Lipase-catalyzed kinetic resolution of 7-, 8- and 12-membered alicyclic β-amino esters and N-hydroxymethyl-β-lactam enantiomers

Article abstract of DOI:10.1016/j.tetasy.2003.08.028

Enzymatic kinetic resolutions of methyl cis-2-aminocycloheptane-, 2-aminocyclooctane- and 2-aminocyclododecanecarboxylates with Candida antarctica lipase A in diisopropyl ether (E >200) and of the corresponding N-hydroxymethyl-β-lactams with Pseudomonas cepacia lipase in dry acetone (E from 27 to >200) has been performed with 2,2,2-trifluoroethyl butanoate as the best acyl donor, with both enantiomers being obtained. trans-13-Hydroxymethyl-13-azabicyclo[10.2.0]tetradecan-14-one was resolved with vinyl butanoate and Candida antarctica lipase B (E=26) in acetone.

Full text of DOI:10.1016/j.tetasy.2003.08.028

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3805–3814
Lipase-catalyzed kinetic resolution of 7-, 8- and 12-membered
alicyclic b-amino esters and N-hydroxymethyl-b-lactam
enantiomers
a,b
a
a
b
Zsuzsanna Cs. Gyarmati, Arto Liljeblad, Mikko Rintola, G a´ bor Bern a´ th and
a,
Liisa T. Kanerva *
a
Laboratory of Synthetic Drug Chemistry and Department of Chemistry, University of Turku, Lemmink a¨ isenkatu 2,
FIN-20520 Turku, Finland
b
Institute of Pharmaceutical Chemistry, University of Szeged and Research Group for Heterocyclic Chemistry,
Hungarian Academy of Sciences and University of Szeged, PO Box 121, H-6701 Szeged, Hungary
Received 6 August 2003; accepted 27 August 2003
Abstract—Enzymatic kinetic resolutions of methyl cis-2-aminocycloheptane-, 2-aminocyclooctane- and 2-aminocyclododecanecar-
boxylates with Candida antarctica lipase A in diisopropyl ether (E >200) and of the corresponding N-hydroxymethyl-b-lactams
with Pseudomonas cepacia lipase in dry acetone (E from 27 to >200) has been performed with 2,2,2-trifluoroethyl butanoate as the
best acyl donor, with both enantiomers being obtained. trans-13-Hydroxymethyl-13-azabicyclo[10.2.0]tetradecan-14-one was
resolved with vinyl butanoate and Candida antarctica lipase B (E=26) in acetone.
©
2003 Elsevier Ltd. All rights reserved.
1
. Introduction
For the preparation of enantiopure compounds, enzy-
matic kinetic resolution is one of the most efficient
methods. In particular, lipase catalysis is increasingly
replacing the classical diastereomer separation of race-
mates. Our studies on lipase catalysis puts us amongst
the pioneers in resolving alicyclic b-amino esters using
enzymes. For instance, various monocyclic (rings con-
taining 5 or 6 carbon atoms) and bicyclic (bicy-
clo[2.2.1]heptane or heptene) b-amino esters have been
resolved in organic solvents, using lipase-catalyzed N-
acylation with activated esters at the stereogenic (2R)
Recently, the preparation and importance of optically
active b-amino acids and b-lactams as versatile building
blocks for synthetic chemistry has been reviewed.
,2-Dipolar cycloaddition of chlorosulfonyl isocyanate
to cycloalkenes is a method widely used for the prepa-
ration of racemic cycloalkane-fused b-lactams in a
stereoselective manner.
1
–6
1
7–9
The hydrolysis or the alco-
holysis of the prepared b-lactams in concentrated (18–
2%) hydrogen chloride in water or in an alcohol
provides easy access to the corresponding b-amino
2
18
center. As another possibility, N-hydroxymethyl-6-
5
,10–14
acids or esters, respectively.
The interest in b-
azabicyclo[3.2.0]heptan-7-one
and
exo-3-azatricy-
amino acids is mainly due to their ability to serve as
starting substances for heterocycles, pharmacons, natu-
ral products and chiral auxiliaries. Most recently, inter-
est has focused on the bioactivity of b-peptides which
are stable against peptidase degradation and often
2,5
clo[4.2.1.0 ]nonan-4-one that can act as precursors for
b-amino acids (hydrolysis of the b-lactam ring in con-
centrated HCl) or b-lactams (removal of the N-hydroxy-
methyl group with NH OH/MeOH) were prepared with
4
2,5,15
paraformaldehyde by sonication and subsequent highly
capable of forming stable tertiary structures.
Ali-
enantioselective lipase-catalyzed O-acylation at the pri-
cyclic b-amino acids comprise of an interesting class
10
mary hydroxymethyl function was reported. The N-
hydroxymethyl-b-lactam method was later successfully
exploited for the resolution of N-hydroxymethyl-9-
azabicyclo[6.2.0]dec-4-en-10-one, in addition to com-
among the b-amino acids. