An effective approach to the enantiomers of alicyclic β-aminonitriles by using lipase catalysis

Article abstract of DOI:10.1016/j.tetasy.2005.10.017

Lipase-catalyzed N-acylations of racemic cis- and trans-2- aminocyclopentane- (and cyclohexane-) carbonitriles with 2,2,2-trifluoethyl butanoate in tert-butyl methyl ether (TBME) and in room-temperature ionic liquids (RTILs) were studied. The racemates were effectively resolved (E >200) on a preparative scale by lipase PS-C II (lipase from Burkholderia cepacia) in TBME, resulting in two enantiomers in their enantiopure forms at 50% conversion. The reactions in RTILs with Novozym 435 (Candida antarctica lipase B) were slow and proceeded with low enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2005.10.017

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3690–3697
An effective approach to the enantiomers of alicyclic
b-aminonitriles by using lipase catalysis
a,b
a
a
b
a,
*
M o´ nika Fitz, Katri Lundell, Maria Lindroos, Ferenc F u¨ l o¨ p and Liisa T. Kanerva
a
Laboratory of Synthetic Drug Chemistry and Department of Chemistry, University of Turku, Lemmink a¨ isenkatu 5 C,
FIN-20520 Turku, Finland
b
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, PO Box 121, Hungary
Received 18 August 2005; accepted 14 October 2005
Available online 11 November 2005
Abstract—Lipase-catalyzed N-acylations of racemic cis- and trans-2-aminocyclopentane- (and cyclohexane-) carbonitriles with
,2,2-trifluoethyl butanoate in tert-butyl methyl ether (TBME) and in room-temperature ionic liquids (RTILs) were studied. The
2
racemates were effectively resolved (E >200) on a preparative scale by lipase PS-C II (lipase from Burkholderia cepacia) in TBME,
resultingin two enantiomers in their enantiopure forms at 50% conversion. The reactions in RTILs with Novozym 435 ( Candida
antarctica lipase B) were slow and proceeded with low enantioselectivity.
ꢀ
2005 Elsevier Ltd. All rights reserved.
1
. Introduction
asymmetric N-acylation, as N-hydroxymethylated b-lac-
tam intermediates for lipase-catalyzed asymmetric O-
acylation, and as amino acids for direct lipase-catalyzed
2
,3
Alicyclic b -amino acids are structural units of oligo-
peptides, intermediates in the preparation of pharma-
ceutically important 1,3-heterocycles, and building
blocks of potential pharmacons. They include, for
instance, cispentacin [FR 109615, (1R,2S)-2-amino-
8
–11
hydrolysis of the b-lactam ring.
These examples indi-
cate a wide area of economical application of the readily
availability lipases compared to enzymes with more tar-
geted substrate specificities.
1
cyclopentanecarboxylic acid] and its derivatives, which
2
,3
exhibit antifungal activity against Candida strains.
Herein, we report the application of the lipase-induced
asymmetric acylation of b-aminonitriles rac-1–4 in
tert-butyl methyl ether (TBME) and in room-tempera-
ture ionic liquids (RTILs) for the preparation of enan-
tiopure counterparts (Schemes 1 and 2). To the best of
our knowledge, the asymmetric N-acylation of 3-amino-
4-(1H-3-indolyl)butanenitrile is the only reported
lipase-catalyzed kinetic resolution of b-aminonitriles
Nitriles are known to be highly valuable intermediates in
synthetic chemistry. Both acid- and base-induced hydro-
lysis of a nitrile gives a carboxylic acid, while metal
hydrides reduce nitriles to give primary amines.
Accordingly, b-aminonitriles are valuable intermediates
in the preparation of b-amino acids and the correspond-
ingdiamines. Besides chemical transformations, nitrile-
convertingenzymes are used to hydrolyze nitriles in the
1
2
so far. On the other hand, the enzymatic acylation of
a-aminonitriles in the presence of lipases has already been
4
13
formation of carboxylic acids and amides. Thus, enan-
described. Although nitriles are not carbonyl com-
tioselective hydrolysis of the nitrile group by nitrilases
has provided an attractive approach for the production
pounds, we found it interestingto compare the enzy-
matic enantioselectivities for the acylation of alicyclic
b-aminonitriles herein with those observed earlier
for the corresponding b-amino esters. We expected that
the absolute configurations of the lipase-catalyzed reso-
lution products 1–8 would be the same as in the case of
2
,3
of alicyclic b -amino acids from the corresponding
5
–7
racemic b-aminonitriles.
Interestingly, the enantio-
2
,3
mers of the same alicyclic b -amino acids have previ-
ously been resolved as amino esters for lipase-catalyzed
8
the corresponding b-amino esters. In order to verify
this expectation, (1R,2S)-2 was reduced with LiAlH4
*
Correspondingauthor. Tel.: +358 2333 6773; fax: +358 2333 7955;
e-mail: lkanerva@utu.fi
to the (1S,2S)-diamine, and (1S,2S)-4 to the (1S,2R)-
diamine, with known specific rotations (Scheme 3).
1
4,15
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.017

M. Fitz et al. / Tetrahedron: Asymmetry 16 (2005) 3690–3697
3691
O
O
1
. CSI/CH Cl2
Boc O, DMAP
2
2
(
)n
( )n
(
)n
2
. Na SO , K CO
NH
N
2
3
2
3
Boc
9
(n = 1)
11 (n = 1)
12 (n = 2)
13 (n = 1)
14 (n = 2)
1
0 (n = 2)
2
5% NH /MeOH
3
O
CN
NH2
1
. POCl , DMF
3
(
)n
( )n
2
. Pyridine
Boc
Boc
N
N
H
H
3
3% CF CO H/
17 (n = 1)
8 (n = 2)
15 (n = 1)
16 (n = 2)
3
2
1
CH Cl2
2
CN
CN
NC
Lipase
O
(
)n
( )
n
+
( )
n
PrCO R
2
NH2
NH2
Pr
N
H
rac-1 (n = 1)
rac-2 (n = 2)
(1
(1
R
R
,2
S
)-1 (n = 1)
)-2 (n = 2)
(1
(1
S
S
,2
R
R
)-5 (n = 1)
)-6 (n = 2)
,2
S
,2
Scheme 1. Transformation of cyclopentene and cyclohexene into the enantiomers of cis-b-aminonitriles 1 and 2.
