Chemoenzymatic synthesis of optically active cis- and trans-2-(1H-Imidazol- 1-yl)cycloalkanamines

Article abstract of DOI:10.1002/ejoc.201001299

The preparation of enantiopure 2-(1H-imidazol-1-yl)cycloalkanamines has been studied by independent chemoenzymatic approaches. We first explored a route involving the enzymatic resolution of racemic cycloalkanol analogs for the preparation of the correspo

Full text of DOI:10.1002/ejoc.201001299

FULL PAPER
DOI: 10.1002/ejoc.201001299
Chemoenzymatic Synthesis of Optically Active cis- and trans-2-(1H-Imidazol-
1-yl)cycloalkanamines
Sergio Alatorre-Santamaría,[a] Vicente Gotor-Fernández,*[a] and Vicente Gotor*[a]
Keywords: Amines / Chirality / Enzyme catalysis / Nitrogen heterocycles / Kinetic resolution
The preparation of enantiopure 2-(1H-imidazol-1-yl)cyclo-
alkanamines has been studied by independent chemo-
enzymatic approaches. We first explored a route involving
the enzymatic resolution of racemic cycloalkanol analogs for
the preparation of the corresponding optically active amines
by diverse substitution methodologies including (a) the for-
mation of a mesylated intermediate that could be later substi-
tuted by an amine group and (b) the combination of Mitsu-
nobu inversion of the hydroxy group followed by a deprotec-
tion step. In order to overcome low isolated yields of the de-
sired optically active amines, racemic-trans-2-(1H-imidazol-
1-yl)cycloalkanamines were prepared, and their lipase-cata-
lyzed enzymatic resolutions were studied. These efforts re-
vealed that lipase from Candida antarctica type B was an ef-
ficient biocatalyst. A combination of both chemoenzymatic
methodologies has allowed us to obtain the four different
enantiopure cis- and trans-(1H-imidazol-1-yl)cycloalkan-
amine isomers.
N,N-disubstituted-cycloalkane-1,2-diamines has led us to
focus our attention on the synthesis of related enantiopure
cis- and trans-2-(1H-imidazol-2-yl)cycloalkanamines con-
taining five- and six-membered rings. Here we present the
chemoenzymatic production of imidazolium cycloalkanam-
ines and describe how different strategies have been consid-
ered for the effective asymmetric synthesis of enantiomers
of both the cis and trans derivatives.
Introduction
The 1,2-diamine subunit is present in several natural
products and therapeutic agents that possess a wide variety
of biological activities.[1] Additionally, this structural fea-
ture possesses multiple applications because of its presence
in semiconducting materials,[2] ligands, and resolving agents
used in organic synthesis.[3] Within the 1,2-diamine family,
optically active cycloalkane-1,2-diamines are of remarkable
importance because of their applications as catalysts and
ligands in asymmetric synthesis.[4] Most work presented in
the literature has focused on the production of nonracemic
trans-cyclohexane-1,2-diamine derivatives because of their
special properties as chiral molecular receptors,[5] as chiral
shift reagents,[6] or because of their ability to form metal–
diamine complexes.[7] However, the synthesis of trans-cyclo-
pentane-1,2-diamine[8] and related cis-derivatives[9] remains
a challenging task.
Recently, we described the chemoenzymatic synthesis of
novel enantiopure salts and ionic liquids through the kinetic
resolution of racemic trans- and cis-2-(1H-imidazol-1-yl)cy-
cloalkanols using lipases.[10] These examples constitute an
elegant approach for the synthesis of interesting chiral 1,2-
amino alcohols, a group of organic compounds with impor-
tant applications in asymmetric synthesis and one that is
easily obtained from inexpensive cyclohexene oxide.[11]
Continued interest in the production of optically active
Results and Discussion
Following a chemical method already described, racemic
cyclohexanol 1a was prepared from imidazole and cyclo-
hexene oxide[12] and then used for the synthesis of racemic
cycloalkanamine 3a (Scheme 1). In a fashion similar to the
synthesis of a family of (Ϯ)-trans-cyclohexandiamines,[13]
(Ϯ)-trans-1a was treated with mesyl chloride and sub-
sequently with aqueous ammonia, all in one pot, to gener-
ate racemic (Ϯ)-trans-3a. Unfortunately, we failed to ob-
serve formation of this adduct to any significant extent and
instead detected only trace amounts of mesylate (Ϯ)-trans-
2. These observations are perhaps best rationalized by com-
peting formation of a labile aziridinium species leaving (Ϯ)-
trans-2 as a minor product. Surprisingly, significantly dif-
ferent results were obtained when starting from enantiopure
(1S,2S)-trans-1a prepared by using previously known meth-
odology.[10a] In this case, (1S,2S)-alcohol 1a was treated
with mesyl chloride (MsCl) in the presence of pyridine (Py)
in dichloromethane (CH2Cl2), which afforded protected
alcohol (1S,2S)-trans-2 in moderate yield (58%). The pro-
tected alcohol was then treated with sodium azide (NaN3)
in N,N-dimethylformamide (DMF) to afford (1R,2S)-cis-
azide 4, which was subsequently hydrogenated by using pal-
[a] Departamento de Química Orgánica e Inorgánica,
Instituto Universitario de Biotecnología,
Universidad de Oviedo
C./Julián Clavería s/n 33071 Oviedo, Spain
Fax: +34-98-5103448
E-mail: vicgotfer@uniovi.es
vgs@fq.uniovi.es
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Scheme 1. Initial attempt to synthesize racemic and enantiopure amine trans-3a from mesylated derivative 2.
ladium on activated carbon (Pd/C) in deoxygenated EtOH. cleavage of the phthalimide moiety with hydrazine monohy-
In this manner, (1R,2S)-cis-cyclohexanamine 3a was ob- drate in refluxing THF/EtOH.
tained in almost quantitative yield. Preparation of the cor-
responding trans enantiomer of 3a by using a similar ap-
proach was marked by dramatically diminished yields;
(1S,2S)-trans-3a was produced in only 4% overall yield.
These results necessitated the development of a new syn-
thetic approach to such compounds.
To better prepare these amine derivatives, we sought to
exploit the synthetic usefulness of enantiopure alcohols
(1S,2S)-1a,b, easily obtained by known chemoenzymatic
methods.[10] Alcohols (1S,2S)-1a,b were employed as inter-
mediates for the production of amines cis-(1R,2S)-3a,b and
trans-(1S,2S)-3a,b. The corresponding cis derivatives were
produced by using Mitsunobu chemistry to invert the ste-
reochemistry at the hydroxy-bearing carbon atom. Enantio-
merically pure (1R,2S)-cis-2-(1H-imidazol-1-yl)cycloalkan-
amines 3a,b were obtained in moderate yields (34–63%,
Scheme 2) following treatment of (1S,2S)-1a,b with phthal-
imide, triphenylphosphane (PPh3), and diethyl azodicarbox-
ylate (DEAD) in tetrahydrofuran (THF) and subsequent
The synthesis of optically active trans-amines 3a,b re-
quired a combination of (i) initial inversion of the hydroxy
group configuration in (1S,2S)-trans-cycloalkanols 1a,b fol-
lowed by (ii) amino group installation by using Mitsunobu
chemistry, and (iii) subsequent phthalimide cleavage to lib-
erate the free amine (Scheme 3). Initial Mitsunobu reaction
with either p-nitrobenzoic acid as the nucleophile for 1a or
acetic acid as the nucleophile for 1b by employing condi-
tions similar to those used in making 3a,b resulted in the
first of two stereochemical inversions. This produced cis-
esters 6 and 7, which were subsequently deprotected under
alkaline conditions to afford (1R,2S)-cis-cycloalkanols
1a,b.[10b] The cis-alcohols were then submitted to another
Mitsunobu reaction in which each hydroxy moiety under-
went replacement with the amine source phthalimide. The
phthalimide moiety of each resulting intermediate (1S,2S)-
trans-5a,b was then deprotected with hydrazine to provide
the corresponding (1S,2S)-trans-cycloalkanamines 3a,b in
moderate to low yields (12–41%). It is notable that the over-
all yield for six-membered (1S,2S)-cis-3a was significantly
lower than that for cyclopentanamine (1S,2S)-cis-3b (9 and
25% overall yield, respectively).
As noted with nucleophilic substitutions of the mesyl
moiety, low reaction yields were obtained with both strate-
gies used to prepare (1S,2S)-trans-cyclohexanamine 3a. We
attribute this observation to a structural feature that pre-
vents the cis intermediate from undergoing nucleophilic at-
tack with nucleophiles that differ in size; examples include
ammonia, sodium azide, and phthalimide, which all have
different stereoelectronic demands and capabilities. Conse-
Scheme 2. Synthesis of enantiopure (1R,2S)-cis-cycloalkanamines
3a,b by using a two–step sequence: Mitsunobu inversion and amine
liberation following phthalimide cleavage.
Scheme 3. Synthesis of enantiopure (1S,2S)-trans-cycloalkanamines 3a,b.
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Chiral 2-(1H-Imidazol-1-yl)cycloalkanamines by Enzymatic Resolution
quently, we sought to overcome this limitation by preparing Table 1. Enzymatic acylation of (Ϯ)-trans-cycloalkanamines 3a,b
after 24 h at 250 rpm. Reaction conditions: amine (0.15 m) in sol-
vent (1.5 mL) using CAL-B/amine 3a,b (1:1 in weight).
enantiopure trans-amines 3a,b directly through the lipase-
catalyzed kinetic resolution of their racemates. Thus, (Ϯ)-
[a]
[b]
Entry Amine Ester
T
[°C]
eeS
[%]
eeP
[%]
c[c]
[%]
E[d]
trans-cycloalkanamines 3a,b were synthesized starting from
corresponding cycloalkane oxides 8a,b. Treatment of each
epoxide with sodium azide (NaN3) in a mixture of water
and acetone afforded (Ϯ)-trans-9a,b (Scheme 4). Azido
alcohols 9a,b were later transformed into bicyclic aziridines
10a,b under Staudinger reaction conditions with the ad-
dition of PPh3 in THF at 66 °C. Aziridine intermediates
10a,b were ultimately treated with imidazole and trifluoro-
acetic acid (TFA) in THF[14] to render ring-opened (Ϯ)-
trans-cycloalkanamines 3a,b in good overall yields (47–
56%) over three steps.
1
2
3
4
5
3a
3b
3a
3a
3b
11
11
12
11
11
30
30
30
45
45
31
36
82
92
96
Ͼ99
Ͼ99
94
Ͼ99
49
24
26
47
48
67
Ͼ200
Ͼ200
80
Ͼ200
11
[a] Determined by HPLC by using carbamates 15a,b. [b] Deter-
mined by HPLC. [c] c = eeS/(eeS + eeP). [d] E = ln[(1 – c)ϫ(1 –
eeP)]/ln[(1 – c)ϫ(1 + eeP)].
Initially, Pseudomonas cepacia lipase (PSL-C) and CAL-
B were tested as possible stereoselective catalysts in the
acetylation reaction with ethyl acetate (11) as solvent. Even
though PSL-C did not display activity, CAL-B[16] showed
excellent enantioselectivity, yielding enantiopure (1R,2R)-
trans-acetamides 13a,b with moderate conversions (Table 1,
Entries 1 and 2). Unfortunately, longer reaction periods led
to a loss of selectivity, perhaps due to partial enzyme inacti-
vation (data not shown). To optimize the conversion values,
we used a more highly activated ester, ethyl methoxyacetate
(12), in the resolution of (Ϯ)-trans-3a. This provided a
higher conversion to methoxyacetamide (1R,2R)-trans-14a
but with an important decrease in selectivity (Table 1, En-
try 3). Accordingly, we continued enzymatic studies by
using ethyl acetate as the acyl donor instead of meth-
Scheme 4. Preparation of (Ϯ)-trans-cycloalkanamines 3a,b.
With racemic trans-amines 3a,b in hand, we studied their oxyacetate and also raised the reaction temperature from 30
amenability to enzymatic kinetic resolution by using Can- to 45 °C. These parameter alterations changed considerably
dida antarctica lipase B (CAL-B)-catalyzed acylation with between substrates. The best results were found by using
ethyl acetate (11) or ethyl methoxyacetate (12); these non- six-membered (Ϯ)-trans-3a; about 50% conversion with ex-
activated esters are commonly used in stereoselective trans- cellent enantioselectivity was observed (Table 1, Entry 4).
formations of primary amines.[15] Esters 11 and 12 not only However, under the same experimental conditions using
act as effective acyl donors but also serve as their own sol- (Ϯ)-trans-3b as substrate, the enzyme suffered a dramatic
vents in the biocatalyzed process.[13a,13b] As shown in decrease in enantioselectivity despite allowing (1S,2S)-
Scheme 5, enzymatic kinetic resolution of trans-amines 3a,b trans-amine-3b to be isolated in 96%ee (Table 1, Entry 5).
was attempted under different reaction conditions. Derivati- In short, CAL-B catalyzed the formation of both (1S,2S)-
zation of the remaining trans-cycloalkanamines 3a,b with trans-amines 3a,b with 92 and 96%ee, respectively, when
di-tert-butyl dicarbonate (Boc2O) was necessary to obtain the process was carried out at 45 °C. Additionally, (1R,2R)-
carbamates 15a,b. Production of 15a,b allowed easy deter- trans-acetamide 13a was isolated in enantiopure form at
mination of their enantiomeric excess values by using chiral both 30 and 45 °C, and enantiopure five-membered
HPLC methods (Table 1).
(1R,2R)-trans-acetamide 13b was obtained at 45 °C.
Scheme 5. Enzymatic kinetic resolution of racemic trans-cycloalkanamines 3a,b.
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S. Alatorre-Santamaría, V. Gotor-Fernández, V. Gotor
FULL PAPER
136.9 (C8) ppm. HRMS (ESI+): calcd. for [M + H]+ 245.0954;
found 245.0962.
Conclusions
Complementary synthetic approaches have been devel-
oped for the production of enantiopure 2-(1H-imidazol-1-
yl)cycloalkanamines from inexpensive commercially avail-
able starting materials. Lipase-catalyzed kinetic resolutions
of these amines or the corresponding cycloalkanols have
been shown to be remarkably important for the production
of optically active imidazole derivatives. Meanwhile, access
to (1R,2S)-cis-amines 3a,b has been achieved in a straight-
forward manner from racemic alcohols 1a,b, and CAL-B
has proven to be an excellent biocatalyst in the stereoselec-
tive production of the (1S,2S)-trans-amines 3a,b.
Procedure for Synthesis of (1R,2S)-cis-Cycloalkanamine 3a by For-
mation of Azide Intermediate (1R,2S)-cis-4: To a solution of mesyl-
ated compound (1S,2S)-trans-2 (30 mg, 0.12 mmol) in DMF
(1.0 mL) was added sodium azide (24 mg, 0.37 mmol) under an
inert atmosphere. The mixture was heated to 120 °C for 24 h. After
this time no more starting material was detected by TLC (10%
MeOH/CH2Cl2), and the solvent was evaporated under reduced
pressure. The solid thus obtained was washed with Et2O
(5ϫ3 mL), and the organic fractions were combined and dried
with Na2SO4. Solids were filtered, and the solvent was evaporated
under reduced pressure. The crude product was employed without
further purification in the next step. Hence, this solid was treated
with activated Pd/C (15 mg, 0.01 mmol) in a round-bottomed flask,
which was closed hermetically with a septum and put under vac-
uum. To this mixture was added deoxygenated EtOH (1.0 mL). The
reaction mixture was then blanketed with hydrogen by application
of a hydrogen-filled balloon. The suspension was stirred vigorously
for 12 h, then filtered over Celite, and the solvent was evaporated
under reduced pressure. The crude material obtained was purified
by flash chromatography (20% MeOH/CH2Cl2) to afford (1R,2S)-
cis-3a as a yellowish oil (20 mg, 97% isolated yield).
Experimental Section
General Methods: Candida antarctica lipase type B (CAL-B, Novo-
zyme 435, 7300 PLU/g) was a gift from Novo Nordisk Co. Pseu-
domonas cepacia lipase was acquired from Sigma–Aldrich as
Amano Lipase PS/C I immobilized on ceramic (1061 U/g). All
other reagents were purchased from different commercial sources
(Acros, Fluka, and Sigma–Aldrich) and used without further puri-
fication. Solvents were distilled from an adequate desiccant under
an atmosphere of nitrogen. Flash chromatography was performed
by using silica gel 60 (230–240 mesh). Melting points were taken
on samples in open capillary tubes. IR spectra were recorded b
using NaCl plates or KBr pellets with a Perkin–Elmer 1720-X F7.
1H NMR, 13C NMR, DEPT, and 1H–13C heteronuclear experi-
ments were obtained using AC-300 (1H, 300.13 MHz and 13C,
75.5 MHz) or DPX-300 (1H, 300.13 MHz and 13C, 75.5 MHz)
Bruker spectrometers. The chemical shifts are expressed in parts
per million (ppm) using deuterated solvents as indicated for each
compound. APCI+ and ESI+ using an HP1100 chromatograph
mass detector were used to record mass spectra. High-resolution
mass spectrometry was carried out by ESI+ with a Bruker Micro-
TofQ spectrometer or by EI+ with a VG autospec spectrometer.
Measurement of the optical rotation was done with a Perkin–Elmer
241 polarimeter. High-performance liquid chromatography
(HPLC) analyses were carried out with a Hewlett Packard 1100
chromatograph UV detector at 210 and 215 nm by using a Daicel
CHIRALCEL OD, CHIRALCEL OD-H, or CHIRALPAK AS
column (25 cmϫ4.6 mm i.d.), varying the conditions depending on
the specific substrate.
Synthesis of (1S,2S)-cis-Cycloalkanamines-3a,b as a Representative
Procedure for the Mitsunobu Reaction and Subsequent Deprotection
of Alcohols (1S,2S)-trans-1a,b: To a solution of (1S,2S)-trans-1a,b
(3.01 mmol) in dry THF (19.8 mL) was successively added PPh3
(0.95 g, 3.61 mmol) and phthalimide (443 mg, 3.01 mmol) under a
nitrogen atmosphere. The resulting solution was cooled to 0 °C and
DEAD (662 μL, 3.61 mmol) was added carefully dropwise. The
mixture was warmed to room temperature and stirred for 4 h. After
this time, no starting material was apparent as assessed by TLC
(90% MeOH/CH2Cl2 for 1a; 20% MeOH/CH2Cl2 for 1b). The or-
ganic solvent was evaporated under reduced pressure, and crude
product 5a,b was used for the second step without further purifica-
tion. Thus, to a solution of crude 5a or 5b (3.01 mmol) in THF
(43.1 mL) and EtOH (7.1 mL) was added hydrazine monohydrate
(703 μL, 22.6 mmol), and the mixture was stirred at 70 °C over-
night. The white suspension formed during this time was filtered
off and washed with THF, and the organic solvent was evaporated
under reduce pressure, rendering a crude material that was purified
by flash chromatography (10–50% MeOH/CH2Cl2) to afford
(1R,2S)-cis-3a (313 mg, 63%, isolated yield) and (1R,2S)-cis-3b
(155 mg, 34%, isolated yield) as yellowish oils. Data for (1R,2S)-
cis-3a: R (20% MeOH/EtOAc) = 0.17. IR (NaCl): ν = 3374, 2939,
˜
f
Experimental Procedure for Mesylation Reaction of (1S,2S)-trans- 2359, 2166, 1644, 1500, 1452, 1296, 1112, 1086, 1034, 919, 820,
Cyclohexanol 1a: To a solution of (1S,2S)-trans-1a (100 mg,
0.6 mmol) in dry CH2Cl2 (7.5 mL) under an inert atmosphere was
added pyridine (97 μL, 1.2 mmol). This mixture was kept at 0 °C
and mesyl chloride (87 μL, 1.2 mmol) was added dropwise. During
the course of reaction, up to 6 equiv. of the chloride was added
(3ϫ87 μL, 3.6 mmol). The solution was stirred at room tempera-
ture for 48 h until complete consumption of the starting material,
as detected by TLC (10% MeOH/CH2Cl2). Product (1S,2S)-2
(85 mg, 58% isolated yield) was obtained as a white solid. Rf (10%
748 cm–1. 1H NMR (300.13 MHz, MeOD): δ = 1.50–1.68 (m, 3 H,
2 4-H, 5-H), 1.79–1.97 (m, 4 H, 3-H, 5-H, 2 6-H), 2.16–2.30 (m, 1
H, 3-H), 3.33 (q, J = 3.5 Hz, 1 H, 1-H), 4.32 (q, J = 3.6 Hz, 1 H,
2-H), 7.01 (s, 1 H, 11-H), 7.28 (s, 1 H, 10-H), 7.79 (s, 1 H, 8-H)
ppm. 13C NMR (75.5 MHz, MeOD): δ = 20.8 (C-5), 25.5 (C-4),
27.1 (C-3), 30.1 (C-6), 53.5 (C-1), 58.5 (C-2), 120.3 (C-11), 129.7
(C-10), 137.9 (C-8) ppm. HRMS (ESI+): calcd. for [M + H]+
152.1182; found 152.1179. [α]2D0 = –59.9 (c = 1.0, MeOH) for the
(1R,2S)-enantiomer with Ͼ99%ee by inversion of configuration.
