ =3472, 3344, 1666 cmÀ1; MS (ESI+): m/z (%): 212.1 (100)
[M+H]+, 234.1 (12) [M+Na]+; elemental analysis calcd (%) for
C11H21N3O: C 62.52, H 10.02, N 19.89; found: C 62.68, H 10.11, N 19.80.
(CH), 67.18 (CH2), 169.74 ppm (C=O); IR (KBr): n˜ =3270, 1652 cmÀ1
;
MS (ESI+): m/z (%): 227.1 (20) [M+H]+, 249.1 (100) [M+Na]+; elemen-
tal analysis calcd (%) for C12H22N2O2: C 63.68, H 9.80, N 12.38; found: C
63.75, H 9.92, N 12.29.
Methyl (1R,2R)-1-[2-(acetylamino)cyclohexyl]piperidine-4-carboxylate
((1R,2R)-6d): Yield: 43%; oil; [a]2D0 =+11.25 (c=0.93 in CHCl3); 94%
ee; 1H NMR (300 MHz, CDCl3): d=0.89–1.28 (m, 4H), 1.43 (m, 1H),
1.51–1.85 (m, 6H), 1.88 (s, 3H; CH3), 2.02 (dt, J=2.6, 11.4 Hz, 1H),
2.10–2.25 (m, 2H), 2.32–2.55 (m, 3H), 2.67 (dt, J=11.1, 3.7 Hz, 1H), 3.43
(m (dt, J1,6eq =3.9, J1,2 =J1,6ax =10.6 Hz, after amide NH to ND exchange
with D2O), 1H; H-1), 3.59 (s, 3H; CH3), 6.14 ppm (brs, 1H; NH);
13C NMR (75.5 MHz, CDCl3): d=22.90 (CH2), 23.09 (CH3), 24.28 (CH2),
25.15 (CH2), 28.63 (CH2), 28.69 (CH2), 32.49 (CH2), 41.03 (CH), 44.48
(CH2), 50.11 (CH), 51.19 (CH3), 59.84 (CH2), 66.93 (CH), 169.97 (C=O),
175.26 ppm (C=O); IR (Nujol): n˜ =3296, 1732, 1651 cmÀ1; MS (ESI+): m/
z (%): 283.1 (100) [M+H]+, 305.1 (5) [M+Na]+; elemental analysis calcd
(%) for C15H26N2O3: C 63.80, H 9.28, N 9.92; found: C 63.95, H 9.35, N
10.01.
(Æ)-trans-N-Isopropyl-N-methylcyclohexane-1,2-diamine
((Æ)-4 f):
Yield: 86%; b.p. 48–508C (0.5 Torr); 1H NMR (200 MHz, CDCl3): d=
1.00–1.30 (m+2t, J=6.3 Hz, 11H), 1.60–1.80 (m, 3H), 1.85–2.00 (m,
2H), 2.10–2.20 (m+s, 4H; CH, CH3), 2.45–2.60 (m, 1H), 2.84 ppm
(heptet, J=6.3 Hz, 1H); 13C NMR (75.5 MHz CDCl3): d=20.38 (CH3),
20.83 (CH3), 24.82 (CH2), 25.47 (CH2), 25.74 (CH2), 30.57 (CH3), 34.72
(CH2), 51.00 (CH), 51.93 (CH), 66.33 ppm (CH); IR (neat): n˜ =3354,
3302 cmÀ1; MS (ESI+): m/z (%): 171.2 (100) [M+H]+; elemental analysis
calcd (%) for C10H22N2: C 70.53, H 13.02, N 16.45; found: C 70.65, H
12.99, N 16.40.
