Methyl-substituted trans-1,2-cyclohexanediamines as new ligands for oxaliplatin-type complexes

Article abstract of DOI:10.1016/j.tet.2007.10.069

Three different pathways for the synthesis of substituted trans-(±)-1,2-cyclohexanediamines as new ligands for oxaliplatin-type compounds are presented. The different synthetic routes lead (i) by the synthesis of the compound via ortho-bromination of a su

Full text of DOI:10.1016/j.tet.2007.10.069

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 137e146
www.elsevier.com/locate/tet
Methyl-substituted trans-1,2-cyclohexanediamines as new
ligands for oxaliplatin-type complexes
a,y
Ladislav Habala a, Claudia Dworak a, Alexey A. Nazarov a, , Christian G. Hartinger ,
*
Sergey A. Abramkin a, Vladimir B. Arion a, Wolfgang Lindner b, Markus Galanski a,
,
*
Bernhard K. Keppler a
a Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria
b Institute of Analytical Chemistry, University of Vienna, Waehringer Strasse 38, A-1090 Vienna, Austria
Received 22 August 2007; received in revised form 12 October 2007; accepted 19 October 2007
Available online 22 October 2007
Abstract
Three different pathways for the synthesis of substituted trans-(ꢀ)-1,2-cyclohexanediamines as new ligands for oxaliplatin-type compounds
are presented. The different synthetic routes lead (i) by the synthesis of the compound via ortho-bromination of a substituted cyclohexanone
followed by reaction with hydroxylamine and reduction by hydrogen, (ii) by addition of azide to cyclohexene mediated by manganese(III)
acetate and reduction by hydrogen, or (iii) by trans-dihydroxylation of cyclohexene, and subsequent conversion into the respective mesylate
or tosylate, followed by substitution by azide, and reduction in the case of 4-methyl-trans-(ꢀ)-1,2-cyclohexanediamine to a preferentially equa-
torially, mainly axially, or exclusively equatorially or axially oriented 4-methyl group, respectively.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
one of the isomers were found to be advantageous for pharma-
ceutical purposes, when only one isomer is active or has ad-
vantageous pharmacological properties in contrast to the
other, which causes adverse effects.11
Vicinal diamines are compounds of great importance in
chemical and biological processes, e.g., as chiral auxiliaries,
as metal ligands in catalytic asymmetric synthesis, or in the
synthesis of the anticancer drug oxaliplatin.1,2 Biotin (vitamin
H),3 peptidic antibiotics,4,5 bleomycins,6 antitumor agents,7e9
or the anti-avian influenza drug Tamiflu10 contain as an impor-
tant structural element the diamine function.
Chirality is one of the main features of biology and many of
the processes essential for life are stereospecificdtherefore
one out of two or more isomers works best in a particular
physiological situation. The isolation and application of only
(1R,2R)-1,2-Cyclohexanediamine [(1R,2R)-chxn] is the
non-leaving group in the recently worldwide approved anti-
cancer drug oxaliplatin [(SP-4-2)-{[(1R,2R)-1,2-cyclohexane-
diamine-k2N,N0][ethanedioato(2-)-k2O1,O2]platinum(II)}]. For
oxaliplatin and its closest analogs with the (1S,2S )- and
(1R,2S )-chxn ligands, the following order of activity for the
platinum(II) compounds was found in studies on the struc-
tureeactivity relationships in vitro and in vivo: (1R,2R)-chxn
(trans-isomer)>(1S,2S)-chxn (trans-isomer)>(1R,2S)-chxn (cis-
isomer).12e19 The advantage of using the (1R,2R)-chxn isomer
was found to be even more marked in cells with acquired
resistance to cisplatin.15e17,19 This enhancement of activity
when compared to that of the cis-isomer could be explained
by a favored binding of complexes with trans-oriented
amino-groups to DNA. In complexes with trans-chxn ligands,
the platinum center and the cyclohexane ring are almost
* Corresponding authors. Tel.: þ43 1 4277 52609; fax: þ43 1 4277 52680.
E-mail addresses: alex.nazarov@univie.ac.at (A.A. Nazarov), markus.
galanski@univie.ac.at (M. Galanski).
y
´
´
Current address: Laboratoire de Chimie Organometallique et Medicinale,
´
Institut des Sciences et Ingenierie Chimiques, Ecole Polytechnique Federale
de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
´ ´
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.069

138
L. Habala et al. / Tetrahedron 64 (2008) 137e146
(ESI-MS) detection of selectively functionalized compounds,
as well as by NMR spectroscopy.
2. Results and discussion
Figure 1. ORTEP plot of the molecular structures of oxaliplatin (left, adopted
from Ref. 24) and the analogous complex with the cis-chxn ligand (right,
adopted from Ref. 25) drawn at 50% probability level (ORTEP-3 for Win-
dows; hydrogen atoms are omitted for clarity).
For the synthesis of mono-, di-, and tetramethyl-substituted
1,2-cyclohexanediamines 4aIeIII, 4b, and 4c, respectively,
with exclusively trans-oriented amino-groups three reaction
pathways were evaluated. (i) The corresponding methyl-
substituted cyclohexanones 1aec can be converted into the
a-bromo-ketones followed by reaction with hydroxylamine
and generation of oximes, which can be reduced by hydrogen
(sodium/ethanol) to the diamines 4aI, 4b, and 4c (see Fig. 2).
(ii) The substituted cyclohexenes are transformed via an addi-
tion reaction with sodium azide in the presence of mangane-
se(III) m3-oxo acetate into the diazides, and then reduced to
the diamines (see Fig. 3, 5/9aII/4aII). (iii) The cyclohex-
enes are converted into the diazides via vicinal diols and the
corresponding mesylates or tosylates as main products [see
Fig. 3, 5/6/7 (8)/9aIII/4aIII].
coplanar, while in the cis-isomer they are nearly perpendicular
(Fig. 1) and lead to steric hindrance of DNA binding.20e23
The majority of oxaliplatin analogs was obtained by replac-
26e30
ing the oxalato ligand by other carboxylic acids
and did
not involve derivatization of the cyclohexane ring. The attach-
ment of a substituent to the cyclohexane ring results in the for-
mation of a third chiral center. This leads in turn to an
additional pair of diastereomers for the cis- and trans-isomer.
In order to simplify the separation work, there is need for a se-
lective synthetic procedure to introduce an amine functionality
to the cyclohexane ring and for a suitable method for the anal-
ysis of stereoisomeric mixtures.
In this study, three different synthetic pathways with differ-
ent directing capabilities for methyl substituents are reported
in order to obtain substituted trans-1,2-diaminocyclohexanes
as ligands for new oxaliplatin-type coordination compounds.
The ratio between the different isomers was determined by
liquid chromatography with ultravioletevisible (UVevis)
spectroscopy and electrospray ionization-mass spectrometry
2.1. Pathway I
Following pathway I the conversion of cyclohexanones
1aec into a-bromo-ketones was performed by reaction with
bromine in aqueous acetic acid. The a-bromo-ketones were
found to be of different stability: 2-bromo-4-methylcyclohex-
anone 2a (slightly yellow liquid) is significantly more stable
than the solid compounds 2-bromo-4,4-dimethylcyclohexa-
none 2b and 2-bromo-3,3,5,5-tetramethylcyclohexanone 2c
(decomposition at room temperature occurs already in 1e2 h
accompanied by changing color from white to orange).