Data for (1R,2S)-cis-3b: Rf (20% MeOH/EtOAc) = 0.06. IR
MeOH/CH Cl ) = 0.55. M.p. 99–102 °C. IR (KBr): ν = 3428, 2943,
˜
2
2
2868, 1646, 1501, 1347, 1236, 1174, 1085, 946, 884, 833, 749 cm–1. (NaCl): ν = 3362, 3106, 2966, 2350, 2170, 1990, 1644, 1567, 1504,
˜
1H NMR (300.13 MHz, CDCl3): δ = 1.36–1.51 (m, 2 H, 4-H), 1.60– 1236, 1111, 1086, 1018, 913, 823, 746 cm–1. 1H NMR (300.13 MHz,
1.73 (m, 1 H, 5-H), 1.80–1.90 (m, 3 H, 5-H, 2 6-H), 2.33 (s, 3 H, MeOD): δ = 1.61–1.73 (m, 1 H, 4-H), 1–77–1.88 (m, 1 H, 4-H),
14-H), 3.95–4.04 (m, 1 H, 1-H), 4.47–4.55 (m, 1 H, 2-H), 7.06 (d, 2.01–2.38 (m, 4 H, 2 3-H, 2 5-H), 3.57 (q, J = 6.3 Hz, 1 H, 1-H),
J = 12.5 Hz, 2 H, 10-H, 11-H), 7.63 (s, 1 H, 8-H) ppm. 13C NMR 4.64 (q, J = 6.6 Hz, 1 H, 2-H), 7.08 (s, 1 H, 10-H), 7.26 (s, 1 H, 9-
(75.5 MHz, CDCl3): δ = 23.7 (C-5), 24.2 (C-4), 32.0 (C-3), 33.2 (C- H), 7.78 (s, 1 H, 7-H) ppm. 13C NMR (75.5 MHz, MeOD): δ =
6), 36.7 (C-14), 59.6 (C-2), 83.7 (C-1), 116.8 (C-11), 129.4 (C-10),
21.9 (C-4), 24.6 (C-3), 32.2 (C-5), 56.5 (C-1), 62.7 (C-2), 120.8 (C-
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Chiral 2-(1H-Imidazol-1-yl)cycloalkanamines by Enzymatic Resolution
10), 129.8 (C-9), 138.8 (C-7) ppm. HRMS (ESI+): calcd. for [M +
H]+ 166.1339; found 166.1343. [α]2D0 = –26.1 (c = 1.5, MeOH) for
the (1R,2S)-enantiomer with Ͼ99%ee by inversion of configura-
tion.
room temperature. and stirred for 6 h. After this time, no starting
material was detected by TLC analysis (10% MeOH/CH2Cl2). The
organic solvent was evaporated under reduced pressure, and the
crude material was used without further purification for the second
step. The crude material was dissolved in MeOH (5 mL), and to
the solution was added K2CO3 (829.3 mg, 6.0 mmol) and H2O
(5 mL). The reaction was stirred overnight, and after this time the
solvent was evaporated and the resulting mixture was resuspended
in H2O (10 mL) and extracted with EtOAc (4ϫ10 mL). The or-
ganic layers were combined and dried with Na2SO4. Solids were
then filtered and EtOAc was evaporated, rendering a crude material
that was purified by flash chromatography (2 to 10% MeOH/
CH2Cl2) to afford (1R,2S)-cis-1a as a white solid (395 mg, 79%
isolated yield). Experimental data have been already described.[10b]
Procedure for the Preparation of (1R,2S)-cis-Cyclopentanol 1b by
Mitsunobu Reaction and Subsequent Deprotection: To a solution of
alcohol (1S,2S)-trans-1b (200 mg, 1.3 mmol) in dry THF (18 mL)
was successively added acetic acid (141 μL, 2.6 mmol) and PPh3
(682 mg, 2.6 mmol) under a nitrogen atmosphere. The resulting
solution was cooled to 0 °C and DEAD (477 μL, 2.6 mmol) was
added slowly. The mixture was left to warm to room temperature
and stirred for 2 h. After this time, no starting material could be
observed by TLC analysis (90% CH2Cl2/MeOH). The organic sol-
vent was evaporated under reduced pressure, and without further
purification the crude reaction was used for the second step. The
crude reaction mixture was dissolved in MeOH (2.2 mL), and to
the solution was added K2CO3 (359 mg, 2.6 mmol) and H2O
(2.2 mL) to favor the solubility of the mixture. The reaction was
stirred overnight, and after this time, the solvent was evaporated,
and the resulting mixture was resuspended in H2O (10 mL) and
extracted with EtOAc (4ϫ10 mL). The organic phases were com-
bined and dried with Na2SO4. The solids were filtered and EtOAc
was then evaporated, leaving a crude material that was purified by
flash chromatography (2–10% MeOH/CH2Cl2) to render (1R,2S)-
cis-1b as a white solid (136 mg, 68% isolated yield). Experimental
data already published.[10b]
Procedure for the Synthesis of (1S,2S)-trans-Cyclohexanamine 3a:
To a solution of (1R,2S)-cis-1a (200 mg, 1.2 mmol) in dry THF
(6 mL) was added PPh3 (378 mg, 1.4 mmol) and phthalimide
(177 mg, 1.2 mmol) under a nitrogen atmosphere. The resulting
solution was cooled to 0 °C and DEAD (257 μL, 1.4 mmol) dis-
solved in dry THF (1.9 mL) was added. The mixture was allowed
to warm to room temperature and stirred overnight. After this time
no starting material could be detected by TLC analysis (10%
MeOH/CH2Cl2). The organic solvent was evaporated under re-
duced pressure, and the crude reaction was used for the second step
without further purification. This mixture was dissolved in THF
(17.2 mL) and EtOH (2.8 mL), and to this mixture was then added
hydrazine monohydrate (280 μL, 9.0 mmol). The clear solution was
stirred at 70 °C for 12 h. The white suspension formed during this
time was filtered off and washed with THF (3ϫ10 mL), and the
organic solvent was evaporated under reduced pressure to afford a
crude material that was purified by flash chromatography (10–50%
MeOH/CH2Cl2). Product (1S,2S)-trans-3a was obtained as a yel-
lowish oil (24 mg, 12% isolated yield). Rf (20% MeOH/CH2Cl2) =
Procedure for the Synthesis of (1S,2S)-trans-Cyclopentanamine-3b:
To a solution of alcohol (1R,2S)-cis-1b (135 mg, 0.9 mmol) in dry
THF (6.0 mL) was added PPh3 (279 mg, 1.1 mmol) and phthal-
imide (132 mg, 0.9 mmol) under a nitrogen atmosphere. The re-
sulting solution was cooled to 0 °C and DEAD (0.2 mL, 1.1 mmol)
was added carefully. The mixture was left to warm to room tem-
perature and stirred for 5 h. After this time, no starting material
was apparent by TLC analysis (50% MeOH/AcOEt). The organic
solvent was evaporated under reduced pressure, and the crude ma-
terial was used for the second step without further purification. To
the resulting mixture dissolved in THF (13 mL) and EtOH (2 mL)
was added hydrazine monohydrate (210 μL, 6.8 mmol), and the
clear solution was stirred at 70 °C overnight. The white suspension
formed during this time was filtered and washed with THF
(3ϫ10 mL). The organic solvent was evaporated under reduced
pressure to afford a crude material that was purified by flash
chromatography (10–50% MeOH/CH2Cl2), rendering (1S,2S)-
0.08. IR (NaCl): ν = 3282, 2937, 2861, 2424, 1995, 1660, 1556,
˜
1494, 1450, 1375, 1312, 1236, 1162, 1111, 1085, 1039, 993, 918,
1
750 cm–1. H NMR (300.13 MHz, CDCl3): δ = 1.31–1.41 (m, 1 H,
4-H), 1.46–1.54 (m, 2 H, 4-H, 5-H), 1.82–1.92 (m, 3 H, 3-H, 5-H,
6-H), 2.01–2.10 (m, 2 H, 3-H, 6-H), 2.92–3.01 (dt, J = 4.0 Hz, 1
H, 1-H), 3.73–3.82 (m, 1 H, 2-H), 7.06 (s, 1 H, 11-H), 7.26 (s, 1 H,
10-H), 7.77 (s, 1 H, 8-H) ppm. 13C NMR (75.5 MHz, MeOD): δ =
26.7 (C-4), 27.4 (C-5), 35.2 (C-3), 35.9 (C-6), 56.8 (C-1), 66.4 (C-
2), 119.5 (C-11), 130.4 (C-10), 138.8 (C-8) ppm. HRMS (ESI+):
calcd. for [M + H]+ 166.1339; found 166.1345. [α]2D0 = +16.0 (c =
0.8, MeOH) for the (1S,2S)-enantiomer with Ͼ99%ee by inversion
of configuration.
trans-3b as a yellowish oil (55 mg, 41% isolated yield). Rf (20%
MeOH/CH Cl ) = 0.07. IR (NaCl): ν = 3407, 2964, 1995, 1641,
˜
2
2
Procedure for the Synthesis of Racemic trans-Cycloalkanamines 3a,b
1502, 1414, 1385, 1329, 1291, 1236, 1111, 1087, 921 cm–1. 1H NMR
(300.13 MHz, MeOD): δ = 1.50–1.63 (m, 1 H, 4-H), 1.84–2.06 (m,
3 H, 2 5-H, 4-H), 2.11–2.22 (m, 1 H, 3-H), 2.25–2.36 (m, 1 H, 3-
H), 3.38 (q, J = 8.4 Hz, 1 H, 1-H), 4.18 (q, J = 8.3 Hz, 1 H, 2-H),
7.05 (s, 1 H, 9-H), 7.26 (s, 1 H, 10-H), 7.78 (s, 1 H, 7-H) ppm. 13C
NMR (75.5 MHz, MeOD): δ = 21.9 (C-4), 33.0 (C-3), 34.0 (C-5),
60.7 (C-1), 67.9 (C-2), 119.1 (C-10), 130.0 (C-9), 138.2 (C-7) ppm.
through an Aziridine Intermediate: To
a solution of 8a,b
(11.9 mmol) in acetone (6.5 mL) and water (6.5 mL) was added so-
dium azide (1.9 mg, 29.8 mmol). The mixture was heated to reflux
(57 °C) for 14 h, and the course of reaction was followed by TLC
(10% MeOH/CH2Cl2). After 14 h the acetone was evaporated un-
der reduced pressure, and the remaining aqueous mixture was ex-
tracted first with Et2O (3ϫ5 mL) and then with CH2Cl2
(3ϫ5 mL). The organic layers were collected, washed with brine
(2ϫ5 mL), and evaporated under reduced pressure. The resulting
crude material was dissolved in THF (6.1 mL) and PPh3 (3.15 g,
11.9 mmol) was added. The solution was heated to reflux under an
inert atmosphere for 16 h. After this time, the reaction mixture was
cooled to room temperature, and to it was added trifluoroacetic
acid (44.2 mL, 0.6 mmol) followed by imidazole (1.6 g, 23.8 mmol).
This new reaction mixture was again heated to reflux for 16 h. Af-
terwards, the reaction was cooled to room temperature, the solvent
was evaporated under reduced pressure, and the crude reaction
HRMS (ESI+): calcd. for [M + H]+ 152.1182; found 152.1186. [α]
20
= +51.8 (c = 1, MeOH) for the (1S,2S)-enantiomer with
D
Ͼ99%ee by inversion of configuration.
Procedure for the Preparation of (1R,2S)-cis-Cyclohexanol 1a by
Mitsunobu Reaction and Subsequent Deprotection: To a solution of
alcohol (1S,2S)-trans-1a (500 mg, 3.0 mmol) in dry THF (41 mL)
was added PPh3 (1.57 g, 6.0 mmol) and p-nitrobenzoic acid
(1.00 mg, 6.0 mmol) under a nitrogen atmosphere. The resulting
solution was cooled to 0 °C and DEAD (1.1 mL, 6.0 mmol) was
carefully added dropwise. The mixture was allowed to warm to
Eur. J. Org. Chem. 2011, 1057–1063
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1061

S. Alatorre-Santamaría, V. Gotor-Fernández, V. Gotor
FULL PAPER
products were purified by flash chromatography (40–80% MeOH/
EtOAc). Chromatography afforded racemic trans-cycloalkan-
amines 3a,b (1.10 g, 56% isolated yield for 3a; 846 mg, 47%
isolated yield for 3b) as yellowish oils.
Procedure for the Preparation of Racemic Carbamates (؎)-trans-
15a,b: To a solution of amine (Ϯ)-trans-3a,b (0.19 mmol) dissolved
in methanol (1.9 mL) was added Boc2O (50 mg, 0.22 mmol) under
an inert atmosphere, and the mixture was stirred at room tempera-
ture for 4 h. After this time, no evidence of starting material was
detected by TLC (60% MeOH/EtOAc). The solvent was evaporated
under reduced pressure, and the crude material was purified by
flash chromatography (20% MeOH/EtOAc). Chromatography af-
forded (Ϯ)-trans-15a (51 mg, 98% isolated yield) as a white solid
and (Ϯ)-trans-15b (47 mg, 98% isolated yield) as a colorless oil.
Procedure for the Chemical Synthesis of Racemic trans-Acetamides
13a,b and trans-Methoxyacetamides 14a: To a solution of trans-cy-
cloalkanamine 3a,b (0.19 mmol) in CH2Cl2 (280 μL) was added
pyridine (38 μL, 0.48 mmol) under an inert atmosphere. The mix-
ture was cooled to 0 °C and the respective chloride (acetyl chloride:
56 μL, 0.79 mmol; methoxyacetyl chloride: 52 μL, 0.73 mmol) was
added carefully. Reactions were stirred at room temperature for
6 h at which point TLC analysis (60% MeOH/EtOAc) revealed the
absence of starting materials. After this time, the solvent was evapo-
rated under reduced pressure, and the crude reaction mixture was
suspended in water (2 mL). Aqueous solutions were slightly alka-
linized with 1 m NaOH and extracted with CH2Cl2 (3ϫ3 mL). The
organic fractions were combined, and the solvents were evaporated
under reduced pressure. Flash chromatography (20–40% MeOH/
EtOAc) afforded (Ϯ)-trans-13a (37 mg, 95% isolated yield), trans-
13b (33 mg, 89% isolated yield), (Ϯ)-trans-14a (37 mg, 83% iso-
lated yield), and (Ϯ)-trans-14b (23 mg, 55% isolated yield).
tert-Butyl (؎)-trans-2-(1H-Imidazol-2-yl)cyclohexyl Carbamate
(15a): Rf (60% MeOH/EtOAc) = 0.65. M.p. 161–162 °C. IR (KBr):
ν = 3404, 2938, 1695, 1504, 1421, 1366, 1316, 1237, 1171, 1136,
˜
1
1048, 918 cm–1. H NMR (300.13 MHz, CDCl3): δ = 1.33 (s, 9 H,
15-H), 1.41–1.54 (m, 2 H, 2 5-H), 1.89–2.13 (m, 5 H, 2 3-H, 4-H,
2 6-H), 3.65–3.70 (m, 1 H, 1-H), 3.85–3.93 (m, 1 H, 2-H), 6.95 (s,
1 H, 11-H), 7.17 (s, 1 H, 10-H), 7.65 (s, 1 H, 8-H) ppm. 13C NMR
(75.5 MHz, MeOD): δ = 26.5 (C-4), 26.7 (C-5), 29.1 (3C-15), 34.6
(C-3), 34.9 (C-6), 55.6 (C-1), 62.9 (C-2), 80.4 (C-14), 119.7 (C-11),
129.0 (C-10), 138.4 (C-8), 153.0 (C-12) ppm. HRMS (ESI+): calcd.
for [M + H]+ 266.1863; found 266.1861. HPLC (Chiralpak AS col-
umn, hexane/2-PrOH = 97:3, 0.8 mL/min, 40 °C): tR = 28.0,
31.2 min.
(؎)-N-[trans-2-(1H-Imidazol-2-yl)cyclohexyl]acetamide (13a): Pale-
yellow oil. R (60% MeOH/EtOAc) = 0.50. IR (NaCl): ν = 3405,
˜
f
tert-Butyl (؎)-trans-2-(1H-Imidazol-2-yl)cyclopentyl Carbamate
3282, 3114, 2900, 2861, 2374, 1317, 1640, 1562, 1505, 1454, 1376,
(15b): R (60% MeOH/EtOAc) = 0.60. IR (NaCl): ν = 3425, 3055,
˜
1
1279, 1112, 1041, 918, 734 cm–1. H NMR (300.13 MHz, CDCl3):
f
2978, 1699, 1501, 1418, 1367, 1266, 1169, 1079, 737 cm–1. 1H NMR
(300.13 MHz, CDCl3): δ = 1.41 (s, 9 H, 14-H), 1.58–1.70 (m, 1 H,
4-H), 1.85–1.98 (m, 2 H, 4-H, 5-H), 2.00–2.08 (m, 1 H, 5-H), 2.12–
2.20 (m, 1 H, 3-H), 2.23–2.35 (m, 1 H, 3-H), 4.07 (q, J = 6.3 Hz,
1 H, 1-H), 4.30–4.36 (m, 1 H, 2-H), 7.01 (s, 1 H, 10-H), 7.25 (s, 1
H, 9-H), 7.73 (s, 1 H, 7-H) ppm. 13C NMR (75.5 MHz, MeOD): δ
= 21.7 (C-4), 29.2 (3 C-14), 31.4 (C-3), 31.9 (C-5), 59.4 (C-1), 64.6
(C-2), 119.4 (C-10), 129.6 (C-9), 138.1 (C-7), 158.3 (C-11) ppm.
HRMS (ESI+): calcd. for [M + H]+ 252.1707; found 252.11708.
HPLC (Chiralcel OD column, hexane/2-PrOH = 95:5, 0.8 mL/min,
20 °C): tR = 24.3, 27.8 min.
δ = 1.47–1.56 (m, 3 H, 4-H, 2 5-H), 1.78 (s, 3 H, 13-H), 1.86–2.03
(m, 4 H, 3-H, 4-H, 2 6-H), 2.12–2.15 (m, 1 H, 3-H), 3.97–4.13 (m,
2 H, 1-H, 2-H), 6.96 (s, 1 H, 11-H), 7.20 (s, 1 H, 10-H), 7.73 (s, 1
H, 8-H) ppm. 13C NMR (75.5 MHz, MeOD): δ = 22.9 (C-13), 26.3
(C-5), 26.6 (C-4), 34.1 (C-3), 35.1 (C-6), 54.2 (C-1), 64.2 (C-2),
119.6 (C-11), 129.1 (C-10), 133.1 (C-8), 172.8 (C-12) ppm. HRMS
(ESI+): calcd. for [M + H]+ 208.1444; found 208.1444. HPLC (Chi-
ralcel OD-H column, hexane/2-PrOH = 90:10, 0.8 mL/min, 30 °C):
tR = 16.3, 21.7 min.
(؎)-N-[trans-2-(1H-Imidazol-2-yl)cyclopentyl]acetamide
(13b):
White semisolid. R (60% MeOH/EtOAc) = 0.45. IR (NaCl): ν =
˜
f
Typical Procedure for the Enzymatic Kinetic Resolution of Racemic
Amines trans-3a,b by Employing an Acylation Process: To a suspen-
sion of (Ϯ)-trans-3a,b and the enzyme (CAL-B or PSL-C I,
1:1 w/w ratio relative to substrate) was added the corresponding
acylation agent [1.2 mL; ethyl acetate (11) or ethyl methoxyacetate
(12)] under a nitrogen atmosphere. The resulting suspension was
placed on an orbital shaker (250 rpm) for 24 h at either 30 or 45 °C.
The enzyme was then filtered out of the reaction and washed with
THF (3ϫ5 mL). All organic solvents were then evaporated under
reduced pressure, and the crude mixture of products was purified
by flash chromatography (40–80%, MeOH, EtOAc). Acylated
product 13a,b or 14a was subjected to HPLC analysis, and remain-
ing amines were converted into carbamates 15a,b to determine the
enantiomeric excess values.
3399, 3273, 3115, 2968, 2362, 1643, 1563, 1504, 1377, 1313, 1234,
1085, 1038, 918, 823, 736 cm–1. 1H NMR (300.13 MHz, CDCl3): δ
= 1.62–1.75 (m, 1 H, 4-H), 1.91–2.07 (m, 3 H, 3-H, 4-H, 5-H), 1.93
(s, 3 H, 12-H), 2.15–2.26 (m, 1 H, 5-H), 2.29–2.40 (m, 1 H, 3-H)
4.36 (m, 2 H, 1-H, 2-H), 7.01 (s, 1 H, 10-H), 7.27 (s, 1 H, 9-H),
7.79 (s, 1 H, 7-H) ppm. 13C NMR (75.5 MHz, MeOD): δ = 22.1
(C-4), 23.1 (C-12), 31.4 (C-3), 32.4 (C-5), 58.1 (C-1), 84.7 (C-2),
119.5 (C-10), 129.6 (C-9), 138.2 (C-7), 173.6 (C-11) ppm. HRMS
(ESI+): calcd. for [M + H + Na]+ 216.1107; found 216.1107. HPLC
(Chiralcel OD-H column, hexane/EtOH = 97:3, 1.0 mL/min,
30 °C): tR = 37.0, 42.0 min.
(؎)-N-[trans-2-(1H-Imidazol-2-yl)cyclohexyl]methoxyacetamide
(14a): White semisolid. Rf (60% MeOH/EtOAc) = 0.43. IR (NaCl):
ν = 3430, 3310, 2937, 2862, 1655, 1544, 1504, 1450, 1235, 1198,
˜
1113, 921, 733 cm–1. 1H NMR (300.13 MHz, CDCl3): δ = 1.38–
1.52 (m, 3 H, 2 4-H, 5-H), 1.71–1.91 (m, 3 H, 5-H, 2 6-H), 2.08–
2.16 (m, 2 H, 2 3-H), 3.21 (s, 3 H, 15-H), 3.59 (d, J = 15.4 Hz, 1
H, 13-H), 3.76 (d, J = 15.1 Hz, 1 H, 13-H), 3.85–3.93 (m, 1 H, 1-
H), 4.05–4.17 (m, 1 H, 2-H), 6.49 (d, J = 9.1 Hz, 1 H, NH), 6.99
(d, J = 10.8 Hz, 2 H, 10-H, 11-H), 7.47 (s, 1 H, 8-H) ppm. 13C
NMR (75.5 MHz, MeOD): δ = 26.4 (C-4), 26.6 (C-5), 33.9 (C-3),
35.0 (C-6), 54.0 (C-1), 59.9 (C-2), 61.8 (C-15), 72.9 (C-13), 119.6
(C-11), 129.1 (C-10), 138.3 (C-8), 172.4 (C-12) ppm. MS (ESI+):
m/z (%) = 260.1 [M + Na]+ (100). HPLC (Chiralcel OD column,
hexane/2-PrOH = 90:10, 0.8 mL/min, 20 °C): tR = 28.2, 33.7min.
Acknowledgments
Financial support from the Spanish Ministerio de Innovación y
Ciencia (Project CTQ 2007–61126) is gratefully acknowledged.
V.G.-F. thanks the Ramón y Cajal Program for a predoctoral fel-
lowship, and S.A.-S. thanks the Mexican Consejo Nacional de Ci-
encia y Tecnología (CONACYT).
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Eur. J. Org. Chem. 2011, 1057–1063
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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