CN
Chloramine-T
Ph(CH ) Br
TMSCN
NH Ts
( )n
(
)n
(
)n
Ts
3
3
3
Bu NF
4
N
H
9
(n = 1)
19 (n = 1)
20 (n = 2)
21 (n = 1)
22 (n = 2)
1
0 (n = 2)
1
. Boc O, DMAP
2
2. Mg, MeOH
CN
CN
TMSBr, PhOH/
(
)n
( )n
CH Cl2
Boc
2
NH Br
N
H
3
2
5 (n = 1)
23 (n = 1)
24 (n = 2)
2
Na CO3
26 (n = 2)
CN
CN
NC
Lipase
PrCO CH CF
3
O
(
)n
(
)n
+
( )n
2
2
NH2
NH2
Pr
N
H
rac-3 (n = 1)
rac-4 (n = 2)
(1
(1
S
S
,2
,2
S
S
)-3 (n = 1)
)-4 (n = 2)
(1
(1
R
R
,2
R
R
)-7 (n = 1)
)-8 (n = 2)
,2
Scheme 2. Transformation of cyclopentene and cyclohexene into the enantiomers of trans-b-aminonitriles 3 and 4.
2
. Results and discussion
b-lactam, followed by ringopeningthrou gh ammonoly-
sis, gave the Boc-protected amides 15 and 16, as previ-
1
6
2
.1. Preparation of racemic substrates rac-1–4
ously described.
Dehydration of the amide with
1
7
phosphorus oxychloride, followed by N-Boc deprotec-
tion with 2,2,2-trifluoroacetic acid, furnished the race-
mic substrates. A three-step synthesis of rac-1 and rac-
2 has previously been reported, startingfrom adiponit-
rile and heptanedinitrile, respectively, where the cis
Substrates rac-1 and rac-2 (the racemic cis isomers) were
prepared by followingthe protocol shown in Scheme 1.
In this protocol, the alicyclic b-lactams 11 and 12 were
readily available by the cycloaddition of chlorosulfonyl
9
–11
7
isocyanate to cycloalkenes.
N-Boc protection of the
product had to be separated from the trans by-product.

3692
M. Fitz et al. / Tetrahedron: Asymmetry 16 (2005) 3690–3697
Table 1. Lipase screeningfor the enantioselective acylation of rac-1
(0.05 M) with PrCO CH CF (0.1 M) in TBME in the presence of the
enzyme preparation (50 mg/mL) at room temperature
CN
NH2
1
2
LiAlH
4
2
1
2
2
3
NH2
NH2
(1S,2S)-diamine
Entry
Lipase
Time (h)
Conversion (%)
E
(
1
R
,2
S
)-2 (n = 2)
1
2
3
4
Lipase PS
Lipase PS-C II
CAL-A
0.5
2
0.5
1
50
51
83
50
ꢀ200
>200
2 ± 1
>200
CN
NH2
1
LiAlH4
2
CAL-B
2
1
NH2
)-4 (n = 2)
NH2
)-diamine
(
1
S
,2
S
(1S,2R
in Tables 1 and 2. The lipase PS preparations (PS on
Celite and PS-C II on ceramic particles) gave excellent
enantioselectivities for both cis-b-aminonitriles (entries
Scheme 3. Reduction of b-aminonitrile enantiomers to the diamine
enantiomers.
1
and 2, Table 1; entries 2 and 3, Table 2), while
Substrates rac-3 and rac-4 (the racemic trans-isomers)
were prepared by followingthe protocol shown in
Scheme 2. Catalytic aziridination of the cycloalkenes
with chloramine-T gave the N-Ts-aziridines 19 and 20,
and subsequent openingof the aziridine ringwith tri-
methylsilyl cyanide in the presence of tetrabutylammo-
CAL-A resulted in a fast reaction without enantioselec-
tivity. It was impossible to increase the low enantioselec-
tivity of CAL-A by changing the solvent from TBME to
either toluene, acetonitrile, tert-amyl alcohol or ethyl
butanoate, as indicated by the E values constantly being
between 2 and 4. Accordingly, there is a clear difference
in the enantioselective behavior of the two lipases
toward nitrile substrates as compared with the previous
ester substrates with a cis-configuration (entries 3 and 7
as compared with entries 1, 2, and 4–6, Table 3). Good
(entry 5, Table 2) to excellent (entry 4, Table 1) enantio-
selectivities were observed in the case of C. antarctica
lipase B (CAL-B) as catalyst. For acylation in neat ethyl
butanoate, the lipases totally lost their enantioselectivity
(Table 2).
5
,6
nium fluoride proceeded by a known method. In the
next step, the tosyl group in 21 and 22 was changed to
Boc in two steps. The use of the protective groups Ts
and Boc was due to the previous observation that the
6
ringopeningof N-Boc-aziridine was incomplete. More-
over, the removal of Ts with the present procedure was
1
8
clean. Deprotection of 23 and 24 with bromotrimeth-
ylsilane and phenol, and neutralization of the resulting
hydrobromides 25 and 26 with sodium carbonate, fur-
nished the racemic substrates as described in the
Experimental.
On the basis of the lipase screening, the lipase PS-C II-
catalyzed acylation of rac-2 with 2,2,2-trifluoroethyl
butanoate in TBME was further optimized with respect
to the amount of the enzyme. The reason for this was
the observation that, although aminonitrile 1 reacted
rapidly to 50% conversion in the presence of 50 mg/
mL of the enzyme, the reaction in the case of rac-2
tended to slow down at close to 50% conversion (Table
4). Thus, its took 6 h to reach 49% conversion, whereas
the first 46% was reached within only 2 h (entries 3 and
4). In order to obtain both enantiomers in highly enan-
tiopure form in a reasonable time, the gram-scale resolu-
tion of rac-2 was performed at 70 mg/mL of lipase PS-C
II (entries 5 and 6). Chromatographic purification
finally furnished (1R,2S)-1 (ee = 98%) and (1S,2R)-5
(ee = 98%) from rac-1, and (1R,2S)-2 (ee >99%) and
(1S,2R)-6 (ee = 96%) from rac-2, as shown in Section
4.
2
.2. Kinetic resolution of rac-1–4 in TBME
In our earlier studies on the enantioselective N-acylation
i
of alicyclic b-amino esters in ether (Et O, Pr O and
2
2
TBME) solutions, lipase PS from Burkholderia cepacia
(
earlier lipase from Pseudomonas cepacia) was the most
enantioselective lipase, in the case of the racemic trans-
isomers, as was Candida antarctica lipase A (CAL-A)
8
in the case of the racemic cis-isomers. As an exception
to this rule, lipase PS also exhibited excellent enantio-
selectivity for the acylation of cispentacin ethyl ester.