In the next step, compounds 2aec were reacted with
hydroxylamine to give the corresponding vicinal dioximes
3aec, which can be isolated from the reaction mixture by
extraction with aromatic hydrocarbons. The trans-configured
diamines 4aIec were obtained by reduction of the dioximes
3aec by hydrogen (Na/EtOH). The diamines were isolated
as sulfates (4aI, 4b), as L-mandelates (4aI, 4b), and as chlo-
rides (4c). 4,4-Dimethyl-trans-(ꢀ)-1,2-cyclohexanediamine
4b was isolated as both sulfate and L-mandelate but the latter
was chosen for further studies because of the higher yield and
purity of the product.
R1
R1
R2
R3
R4
R2
R3
R4
Br2
NH2OH·HCl
CH3COONa
O
O
CH3COOH
R5
R5
Br
R6
2a–c
R6
1a–c
R1
R1
R2
R3
R4
R2
R3
R4
Na / EtOH
N
OH
NH2
R5
R5
N
OH
NH2
R6
3a–c
R6
4aI–c
a
R1=R2=R3=R5=R6=H, R4=CH3
R1=R2=R5=R6=H, R3=R4=CH3
R1=R2=R5=R6=CH3, R3=R4=H
b
c
Figure 2. Synthesis of trans-(ꢀ)-1,2-cyclohexanediamines via pathway I.
Mn3O(CH3COO)7
Pd / CaCO3
H3C
H3C
N3
H3C
NH2
NaN3
H2 (3 bar)
N3
NH2
4aII or 4aIII
9aII or 9aIII
5
H2O2
HCOOH
NaN3
MsCl (TsCl)
Py
H3C
OH
OH
H3C
OMs (OTs)
OMs (OTs)
7 (8)
6
Figure 3. Synthetic pathways II (5/9aII/4aII) and III [5/6/7 (8)/9aIII/4aIII] to obtain 4-methyl-trans-(ꢀ)-1,2-cyclohexanediamine.

L. Habala et al. / Tetrahedron 64 (2008) 137e146
139
All diamines synthesized by this method are racemic mix-
tures with exclusively trans-configured amino-groups. The
amine 4aI was obtained as a diastereomeric mixture with the
4-methyl substituent being in equatorial or axial position
with a ratio of ca. 90:10% (HPLC and NMR) in the case of
the sulfate and of ca. 98:2% if the optically active L-mandelic
acid was employed for isolation and the product was recrystal-
lized from an ethanol/diethyl ether mixture. By applying this
synthetic pathway, mainly the thermodynamically most stable
form with the 4-methyl group in equatorial position was
obtained.
2.2. Pathway II
Figure 4. The structure of the tosylate 8 modeled with the ratio of SOF for C11
and C110 of 0.5:0.5.
In contrast to pathway I, the following synthetic procedure
leads to 4-methyl-trans-(ꢀ)-1,2-cyclohexanediamine with the
methyl substituent preferentially in axial position with a ratio
of 88:12% according to HPLC and NMR analyses.
positions with SOF as 0.5:0.5, which are related through
a two-fold rotation axis.
The mesylated or tosylated product was converted, by anal-
ogy to pathway II, into the diazide 9aIII and then reduced to
4aIII. The pure amine was isolated as in the case of 4aII as di-
aminium sulfate. This type of reaction via the tosylate or the
mesylate leads to an inversion of the chiral centers in 1- and
2-position (in those mean products the methyl group is in an
equatorial position and the OTs or OMs groups are axially ori-
ented), while via pathway II no inversion step is part of the
synthetic scheme. Therefore, in that case the mainly axially ar-
ranged product is obtained while by using the synthetic proce-
dure described in pathway III the equatorially substituted
product is isolated.
The synthesis started from 4-methylcyclohexene 5, which
was converted into the diazide 9aII by reaction with sodium
azide in the presence of Mn3O(CH3COO)7.31,32 In the next
step the azide was reduced with hydrogen at 3 bar in the pres-
ence of Pd to the diamine 4aII. The diastereomeric mixture of
4-methyl-trans-(ꢀ)-1,2-cyclohexanediamines was isolated as
the respective diaminium sulfates. Addition of L-mandelic
acid and recrystallization from an ethanol/diethyl ether mix-
ture was applied for increasing the yield of the axial isomer.
However, the isomeric ratio changed to 80:20%, and further
decreased upon a second recrystallization step. The isomer
with an axial methyl group with maximal purity (98%) was
obtained from (4S )-4-methylcyclohexene, which was synthe-
sized from commercially available (S )-(ꢁ)-citronellal
(98%).33
2.4. Synthesis of cis-configured 1,2-cyclohexanediamines
Only one way for the synthesis of cis-configured 1,2-cyclo-
hexanediamines was reported in the literature so far. The 1,2-
cyclohexanedicarboxylic acid anhydride was hydrolyzed in
aqueous solution with sulfuric acid yielding the respective di-
acid, which was then converted into the diamine via an SN2
reaction of the diazide intermediate. This pathway yields ex-
clusively cis-configured diamines and was used for prepara-
tion of several representatives of this family of compounds
(see Fig. 5 for the 4-methyl derivative).34e36
2.3. Pathway III
Only a pair of enantiomers of the diamine 4aIII with the 4-
methyl group exclusively in equatorial position was obtained
by modification of the synthetic pathway II: in a first step 4-
methylcyclohexene 5 was trans-dihydroxylated with H2O2/
HCOOH with formation of the vicinal diol 6, which was
isolated as the (1S,2S,4R)- and (1R,2R,4S )-enantiomers by
recrystallization. Reaction with methanesulfonyl chloride or
p-toluenesulfonyl chloride gave the mesyl- and tosyl-deriva-
tive 7 and 8, respectively. An X-ray diffraction quality single
crystal of 4-methyl-O,O0-di( p-toluenesulfonate)-trans-(ꢀ)-
1,2-cyclohexanediol 8 was obtained by slow crystallization
from a n-hexane/2-propanol mixture (9:1). Product 8 crystal-
lized as a mixture of enantiomers in the monoclinic centro-
symmetric space group S2/c. The result of the X-ray
diffraction study is shown in Figure 4 and bond lengths and
angles of 8 are given in Table S1 (Supplementary data). The
cyclohexane ring adopts chair conformation with the two
OTs-groups in axial and the methyl group in equatorial posi-
tions. The refinement of this structure revealed that 8 as
a whole is statistically disordered over two resolvable
2.5. Characterization by NMR
For compounds 4aI and 4aII two sets of resonances were
found in the 13C NMR spectrum due to the stereochemistry
of the methyl group in trans-(ꢀ)-1,2-cyclohexanediaminium
sulfate at the C-4 atom, while applying pathway III leads to
only one set of resonances. As a consequence of the equatorial
position of the 4-methyl group, the 13C resonances of C-1 and
C-2 (both CHeNH2 groups) at 52.4 and 52.5 ppm, respec-
tively, were shifted similarly. However, in the case of an axi-
ally oriented 4-methyl group (minor isomer via pathway I
and main product via pathway II) the chemical shifts for

140
L. Habala et al. / Tetrahedron 64 (2008) 137e146
O
COOH
NH2
NH2
H2O, H2SO4
H2SO4, NaN3
O
H3C
H3C
COOH
H3C
O
Figure 5. Synthetic pathway to 4-methyl-cis-(ꢀ)-1,2-cyclohexanediamine.
R1
R6
C-1 and C-2 (48.7 and 51.2 ppm) show a marked difference
(see Fig. 6).
R2
R3
R4
R1
R2
R3
R4
ClC(O)OCH2Ph
NEt3
CBz
NH
NH2
NH2
Contrary, in the case of 4-methyl-cis-(ꢀ)-1,2-cyclohexane-
diamine, the resonances for C-1 and C-2 of the equatorially-
and axially-substituted derivatives were found between 48.7
and 51.1 ppm. Consequently, these resonances are well sepa-
rated from those of the trans-analogs, allowing to distinguish
between the cis- and trans-isomer.
R5
R5
HN CBz
R6
10a–c
4a–c
a R1=R2=R3=R5=R6=H, R4=CH3
b R1=R2=R5=R6=H, R3=R4=CH3
c R1=R2=R5=R6=CH3, R3=R4=H
Homonuclear decoupling experiments have been performed
in order to receive further stereochemical information about
the carbon atoms 1, 2, and 4. When equatorial protons H-3
and H-6 were irradiated, residual multiplets for protons H-1
and H-2 with two vicinal coupling constants of 11 Hz were
found clearly confirming the axial position of both protons
(trans-configuration at C-1 and C-2). Analogously, the config-
uration at C-4 was determined via irradiation in the methyl
resonance.
For analogs 4b and 4c, both trans-configuration and equato-
rial arrangement of the amino functionality are indicated by
the coupling constants of H-1 and H-2 signals (ca. 11 Hz),
respectively.
Figure 7. Synthesis of derivatized diamines equipped with an UVactive group.
preferentially in equatorial (4aI) and in axial (4aII), or exclu-
sively in equatorial position (4aIII). Prior to the reaction with
benzyloxycarbonylchloride in the presence of triethylamine,
the amines were recovered from their stable salts by dissolu-
tion in NaOH solution (5 M). Single crystals of 10a and 10c
suitable for X-ray diffraction study were obtained by recrystal-
lization from methanol (see Figs. 8 and 9, respectively; for
crystallographic data see Table 1). Bond lengths and angles
for 10a and 10c are given in Tables S3 and S5 (Supplementary
data). The CBz-diamines 10a and 10c crystallize in the tri-
clinic centrosymmetric space group P-1. The cyclohexane
ring in compounds 10a and 10c has a chair conformation.
Determination of the ratios between the different isomers
was done by HPLC on a Chiralcel OD column at 5 ꢂC with
an eluent mixture of n-hexane and 2-propanol (9:1) with
a flow rate of 0.5e1.0 mL. Detection was done with an
UVevis-detector at 210 nm or by coupling to ESI-MS: after
splitting the flow (1:100), the eluent was mixed online with
methanol containing NaOH (0.5%, 0.1 M) in order to assist
the spraying process (for experimental details see Table 2).
2.6. HPLC analysis
In order to determine the ratio between the axially and
equatorially substituted isomers, the synthesized diamines
were functionalized with an UV active component (see
Fig. 7) suitable for UVevis detection after separation with
HPLC.
N,N0-Bis(benzyloxycarbonyl)-4-methyl-trans-(ꢀ)-1,2-cyclo-
hexanedicarbamates were synthesized from the respective di-
amines obtained via pathways IeIII with the 4-methyl group
Figure 6. 13C NMR spectra showing the region of the CHeNH2 resonances of
4-methyl-trans-(ꢀ)-1,2-cyclohexanediamines 4aIeIII; respectively.
Figure 8. ORTEP view of 10a with thermal ellipsoids drawn at the 50% prob-
ability level.

L. Habala et al. / Tetrahedron 64 (2008) 137e146
141
Table 2
Measurement parameters applied for the HPLCeESI-MS study
Parameter
Settings
Eluent
Flow rate
n-hexane/2-propanol¼9:1
0.5 mL/min
5 ꢂC
Column temperature
Spray assistance
NaOH (0.5%, 0.1 M) in
MeOH at 180 mL/h
1:100
Splitter
Accumulation time
ICC Target
Averages
3 ms
200.000
21 spectra
m/z 50e1200
23.6
Scan range
Trap Drive
Skim 1
29.0 V
10.0 V
4500 V
300 ꢂC
9 L/min
10.0 psi
Skim 2
HV capillary
Dry temperature
Dry gas
Figure 9. ORTEP view of 10c with thermal ellipsoids drawn at the 50%
probability level.
Nebulizer
The HPLCeUVevis chromatogram of 10aII (see Fig. 10,
dashed line) contained two main signals at 24.5 and
38.1 min, which were assignable to the two enantiomers
(peak area ca. 1:1). Additionally, a small peak was detected
at 27.9 min. When performing the same HPLC experiment
with 10aI, a converse result was obtained: the ratio between
the two faster eluting peaks was reversed (see Fig. 10, solid
line). When comparing the elution behavior with that of enan-
tiomerically pure unsubstituted (1R,2R)- or (1S,2S )-CBz-
chxn, it can be concluded that the fastest eluting species is
the (1S,2S )-enantiomer. Taking into account the NMR data,
it is suggested that the successfully separated peaks at about
25 and 28 min are the diastereomers with (1S,2S,4R)- and
(1S,2S,4S )-configuration which are followed by the non-
resolved (1R,2R,4R)- and (1R,2R,4S )-species (see Fig. 10,
dashed line).
was developed allowing the identification of the species (for
an extracted ion chromatogram [m/z 419.3ꢀ0.5] see
Fig. 11). The measured extracted ion chromatogram of the
[MþNa]þ species (m/z 419.2) resembles accurately the result
obtained by HPLCeUVevis (compare Figs. 10 and 11) and
the concluded facts based on NMR experiments.
In contrast to the 4-methyl derivatives, the 4,4-dimethyl de-
rivative 10b and the 3,3,5,5-tetramethyl compound 10c were
obtained only in a mixture of two enantiomers. The chromato-
gram shows in the case of 10b only two peaks for the
separated enantiomers. A HPLC study with N,N0-bis(benzyl-
oxycarbonyl)-3,3,5,5-tetramethyl-trans-(ꢀ)-1,2-cyclohexane-
dicarbamate 10c did not allow to separate the two enantiomers
under the same conditionsdlowering the flow rate to 0.1 mL/
min gave a satisfying result accompanied by the shortcoming
of very long analysis time (about 3e4 h for one run).
In the case of 10aIII only two peaks were visible (see
Fig. 10, inset). In order to prove that all assigned peaks in
the HPLCeUVevis chromatogram are isomeric forms of
4-methyl-1,2-cyclohexanediamine, a HPLCeESI-MS method
Table 1
Crystallographic data for 8, 10a, and 10c
Compound
8
10a
10c
Chemical formula
Formula weight
T/K
C
21H26O6S2
C23H28N2O4
396.47
120
C26H34N2O4
438.55
120
438.54
120
C2/c
Space group
˚
P-1
P-1
a/A
˚
13.355(3)
13.242(3)
13.723(3)
9.110(2)
10.658(2)
11.818(2)
115.16(3)
92.27(3)
92.72(3)
1035.2(3)
2
10.881(2)
17.294(3)
19.767(4)
87.05(3)
76.85(3)
86.55(3)
3612.8(12)
6
b/A
˚
c/A
a/ꢂ
b/ꢂ
g/ꢂ
115.30(3)
3
˚
V/A
2194.1(8)
4
2.77
Z
Figure 10. Chromatograms recorded for the separation of N,N0-bis(benzyloxy-
carbonyl)-4-methyl-trans-(ꢀ)-1,2-cyclohexanedicarbamates 10aI (4-methyl
group mainly axial, solid line) and 10aII (4-methyl group mainly equatorial,
dashed line) on a Chiracel OD column (0.5 mL/min, 5 ꢂC). The inset shows
the chromatogram of the isomer with exclusively equatorially oriented
mcalcd/cmꢁ1
0.87
0.0507
0.1491
0.81
0.0706
0.2003
a
R1
wR2
0.0405
0.1169
b
P
P
a
R1
¼
jjFoj ꢁ jFcjj= jFoj.
P
P
2
2 1=2
b
wR2 ¼ ½ ðwjF2oj ꢁ jFc2jÞ = wjF2oj ꢃ
.
methyl-group 10aIII
.

142
L. Habala et al. / Tetrahedron 64 (2008) 137e146
the reactions were carried out in dry solvents and under argon
atmosphere. The NMR spectra were recorded on a Bruker
Avance DPX 400 instrument (UltrashieldÔ Magnet) at
400.13 MHz (1H) and 100.63 MHz (13C) at 25 ꢂC in DMSO-
d or CDCl . Melting points were determined with a Buchi
¨
6
3
B-540 apparatus and are uncorrected. Electrospray ioniza-
tion-mass spectra were recorded on a Bruker esquire3000 in
positive ion mode. The elemental analyses were performed
by the Microanalytical Laboratoty of the University of Vienna
with a PerkineElmer 2400 CHN Elemental Analyzer. Silica
gel (PolygramÒ SIL G/UV254) was used for thin layer chroma-
tography. X-ray diffraction measurements were performed on
a Nonius Kappa CCD diffractometer at 120 K. Single crystals
were positioned at 30 mm from the detector, and 344, 297, and
502 frames were measured, each for 125, 50, and 170 s over
2ꢂ, 2ꢂ, and 1.5ꢂ scan width for 8, 10a, and 10c, respectively.
The data were processed using Denzo-SMN software.37 Crys-
tal data, data collection parameters, and structure refinement
details are given in Table 1. The structures were solved by di-
rect methods and refined by full-matrix least-squares tech-
niques. Non-hydrogen atoms were refined with anisotropic
displacement parameters, all hydrogen atoms were inserted
in calculated position and refined using a riding model. The
structure of 8 was solved in the monoclinic space group
C2/c with assumed disorder consisting in interchange of H
atom and CH3 group at the cyclohexane ring. Our attempt to
solve the structure in the space group Cc resulted in a severe
disorder for the whole molecule and unusual interatomic
bond lengths and bond angles. The following computer pro-
grams were used: structure solution, SHELXS-97;38 refine-
ment, SHELXL-97;39 molecular diagrams, ORTEP;40
computer, and Pentium IV; scattering factors.41
Figure 11. Extracted ion chromatogram (m/z 419.3ꢀ0.5) recorded for the sep-
aration of 10aI on a Chiracel OD column after mixing the eluent online with
a solution of NaOH (0.5%, 0.1 M) in MeOH at a ratio of 1:0.6. In the inset the
electrospray ionization mass spectrum at ca. 16 min (mass range m/z 380e
460) is depicted.
3. Conclusions
A number of selectively trans-configured 1,2-cyclohexane-
diamines, bearing either 1, 2, or 4 methyl groups, were synthe-
sized and characterized. The syntheses of the 4-Me-chxn
derivatives were done applying different methods each with
certain potential to yield compounds with the methyl group
preferentially in axial, equatorial, or exclusively in equatorial
position.
HPLC (after suitable derivatization of the amino-function-
alities with CBz) with UVevis and ESI-MS detection and
NMR experiments allowed the determination of the ratio
between axially and equatorially oriented methyl groups of
4-methyl-trans-(ꢀ)-1,2-cyclohexanediamine. Pathway I (via
the vicinal hydroxime) yielded products with the methyl group
oriented mainly equatorially, while the addition reaction of
azide to cyclohexene derivatives mainly generates axially con-
figured isomers (pathway II). The third synthetic method (via
the diol and the mesylate or tosylate), including an inversion
of the chiral center (SN2 from tosylate or mesylate to the
azide), yields exclusively the equatorially substituted com-
pound 4aIII.
HPLC analysis was carried out on a Dionex SummitÒ
system equipped with a DAD controlled by the Dionex
ChromeleonÒ 6.60 software. The sample concentration was
1.0 mg/mL with an injection volume of 5e15 mL introduced
onto a Daicel Chiralcel OD column (250ꢄ4.6 mm, purchased
from Chiral Technologies, Illkirch, France) with a guard column
(50ꢄ4.6 mm) operated at 5 ꢂC. The flow rate of the mobile
phase (n-hexane/2-propanol¼9:1) was 0.5 or 1.0 mL/min. For
experimental setup of the HPLCeESI-MS study see Table 2.
4.1.1. 4-Methyl-trans-(ꢀ)-1,2-cyclohexanediamine 4aI
Bromine (23.8 mL, 0.46 mol) was added dropwise to a solu-
tion of 4-methylcyclohexanone 1a (50.0 g, 0.45 mol) in a mix-
ture of acetic acid (92 mL) and water (120 mL) at 35e40 ꢂC.
The reaction mixture was stirred for 1 h and then allowed to
cool to room temperature. The crude 2-bromo-4-methylcyclo-
hexanone was separated from the supernatant in a separator
funnel and dried over Na2CO3. 2-Bromo-4-methylcyclohexa-
none (33.2 g, 0.17 mol) was added dropwise to a boiling solu-
tion of hydroxylamine hydrochloride (70.4 g, 1.0 mol) and
sodium acetate (145.3 g, 1.1 mol) in a mixture of methanol
(126 mL) and water (146 mL). The reaction mixture was re-
fluxed for 1 h and, after cooling to room temperature, the
methanol was removed almost completely, and the product
was extracted with toluene (5ꢄ150 mL). The volume of the
The diamines were structurally characterized on the basis
of the CBz-protected compounds by X-ray diffraction analy-
sis. Additionally, the molecular structure of a mean product
of method III, i.e., the tosylate 8, was determined in the solid
state giving important information on the stereoselectivity of
the reaction pathway.
4. Experimental section
4.1. General
All chemicals obtained from commercial suppliers were
used as received and were of analytical grade. If necessary

L. Habala et al. / Tetrahedron 64 (2008) 137e146
143
combined organic fractions was reduced to 70 mL and the
white or slightly pink oxime was slowly precipitated by addi-
tion of n-hexane (usually in 3e4 days). Sodium in small
pieces (30 g, 1.3 mol) was added to a solution of 4-methylcy-
clohexane-1,2-dioxime (4 g, 25.6 mmol) in absolute ethanol
(150 mL) and allowed to react completely. The product was
isolated by water steam distillation (caution: be careful that
the complete sodium has reacted) and treated with sulfuric
acid (3 M) until pH 7 was reached. The solvent was removed
in vacuum and the sulfate salt, consisting of two isomers, was
obtained as a white solid.
the semicrystalline compound was dissolved in 2-propanol,
and the L-mandalate was finally obtained as a white solid
upon addition of diethyl ether.
Yield: 1.31 g (25%), mp 196e197 ꢂC. Elemental
analysis found: C, 64.39; H, 7.70; N, 6.12. Calcd for
C8H18N2$2C8H8O3: C, 64.55; H, 7.67; N, 6.27. MS (ESIþ)
1
m/z 143.1 [MþH]þ. H NMR in D2O: d¼0.82 [s, 3H, CH3],
0.88 [s, 3H, CH3], 1.22 [m, 1H, H-5], 1.31 [t, 1H, H-3,
3J¼13.0 Hz], 1.41 [m, 1H, H-5], 1.61 [m, 1H, H-6], 1.72
3
2
[dt, 1H, H-30, J¼3.0 Hz, J¼13.0 Hz], 1.89 [m, 1H, H-60],
3.16 [td, 1H, H-1, 3J¼5.0, 12.0 Hz], 3.41 [td, 1H, H-2,
3J¼4.5, 12.0 Hz], 4.87 [s, 2H, Ph(OH)CH], 7.31e7.25 [m,
10H, H-Ar]. 13C NMR in D2O: d¼23.3 [CH3], 26.0 [C-6],
30.6 [CH3], 31.1 [C-4], 35.7 [C-5], 41.9 [C-3], 50.0 [C-2],
52.9 [C-1], 75.3 [Ph(OH)CH], 127.4 [C-Ar], 128.6 [C-Ar],
129.1 [C-Ar], 140.8 [C-Ar], 179.8 [C(O)OH].
Yield: 3.06 g (52%), mp>400 ꢂC. Elemental analysis
found: C, 37.27; H, 7.80; N, 12.17. Calcd for
C7H16N2$H2SO4: C, 37.15; H, 8.02; N, 12.38. MS (ESIþ)
1
m/z 129.1 [MþH]þ. H NMR in D2O: d¼0.85 [d, 3H, CH3
3
3
equatorial, J¼6.5 Hz], 0.90 [d, 3H, CH3 axial, J¼7.0 Hz],
0.99 [m, 1H, H-5], 1.15 [m, 1H, H-3], 1.42e1.55 [m, 2H,
H-4, H-6], 1.72 [m, 1H, H-50], 1.99e2.10 [m, 2H, H-60, H-
30], 3.23e3.39 [m, 2H, H-1, H-2]. 13C NMR in D2O: isomer
with equatorial 4-methyl group (90%) d¼20.7 [CH3], 29.5
[C-6], 30.2 [C-4], 31.5 [C-5], 37.6 [C-3], 52.4 [C-1], 52.5
[C-1]; isomer with axial 4-methyl group (10%) d¼17.9
[CH3], 24.0 [C-6], 25.8 [C-4], 27.8 [C-5], 33.8 [C-3], 48.7
[C-1], 51.2 [C-2].
4.1.3. 3,3,5,5-Tetramethyl-trans-(ꢀ)-1,2-cyclohexane-
diamine 4c
Bromine (7.8 mL, 150 mmol) was added dropwise to a solu-
tion of 4,4-dimethylcyclohexanone 1c (23.1 g, 150 mmol) in
a mixture of acetic acid (25 mL) and water (10 mL) at 50e
55 ꢂC. The reaction mixture was stirred for 1 h, cooled to
0 ꢂC, and the crude product was allowed to crystallize from
the mother liquid, which was decanted. The product was puri-
fied by recrystallization from hexane (at ꢁ50 ꢂC). A solution
of 2-bromo-3,3,5,5-tetramethylcyclohexanone 2c (27.8 g,
120 mmol) in methanol (50 mL) was added dropwise to a
boiling solution of hydroxylamine hydrochloride (57 g,
0.82 mmol) and sodium acetate (111 g, 820 mmol) in a mixture
of methanol (120 mL) and water (130 mL). The reaction mix-
ture was refluxed for 2 h and, after cooling to room tempera-
ture, the methanol was removed and the product was
extracted with toluene (5ꢄ150 mL). The volume of the com-
bined organic fractions was reduced to 70 mL and the white
or slightly pink oxime 3c was precipitated by addition of n-
hexane. Sodium in small pieces (15 g, 650 mmol) was added
to a solution of 3,3,5,5-tetramethylcyclohexane-1,2-dioxime
3c (2.4 g, 1.2 mmol) in absolute ethanol (150 mL) and allowed
to react until no sodium was observable. The reaction mixture
was cooled to room temperature and acidified with concen-
trated hydrochloric acid until pH 1 was reached (caution: be
careful that the complete sodium has reacted). The white pre-
cipitate was filtered off and the solvent was evaporated under
reduced pressure. The crude semicrystalline compound was
dissolved in 2-propanol and the chloride was precipitated as
a white solid by addition of diethyl ether.
4.1.2. 4,4-Dimethyl-trans-(ꢀ)-1,2-cyclohexanediamine 4b
Bromine (7.8 mL, 0.15 mol) was added dropwise to a solu-
tion of 4,4-dimethylcyclohexanone 1b (19.0 g, 0.15 mol) in
a mixture of acetic acid (25 mL) and water (40 mL) at 50e
55 ꢂC. The reaction mixture was stirred for 1 h, cooled to
0 ꢂC, and the crude product was allowed to crystallize from
the mother liquid, which was decanted and the product was
purified by recrystallization from hexane (at ꢁ50 ꢂC) as white
solid with a melting point of 60e62 ꢂC being in accordance to
the literature data.42 A solution of 2-bromo-4,4-dimethylcy-
clohexanone 2b (25.0 g, 0.12 mol) in methanol (50 mL) was
added dropwise to a boiling solution of hydroxylamine hydro-
chloride (57.0 g, 0.82 mol) and sodium acetate (111.0 g,
0.82 mol) in a mixture of methanol (120 mL) and water
(130 mL). The reaction mixture was refluxed for 2 h and, after
allowing the solution to cool to room temperature, most of the
solvent was removed and the product was extracted with tolu-
ene (5ꢄ150 mL). The volume of the combined organic frac-
tions was reduced to 70 mL and the white or slightly pink
oxime was precipitated by addition of n-hexane. Sodium in
small pieces (15 g, 650 mol) was added to a solution of 4,4-di-
methylcyclohexane-1,2-dioxime 3b (2 g, 12 mmol) in absolute
ethanol (150 mL). The mixture was allowed to react com-
pletely, and then it was cooled to room temperature and treated
with concentrated hydrochloric acid (caution: be careful that
the complete sodium has reacted) until pH 1 was reached.
The white precipitate was filtered off and the solvent evapo-
rated under reduced pressure. The brown oil was treated
with 5 M NaOH solution and extracted with diethyl ether
(3ꢄ50 mL). The combined ether fractions were evaporated,
and the resulting oil was dissolved in water and neutralized
with L-mandelic acid. The solvent was removed in vacuum,
Yield: 0.95 g (33%), mp 290e293 ꢂC. Elemental
analysis found: C, 49.57; H, 10.04; N, 11.75. Calcd for
C10H22N2$2HCl: C, 49.38; H, 9.94; N, 11.51. MS (ESIþ) m/z
1
171.2 [MþH]þ. H NMR in D2O: d¼0.91 [s, 3H, CH3], 1.01
[s, 3H, CH3], 1.06 [s, 3H, CH3], 1.07 [s, 3H, CH3], 1.35e1.51
[m, 3H, H-4, H-40, H-6], 1.87 [m, 1H, H-60], 3.14 [d, 1H, H-2,
3J¼11.0 Hz], 3.68 [td, 1H, H-1, 3J¼3.5, 11.0 Hz]. 13C NMR in
D2O: d¼21.4 [CH3], 26.0 [CH3], 30.2 [CH3], 30.6 [C-5], 33.35
[CH3], 35.21 [C-3], 42.87 [C-6], 48.79 [C-1], 51.30 [C-4],
61.27 [C-2].

144
L. Habala et al. / Tetrahedron 64 (2008) 137e146
4.1.4. 4-Methyl-trans-(ꢀ)-1,2-cyclohexanediol 6
H, 5.98. MS (ESIþ) m/z 461.1 [MþNa]þ. 1H NMR in
3
4-Methylcyclohexene 5 (79.9 g, 0.83 mol) was added drop-
wise to a vigorously stirred mixture of hydrogen peroxide
(30%, 160 mL, 1.56 mol) and formic acid (85%, 360 mL,
7.91 mol) at 40e45 ꢂC. The reaction mixture was stirred for
1 h at 40 ꢂC and for 3 h at room temperature. The solvents
were removed in vacuum and NaOH (8 M, 200 mL) was added
dropwise at 0 ꢂC. Then it was stirred for 12 h at room temper-
ature and water (100 mL) was added. The crude product was
extracted from the reaction mixture with ethyl acetate
(3ꢄ100 mL). The combined organic fractions were washed
with water (2ꢄ100 mL), dried over Na2SO4, and the solvent
was removed in vacuum to give a yellowish viscous liquid,
which solidified overnight. The pure product was obtained af-
ter recrystallization from an ethanol/petroleum ether mixture
(1:1).
CDCl3: d¼0.85 [d, 3H, CH3, J¼7.0 Hz], 1.23 [m, 1H, H-5],
1.34e1.50 [m, 2H, H-3, H-50], 1.54e1.67 [m, 2H, H-6, H-
30], 1.68e1.72 [m, 2H, H-4, H-60], 2.50 [s, 6H, CH3], 4.49
[m, 1H, H-2], 4.54 [m, 1H, H-1], 7.37e7.76 [m, 10H, H-Ar].
13C NMR in CDCl3: d¼21.9 [CH3], 22.1 [CH3], 25.6 [C-4],
26.1 [C-6], 27.7 [C-5], 34.4 [C-3], 76.1 [C-2], 76.9 [C-1],
128.3 [C-Ar], 130.3 [C-Ar], 133.6 [C-Ar], 145.4 [C-Ar].
4.1.7. 4-Methyl-trans-(ꢀ)-1,2-cyclohexanediamine 4aII
A solution of 4-methyl-1-cyclohexene 5 (20 g, 0.21 mol) in
trifluoroacetic acid (240 mL) was added to a mixture of
Mn3O(CH3COO)7 (176 g, 0.62 mol) and NaN3 (68 g, 1.04 mol)
in acetonitrile (2400 mL) under N2 atmosphere at ꢁ20 ꢂC. The
reaction mixture was stirred for 3 h at ꢁ19 to ꢁ21 ꢂC and after-
ward NaHSO3 (10%, 600 mL) was added. The product was
extracted with petroleum ether (3ꢄ500 mL), washed with satu-
rated Na2CO3 solution (2ꢄ200 mL) and brine (2ꢄ200 mL), and
dried over Na2SO4. The solvent was removed in vacuum. A
mixture of 4-methyl-trans-(ꢀ)-1,2-cyclohexanediazide 9aII
(4.0 g, 22.2 mmol) and palladium on CaCO3 (5% Pd, 1.6 g)
in dry ethanol (50 mL) was stirred for 24 h under hydrogen at-
mosphere (3 bar). The catalyst was filtered off, the solvent was
removed, and the product was precipitated by addition of sulfu-
ric acid (3 M) until neutralization of the solution. Then the sul-
fate was filtered off, washed with diethyl ether (2ꢄ50 mL), and
dried in vacuum.
Yield: 88.1 g (81%), mp 68e69 ꢂC. Elemental analysis
found: C, 64.63; H, 10.92. Calcd for C7H14O2: C, 64.58; H,
1
10.84. MS (ESIþ) m/z 153.1 [MþNa]þ. H NMR in CDCl3:
3
d¼1.00 [d, 3H, CH3, J¼7.0 Hz], 1.40e1.64 [m, 4H, H-5,
H-3, H-6, H-50], 1.66e1.89 [m, 2H, H-30, H-60], 2.04 [m,
1H, H-4], 2.69 [br s, 1H, OH], 2.79 [s, 1H, OH], 3.43 [m,
1H, H-1], 3.67 [m, 1H, H-2]. 13C NMR in CDCl3: d¼19.5
[CH3], 28.0 [C-4], 28.1 [C-6], 29.8 [C-5], 38.5 [C-3], 71.8
[C-2], 75.7 [C-1].
4.1.5. O,O0-Di(methanesulfonate)-4-methyl-trans-(ꢀ)-1,2-
cyclohexanediol 7
Yield: 2.7 g (53%), mp 385e390 ꢂC. Elemental analysis
found: C, 37.31; H, 7.86; N, 12.25. Calcd for
C7H16N2$H2SO4: C, 37.15; H, 8.02; N, 12.38. MS (ESIþ)
Methanesulfonyl chloride (114.2 mL, 1.47 mol) was added
dropwise to a solution of 4-methyl-trans-(ꢀ)-1,2-cyclohexane-
diol 6 (66.6 g, 0.51 mol) in dry pyridine (380 mL) at 0 ꢂC. The
reaction mixture was stirred for 2 h and then cold water
(400 mL) was slowly added. The crude product was extracted
with CH2Cl2 (3ꢄ200 mL), the combined organic fractions
were washed with water (3ꢄ100 mL), dried over Na2SO4,
and the solvent was removed in vacuum. The resulting viscous
liquid was washed with petroleum ether to remove the pyri-
dine. The pure product was obtained after recrystallization
from an ethanol/n-hexane mixture (3:1).
1
m/z 129.1 [MþH]þ. H NMR in D2O: d¼0.86 [d, 3H, CH3
3
3
equatorial, J¼6.7 Hz], 0.88 [d, 3H, CH3 axial, J¼7.0 Hz],
1.38 [m, 1H, H-5], 1.56 [m, 1H, H-50], 1.62e1.82 [m, 3H,
H-3, H-6, H-30], 1.82e1.98 [m, 2H, H-60, H-4], 3.37 [m, 1H,
H-1], 3.54 [m, 1H, H-2]. 13C NMR in D2O: isomer with axial
4-methyl group (88%) d¼18.0 [CH3], 24.0 [C-6], 25.8 [C-4],
27.8 [C-5], 33.8 [C-3], 48.7 [C-1], 51.2 [C-2]; isomer with
equatorial 4-methyl group (12%) d¼20.7 [CH3], 29.5 [C-6],
30.2 [C-4], 31.5 [C-5], 37.7 [C-3], 52.4 [C-1], 52.5 [C-2].
Yield: 94.1 g (71%), mp 93e94 ꢂC. Elemental analysis
found: C, 37.73; H, 6.42. Calcd for C9H18O6S2: C, 37.74; H,
1
6.34. MS (ESIþ) m/z 309.1 [MþNa]þ. H NMR in CDCl3:
4.1.8. 4-Methyl-trans-(ꢀ)-1,2-cyclohexanediamine 4aIII
3
d¼1.00 [d, 3H, CH3, J¼6.5 Hz], 1.41 [m, 1H, H-5], 1.62
NaN3 (14.0 g, 210 mol) in dry DMF (100 mL) was added to
O,O0-di(methanesulfonate)-4-methyl-trans-(ꢀ)-1,2-cyclohex-
anediol 7 (15.1 g, 53 mmol) and the reaction mixture was kept
for 48 h at 120 ꢂC. After allowing the reaction mixture to cool
to room temperature, water (300 mL) was added and the prod-
uct was extracted with petroleum ether (3ꢄ100 mL). The com-
bined organic fractions were washed with water (3ꢄ100 mL)
and dried over Na2SO4. The crude diazide (4.3 g, yield:
46%) was obtained after removing the solvent in vacuum. A
mixture of 4-methyl-trans-(ꢀ)-1,2-cyclohexanediazide 9aIII
(2.5 g, 14.3 mmol) and palladium on CaCO3 (5% Pd, 500 mg)
in dry ethanol (30 mL) was stirred for 24 h under hydrogen at-
mosphere (3 bar). The catalyst was filtered off, the solvent was
removed, and the product was precipitated by addition of di-
luted sulfuric acid until pH 7 was reached. The sulfate was
[m, 1H, H50], 1.78 [m, 1H, H-3], 1.87e2.11 [m, 4H, H-30,
H-6, H-4, H-60], 3.08 [s, 3H, CH3], 3.09 [s, 3H, CH3], 4.75
[m, 1H, H-1], 4.87 [m, 1H, H-2]. 13C NMR in CDCl3:
d¼20.7 [CH3], 26.4 [C-4], 26.8 [C-6], 28.2 [C-5], 35.8 [C-
3], 38.9 [CH3], 77.4 [C-2], 77.8 [C-1].
4.1.6. 4-Methyl-O,O0-di( p-toluenesulfonate)-trans-(ꢀ)-1,2-
cyclohexanediol 8
Following the same procedure as described for 7, compound
8 was obtained from 4-methyl-trans-(ꢀ)-1,2-cyclohexanediol
(20.0 g, 0.15 mol), pyridine (140 mL), and p-toluenesulfonyl
chloride (82.4 g, 0.43 mol).
Yield: 57.5 g (81%), mp 108e109 ꢂC. Elemental analysis
found: C, 57.39; H, 5.79. Calcd for C21H26O6S2: C, 57.51;

L. Habala et al. / Tetrahedron 64 (2008) 137e146
145
filtered off, washed with diethyl ether (2ꢄ50 mL), and dried in
vacuum.
[m, 6H, OCH2, NH], 7.35 [s, 10H, H-Ar]. 13C NMR in
CDCl3: isomer with axial 4-methyl group (88%) d¼18.6
[CH3], 27.6 [C-5], 27.7 [C-4], 30.3 [C-6], 38.3 [C-3], 50.9
[C-2, C-1], 67.1 [OCH2], 128.3 [C-Ar], 128.4 [C-Ar], 128.9
[C-Ar], 137.0 [C-Ar], 157.1 [C(O)]; isomer with equatorial
4-methyl group (12%) d¼22.1 [CH3], 31.9 [C-4], 32.7 [C-5],
33.7 [C-6], 41.6 [C-3], 55.5 [C-2], 55.7 [C-1], 67.1 [OCH2],
128.3 [C-Ar], 128.4 [C-Ar], 128.9 [C-Ar], 137.0 [C-Ar],
157.1 [C(O)].
Yield: 3.3 g (28%), mp>400 ꢂC. Elemental analysis found:
C, 37.28; H, 8.11; N, 12.54. Calcd for C7H16N2$H2SO4: C,
1
37.15; H, 8.02; N, 12.38. MS (ESIþ) m/z 129.1 [MþH]þ. H
3
NMR in D2O: d¼0.85 [d, 3H, CH3, J¼6.5 Hz], 0.99 [m, 1H,
H-5], 1.15 [m, 1H, H-3], 1.41e1.58 [m, 2H, H-4, H-6], 1.71
[m, 1H, H-50], 1.98e2.10 [m, 2H, H-60, H-30], 3.20e3.38 [m,
2H, H-1, H-2]. 13C NMR in D2O: d¼20.7 [CH3], 29.5 [C-6],
30.2 [C-4], 31.5 [C-5], 37.6 [C-3], 52.4 [C-1], 52.5 [C-2].
4.1.11. 4-Methyl-N,N0-bis(benzyloxycarbonyl)-trans-(ꢀ)-
1,2-cyclohexanedicarbamate 10aIII
4.1.9. N,N0-Bis(benzyloxycarbonyl)-4-methyl-trans-(ꢀ)-1,2-
cyclohexanedicarbamate 10aI
Following the same procedure as described for 10aI, an en-
antiomeric mixture was obtained from 4-methyl-trans-(ꢀ)-
1,2-cyclohexanediaminium sulfate (0.3 g), triethylamine
(0.55 mL), and benzyloxycarbonylchloride (0.45 mL).
Yield: 0.16 g (31%), mp 175e176 ꢂC. Elemental analysis
found: C, 69.45; H, 7.18; N, 7.36. Calcd for C23H28N2O4: C,
4-Methyl-trans-(ꢀ)-1,2-cyclohexanediamine 4aI (0.30 g)
was recovered from the respective diaminium sulfate by disso-
lution in aqueous NaOH solution (5 M, 15 mL) and extraction
with dichloromethane (3ꢄ10 mL). Triethylamine (0.55 mL,
3.98 mmol) was added at 0e5 ꢂC under Ar atmosphere to the
combined CH2Cl2 fractions. The reaction mixture was treated
with benzyloxycarbonylchloride (0.45 mL, 3.18 mmol) under
vigorous stirring and kept at 0e5 ꢂC for 15 min. Then it was al-
lowed to warm to room temperature and stirred for another 3 h
(TLC control, n-hexane/ethyl acetate¼3:1). The reaction mix-
ture was diluted with CH2Cl2 (5 mL), washed with brine
(2ꢄ10 mL), and dried over Na2SO4. The solvent was removed
to give a slightly brown crude product, which was purified by
recrystallization from MeOH.
1
69.66; H, 7.12; N, 7.07. MS (ESIþ) m/z 419.2 [MþNa]þ. H
NMR in CDCl3: d¼0.94 [d, 3H, 3J¼6.5 Hz, CH3], 0.93e
1.08 [m, 2H, H-3, H-5], 1.32 [m, 1H, H-6], 1.54 [m, 1H, H-
4], 1.72 [m, 1H, H-50], 2.05e2.09 [m, 2H, H-30, H-60],
3.36e3.46 [m, 2H, H-2, H-1], 5.04e5.12 [m, 6H, OCH2,
NH], 7.34 [s, 10H, H-Ar]. 13C NMR in CDCl3: d¼22.0
[CH3], 31.9 [C-4], 32.6 [C-5], 33.7 [C-6], 41.6 [C-3], 55.5
[C-1], 55.7 [C-2], 67.0 [OCH2], 128.3 [C-Ar], 128.4 [C-Ar],
128.9 [C-Ar], 137.0 [C-Ar], 157.23 [C(O)].
Yield: 0.24 g (47%), mp 154e155 ꢂC. Elemental analysis
found: C, 69.62; H, 7.04; N, 7.24. Calcd for C23H28N2O4: C,
4.1.12. N,N0-Bis(benzyloxycarbonyl)-4,4-dimethyl-trans-
(ꢀ)-1,2-cyclohexanedicarbamate 10b
1
69.66; H, 7.12; N, 7.07. MS (ESIþ) m/z 419.2 [MþNa]þ. H
3
NMR in CDCl3: d¼0.94 [d, 3H, CH3 equatorial, J¼6.5 Hz],
Following the same procedure as described for 10aI, com-
pound 10b was obtained from 4,4-dimethyl-trans-(ꢀ)-1,2-
cyclohexanediaminium L-mandelate (0.52 g), triethylamine
(0.60 mL), and benzyloxycarbonylchloride (0.49 mL).
Yield: 0.14 g (29%), mp 151e152 ꢂC. Elemental analysis
found: C, 69.93; H, 7.29; N, 6.86. Calcd for C24H30N2O4: C,
3
1.04 [d, 3H, CH3 axial, J¼7.0 Hz], 0.93e1.08 [m, 2H, H-3,
H-5], 1.32 [m, 1H, H-6], 1.54 [m, 1H, H-4], 1.72 [m, 1H,
H-50], 2.05e2.09 [m, 2H, H-30, H-60], 3.36e3.46 [m, 2H, H-
2, H-1], 5.04e5.12 [m, 6H, OCH2, NH], 7.34 [s, 10H, H-
Ar]. 13C NMR in CDCl3: isomer with equatorial 4-methyl
group (90%) d¼22.0 [CH3], 31.9 [C-4], 32.6 [C-5], 33.7 [C-
6], 41.6 [C-3], 55.5 [C-1], 55.7 [C-2], 67.0 [OCH2], 128.3
[C-Ar], 128.4 [C-Ar], 128.9 [C-Ar], 137.0 [C-Ar], 157.2
[C(O)]; isomer with axial 4-methyl group (10%) d¼18.6
[CH3], 27.6 [C-5], 27.7 [C-4], 30.3 [C-6], 38.3 [C-3], 50.9
[C-1, C-2], 67.1 [OCH2], 128.3 [C-Ar], 128.4 [C-Ar], 128.9
[C-Ar], 137.0 [C-Ar], 157.1 [C(O)].
1
70.22; H, 7.36; N, 6.82. MS (ESIþ) m/z 433.2 [MþNa]þ. H
NMR in CDCl3: d¼0.97 [s, 3H, CH3], 1.01 [s, 3H, CH3],
1.16 [m, 1H, H-3], 1.31 [m, 1H, H-5], 1.40e1.49 [m, 2H,
H-50, H-6], 1.77 [m, 1H, H-30], 1.95 [m, 1H, H-60], 3.33 [m,
1H, H-1], 3.62 [m, 1H, H-2], 4.96e5.17 [m, 6H, OCH2,
NH], 7.34 [s, 10H, H-Ar]. 13C NMR in CDCl3: d¼25.0
[CH3], 29.1 [C-6], 31.9 [C-4], 32.7 [CH3], 38.0 [C-5], 45.9
[C-3], 52.3 [C-1], 56.6 [C-2], 67.0 [OCH2], 128.3 [C-Ar],
128.4 [C-Ar], 128.9 [C-Ar], 137.0 [C-Ar], 157.17 [C(O)].
4.1.10. N,N0-Bis(benzyloxycarbonyl)-4-methyl-trans-(ꢀ)-
1,2-cyclohexanedicarbamate 10aII
Following the same procedure as described for 10aI, a dia-
stereomeric mixture was obtained from 4-methyl-trans-(ꢀ)-
1,2-cyclohexanediaminium sulfate (0.13 g), triethylamine
(0.24 mL), and benzyloxycarbonylchloride (0.20 mL).
Yield: 74 mg (30%), mp 112e113 ꢂC. Elemental analysis
found: C, 69.57; H, 7.12; N, 7.09. Calcd for C23H28N2O4: C,
4.1.13. N,N0-Bis(benzyloxycarbonyl)-3,3,5,5-tetramethyl-
trans-(ꢀ)-1,2-cyclohexanedicarbamate 10c
Following the same procedure as described for 10aI, com-
pound 10c was obtained from 3,3,5,5-tetramethyl-trans-(ꢀ)-
1,2-cyclohexanediaminium chloride (0.30 g), triethylamine
(0.63 mL), and benzyloxycarbonylchloride (0.42 mL).
Yield 0.10 g (20%), mp 120e121 ꢂC. Elemental analysis
found: C, 70.94; H, 7.57; N, 6.38. Calcd for C26H34N2O4: C,
1
69.66; H, 7.12; N, 7.07. MS (ESIþ) m/z 419.2 [MþNa]þ. H
3
NMR in CDCl3: d¼0.94 [d, 3H, CH3 equatorial, J¼6.5 Hz],
3
1
1.04 [d, 3H, CH3 axial, J¼7.0 Hz], 1.44e1.57 [m, 4H, H-3,
71.21; H, 7.81; N, 6.37. MS (ESIþ) m/z 461.3 [MþNa]þ. H
H-30, H-5, H-6], 1.79e1.90 [m, 2H, H-50, H-60], 2.05 [m,
1H, H-4], 3.41 [m, 1H, H-1], 3.69 [m, 1H, H-2], 4.96e5.18
NMR in CDCl3: d¼0.94 [s, 3H, CH3], 0.97 [s, 3H, CH3],
1.04 [s, 3H, CH3], 1.10 [s, 3H, CH3], 1.20e1.43 [m, 3H, H-

146
L. Habala et al. / Tetrahedron 64 (2008) 137e146
6, H-4, H-40], 1.81 [m, 1H, H-60], 3.28 [m, 1H, H-2], 3.80 [m,
1H, H-1], 4.88e4.98 [m, 3H, OCH2, NH], 5.08e5.11 [m, 3H,
OCH2, NH], 7.34 [s, 10H, H-Ar]. 13C NMR in CDCl3: d¼22.5
[CH3], 27.7 [CH3], 31.9 [C-5], 32.0 [CH3], 34.9 [CH3], 36.4
[C-3], 46.7 [C-6], 49.8 [C-1], 53.1 [C-4], 63.9 [C-2], 67.1
[OCH2], 128.2 [C-Ar], 128.2 [C-Ar], 128.9 [C-Ar], 137.0
[C-Ar], 157.2 [C(O)], 158.1 [C(O)].
Crystallographic data for the structural analysis has been
deposited with the Cambridge Crystallographic Data Centre,
CCDC No. 663505 (8), 663504 (10c), 663503 (10a). Copies
of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax:
þ44 1223 336033 or e-mail: deposit@ccdc.ac.uk).
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Austrian Council for Research and Technology Development,
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the FFGdAustrian Research Promotion Agency (Project FA
526003), the FWFdAustrian Science Fund (Schrodinger Fel-
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