(1R,2R)-N-[2-(4-Formylpiperazin-1-yl)cyclohexyl]acetamide ((1R,2R)-
6e): Yield: 38%; m.p. 140–1428C; [a]2D0 =À27.7 (c=0.9 in MeOH); 98%
ee; 1H NMR (200 MHz, CD3OD): d=1.15–1.27 (m, 4H), 1.65–1.97 (m+
s, 7H), 2.30–2.48 (m, 3H), 2.64–2.78 (m, 2H), 3.30–3.51 (m, 4H), 3.75
(Æ)-trans-N-Benzyl-N-methylcyclohexane-1,2-diamine ((Æ)-4g): Yield:
84%; b.p. 100–1018C (0.5 Torr); 1H NMR (300 MHz, CDCl3): d=1.00–
1.30 (m, 4H), 1.60–2.00 (m, 6H), 2.10–2.25 (m+s, 4H; CH, CH3), 2.67
(dt, J1,6eq =4.3, J1,2 =J1,6ax =10.3 Hz, 1H; H-1), 2.37–2.50 (m, 3H), 3.45,
(dt,
J1,6eq =4.3, J1,2 =J1,6ax =10.3 Hz, 1H; H-1,), 7.97 ppm (s, 1H);
3.67, (AB system,
JAB =13.4 Hz; CH2), 7.15–7.35 ppm (m, 5H; Ph);
13C NMR (75.5 MHz, CD3OD): d=22.79 (CH3), 25.41 (CH2), 26.14
(CH2), 26.37 (CH2), 34.14 (CH2), 41.94 (CH2), 47.82 (CH2), 49.15 (CH2),
50.20 (CH2), 50.71 (CH), 68.70 (CH), 162.97 (CH), 172.52 ppm (C=O);
IR (KBr): n˜ =3325, 1644 cmÀ1; MS (ESI+): m/z (%): 254.1 (8) [M+H]+,
276.1 (100) [M+Na]+; elemental analysis calcd (%) for C13H23N3O3: C
57.97, H 8.61, N 15.60; found: C 58.04, H 8.50, N 15.88.
13C NMR (75.5 MHz, CDCl3): d=21.83 (CH2), 24.91 (CH2), 25.58 (CH2),
34.99 (CH2), 36.20 (CH3), 51.21 (CH), 57.91 (CH2), 69.36 (CH), 126.55
(CH), 128.00 (CH), 128.42 (CH), 140.15 ppm (C); IR (neat): n˜ =3356,
3302 cmÀ1; MS (ESI+): m/z (%): 219.1 (100) [M+H]+; elemental analysis
calcd (%) for C14H22N2: C 77.01, H 10.16, N 12.83; found: C 76.85, H
10.08, N 13.07.
(1R,2R)-N-[2-(N’-Isopropyl-N’-methylamino)cyclohexyl]acetamide
((1R,2R)-6 f): Yield: 43%; oil; [a]2D0 =À64.5 (c=1.0 in CHCl3); 92% ee;
1H NMR (300 MHz, CDCl3): d=0.90–0.98 (t, J=6.8 Hz, 6H), 1.05–1.30
(m, 4H), 1.50–1.80 (m, 3H), 1.86 (s, 3H; CH3), 2.06 (s, 3H; CH3), 2.28–
General procedure for the enzymatic acetylation of (Æ)-trans-4a–g:
Ethyl acetate (12 mL) was added to a mixture of the appropriate racemic
diamine 4a–g (2.0 mmol) and CAL-B (200 mg) under a nitrogen atmos-
phere. The resulting mixture was shaken at 288C and 200 rpm for 5–8 h.
Afterward, the enzyme was filtered and washed with ethyl acetate. For
the reactions with 4a–f, the resulting solution was cooled to 08C and
then treated with benzyl chloroformate (1.6 mmol). After 15 h, the sol-
vent was evaporated, then the acetamide and carbamate present in the
residue were separated by flash chromatography (ethyl acetate/methanol
mixtures). For the reaction with 4g, after filtration of the enzyme, the
corresponding acetamide and the remaining diamine were separated by
flash chromatography with ethyl acetate/methanol (6:1).
2.45 (m, 2H), 2.75 (heptet, J=6.4 Hz, 1H), 3.34 (m (dt, J1,6eq =3.9, J1,2
=
J
1,6ax =10.6 Hz, after amide NH to ND exchange with D2O), 1H; H-1),
6.20 ppm (brs, 1H; NH); 13C NMR (75.5 MHz, CDCl3): d=20.33 (CH3),
21.45 (CH3), 23.31 (CH3), 24.34 (CH2), 25.35 (CH2), 25.46 (CH2), 30.90
(CH3), 32.42 (CH2), 50.22 (CH), 50.89 (CH), 63.75 (CH), 170.16 ppm (C=
O); IR (KBr): n˜ =3289, 1650 cmÀ1; MS (ESI+): m/z (%): 213.2 (100)
[M+H]+, 235.1 (8) [M+Na]+; elemental analysis calcd (%) for
C12H24N2O: C 67.88, H 11.39, N 13.19; found: C 68.05, H 11.30, N 12.99.