Herein, these lipases, together with some others, were
screened for the acylation of rac-1 and rac-2 with
2
,2,2-trifluoroethyl butanoate in TBME. The enantio-
selectivities observed in terms of the enantiomeric ratios
E and conversions after a certain time are reported
2
Table 2. Lipase screeningfor the enantioselective acylation of rac-2 with PrCO R in TBME at room temperature
a
b
Entry
Lipase
R = Et
2 3
R = CH CF
Time (h)
Conversion (%)
E
Time (h)
Conversion (%)
E
1
2
3
4
5
6
7
Lipase AK
Lipase PS
Lipase PS-C II
CAL-A
CAL-B
PPL
40
40
—
—
40
40
40
33
49
—
—
62
29
39
1.3 ± 0.1
3.2 ± 0.2
—
—
9 ± 1
6
4
4
0.5
6
12
43
48
83
48
—
—
30 ± 0.3
>200
>200
2 ± 1
79 ± 5
—
1.1 ± 0.01
1.2 ± 0.1
—
—
CRL
—
a
Reaction of rac-2 (0.1 M) in neat ethyl butanoate in the presence of the enzyme preparation (100 mg/mL).
Reaction of rac-2 (0.05 M) with the acyl donor (0.1 M) in TBME in the presence of the enzyme preparation (50 mg/mL).
b

M. Fitz et al. / Tetrahedron: Asymmetry 16 (2005) 3690–3697
3693
Table 3. Enantioselectivity for the lipase-catalyzed N-acylation of ethyl cis-2-aminocyclopentyl- 1a and cis-2-aminocyclohexyl- 2a 1-carboxylates and
that of rac-1 and rac-2
Entry
Ref.
Substrate
Acyl donor
Solvent
Lipase PS
CAL-A
E
E
a
1
2
3
4
5
6
7
8
8
—
8
8
1a (CO
1a (CO
1 (CN)
2a (CO
2a (CO
2a (CO
2 (CN)
2
Et)
Et)
AcOCH
AcOCH
2
CF
CF
3
Et
TBME
TBME
2
O
ꢀ100
31
37
2
a
2
2
3
>100
a
b
b
PrCO
AcOCH
PrCO CH
AcOCH
PrCO CH
2
CH
2
CF
3
3
3
>200 />200
2
2
2
Et)
Et)
Et)
2
CF
3
Et
Et
2
O
O
6
2
7
51
2
2
CF
2
ꢀ100
8
—
2
CF
3
TBME
TBME
57
a
2
2
CF
>200 />200
2
In 1a and 2a CO
2
Et is in the place of CN of compounds 1 and 2.
a
Lipase PS preparation on Celite.
Lipase PS-C II.
b
Table 4. Effect of the amount of the lipase PS-C II on the enantioselective acylation of rac-2 (0.05 M) with PrCO
2
2
CH CF
3
(0.1 M) in TBME at room
temperature
(1R,2S)-2
(1S,2R)-6
Entry
Enzyme (mg/mL)
Time (h)
Conversion (%)
ee
(%)
ee
(%)
E
1
2
3
4
5
6
25
25
50
50
70
70
2
8
2
6
2
4
42
50
46
49
49
50
70
96
83
92
93
97
99
97
98
97
98
96
>200
>200
>200
>200
>200
>200
Excellent enantioselectivities (E ꢀ200) for the acyla-
tions of rac-3 and rac-4 (racemic trans isomers) with
reaction media. The results for lipase-catalyzed reac-
tions in RTILs have been promisingwith respect to
enhanced enzymatic activities and stabilities and to
enzymatic regio- and enantioselectivities. CAL-B
(Novozyme 435) is perhaps the most commonly used
2
,2,2-trifluoroethyl butanoate were observed in the pres-
ence of lipase PS-C II (Table 5). Accordingly, the trans-
aminonitriles behaved as expected on the basis of the
previous results for the corresponding b-aminocarboxyl-
enzyme in RTILs. Most of these studies relate to the
8
19,20
ates as substrates. Due to the low solubility of rac-3 in
transformations of secondary alcohols.
served as substrates less commonly.
Amines have
2
1
particular, tert-amyl alcohol was added to the TBME.
However, the presence of tert-amyl alcohol somewhat
lowered the reactivity as compared with the reaction in
neat TBME, as shown for rac-4 (entries 3 and 4). For
this reason, and because of the somewhat better solubil-
ity of rac-4, its gram-scale kinetic resolution was
performed in TBME at 45 ꢁC, as described in Section
The acylation of rac-2 with 2,2,2-trifluoroethyl butano-
ate in TBME in the presence of CAL-B gave good (entry
5, Table 2), but not excellent enantioselectivity, as
observed in the case of rac-1 (entry 4, Table 1). It was
also clear that an enzyme content of 30 mg/mL or higher
had no effect on the reactivity of rac-2 (entries 3–5, Table
6), with identical progression curves being obtained (not
shown here). As RTILs have been described, which have
several attractive properties, with enantioselectivity
enhancement for biocatalysis in particular, we decided
to study the CAL-B-catalyzed acylation of rac-2 in
RTILs. The RTILs were selected accordingto our previ-
4
9
3
, which allowed the preparations of (1S,2S)-4 (ee =
9%) and (1R,2R)-8 (ee >99%) at 50% conversion. rac-
was resolved in TBME/tert-amyl alcohol (9:1) at room
temperature, yielding(1 S,2S)-3 (ee = 98%) and (1R,2R)-
7
(ee >99%).
2.3. Asymmetric acylation of rac-2 with CAL-B in TBME
and in RTILs
2
2
ous work and are described in Scheme 4. The results in
Table 6 did not meet fully with our expectations (entries
6–12). The reactions in all cases proceeded slowly as
compared with the reaction in TBME. The reactivity
RTILs serve as non-toxic, non-volatile, and non-flam-
mable alternatives to classical organic solvents in vari-
ous applications, includingtheir use as biocatalytic
was best in hydrophobic EMIMÆNTf (entry 9), while
2
2 2 3
Table 5. Acylation of rac-3 (0.05 M) and rac-4 (0.05 M) with PrCO CH CF (0.1 M) in TBME in the presence of lipase PS-C II (50 mg/mL)
Entry
Substrate
Solvent
Temperature (ꢁC)
Conversion (%)
E
1
2
3
4
5
rac-3
rac-3
rac-4
rac-4
rac-4
TBME/tert-amyl alcohol (8/2)
TBME/tert-amyl alcohol (9/1)
TBME/tert-amyl alcohol (9/1)
TBME
23
23
23
23
65
49
50
17
30
32
ꢀ200
ꢀ200
ꢀ200
ꢀ200
ꢀ200
TBME
Reaction time 24 h.

