Enzyme-catalysed kinetic resolution of N,O-diacetyl derivatives of cyclic 1,3-amino alcohols

Article abstract of DOI:10.1016/S0957-4166(01)00318-4

Racemates of N,O-diacetyl derivatives of cis- and trans-2-aminomethylcyclopentanols 5 and 6 and cis- and trans-2-aminomethylcyclohexanols 7 and 8 were resolved through lipase-catalysed asymmetric O-deacylation at the (1R) stereogenic centre. The gram-scal

Full text of DOI:10.1016/S0957-4166(01)00318-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1881–1886
Enzyme-catalysed kinetic resolution of N,O-diacetyl derivatives
of cyclic 1,3-amino alcohols
Judit Ka´ma´n, Eniko3 Forro´ and Ferenc Fu¨lo¨p*
Institute of Pharmaceutical Chemistry, University of Szeged, PO Box 121, H-6701 Szeged, Hungary
Received 13 June 2001; accepted 11 July 2001
Abstract—Racemates of N,O-diacetyl derivatives of cis- and trans-2-aminomethylcyclopentanols 5 and 6 and cis- and trans-2-
aminomethylcyclohexanols 7 and 8 were resolved through lipase-catalysed asymmetric O-deacylation at the (1R) stereogenic
centre. The gram-scale resolutions of 5–8 were carried out with ethanol in di-iso-propyl ether in the presence of Novozym 435.
The unreacted N,O-diacetyl compounds 5a–8a were transformed to the corresponding alcohols 5c–8c without loss of enantio-
purity. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
ric acylation of the alcohol function of the N-protected
compound is practical,11,12 because the hydroxy group
is attached directly to the stereogenic centre. Another
efficient method is to prepare the N,O-diacetyl deriva-
tive and investigate the enzyme-catalysed O-deacylation
in the presence of water13 or alcohol.14
Many 1,2- and 1,3-amino alcohols play important roles
in the synthesis of pharmacologically active com-
pounds.1–4 For this reason, and because of the wide
variety of their possible transformations and applica-
tions,5–8 their preparation in enantiomerically pure
form is very important.
On the basis of our earlier studies on the resolution of
cyclic 1,3-amino alcohols,9,10 we decided to investigate
the enzyme-catalysed kinetic resolution of cis- and
trans-2-aminomethylcyclopentanols and cis- and trans-
2-aminomethylcyclohexanols 1–4. Since these com-
pounds have two functional groups, there are several
possibilities for their resolution. For example, asymmet-
2. Results and discussion
The aim of our present work was to establish appropri-
ate conditions for the resolution of 5–8 (Scheme 1). In
order to find the optimal conditions for the gram-scale
resolutions of these compounds, the effects of enzyme,
alcohol, solvent and temperature on the enantioselectiv-
Scheme 1.
* Corresponding author. Tel.: 36 62 545564; fax: 36 62 545705; e-mail: fulop@pharma.szote.u-szeged.hu
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00318-4

1882
J. Ka´ma´n et al. / Tetrahedron: Asymmetry 12 (2001) 1881–1886
ity ratio (E) and the reaction rate were investigated.
The excellent result reported for the resolution of the
N,O-diacetyl derivative of cis-1-amino-2-indanol
through lipase-catalysed O-deacylation in organic
media14 prompted us to start our experiments with
Novozym 435 at 45°C. The model compound for pre-
liminary experiments was ( )-trans-N,O-diacetyl-2-
aminomethylcyclohexanol 8.
Since the ideal working temperature for Novozym 435
is 60°C, some preliminary experiments were carried out
at this temperature. The reaction rate increased slightly,
with no change in the E value (Table 1, rows 8 and 10).
When the amount of ethanol was decreased to 4 mL
mL−1 (about 6–7 equiv. for the substrate), the reaction
time decreased markedly (Table 1, rows 12 and 13). For
reasons of economy, the amount of enzyme was
decreased (Table 1, rows 13–15); under the same reac-
tion conditions, the same good results were obtained
with 50 mg mL−1 of enzyme as with 100 mg mL−1.