(1R,2R)-N-[2-(N’-Benzyl-N’-methylamino)cyclohexyl]acetamide
(1R,2R)-N-[2-(Pyrrolidin-1-yl)cyclohexyl]acetamide ((1R,2R)-6a): Yield:
41%; m.p. 88–908C; [a]D20 =À63.2 (c=1.0 in CHCl3); 94% ee; 1H NMR
(300 MHz, CDCl3): d=1.05–1.40 (m, 4H), 1.60–1.82 (m, 7H), 1.97 (s,
3H; CH3), 2.40–2.65 (m, 6H), 3.51 (m (J1,6eq =3.9, J1,2 =J1,6ax =10.4 Hz
measured after irradiation of NH signal), 1H; H-1), 6.20 ppm (brs, 1H;
NH); 13C NMR (75.5 MHz, CDCl3): d=21.99 (CH2), 23.59 (CH2), 23.64
((1R,2R)-6g): Yield: 45%; m.p. 143–1458C; [a]2D0 =À16.5 (c=1.0 in
CHCl3); >99% ee; 1H NMR (200 MHz, CDCl3): d=0.95–1.40 (m, 4H),
1.60–2.05 (m+s, 6H), 2.18 (s, 3H; CH3), 1.86 (s, 3H; CH3), 2.35 (dt, J=
3.1, 11.0 Hz, 1H), 2.53 (m, 1H), 3.39, 3.69 (AB system, JAB =13.3 Hz;
CH2), 3.59 (m, 1H), 6.09 (brs, 1H; NH), 7.15–7.35 ppm (m, 5H; Ph);
5792
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5788 – 5794

trans-Cyclohexane-1,2-diamine Derivatives
5788 – 5794
13C NMR (75.5 MHz, CDCl3): d=22.42 (CH2), 23.57 (CH3), 24.50 (CH2),
25.34 (CH2), 32.67 (CH2), 36.73 (CH3), 50.92 (CH), 56.94 (CH2), 65.27
(CH), 126.87 (CH), 128.22 (CH), 128.39 (CH), 139.77 (C), 170.12 ppm
(C=O); IR (KBr): n˜ =3285, 1638 cmÀ1; MS (ESI+): m/z (%): 261.1 (100)
[M+H]+, 283.1 (20) [M+Na]+; elemental analysis calcd (%) for
C16H24N2O: C, 73.81, H 9.29, N 10.76; found: C 74.01, H 9.26, N 10.73.
CH2), 5.64 (brs, 1H; NH), 7.20–7.35 ppm (m, 5H; Ph); 13C NMR
(75.5 MHz, CDCl3): d=20.42 (CH3), 21.37 (CH3), 24.34 (CH2), 25.33
(CH2), 25.49 (CH2), 30.96 (CH3), 32.67 (CH2), 50.56 (CH), 51.95 (CH),
63.64 (CH), 65.90 (CH2), 127.62 (CH), 127.70 (CH), 128.16 (CH), 136.75
(C), 156.50 ppm (C=O); IR (neat): n˜ =3349, 1723 cmÀ1; MS (ESI+): m/z
(%): 305.1 (100) [M+H]+, 327.1 (15) [M+Na]+; elemental analysis calcd
(%) for C18H28N2O2: C 71.02, H 9.27, N 9.20; found: C 71.28, H 9.40, N
8.99.
Benzyl (1S,2S)-N-[2-(pyrrolidin-1-yl)cyclohexyl]carbamate ((1S,2S)-7a):
Yield: 44%; oil; [a]2D0 =+49.2 (c=1.05 in CHCl3); 99% ee; 1H NMR
(200 MHz, CDCl3): d=1.05–1.40 (m, 4H), 1.60–1.85 (m, 7H), 2.35–2.75
(m, 6H), 3.35 (m, 1H), 5.12, 5.09 (AB system, JAB =12.0 Hz; CH2), 5.73
(brs, 1H; NH), 7.20–7.35 ppm (m, 5H; Ph); 13C NMR (75.5 MHz,
CDCl3): d=22.06 (CH2), 23.57 (CH2), 24.04 (CH2), 24.51 (CH2), 31.98
(CH2), 47.06 (CH2), 52.89 (CH), 61.78 (CH), 66.11 (CH2), 127.79 (CH),
127.83 (CH), 128.30 (CH), 136.75 (C), 156.42 ppm (C=O); IR (neat): n˜ =
3337, 1715 cmÀ1; MS (ESI+): m/z (%): 303.2 (100) [M+H]+; elemental
analysis calcd (%) for C18H26N2O2: C 71.49, H 8.67, N 9.26; found: C
71.56, H 8.70, N 9.15.