3
694
M. Fitz et al. / Tetrahedron: Asymmetry 16 (2005) 3690–3697
CH CF
Table 6. Solvent screeningfor the CAL-B-catalyzed acylation of rac-2 (0.05 M) with PrCO
2
2
3
(0.1 M) at room temperature
Conversion (%)
Entry
Solvent
CAL-B (mg/mL)
Time (h)
E
1
2
3
4
5
6
7
8
9
TBME
TBME
TBME
TBME
TBME
BMIMÆPF
BMPyrÆBF
EMIMÆBF
EMIMÆNTf
EMIMÆTfO
EMIMÆTfO
10
20
30
50
70
50
50
50
50
50
75
75
6
6
6
6
6
96
96
96
96
96
96
96
35
45
48
48
48
11
32
9
46
23
26
46
57 ± 2
63 ± 2
74 ± 10
79 ± 5
73 ± 4
14 ± 3
24 ± 3
12 ± 1
22 ± 1
51 ± 6
71 ± 4
89 ± 4
6
4
4
2
10
11
12
a
EMIMÆTfO/TBME
a
A mixture of 1:1; two-phase medium.
X-
+
+
R1
X-
N
N
N
R1
1
1
[
[
[
[
EMIM][BF ]: R = Et, X = BF
[BMPyr][BF ]: R = Bu, X = BF
4 4
4
4
1
BMIM][PF ]: R = Bu, X = PF
6
6
1
EMIM][NTf ]: R = Et, X = (CF SO ) N
2
3
2 2
1
EMIM][TfO]: R = Et, X = CF SO
3
3
Scheme 4. Imidazolium- and pyridinium-based ionic liquids.
the enantioselectivity reached the same level as in TBME
determination of absolute configurations, and need
more optimization in order to be used for preparative
purposes.
only in the case of hydrophilic EMIMÆTfO (entry 11). In
2
3
accordance with what we have seen before, the higher
reactivity and enantioselectivity of rac-2 are evident in
a solvent mixture of EMIMÆTfO and TBME (entry 12).
4. Experimental
3. Conclusions
4.1. Materials and methods
We have shown that alicyclic cis- and trans-aminonitr-
iles rac-1–4 can be effectively resolved on a preparative
scale by lipase PS-C II, on acylation with 2,2,2-trifluoro-
ethyl butanoate in TBME. Thus, both enantiomers are
simultaneously present at 50% conversion, one as the
unreacted aminonitrile 1–4 and the other as the pro-
duced N-butanoylated counterpart 5–8 (Schemes 1 and
2,2,2-Trifluoroethyl butanoate was prepared from 2,2,2-
trifluoroethanol and butanoyl chloride. Organic solvents
were of the highest analytical grade. BMPyrÆBF and
4
EMIMÆTfO were products of Fluka. The other RTILs
were prepared by slightly modifying methods described
1
9,23,24
in the literature.
C. antarctica lipase A (lipase SP
526) and B (Novozym 435) were purchased from Roche
and Novozyme, respectively. Lipases PS and PS-C II
from B. cepacia (former P. cepacia) and lipase AK from
Pseudomonas fluorescens were product of Amano Eur-
ope, England. Before use, CAL-A and lipases PS and
AK were adsorbed on Celite (4.0 g) by dissolving the
enzyme and sucrose (0.24 g) in Tris–HCl buffer (pH 7.9),
and thereafter left to dry at room temperature, with
the final lipase content in the enzyme preparation being
2
). For both cis- and trans-isomers, the enantiomer in
which the amino group is at the (R)-stereocenter reacts.
This is in accordance with the previously observed enan-
tiopreference in the N-acylation of the corresponding
8
cis- and trans-amino esters. In disagreement with the
previous results, however, the highly enantioselective
(
E >200) N-acylation of rac-2 proceeded quickly in
TBME. The reactions in RTILs with CAL-B catalysis
were less successful.
2
5
20% (w/w). Porcine pancreatic lipase (PPL) and Can-
dida rugosa lipase (CRL) were purchased from Sigma.
We have also demonstrated that reduction by LiAlH4
can produce cis-(1S,2S)-1-amino-2-aminomethylcyclo-
hexane from (1R,2S)-2, and trans-(1S,2R)-1-amino-2-
aminomethylcyclohexane from (1S,2S)-4 (Scheme 3).
In this process, however, the enantiomeric excess tended
to drop somewhat. These reductions were used for the
1
13
H and C NMR spectra were recorded in CDCl and
3
D O at ambient temperature on a Bruker DRX400 spec-
2
trometer. Chemical shifts are given in d (parts per mil-
lion) relative to TMS as the internal standard;
multiplicities were recorded as s (singlet), br s (broad

M. Fitz et al. / Tetrahedron: Asymmetry 16 (2005) 3690–3697
3695
1
3
singlet), d (doublet), t (triplet), m (multiplet), or om
overlappingmultiplet). Optical rotations were mea-
sured with a Perkin Elmer 341 polarimeter, and [a] val-
3.59 (1H, m, H-2) ppm, C NMR (100 MHz, CDCl3):
d 22.8 (C4), 29.2 (C5), 33.6 (C3), 37.1 (C2), 54.9
(C1), 121.0 (CN) ppm. Anal. Calcd for C H N : C,
(
D
6
10
2
ꢁ
1
2
ꢁ1
ues are given in units of 10 degcm g
.
65.42; H, 9.15; N, 25.43. Found: C, 65.23; H, 9.05; N,
5.12.
2
In a typical small-scale experiment, one or more of race-
mates 1–4 (0.05 M) was dissolved in TBME (or some
other organic solvent) or in one of the RTILs (1 mL),
followed by addition of the enzyme preparation (10–
4.3. Preparation of cis-2-aminocyclohexanecarbonitrile,
rac-2
7
5 mg/mL). The addition of 2,2,2-trifluoroethyl butano-
The preparation of rac-2 was performed in the same way
as that of rac-1. Compound 12 in the synthetic path is
well characterized. The characterization of other inter-
mediates is given as below.
ate (0.1 M) initiated the reaction. For the reactions in
ethyl butanoate, the addition of the enzyme initiated
the reaction. The reaction mixture was shaken at room
temperature (23 ꢁC) if not otherwise stated. The pro-
gress of the reactions and the ee values were calculated
by takingsamples (0.05 mL) at intervals, filteringoff
the enzyme, and analyzing them by gas chromatography
on a Chrompack CP-Chirasil-DEX CB column (25 m).
In the case of RTILs, the products were extracted into
TBME before the GC analysis. For good baseline sepa-
ration, the unreacted amino group in the sample was
acylated with acetic anhydride in the presence of pyr-
idine containing1% 4,4-dimethylaminopyridine. The
determination of E was based on the equation
E = ln[(1 ꢁ ee )/(1 + ee /ee )]/ln[(1 + ee )/(1 + ee /ee )],
1
0
4.3.1. 7-tert-Butoxycarbonyl-7-azabicyclo[4,2,0]hexan-8-
1
one, 14. White crystals (yield 65%), mp: 69–72 ꢁC; H
NMR (400 MHz, CDCl ): d 1.52 (9H, m, t-Bu), 1.56–
3
2.06 (8H, om, 4 · CH ), 3.24 (1H, m, J = 3.52 Hz, H-
2
1), 4.10 (1H, m, J = 2.94 Hz, H-2) ppm. Anal. Calcd
for C H NO : C, 63.98; H, 8.50; N, 6.22. Found: C,
1
2
19
3
63.54; H, 8.42; N, 6.14.
4.3.2. cis-2-tert-Butoxycarbonylaminocyclohexanecarb-
oxamide, 16. White crystals (yield 70%), mp: 163–
1
164 ꢁC; H NMR (400 MHz, CDCl ): d 1.42 (9H, s, t-
s
s
p
s
s
p
3
where c = ee /(ee + ee ), with the use of linear regres-
Bu), 1.56–2.04 (8H, om, 4 · CH ), 2.92 (1H, m,
J = 7.23 Hz, H-1), 4.14 (1H, m, J = 7.76 Hz, H-2),
s
s
p
2
sion, E beingthe slope of the line ln[(1 ꢁ c)(1 ꢁ ee )] ver-
s
sus ln[(1 ꢁ c)(1 + ee )] the subscripts referringto the less
5.02 (1H, d, J = 6.72 Hz, NH), 5.32 (1H, s, NH ), 5.70
s
2
2
6
reactive substrate (s) and to the formed product (p).
(1H, s, NH ) ppm. Anal. Calcd for C H N O : C,
2
12 22
2
3
59.48; H, 9.15; N, 11.56. Found: C, 59.15; H, 9.02; N,
4.2. Preparation of cis-2-aminocyclopentanecarbonitrile,
rac-1
11.37.
4.3.3. cis-2-tert-Butoxycarbonylaminocyclohexanecarbo-
The preparation of 15 has already been described
nitrile, 18. White crystals (yield 56%), mp: 105–106 ꢁC;
1
6
1
(
Scheme 1). Compound 15 (3.60 g; 16 mmol) was
H NMR (400 MHz, CDCl ): d 1.45 (9H, s, t-Bu), 1.36–
3
added to a solution of the freshly formed Vilsmeier
2.03 (8H, m, 4 · CH ), 3.33 (1H, br s, H-1), 3.58–3.63
2
reagent (N,N-dimethylformamide and POCl ; 1.47 mL
(1H, m, J = 4.00 Hz, H-2), 4.75 (1H, d, J = 5.47 Hz,
NH) ppm. Anal. Calcd for C H N O : C, 64.26; H,
3
(
19 mmol) and 1.60 mL (18 mmol), respectively) in ace-
1
2
20
2
2
tonitrile (20 mL) under an argon atmosphere at 0 ꢁC,
8.99; N, 12.49. Found: C, 63.91; H, 8.72; N, 12.28.
followed by the addition of pyridine in order to cleave
1
7
the intermediate. Compound 17 was obtained as white
4.3.4. cis-2-Aminocyclohexanecarbonitrile, rac-2. White
1
1
crystals (2.05 g; 60%), mp: 86–88 ꢁC;
H
NMR
crystals (yield 62%), mp: 74–75.5 ꢁC;
H NMR
(
(
400 MHz, CDCl ): d 1.46 (9H, s, t-Bu), 1.55–2.10
6H, om, 3 · CH ), 3.21 (1H, m, H-1), 4.12 (1H, m,
J = 7.28 Hz, H-2), 4.84 (1H, s, NH) ppm; Anal. Calcd
(400 MHz, CDCl ): d 1.25–2.05 (8H, om, 4 · CH ),
1.61 (2H, br s, NH ), 2.86 (1H, m, H-1), 2.97 (1H, m,
2
H-2), C NMR (100 MHz, CDCl ): d 22.3 (C4), 24.6
3
3
2
2
1
3
3
for C H N O : C, 62.83; H, 8.63; N, 13.32. Found:
(C6), 28.1 (C5), 33.0 (C3), 38.0 (C2), 51.0 (C1), 120.9
1
1
18
2
2
C, 62.40; H, 8.52; N, 13.01.
(CN) ppm. Anal. Calcd for C H N : C, 67.70; H,
7
12
2
9.74; N, 22.56. Found: C, 67.45; H, 9.65; N, 22.25.
Boc-deprotection of 17 involved standard procedures.
Compound 17 (1.26 g, 6 mmol) was dissolved in dichlo-
romethane (60 mL), which contained 33% trifluoroace-
tic acid. The reaction mixture was stirred at room
temperature for 49 h before evaporation, leadingto
the trifluoroacetic salt as an oily residue (4.9 g). The
residue (1.0 g) was dissolved in 0.5 M aqueous sodium
carbonate (70 mL) and this mixture extracted three
times with dichloromethane. After dryingof the or ga nic
phases and evaporation, the free aminonitrile was
purified by column chromatography, using dichloro-
4.4. Preparation of trans-2-aminocyclopentanecarbo-
nitrile, rac-3
The preparation of rac-3 was performed in the same way
as that of rac-4 below, the synthetic path to intermediate
5
,6
23 followingthe known procedure ( Scheme 2).
4.4.1. trans-2-Aminocyclopentanecarbonitrile hydro-
bromide, 25. Light-yellowish crystals (yield 67%), mp:
1
212–214 ꢁC; H NMR (400 MHz, D O): d 1.30–2.25
2
methane/methanol (19:1) as eluent resultingin rac-1
(6H, om, 3 · CH ), 1.45 (2H, br s, NH ), 2.92 (1H, m,
H-1), 3.55 (1H, m, H-2) ppm. Anal. Calcd for
2
2
1
(
0.089 g, 60%) as white crystals, mp: 59–61 ꢁC;
H
NMR (400 MHz, CDCl ): d 0.90–2.35 (6H, om,
C H N ÆHBr: C, 37.72; H, 5.80; N, 14.66. Found: C,
3
6
10
2
3
· CH ), 1.63 (2H, br s, NH ), 2.92 (1H, m, H-1),
37.49; H, 5.76; N, 14.41.
2
2

3696
M. Fitz et al. / Tetrahedron: Asymmetry 16 (2005) 3690–3697
1
3
4
.4.2. trans-2-Aminocyclopentanecarbonitrile, rac-3.
(1H, m, H-2), 5.98 (1H, br s, NH) ppm. C NMR
1
White crystals (yield 63%), mp: 72–74 ꢁC, H NMR
(100 MHz, CDCl ): d 14.3 (CH ), 19.7 (CH CH CH ),
3
3
2
2
3
(
1
400 MHz, CDCl ): d 1.30–2.30 (6H, om, 3 · CH ),
22.2 (C4), 29.4 (C5), 30.8 (C3), 35.0 (CH CH CH ),
3
2
2 2 3
.70 (2H, br s, NH ), 2.42 (1H, m, H-1), 3.54 (1H,
47.1 (C2), 52.3 (C1), 121.0 (CN), 174.1 (NHCO) ppm.
Anal. Calcd for C H N O: C, 66.64; H, 8.95; N,
2
1
3
m, H-2) ppm. C NMR (100 MHz, CDCl ): d 23.0
3
10 16
2
(
C4), 29.8 (C5), 35.1 (C3), 39.2 (C2), 59.2 (C1), 122.8
15.54. Found: C, 66.36; H, 9.21; N, 15.10.
(
CN) ppm. Anal. Calcd for C H N : C, 65.42; H,
6
10
2
9
.15; N, 25.43. Found: C, 65.06; H, 9.07; N, 25.12.
4.7. Preparative-scale resolution of rac-2
4.5. Preparation of trans-2-aminocyclohexanecarbo-
nitrile, rac-4
rac-2 (0.4 g, 3.23 mmol) was dissolved in TBME
(65 mL) and lipase PS-C II (4.52 g, 70 mg/mL) added.
The reaction was started by the addition of 2,2,2-triflu-
oroethyl butanoate (0.97 mL, 6.43 mmol). The reaction
mixture was shaken at room temperature. The reaction
was then stopped after 2.25 h at 50% conversion
The preparation of intermediate 24 has been described
5
,6
before (Scheme 2). Boc-deprotection in 24 was per-
formed by adding 24 (0.4 g, 1.8 mmol) in dry dichloro-
methane (4 mL) to a solution of bromotrimethylsilane
(1R,2S)-2
(1S,2R)-6
[ee
= 95%, ee
= 95%], with the following
(
0.41 g, 2.7 mmol) and phenol (0.01 g, 0.12 mmol) in
work-up as above, yielding(1 R,2S)-2 {0.136 g,
1.1 mmol; white crystals, mp: 74–76 ꢁC, ee >99%,
dry dichloromethane (5 mL) under an argon atmosphere
at room temperature. After stirringfor 2.5 h the white
crystals produced were filtered off and washed with
2
0
1
13
½aŠ ¼ þ13:2 (c 0.5, MeOH); the H and C NMR
D
and elemental analysis data were identical to those of
diethyl ether, resultingin 26 (0.23 g, 66%), mp: 248–
the racemic rac-2} and (1S,2R)-6 {0.126 g, 0.65 mmol;
1
20
2
50 ꢁC; H NMR (400 MHz, D O): d 1.20–2.30 (8H,
white crystals, mp: 87–89 ꢁC, ee = 96%, ½aŠD ¼ þ98:7
2
1
om, 4 · CH ), 1.45 (2H, br s, NH ), 2.89 (1H, m, H-
(c 0.5, MeOH)}. Spectral data for (1S,2R)-6: H NMR
2
2
1
), 3.48 (1H, m, H-2) ppm. Anal. Calcd for
(400 MHz, CDCl ): d 0.96 (3H, t, J = 7.38 Hz, CH ),
3
3
C H N ÆHBr: C, 40.99; H, 6.39; N, 13.66. Found: C,
1.30–2.10 (8H, om, 4 · CH ), 1.66 (2H, m,
7
12
2
2
4
0.62; H, 6.29; N, 13.32.
CH CH CH ), 2.18 (2H, t, J = 7.46 Hz, CH CH CH ),
3
2
2
2
2
3
2
.74 (1H, m, H-1), 4.24 (1H, m, H-2), 7.46 (1H, br s,
1
3
Hydrobromide 26 (0.17 g, 0.83 mmol) was neutralized
with sodium carbonate (0.5 M, 5 mL) and the aqueous
phase extracted with 3 · 50 mL dichloromethane. The
combined organic phase was dried and evaporated.
The residue was purified by column chromatography,
usingdichloromethane/methanol (19:1) as eluent yield-
NH) ppm.
C NMR (100 MHz, CDCl ): d 14.3
3
(CH ), 19.8 (CH CH CH ), 21.9 (C4), 25.2 (C6), 28.0
3
2
2
3
(C5), 29.2 (C3), 34.5 (CH CH CH ), 39.1 (C2), 48.8
2
2
3
(C1), 120.7 (CN), 172.0 (NHCO) ppm. Anal. Calcd for
C H N O: C, 68.01; H, 9.34; N, 14.42. Found: C,
1
1
18
2
67.64; H, 9.87; N, 14.37.
1
ing rac-4 (0.26 g, 83%) as a yellowish oil; H NMR
(
1
400 MHz, CDCl3): d 1.10–2.20 (8H, om, 4 · CH ),
4.7.1. Absolute configuration of (1R,2S)-2. The sepa-
rated unreacted 2 (50 mg, 0.403 mmol) was reduced with
lithium–aluminum hydride in the formation of 1-amino-
2
,65 (2H, br s, NH ), 2.46 (1H, m, H-1), 3.47 (1H, m,
2
1
3
H-2) ppm. C NMR (100 MHz, CDCl ): d 19.0 (C4),
3
2
1
6
2
4.9 (C6), 29.4 (C5), 34.4 (C3), 38.8 (C2), 52.9 (C1),
2-aminomethylcyclohexane (30 mg, 0.234 mmol; a yel-
1
22.0 (CN) ppm. Anal. Calcd for C H N ÆHBr: C,
low oil, ee = 92%) with the followingspectral data:
H
7
12
2
7.70; H, 9.74; N, 22.56. Found: C, 67.43; H, 9.62; N,
2.26.
NMR (400 MHz, CDCl ): d 1.20–2.00 (9H, om, H-2-
3
6), 1.58 (2H, s, CH NH ), 2.80 (2H, br s, CH NH ),
2
2
2
2
3
.40 (1H, m, H-1), 5.10 (2H, br s, CHNH ) ppm. Anal.
2
4
.6. Preparative-scale resolution of rac-1
Calcd for C H N : C, 65.57; H, 12.58; N, 21.85. Found:
7 16 2
C, 65.64; H, 12.87; N, 22.07.
rac-1 (0.5 g, 4.54 mmol) was dissolved in TBME
80 mL) and lipase PS-C II (4.50 g, 50 mg/mL) was
added. The reaction was started by the addition of
,2,2-trifluoroethyl butanoate (1.38 mL, 9.14 mmol).
2
D
0
(
The obtained ½aŠ ¼ þ20:5 (c 1.0, EtOH) corresponds
1
5
20
D
to the literature value ½aŠ ¼ þ21:8 (c 2.18, EtOH)
2
for (1S,2S)-cis-(+)-1-amino-2-aminomethylcyclohexane.
This indicates a (1R,2S)-absolute configuration for the
unreacted 2 (Scheme 3).
The reaction mixture was shaken at room temperature.
The reaction was stopped after 5 h at 50% conver-
(1R,2S)-1
(1S,2R)-5
sion (ee
= 98%, ee
> 99%) by filteringoff
the enzyme. After evaporation, the resolution products
were separated by column chromatography, using
CH Cl /MeOH (19:1), yielding(1 R,2S)-1 {0.182 g,
4.8. Preparative-scale resolution of rac-3
rac-3 (0.255 g, 2.32 mmol) was dissolved in a mixture of
TBME and tert-amyl alcohol (9:1), after which lipase
PS-C II (2.26 g, 50 mg/mL) was added. The reaction
was started by the addition of 2,2,2-trifluoroethyl but-
anoate (0.68 mL, 4.50 mmol). The mixture was shaken
at room temperature. The reaction was stopped after
2
2
1
.65 mmol; white crystals, mp: 59–61 ꢁC, ee = 98%,
D
20
1 13
½
aŠ ¼ ꢁ5:9 (c 1.0, MeOH); the H and C NMR and
elemental analysis data were identical with those for
rac-1} and (1S,2R)-5 {0.280 g, 1.55 mmol; light-yellow
20
oil, ee = 98%, ½aŠ ¼ þ127:5 (c 0.53, MeOH)}. Spectral
D
1
(1S,2S)-3
(1R,2R)-7
data for (1S,2R)-5: H NMR (400 MHz, CDCl ): d 0.97
9.5 h at 50% conversion (ee
= 98%, ee
3
(
3H, t, J = 7.39 Hz, CH ), 1.55–2.25 (6H, om, 3 ·
>99%), with the followingwork-up as above, yielding
3
CH ), 1.69 (2H, m, CH CH CH ), 2.21 (2H, t,
J = 7.13 Hz, CH CH CH ), 3.29 (1H, m, H-1), 4.39
(1S,2S)-3 {0.085 g, 0.77 mmol; colorless crystals, mp:
2
3
2
2
20
72–74 ꢁC, ee = 98%, ½aŠ ¼ þ54:1 (c 0.5, MeOH); the
2
2
3
D

M. Fitz et al. / Tetrahedron: Asymmetry 16 (2005) 3690–3697
3697
1
13
H and C NMR and elemental analysis data were
identical with those for racemic 3} and (1R,2R)-7
Acknowledgments
{
>
0.105 g, 0.58 mmol; white crystals, mp: 73–74 ꢁC, ee
M.F. is grateful for a grant from the Centre for Interna-
tional Mobility (CIMO) in Finland. The authors also
acknowledge receipt of Hungarian Research Founda-
tion (OTKA) grant T 049407.
2
0
99%, ½aŠ ¼ ꢁ44:2 (c 0.5, MeOH)}. Spectral data for
D
1
(
1R,2R)-7: H NMR (400 MHz, CDCl ): d 0.95 (3H, t,
3
J = 7.36 Hz, CH ), 1.55–2.25 (6H, om, 3 · CH ), 1.69
3
2
(
2H, m, CH CH CH ), 2.16 (2H, t, J = 7.30 Hz,
3 2 2
CH CH CH ), 2.87 (1H, m, H-1), 4.35 (1H, m, H-2),
2
2
3
1
3
5
.94 (1H, br s, NH) ppm. C NMR (100 MHz, CDCl3):
References
d 14.3 (CH ), 19.7 (CH CH CH ), 23.5 (C4), 29.9 (C5),
3
2
2
3
1
2
. F u¨ l o¨ p, F. Chem. Rev. 2001, 101, 2181–2204.
. Konishi, M.; Nishio, M.; Saitoh, K.; Miyaki, T.; Oki, T.;
Kawaguchi, H. J. Antibiot. 1989, 42, 1749–1755.
3
1
2.1 (C3), 35.3 (CH CH CH ), 39.1 (C2), 56.2 (C1),
2 2 3
22.1 (CN), 173.8 (NHCO) ppm. Anal. Calcd for
C H N O: C, 66.64; H, 8.95; N, 15.54. Found: C,
1
0
16
2
3
. Mittendorf, J.; Kunisch, F.; Matzke, M.; Militzer, H.-C.;
Schmidt, A.; Sch o¨ nfeld, W. Bioorg. Med. Chem. Lett.
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6.39; H, 9.30; N, 15.53.
2
003, 13, 433–436.
4
.9. Preparative-scale resolution of rac-4
4
. Faber, K. Biotransformations in Organic Chemistry: A
Textbook, 4th ed.; Springer: Berlin, 2000; pp 149–159.
rac-4 (0.22 g, 1.77 mmol) was dissolved in TBME
39 mL) and lipase PS-C II (1.95 g, 50 mg/mL) was
added. The reaction was started by the addition of
,2,2-trifluoroethyl butanoate (0.59 mL, 3.91 mmol).
The mixture was shaken at 45 ꢁC. The reaction was
5. Preiml, M.; Hillmayer, K.; Klempier, N. Tetrahedron Lett.
2003, 44, 5057–5059.
6. Preiml, M.; H o¨ nig, H.; Klempier, N. J. Mol. Catal. B:
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(
2
7
. Winkler, M.; Mat ´ı nkov a´ , L.; Knall, A. C.; Krahulec, S.;
(
1S,2S)-4
Klempier, N. Tetrahedron 2005, 61, 4249–4260.
8. Kanerva, L. T.; Csom o´ s, P.; Sundholm, O.; Bern a´ th, G.;
stopped after 206 h at 50% conversion [ee
=
(1R,2R)-8
9
9%, ee
>99%], with the followingwork-up
F u¨ l o¨ p, F. Tetrahedron: Asymmetry 1996, 7, 1705–1716.
as above, yielding(1 S,2S)-4 {0.101 g, 0.81 mmol;
9
. Csom o´ s, P.; Kanerva, L. T.; Bern a´ th, G.; F u¨ l o¨ p, F.
2
D
0
a slowly crystallizingyellowish oil, ee = 98% ½aŠ
¼
Tetrahedron: Asymmetry 1996, 7, 1789–1796.
1
13
þ34:6 (c 0.5, MeOH); the H and C NMR and elemen-
1
0. K a´ m a´ n, J.; Forr o´ , E.; F u¨ l o¨ p, F. Tetrahedron: Asymmetry
2000, 11, 1593–1600.
tal analysis data were identical with those for racemic
4
}; and (1R,2R)-8 (0.110 g, 0.57 mmol), white crystals,
11. Forr o´ , E.; F u¨ l o¨ p, F. Org. Lett. 2003, 5, 1209–1212.
12. Li, X.-G.; Kanerva, L. T. Tetrahedron: Asymmetry 2005,
20
mp: 76–78 ꢁC, ee >99% ½aŠ ¼ ꢁ6:7 (c 0.5, MeOH).
D
1
1
6, 1709–1714.
Spectral data for (1R,2R)-8: H NMR (400 MHz,
CDCl ): d 0.97 (3H, t, J = 7.38 Hz, CH ), 1.20–2.25
1
1
3. L o´ pez-Serrano, P.; Jongejan, J. A.; van Rantwijk, F.;
3
3
Sheldon, R. A. Tetrahedron: Asymmetry 2001, 12, 219–
(
(
8H, om, 4 · CH ), 1.69 (2H, m, CH CH CH ), 2.19
2
3
2
2
2
28.
4. Armarego, W. L. F.; Kobayashi, T. J. Chem. Soc. (C)
969, 1635–1641.
15. Armarego, W. L. F.; Kobayashi, T. J. Chem. Soc. (C)
970, 1597–1600.
2H, t, J = 7.42 Hz, CH CH CH ), 2.66 (1H, m, H-1),
2 2 3
1
3
3
.99 (1H, m, H-2), 5.84 (1H, s, NH) ppm. C NMR
1
(
100 MHz, CDCl ): d 14.3 (CH ), 19.9 (CH CH CH ),
3 3 2 2 3
2
4.5 (C4), 29.4 (C6), 32.3 (C5), 35.0 (C3), 39.4
1
(
CH CH CH ), 49.2 (C2), 50.2 (C1), 121.2 (CN),
16. Csom o´ s, P.; Bern a´ th, G.; F u¨ l o¨ p, F. Monatsh. Chem. 2002,
133, 1077–1084.
17. Bargar, T. M.; Riley, C. M. Synth. Commun. 1980, 10,
2
2
3
1
6
1
73.4 (NHCO) ppm. Anal. Calcd for C H N O: C,
11 18 2
8.01; H, 9.34; N, 14.42. Found: C, 67.83; H, 9.14; N,
3.98.
4
79–487.
8. Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun.
997, 1017–1018.
9. Park, S.; Kazlauskas, R. J. J. Org. Chem. 2001, 66, 8395–
401.
0. Sheldon, R. A.; Lau, R. M.; Sorgedrager, M. J.; van
Rantwijk, F.; Seddon, K. R. Green Chem. 2002, 4, 147–
151.
1
1
2
1
4
.9.1. Absolute configuration of (1S,2S)-4. The sepa-
rated unreacted 4 (30 mg, 0.242 mmol) was reduced with
lithium–aluminum hydride in the formation of 1-amino-
2
8
-aminomethylcyclohexane (19 mg, 0.148 mmol) as a
20
light-yellowish oil, ee = 90%, ½aŠ ¼ þ21:1 (c 0.5,
D
1
EtOH) with the followingspectral data:
H NMR
21. Irimescu, R.; Kato, K. J. Mol. Catal. B: Enzym. 2004, 30,
189–194.
22. Lundell, K.; Kurki, T.; Lindroos, M.; Kanerva, L. T. Adv.
Synth. Catal. 2005, 347, 1110–1118.
(
(
400 MHz, CDCl ): d 1.05–2.20 (9H, om, H-2-6), 1.50
2H, s, CH NH ), 2.45 (1H, m, H-1), 2.90 (2H, m,
3
2
2
CH NH ), 5.04 (2H, br s, CHNH ) ppm. Anal. Calcd
for C H N : C, 65.57; H, 12.58; N, 21.85. Found: C,
6
2
2
2
2
3. Bonh oˆ te, P.; Dias, A.-P.; Papageorgiou, N.; Kalyanasun-
daram, K.; Gr a¨ tzel, M. Inorg. Chem. 1996, 35, 1168–1178.
4. Huddleston, J. G.; Willauer, H. D.; Swatloski, R. P.;
Visser, A. E.; Rogers, R. D. J. Chem. Soc., Chem.
Commun. 1998, 1965–1966.
7
16
2
5.72; H, 12.27; N, 21.97.
2
20
The obtained ½aŠ ¼ þ21:1 (c 0.5, EtOH) corresponds to
D
14
20
the literature value ½aŠ ¼ þ22:8 (c 0.724, EtOH) for
D
25. Kanerva, L. T.; Sundholm, O. J. Chem. Soc., Perkin
Trans. 1 1993, 2407–2410.
(
1S,2R)-trans-(+)-1-amino-2-aminomethylcyclohexane.
This indicates a (1S,2S)-absolute configuration for the
unreacted 4 (Scheme 3).
26. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J.
J. Am. Chem. Soc. 1982, 104, 7294–7299.