Good enantioselectivity, but a very low reaction rate,
was observed when ( )-8 was deacetylated in n-BuOH
in the presence of Novozym 435 (50 mg mL−1) and the
mixture was shaken at 45°C (Table 1, row 1). In order
to decrease the reaction time, the Novozym-catalysed
alcoholysis of 8 with n-BuOH was tested in several
solvents: tetrahydrofuran, dioxan and di-iso-propyl
ether (Table 1, rows 2–4). The fastest reaction was
observed in di-iso-propyl ether. Besides Novozym 435
(lipase from Candida antartica B), lipase PS (Pseu-
domonas cepacia), as the enzyme most commonly used
for the resolution of secondary alcohols,15–18 was tested
under the same conditions (iso-Pr2O:n-BuOH=1:1, at
45°C). Surprisingly, there was no reaction after 72 h.
In conclusion, the best results for the enzymatic resolu-
tion of 8 were observed with Novozym 435 (50 mg
mL−1) in di-iso-propyl ether solvent and performing the
reaction at 60°C with ethanol as the acetyl acceptor.
When small-scale resolutions of 5–7 were carried out
under these conditions, to our surprise a low E value
(after 1 h, conv.=50%, e.e.s=77%, e.e.p=77%, E=17)
was observed in the case of 6. In order to obtain 6a and
6b with higher e.e., the enzymatic reaction was stopped
at 28% conversion (e.e.6a=92%), and the unreacted
enantiomerically enriched substrate was then subjected
to a further enzymatic resolution. This second resolu-
tion was overrun and afforded the enantiopure 6b
(e.e.6b=92%).
The rate of the enzymatic reaction could be increased
by increasing the amount of Novozym from 50 mg
mL−1 to 100 mg mL−1 (Table 1, rows 4 and 5). In
efforts to further decrease the reaction time, the
deacetylation agent n-BuOH was replaced with either
EtOH or MeOH. The data presented in Table 1 (rows
5–7), reveal that EtOH was the most favourable acetyl
acceptor for acceleration of the alcoholysis.
On the basis of the preliminary results, gram-scale
resolution of 5–8 were performed in di-iso-propyl ether
with Novozym 435 in the presence of ethanol, at 60°C.
The results are reported in Table 2 and in Section 3.
The unreacted N,O-diacetyl enantiomers 5a–8a were
alcoholysed to the corresponding alcohols 5c–8c in
K2CO3/MeOH at room temperature without loss of
enantiopurity (Scheme 2).
On increasing the temperature from 45 to 50°C, the
reaction rate was increased without a drop in enantiose-
lectivity (Table 1, rows 6 and 8). When the ratio of
organic solvent:alcohol was changed from 1:1 to 4:1, a
significant increase occurred in the reaction time (Table
1, rows 8 and 9).
The size of the cycloalkane ring had a marked effect on
the rate of enantioselective deacylation: the five-mem-
Table 1. Novozym 435-catalysed deacylation of 8 (0.1 M) in the presence of different alcohols in organic media at different
temperatures
Temp. (°C)
Novozym 435
Solvent
Time (h)
Conv. (%)
E.e.s (%)
E.e.p (%)
E
Row
(mg mL−1
)
45
45
45
45
45
50
50
50
50
100
n-BuOH
504
398
398
120
96
20
20
96
22
22
21
19
16
7
25
44
43
33
40
14
27
22
38
48
38
34
43
49
49
26
32
78
74
50
67
16
37
27
60
92
60
51
75
95
94
34
\99
\99
\99
\99
\99
\99
\99
\99
\99
\99
\99
\99
\99
\99
\99
\99
\200
\200
\200
\200
\200
\200
\200
\200
\200
\200
\200
\200
\200
\200
\200
\200
1
2
3
4
5
THF:n-BuOH (1:1)
Dioxan:n-BuOH (1:1)
iso-Pr2O:n-BuOH (1:1)
iso-Pr2O:n-BuOH (1:1)
45
45
50
50
60
60
60
60
60
60
100
100
100
100
100
75
75
75
50
25
iso-Pr2O:EtOH (1:1)
iso-Pr2O:MeOH (1:1)
iso-Pr2O:EtOH (1:1)
iso-Pr2O:EtOH (4:1)
iso-Pr2O:EtOH (1:1)
iso-Pr2O:EtOH (1:1)
iso-Pr2O:EtOH (4:1)
iso-Pr2O:EtOH (24:1)
iso-Pr2O:EtOH (24:1)
iso-Pr2O:EtOH (24:1)
6
7
8
9
10
11
12
13
14
15
7
7

Table 2. Novozym 435 (50 mg mL−1)-catalysed deacylation of 5–8 (0.1 M) in the presence of ethanol (0.04 mL mL−1) in di-iso-propyl ether at 60°C
/
Time (h)
Conv. (%)
E.e.5a–8a (%)
Isomer 5a–8a
Yielda (%)
[h]2D5
E.e.5b–8b (%)
Isomer 5b–8b
Yielda (%)
[h]2D5
E
5
6
7
8
28
51
98
97
92
98
1S,2S
1S,2R
1S,2S
1S,2R
88
23
87
95
+55.9b
+29.6c
+49.5b
+39.9b
96
92
92
99
1R,2R
1R,2S
1R,2R
1R,2S
83
30
91
86
−5.1b
\200
Resolution in two steps
624
9
−34.5d
−9.8b
−9.1b
50
50
78
\200
a Yield 100% at 50% conversion.
b c=0.8, MeOH.
1
(
c c=1.0, MeOH.
d c=0.95, MeOH.
188
8

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J. Ka´ma´n et al. / Tetrahedron: Asymmetry 12 (2001) 1881–1886
Optical rotations were measured with a Perkin–Elmer
1
341 polarimeter. H NMR spectra were recorded on a
Bruker Avance DRX 400 spectrometer. Melting points
were determined on a Kofler apparatus.
3.2. Preparation of N,O-diacetyl derivative of ( )-cis-2-
aminocyclopentanol ( )-5
Scheme 2.
cis-2-Aminocyclopentanol 1 (1 g, 8.68 mmol) was dis-
solved in pyridine (3 mL), and acetic anhydride (3.5
mL) was added. The solution was stirred at rt for one
night, and toluene (10 mL) was then added to the
mixture (in order to facilitate evaporation of pyridine).
The residue was chromatographed on silica. Elution
with toluene:acetone (9:1) afforded an oil of 5 (1.13 g,
5.68 mmol). 1H NMR (400 MHz, CDCl3) l (ppm):
1.33–1.90 (6H, m, 3×CH2), 1.96 (3H, s, CH3), 2.03–2.06
(1H, m, H-2), 2.07 (3H, m, CH3), 2.69–2.76 (1H, m,
CH2NHCOCH3), 3.65–3.72 (1H, m, CH2NHCOCH3),
5.23–5.25 (1H, m, H-1), 6.08 (1H, br, NH). Anal. calcd
for C10H17NO3: C, 60.28; H, 8.60; N, 7.03. Found: C,
60.03; H, 8.78; N, 7.09%.
bered amino alcohol derivatives 5 and 6 reacted faster
than the six-membered derivatives, 7 and 8. It was also
observed that the trans isomers 6 and 8 deacetylated
faster than the cis isomers 5 and 7.
2.1. Absolute configurations
On the basis of the Kazlauskas model for the active site
of the lipases,19,20 1R-selectivity was predicted for the
Novozym 435-catalysed deacetylation of 5–8. The
validity of this was proved in the case of 8b, which was
hydrolysed to the corresponding enantiomeric amino
alcohol hydrochloride. The value of [h]2D5=−26.7 (c 1.0,
H2O) obtained for the amino alcohol hydrochloride,
and the literature value for the (1R,2S)-trans-
aminomethylcyclohexanol hydrochloride [h]2D5=−27.1
(c 2, H2O),21 indicate the R selectivity of the enzyme, in
accordance with the Kazlauskas model. The (1R,2S)
configuration is therefore accepted for the produced
trans isomers 6b and 8b, and the (1R,2R) configuration
for the produced cis isomers 5b and 7b.
3.3. Preparation of N,O-diacetyl derivative of ( )-
trans-2-aminocyclopentanol ( )-6
Using the procedure described above, trans-2-aminocy-
clopentanol 2 (1.4 g, 12.17 mmol) afforded ( )-6 as a
1
colourless oil (1.81 g, 9.13 mmol). H NMR (400 MHz,
CDCl3) l (ppm): 1.18–2.08 (7H, m, 3×CH2 and H-2),
1.99 (3H, s, CH3), 2.05 (3H, s, CH3), 3.02–3.06 (1H, m,
CH2NHCOCH3), 3.27–3.32 (1H, m, CH2NHCOCH3),
4.81–4.84 (1H, m, H-1), 6.75 (1H, br, NH). Anal. calcd
for C10H17NO3: C, 60.28; H, 8.60; N, 7.03. Found: C,
60.65; H, 8.41; N, 6.93%.
3. Experimental
3.1. Materials and methods
3.4. Preparation of N,O-diacetyl derivative of ( )-cis-2-
The cis-2-aminomethylcycloalkanols 1 and 3 were
obtained by reduction of the corresponding 5,6-dihy-
dro-4H-1,3-oxazines.22 The reduction of trans-2-
cyanocycloalkanols resulted in the trans-2-amino-
methylcyclanols 2 and 4.21 n-Butanol was purchased
from Aldrich Co., and methanol and ethanol from
Reanal. Lipase PS was obtained from Amano Pharma-
ceuticals, and Novozym 435 as an immobilised prepara-
tion from NOVO Nordisk. Before use, lipase PS (5 g)
was dissolved in Tris–HCl buffer (0.02 M, pH 7.8) in
the presence of sucrose (3 g), followed by adsorption on
Celite (17 g, Sigma). The lipase preparations thus
obtained contained 20% (w/w) of lipase. All the sol-
vents were of the highest analytical grade. For column
chromatography, Merck silica gel 60/63–200 mesh was
used.
aminocyclohexanol ( )-7
With the procedure described above, cis-2-aminocyclo-
hexanol 3 (1 g, 7.74 mmol) afforded white crystals of
1
( )-7 (1.32 g, 6.19 mmol); mp 73–76°C. H NMR (400
MHz, CDCl3) l (ppm): 1.26–1.84 (9H, m, 4×CH2 and
H-2), 1.97 (3H, s, CH3), 2.11 (3H, m, CH3), 2.51–2.57
(1H, m, CH2NHCOCH3), 3.43–3.50 (1H, m,
CH2NHCOCH3), 5.12–5.13 (1H, m, H-1), 6.15 (1H, br,
NH). Anal. calcd for C11H19NO3: C, 61.95; H, 8.98; N,
6.57. Found: C, 61.65; H, 8.79; N, 6.73%.
3.5. Preparation of N,O-diacetyl derivative of ( )-
trans-2-aminocyclohexanol ( )-8
With the procedure described above, trans-2-aminocy-
clohexanol 4 (1 g, 7.74 mmol) afforded white crystals of
The e.e. values of the unreacted N,O-diacetyl analogues
5a–8a and the produced alcohols 5b–8b were deter-
mined by gas chromatography on a Chrompack CP-
Chirasil-DEX CB column (25 m). The produced
alcohols 5b–8b in the samples were derivatised with
propionic anhydride in the presence of 4-dimethyl-
aminopyridine and pyridine before the gas chromato-
graphic analysis.
1
( )-8 (1.28 g, 6.01 mmol; mp 94–97°C). H NMR (400
MHz, CDCl3) l (ppm): 1.12–1.96 (9H, m, 4×CH2 and
H-2), 1.96 (3H, s, CH3), 2.08 (3H, m, CH3), 2.93–2.96
(1H, m, CH2NHCOCH3), 3.51–3.56 (1H, m,
CH2NHCOCH3), 4.56–4.61 (1H, m, H-1), 5.85 (1H, br,
NH). Anal. calcd for C11H19NO3: C, 61.95; H, 8.98; N,
6.57. Found: C, 62.23; H, 8.83; N, 6.46%.

J. Ka´ma´n et al. / Tetrahedron: Asymmetry 12 (2001) 1881–1886
1885
1
3.6. General procedure for a typical small-scale
experiment
The H NMR (400 MHz, CDCl3) l (ppm) data for 6a
are similar to those for ( )-6. Anal. found: C, 60.45; H,
8.68; N, 7.13%.
Lipase PS (50 mg mL−1) or Novozym 435 (25, 50, 75 or
100 mg mL−1) was added to the appropriate N,O-
diacetyl derivative 5–8 (0.1 M solution) in organic sol-
vent: R1OH (1 mL) and the mixture was shaken at 30,
45, 50 or 60°C. The progress of the reaction was fol-
lowed by taking samples (0.1 mL) from the reaction
mixture at intervals and analysing them by gas
chromatography.
1H NMR (400 MHz, CDCl3) l (ppm) data for 6b: 1.23–
1.97 (7H, m, 3×CH2 and H-2), 1.99 (3H, s, CH3), 2.63
(1H, s, OH), 3.11–3.13 (1H, m, CH2NHCOCH3), 3.41–
3.46 (1H, m, CH2NHCOCH3), 3.84–3.86 (1H, m, H-1),
6.29 (1H, br, NH). Anal. calcd for C8H15NO2: C, 61.12;
H, 9.62; N, 8.91. Found: C, 61.01; H, 9.53; N, 8.98%.
On stirring in K2CO3/MeOH at rt, N,O-diacetyl
(1S,2R)-6a underwent quantitative deacylation within
3–4 h, resulting in the corresponding alcohol (1S,2R)-6c
3.7. Gram-scale resolution of ( )-5
1
( )-5 (0.7 g, 3.52 mmol) was dissolved in di-iso-propyl
ether (34 mL), Novozym 435 (1.76 g, 50 mg mL−1) and
ethanol (1.40 mL) were added, and the mixture was
shaken at 60°C for 28 h. The enzyme was filtered off at
51% conversion, and the solvent was evaporated. The
residue was chromatographed on silica, with elution
with toluene:acetone (9:1) affording the (1S,2S)-N,O-
diacetyl and (1R,2R)-N-acetyl compounds.
([h]2D5=+36.3 (c 0.5, MeOH), e.e.=97%). The H NMR
(400 MHz, CDCl3) l (ppm) data for 6c are similar to
those for 6b. Anal. found: C, 59.93; H, 9.70; N, 8.83%.
3.9. Gram-scale resolution of 7
Following the procedure described in Section 3.7, the
reaction of ( )-7 (0.6 g, 2.82 mmol) and ethanol (1.12
mL) in di-iso-propyl ether (27 mL) in the presence of
Novozym 435 (2.82 g, 100 mg mL−1) at 60°C afforded
the unreacted (1S,2S)-7a (0.26 g, 1.22 mmol; [h]2D5=
+49.5 (c 0.8, MeOH); e.e.=92%; mp 63–65°C) and N-
acetyl (1R,2R)-7b (0.22, 1.29 mmol; [h]2D5=−9.8 (c 0.8,
MeOH); e.e.=92%; mp 53–55°C) in 26 days.
(1S,2S)-5a was isolated as a colourless oil (0.31 g, 1.56
mmol); [h]2D5=+55.9 (c 0.8, MeOH); e.e.=98%). The 1H
NMR (400 MHz, CDCl3) l (ppm) data for 5a are simi-
lar to those for ( )-5. Anal. found: C, 59.92; H, 8.45; N,
6.81%.
The produced (1R,2R)-5b was obtained as a white crys-
talline product (0.23 g, 1.46 mmol); [h]2D5=−5.1 (c 0.8,
1
The H NMR (400 MHz, CDCl3) l (ppm) data for 7a
are similar to those for ( )-7. Anal. found: C, 61.69; H,
8.83; N, 6.75%.
1
MeOH); e.e.=96%; mp 91–94°C). H NMR (400 MHz,
CDCl3) l (ppm): 1.45–1.87 (7H, m, 3×CH2 and H-2),
2.01 (3H, s, CH3), 3.01–3.06 (1H, m, CH2NHCOCH3),
3.58–3.66 (1H, m, CH2NHCOCH3), 4.03–4.05 (2H, m,
H-1 and OH), 6.05 (1H, br, NH). Anal. calcd for
C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C, 61.38;
H, 9.45; N, 8.77%.
1H NMR (400 MHz, CDCl3) l (ppm) data for 7b: 1.25–
1.91 (9H, m, 4×CH2 and H-2), 2.01 (3H, m, CH3), 2.82–
2.85 (1H, m, CH2NHCOCH3), 3.47–3.57 (2H, m, OH
and CH2NHCOCH3), 3.78–3.81 (1H, m, H-1), 5.89 (1H,
m, NH). Anal. calcd for C9H17NO2: C, 63.13; H, 10.01;
N, 8.18. Found: C, 63.41; H, 10.13; N, 8.32%.
On stirring in K2CO3/MeOH at rt, N,O-diacetyl
(1S,2S)-5a underwent quantitative deacylation within
3–4 h, resulting in the corresponding alcohol (1S,2S)-5c
([h]2D51=+5.5 (c 0.63, MeOH); e.e.=98%; mp 97–100°C).
The H NMR (400 MHz, CDCl3) l (ppm) data for 5c
are similar to those for 5b. Anal. found: C, 61.35; H,
9.53; N, 8.79%.
On stirring in K2CO3/MeOH at rt, N,O-diacetyl
(1S,2S)-7a underwent quantitative deacylation within
3–4 h, resulting in the corresponding alcohol (1S,2S)-7c
([h]2D51=+10 (c 0.70, MeOH); e.e.=92%; mp 55–57°C).
The H NMR (400 MHz, CDCl3) l (ppm) data for 7c
are similar to those for 7b. Anal. found: C, 62.92; H,
10.09; N, 8.27%.
3.8. Gram-scale resolution of ( )-6
Following the procedure described above, the reaction
of ( )-6 (1.42 g, 7.03 mmol) and ethanol (2.86 mL) in di-
iso-propyl ether (68.9 mL) in the presence of Novozym
435 (3.55 g, 50 mg mL−1) at 60°C afforded the unreacted
(1S,2R)-6a as a colourless oil (0.78 g, 3.92 mmol; e.e.=
35%) and N-acetyl (1R,2S)-6b (0.20 g, 1.27 mmol;
[h]2D5=−34.5 (c 0.95, MeOH); e.e.=92%) in 40 min.
3.10. Gram-scale resolution of 8
Following the procedure described in Section 3.7, the
reaction of ( )-8 (0.6 g, 2.82 mmol) and ethanol (1.12
mL) in di-iso-propyl ether (27 mL) in the presence of
Novozym 435 (1.41 g, 50 mg mL−1) at 60°C afforded the
unreacted (1S,2R)-8a (0.28 g, 1.33 mmol; [h]2D5=+39.9 (c
0.8, MeOH); e.e.=98%; mp 117–119°C) and N-acetyl
(1R,2S)-8b (0.21, 1.21 mmol; [h]2D5=−9.1 (c 0.8, MeOH);
e.e.=99%; mp 94–95°C) in 9 h.
The unreacted 6a (0.78 g, 3.92 mmol; e.e.=35%) was
subjected to a second enzymatic resolution. The reaction
in di-iso-propyl ether (38.8 mL) with ethanol (1.6 mL)
and Novozym 435 (2 g, 50 mg mL−1) at 60°C afforded
the unreacted (1S,2R)-6a as an oil (0.21 g, 1.05 mmol;
[h]2D5=+29.6 (c 1.0, MeOH); e.e.=97%) in 2.5 h.
1
The H NMR (400 MHz, CDCl3) l (ppm) data for 8a
are similar to those for ( )-8. Anal. found: C, 62.13; H,
8.87; N, 6.69%.

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J. Ka´ma´n et al. / Tetrahedron: Asymmetry 12 (2001) 1881–1886
1H NMR (400 MHz, CDCl3) l (ppm) data for 8b:
1.06–1.98 (9H, m, 4×CH2 and H-2), 2.01 (3H, m, CH3),
2.79–2.85 (1H, m, CH2NHCOCH3), 3.15–3.22 (1H, m,
CH2NHCOCH3), 3.77–3.92 (2H, m, OH and H-1), 6.13
(1H, m, NH). Anal. calcd for C9H17NO2: C, 63.13; H,
10.01; N, 8.18. Found: C, 62.97; H, 10.11; N, 8.03%.
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Chem. 1998, 69, 349.
On stirring in K2CO3/MeOH at rt, the (1S,2R)-N,O-
diacetyl compound 8a underwent quantitative deac-
ylation within 3–4 h, resulting in the corresponding
alcohol (1S,2R)-8c ([h]2D51=+9.5 (c 0.98, MeOH); e.e.=
98%; mp 88–90°C). The H NMR (400 MHz, CDCl3) l
(ppm) data for 8c are similar to those for 8b. Anal.
found: C, 63.22; H, 10.09; N, 8.12%.
5. Szakonyi, Z.; Martinek, T.; Hete´nyi, A.; Fu¨lo¨p, F. Tetra-
hedron: Asymmetry 2000, 11, 4571.
6. Zhao, H.; Thurkauf, A. Synlett 1999, 1280.
7. Yu, Z.; Lopez-Calahorra, F.; Velasco, D. Tetrahedron:
Asymmetry 2000, 11, 3221.
8. Agami, C.; Dechoux, L.; Hamon, L.; Melaimi, M. J. Org.
Chem. 2000, 65, 6666.
9. Pe´ter, M.; Van der Eycken, J.; Berna´th, G.; Fu¨lo¨p, F.
Tetrahedron: Asymmetry 1998, 9, 1.
3.11. Preparation of (1R,2S)-trans-2-aminocyclohex-
anol hydrochloride
10. Ka´ma´n, J.; Van der Eycken, J.; Pe´ter, A.; Fu¨lo¨p, F.
(1R,2S)-8b (0.2 g, 1.17 mmol) was dissolved in 6N HCl
(3 mL). The solution was stirred under reflux for 5 h,
and the solvent was then evaporated down. Recrystalli-
sation of the crude product from ethanol/diethyl ether
afforded white crystals of (1R,2S)-4·HCl (0.15 g, 9.06
mmol; [h]2D5=−26.7 (c 1.0, H2O); e.e.=99%; mp 150°C).
1H NMR (400 MHz, D2O) l (ppm) data for (1R,2S)-
4·HCl: 1.04–1.94 (9H, 4×CH2 and H-2), 2.91–2.96 (1H,
CH2NH2), 3.16–3.21 (1H, CH2NH2), 3.43–3.44 (1H, m,
H-1). Anal. calcd for C7H16ClNO: C, 50.75; H, 9.74;
Cl, 21.40; N, 8.45. Found: C, 50.86; H, 9.69; Cl, 21.33;
N, 8.41%.
Tetrahedron: Asymmetry 2001, 12, 625.
11. Maestro, A.; Astorga, C.; Gotor, V. Tetrahedron: Asym-
metry 1997, 8, 3153.
12. Luna, A.; Astorga, C.; Fu¨lo¨p, F.; Gotor, V. Tetrahedron:
Asymmetry 1998, 9, 4483.
13. La¨ıb, T.; Ouazzani, J.; Zhu, J. Tetrahedron: Asymmetry
1998, 9, 169.
14. Anilkumar, A. T.; Goto, K.; Takahashi, T.; Ishizaki, K.;
Kaga, H. Tetrahedron: Asymmetry 1999, 10, 2501.
15. Forro´, E.; Lundell, K.; Fu¨lo¨p, F.; Kanerva, L. T. Tetra-
hedron: Asymmetry 1997, 8, 3095.
16. Forro´, E.; Fu¨lo¨p, F. Tetrahedron: Asymmetry 1999, 10,
1985.
17. Forro´, E.; Szakonyi, Z.; Fu¨lo¨p, F. Tetrahedron: Asymme-
Acknowledgements
try 1999, 10, 4619.
18. Forro´, E.; Kanerva, L. T.; Fu¨lo¨p, F. Tetrahedron: Asym-
metry 1998, 9, 513.
19. Kazlauskas, R. J.; Weisfloch, A. N. E.; Rappaport, A. T.;
Cuccia, L. A. J. Org. Chem. 1991, 56, 2656.
20. Cygler, M.; Grochulski, P.; Kazlauskas, R. J.; Schrag, J.
D.; Bouthillier, F.; Rubin, B.; Serreqi, A. N.; Gupta, A.
K. J. Am. Chem. Soc. 1994, 116, 3180.
The authors would like to thank the OTKA (grant nos.
T 030452 and T 034901), and the FKFP (grant 0115/
2001) for financial support.
References
21. Fu¨lo¨p, F.; Huber, I.; Berna´th, G.; Ho¨nig, H.; Seufer-
Wasserthal, P. Synthesis 1991, 43.
22. Fu¨lo¨p, F.; Simon, L.; Simon-Talpas, G.; Berna´th, G.
Synth. Commun. 1998, 12, 2303.
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