(1S,2S)-N-Benzyl-N-methylcyclohexane-1,2-diamine ((1S,2S)-4g): Yield:
49%; [a]2D0 =+48.2 (c=1.1 in CHCl3); 86% ee. Diamine (1S,2S)-4g with
ee>99% ([a]2D0 =+48.2 (c=1.1 in CHCl3)) was isolated if the enzymatic
reaction was conducted for 9 h.
General procedure for the hydrogenolysis of the benzyl carbamates
(1S,2S)-7a–f: A suspension of (1S,2S)-7a–f (0.75 mmol) and Pd/C (10%,
120 mg) in deoxygenated methanol (15 mL) was stirred for 12 h under a
hydrogen atmosphere. The reaction mixture was filtered through Celite,
and the filtrate was evaporated to yield pure (1S,2S)-4a–f.
Benzyl (1S,2S)-N-[2-(piperidin-1-yl)cyclohexyl]carbamate ((1S,2S)-7b):
Yield: 45%; oil; [a]2D0 =+49.5 (c=1.0 in CHCl3); 98% ee; 1H NMR
(200 MHz, CDCl3): d=1.00–1.95 (m, 13H), 2.10–2.30 (m, 3H), 2.45–2.65
(m, 3H), 3.29 (m, 1H), 5.12 (s, 2H; CH2), 5.72 (brs, 1H; NH), 7.20–
7.35 ppm (m, 5H; Ph); 13C NMR (75.5 MHz, CDCl3): d=22.78 (CH2),
24.37 (CH2), 24.70 (CH2), 25.43 (CH2), 26.42 (CH2), 32.74 (CH2), 49.00
(CH2), 51.44 (CH), 65.93 (CH2), 67.66 (CH), 127.64 (CH), 128.22 (CH),
136.85 (C), 156.53 ppm (C=O); IR (neat): n˜3348, 1724 cmÀ1; MS (ESI+):
m/z (%): 317.2 (100) [M+H]+, 339.2 (5) [M+Na]+; elemental analysis
calcd (%) for C19H28N2O2: C 72.12, H 8.92, N 8.85; found: C 72.25, H
8.80, N 8.99.
(1S,2S)-2-(Pyrrolidin-1-yl)cyclohexanamine ((1S,2S)-4a): Yield: 90%;
[a]2D0 =+65.2 (c=1.0 in CHCl3); 99% ee.
(1S,2S)-2-(Piperidin-1-yl)cyclohexanamine ((1S,2S)-4b): Yield: 96%;
[a]2D0 =+54.0 (c=1.0 in CHCl3); 98% ee.
(1S,2S)-2-(Morpholin-4-yl)cyclohexanamine ((1S,2S)-4c): Yield: 97%;
[a]2D0 =+60.1 (c=0.80 in CHCl3); 95% ee.
Methyl (1S,2S)-1-(2-aminocyclohexyl)piperidine-4-carboxylate ((1S,2S)-
4d): Yield: 95%; [a]2D0 =+36.4 (c=1.1 in CHCl3); >99% ee.
(1S,2S)-2-(4-Formylpiperazin-1-yl)cyclohexanamine ((1S,2S)-4e): Yield:
93%; [a]2D0 =+47.2 (c=0.75 in CH3OH); >99% ee.
Benzyl (1S,2S)-N-[2-(morpholin-4-yl)cyclohexyl]carbamate ((1S,2S)-7c):
Yield: 46%; oil; [a]2D0 =+45.7 (c=1.0 in CHCl3); 98% ee; 1H NMR
(200 MHz, CDCl3): d=1.00–1.35 (m, 4H), 1.55–1.92 (m, 3H), 2.16 (dt,
J=3.1, 10.6 Hz, 1H), 2.28–2.50 (m, 3H), 2.55–2.70 (m, 2H), 3.33 (m, (dt,
(1S,2S)-N-Isopropyl-N-methylcyclohexane-1,2-diamine
Yield: 98%; [a]2D0 =+40.7 (c=1.4 in CHCl3); 93% ee.
((1S,2S)-4 f):
(1S,2S)-N-Methyl-2-(pyrrolidin-1-yl)cyclohexanamine ((1S,2S)-8): A so-
lution of carbamate (1S,2S)-7a (0.80 mmol) in THF (3 mL) was added to
a suspension of LiAlH4 (1.25 mmol) in THF (5 mL) under a nitrogen at-
mosphere. The mixture was stirred at room temperature for 21 h. After
this time, the excess LiAlH4 was destroyed by addition of 3n aqueous
Na2CO3, the mixture was filtered through Celite, and the solvents were
evaporated. Diethyl ether (15 mL) was then added, and the organic so-
lution was extracted with 2n aqueous HCl (3”10 mL). The aqueous
phase was washed with diethyl ether (10 mL), and pellets of NaOH were
added until a basic pH value was reached. Extraction with diethyl ether
(4”15 mL) and evaporation of the organic solvent yielded pure diamine
(1S,2S)-8. Yield: 90%; oil; [a]2D0 =+90.3 (c=0.95 in CHCl3); 99% ee (lit-
erature value[15] for (1S,2S)-(+)-8: [a]2D3 =+97.6 (c=0.29 in methanol); >
J
1,6eq =4.7, J1,2 =J1,6ax =10.2 Hz, after NH to ND exchange with D2O),
1H; H-1), 3.58–3.75 (m, 4H), 5.09 (s, 2H; CH2), 5.44 ppm (brd, J=
4.7 Hz, 1H; NH); 7.20–7.35 (m, 5H; Ph); 13C NMR (75.5 MHz, CDCl3):
d=22.81 (CH2), 24.26 (CH2), 24.98 (CH2), 32.72 (CH2), 48.01 (CH2),
50.78 (CH), 65.81 (CH2), 67.02 (CH2), 67.24 (CH), 127.51 (CH), 128.04
(CH), 136.56 (C), 156.11 ppm (C=O); IR (neat): n˜ =3333, 1710 cmÀ1; MS
(ESI+): m/z (%): 319.2 (100) [M+H]+, 341.1 (15) [M+Na]+; elemental
analysis calcd (%) for C18H26N2O3: C 67.90, H 8.23, N 8.80; found: C
68.07, H 8.26, N 8.63.
Benzyl (1S,2S)-N-{2-[4-(methoxycarbonyl)piperidin-1-yl]cyclohexyl}car-
bamate ((1S,2S)-7d): Yield: 50%; oil; [a]2D0 =+33.6 (c=0.93 in CHCl3);
>99% ee; 1H NMR (200 MHz, CDCl3): d=0.95–1.35 (m, 5H), 1.52–1.98
(m, 6H), 2.03–2.30 (m, 3H), 2.45–2.58 (m, 3H), 2.77 (dt, J=3.5, 11.3 Hz,
1
99.5% ee); H NMR (300 MHz, CDCl3): d=0.80–0.98 (m, 1H), 1.00–1.22
(m, 3H), 1.50–1.75 (m, 7H), 1.95–2.15 (m, 2H), 2.31 (s, 3H; CH3), 2.32–
2.55 (m, 5H), 2.71 ppm (brs, 1H; NH); 13C NMR (75.5 MHz, CDCl3):
d=21.16 (CH2), 23.57 (CH2), 24.39 (CH2), 25.17 (CH2), 30.98 (CH2),
34.00 (CH3), 46.69 (CH2), 61.33 (CH), 61.95 ppm (CH); IR (neat): n˜ =
3315, 1357 cmÀ1; MS (ESI+): m/z (%): 183.1 (100) [M+H]+, 205.1 (5)
[M+Na]+, 112.1 (15), 152.1 (10); elemental analysis calcd (%) for
C11H22N2: C 72.47, H 12.16, N 15.37; found: C 72.58, H 12.06, N 15.36.
1H), 3.30 (m, 1H), 3.68 (s, 3H; CH3), 5.12, 5.09 (AB system, JAB
=
12.1 Hz; CH2), 5.51 (brs, 1H; NH), 7.20–7.35 ppm (m, 5H; Ph);
13C NMR (75.5 MHz, CDCl3): d=22.99 (CH2), 24.42 (CH2), 25.37 (CH2),
28.61 (CH2), 28.78 (CH2), 32.86 (CH2), 41.29 (CH), 44.78 (CH2), 50.47
(CH2), 51.45 (CH3), 66.12 (CH2), 67.47 (CH), 127.79 (CH), 127.84 (CH),
128.33 (CH), 136.77 (C), 156.48 (C=O), 175.48 ppm (C=O); IR (neat):
n˜ =3352, 1731 cmÀ1; MS (ESI+): m/z (%): 375.2 (100) [M+H]+, 397.2 (5)
[M+Na]+; elemental analysis calcd (%) for C21H30N2O4: C 67.35, H 8.07,
N 7.48; found: C 67.50, H 8.24, N 7.41.
(1S,2S)-N-Methyl-N-[2-(pyrrolidin-1-yl)cyclohexyl]-2-(3,4-dichlorophen-
yl)acetamide ((1S,2S)-1): Under
a nitrogen atmosphere, (1S,2S)-8
(0.60 mmol) was dissolved in dichloromethane (5 mL), and 3,4-dichloro-
phenylacetyl chloride (0.76 mmol) was added at 08C. After stirring for
5 h, dichloromethane (10 mL) was added, and the organic layer was
washed with saturated aqueous NaHCO3 (2”10 mL) and brine (10 mL),
dried (Na2SO4), and concentrated to yield crude (1S,2S)-1, which was pu-
rified by flash chromatography (hexane/ethyl acetate 1:2): Yield: 95%;
oil. Hydrochloride salt of (1S,2S)-1. [a]2D0 =À34.0 (c=0.7 in methanol);
99% ee; (literature value[15] for (1S,2S)-(À)-1·HCl: [a]2D0 =À36.05 (c=
0.73 in methanol); >99% ee); 1H NMR (300 MHz, CDCl3) correspond-
ing to a 80:20 mixture of rotamers: d=0.90–2.00 (m, 12H), 2.40–2.70 (m,
5H), 2.79 (s, 3H for major rotamer, CH3), 2.80 (s, 3H for minor rotamer,
CH3), 3.46 (dt, J1,6eq =5.0, J1,2 =J1,6ax =10.6 Hz, 1H for minor rotamer; H-
Benzyl
(1S,2S)-N-[2-(4-formylpiperazin-1-yl)cyclohexyl]carbamate
((1S,2S)-7e): Yield: 40%; m.p. 92–948C; [a]2D0 =+38.9 (c=1.7 in
MeOH); 78% ee; 1H NMR (200 MHz, CD3OD): d=1.05–1.40 (m, 4H),
1.65–2.07 (m, 5H), 2.30–2.95 (m, 4H), 3.20–3.55 (m, 5H), 4.79–5.18 (over-
lapping of CH2 and solvent signals), 7.25–7.36 (m, 5H; Ph), 7.94 ppm (s,
1H); 13C NMR (75.5 MHz, CD3OD): d=25.41 (CH2), 26.09 (CH2), 26.16
(CH2), 34.30 (CH2), 41.18 (CH2), 47.00 (CH2), 49.21 (CH2), 50.25 (CH2),
52.17 (CH), 67.17 (CH2), 69.60 (CH), 128.89 (CH), 129.39 (CH), 138.59
(C), 158.57 (C=O), 162.70 ppm (CH); MS (ESI+): m/z (%): 375.2 (100)
[M+H]+, 397.2 (5) [M+Na]+; elemental analysis calcd (%) for
C19H27N3O3: C 66.06, H 7.88, N 12.16; found: C 65.90, H 8.02, N 12.29.
Benzyl (1S,2S)-N-[2-(N’-isopropyl-N’-methylamino)cyclohexyl]carbamate
((1S,2S)-7 f): Yield: 38%; oil; [a]2D0 =+51.5 (c=0.95 in CHCl3); 93% ee;
1H NMR (300 MHz, CDCl3): d=1.05 (t, J=7.1 Hz, 6H), 1.18–1.35 (m,
4H), 1.65–1.92 (m, 3H), 2.18 (s, 3H; CH3), 2.41 (dt, J=3.0, 10.6 Hz, 1H),
2.59 (m, 1H), 2.84 (heptet, J=7.1 Hz, 1H), 3.28 (m, 1H), 5.13 (s, 2H;
1), 3.60, 3.70 (AB system, JAB =15.4 Hz; CH2), 4.49 (dt, J1,6eq =3.6, J1,2 =
J
1,6ax =11.4 Hz, 1H for major rotamer; H-1), 7.10 (m, 1H; Ar), 7.33 ppm
(m, 2H; Ar); 13C NMR (75.5 MHz, CDCl3) corresponding to a 80:20 mix-
ture of rotamers: d=22.32, 23.62, 23.71, 24.94, 25.08, 25.11, 25.21, 27.27,
29.57, 29.74, 30.79, 39.45, 40.44, 46.84, 48.09, 54.82, 58.36, 59.58, 60.43,
Chem. Eur. J. 2004, 10, 5788 – 5794
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5793

V. Gotor, F. Rebolledo, and J. Gonzµlez-Sabín
FULL PAPER
128.07, 128.47, 130.03, 130.51, 130.86, 132.07, 135.66, 135.90, 169.30,
169.59 ppm; IR (neat): n˜ =1634 cmÀ1; MS (ESI+): m/z (%): 369.1 (100)
[M+H]+, 371.1 (65) [M+2+H]+, 373.1 (10) [M+4+H]+; elemental analy-
sis calcd (%) for C19H26Cl2N2O2: C 61.79, H 7.10, N 7.58; found: C 62.05,
H 7.19, N 7.46.
[4] a) J. Szmuszkovicz,
EP 126612, 1984; [Chem. Abstr. 1985, 102,
184969b]; b) C. R. Clark, P. R. Halfpenny, R. G. Hill, D. C. Horwell,
J. Hughes, T. C. Jarvis, D. C. Rees, D. Schofield, J. Med. Chem. 1988,
31, 831–836; c) G. F. Costello, R. James, J. S. Shaw, A. M. Slater,
N. C. J. Stutchbury, J. Med. Chem. 1991, 34, 181–189; d) J. J. Barlow,
T. P. Blackburn, G. F. Costello, R. James, D. J. Le Count, B. G. Main,
R. J. Pearce, K. Russell, J. S. Shaw, J. Med. Chem. 1991, 34, 3149–
3158.
Determination of the enantiomeric excesses: The enantiomeric excess for
each optically active compound isolated from the enzymatic reactions
was determined by chiral HPLC. The following compounds were directly
analyzed: Acetamides 6d, 6e, and 6g were analyzed by using a Chiral-
cel OD column. The resolution is given by Rs. For (Æ)-6d: tR =18.7
(1R,2R) and 20.9 min (1S,2S), Rs =1.5 (hexane/propan-2-ol (95:5),
0.8 mLminÀ1, 208C). For (Æ)-6e: tR =21.1 (1R,2R) and 24.3 min (1S,2S),
Rs =1.9 (hexane/propan-2-ol (88:12), 0.8 mLminÀ1, 358C). For (Æ)-6g:
tR =9.9 (1S,2S) and 11.9 min (1R,2R), Rs =2.3 (hexane/propan-2-ol
(90:10), 0.8 mLminÀ1, 208C). Carbamates 7a–c were analyzed by using a
Chiralcel OD-RH column. For (Æ)-7a: tR =7.5 (1R,2R) and 9.1 min
[5] a) A. Cowan, D. E. Gmerek, Trends Pharmacol. Sci. 1986, 7, 69–72;
b) M. J. Millan, Trends Pharmacol. Sci. 1990, 11, 70–76.
[6] a) B. R. De Costa, W. D. Bowen, S. B. Hellewell, C. George, R. B.
Rothman, A. A. Reid, J. M. Walker, A. E. Jacobson, K. C. Rice, J.
Med. Chem. 1989, 32, 1996–2002; b) B. R. De Costa, W. D. Bowen,
A. Thurkauf, D. T. Finn, S. Vazirani, R. B. Rothman, L. Band, P. C.
Contreras, N. M. Gray, J. Med. Chem. 1990, 33, 3100–3110.
[7] a) S. Hanessian, D. Delorme, S. Beaudoin, Y. Leblanc, J. Am. Chem.
Soc. 1984, 106, 5754–5756; b) A. Alexakis, S. Mutti, P. Mangeney, J.
Org. Chem. 1992, 57, 1224–1237; c) Y. L. Bennani, S. Hanessian,
Tetrahedron 1996, 52, 13837–13866; d) A. Alexakis, A.-S. Chauvin,
R. Stouvenel, E. Vrancken, S. Mutti, P. Mangeney, Tetrahedron:
Asymmetry 2001, 12, 1171–1178.
[8] M. Kaik, J. Gawronski, Tetrahedron: Asymmetry 2003, 14, 1559–
1563, and references therein.
[9] a) P. OꢁBrien, P. Poumellec, Tetrahedron Lett. 1996, 37, 5619–5622;
b) E. Curthbertson, P. OꢁBrien, T. D. Towers, Synthesis 2001, 693–
695.
[10] a) M. Mousseron, J. Jullien, Y. Jolchine, Bull. Soc. Chim. Fr. 1952,
19, 757–766; b) J. Gonzµlez-Sabín, V. Gotor, F. Rebolledo, Tetrahe-
dron: Asymmetry 2004, 15, 1335–1341.
[11] For some applications of aziridinium ions in synthesis, see: a) M.
Couturier, J. L. Tucker, B. M. Andresen, K. M. DeVries, B. C. Van-
derplas, F. Ito, Tetrahedron: Asymmetry 2003, 14, 3517–3523;
b) D. G. Piotrowska, A. E. Wróblewski, Tetrahedron 2003, 59, 8405–
8410; c) D. R. Andrews, V. H. Dahanukar, J. M. Eckert, D. Gala,
B. S. Lucas, D. P. Schumacher, I. A. Zavialov, Tetrahedron Lett. 2002,
43, 6121–6125; d) T.-H. Chuang, K. B. Sharpless, Org. Lett. 2000, 2,
3555–3557.
[12] For some recent reviews, see: a) F. Van Rantwijk, R. A. Sheldon,
Tetrahedron 2004, 60, 501–519; b) I. Alfonso, V. Gotor, Chem. Soc.
Rev. 2004, 33, 201–209; c) E. M. Anderson, K. M. Larsson, O. Kirk,
Biocatal. Biotransform. 1998, 16, 181–204.
(1S,2S), Rs =2.4 (0.5m aq NaClO4/acetonitrile (50:50), 0.4 mLminÀ1
,
208C). For (Æ)-7b: tR =9.7 (1R,2R) and 13.2 min (1S,2S), Rs =2.9 (0.5m
aq NaClO4/acetonitrile (50:50), 0.4 mLminÀ1, 208C). For (Æ)-7c: tR =8.5
(1R,2R) and 11.6 min (1S,2S), Rs =4.0 (0.5m aq NaClO4/acetonitrile
(30:70), 0.4 mLminÀ1, 208C). Carbamates 7d and 7 f were analyzed by
using a Chiralcel OD column (hexane/propan-2-ol (90:10), 0.8 mLminÀ1
,
208C). For (Æ)-7d: tR =8.5 (1R,2R) and 14.5 min (1S,2S), Rs =7.3. For
(Æ)-7 f: tR =5.9 (1R,2R) and 6.8 min (1S,2S), Rs =1.9.
Amine 4g was transformed into the acetamide 6g by conventional treat-
ment with acetyl chloride (1.2 equiv) and 4-dimethylaminopyridine
(1.0 equiv) in dichloromethane (>95% yield). Acetamides 6a–c and 6 f
were hydrolyzed (3n aq NaOH, reflux, 12 h, 93–95% yield), and the re-
sulting amines 4a–c and 4 f were transformed into the corresponding car-
bamates. Carbamate 7e was treated with H2 and Pd/C in methanol, and
the resulting amine 4e was transformed into the acetamide 6e.
Acknowledgement
We thank Novo Nordisk Co. for the generous gift of the CAL-B. This
work was supported by grants from MCYT (Spain; Project PPQ-2001–
2683) and the Principado de Asturias (Spain; Project GE-EXP01–03).
J. G.-S. is grateful to the Spanish MEC for a predoctoral fellowship.
[13] a) I. Alfonso, C. Astorga, F. Rebolledo, V. Gotor, Chem. Commun.
1996, 2471–2472; b) I. Alfonso, F. Rebolledo, V. Gotor, Chem. Eur.
J. 2000, 6, 3331–3338.
[14] C. S. Chen, Y. Fujimoto, G. Girdaukas, C. J. Sih, J. Am. Chem. Soc.
1982, 104, 7294–7299.
[15] B. De Costa, C. George, R. B. Rothman, A. E. Jacobson, K. C. Rice,
FEBS Lett. 1987, 223, 335–339.
[16] R. J. Kazlauskas, A. N. E. Weissfloch, A. T. Rappaport, L. A.
Cuccia, J. Org. Chem. 1991, 56, 2656–2665.
[1] For some reviews, see: a) F. Fache, E. Schulz, M. L. Tommasino, M.
Lemaire, Chem. Rev. 2000, 100, 2159–2231; b) D. Lucet, T. Le Gall,
C. Mioskowski, Angew. Chem. 1998, 110, 2724–2772; Angew. Chem.
Int. Ed. 1998, 37, 2580–2627; c) Y. L. Bennani, S. Hanessian, Chem.
Rev. 1997, 97, 3161–3195. For some recent applications, see: d) T.
Olszewska, M. Gdaniec, T. Po-lonski, J. Org. Chem. 2004, 69, 1248–
1255; e) E. M. McGarrigle, D. M. Murphy, D. G. Gilheany, Tetrahe-
dron: Asymmetry 2004, 15, 1343–1354; f) M. S. Taylor, E. N. Jacob-
sen, J. Am. Chem. Soc. 2003, 125, 11204–11205.
[2] E. T. Michalson, J. Szmuszkovicz, Prog. Drug Res. 1989, 33, 135–
149.
[3] J. Szmuszkovicz, P. F. Von Voigtlander, J. Med. Chem. 1982, 25,
1125–1126.
Received: June 16, 2004
Published online: October 7, 2004
5794
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5788 – 5794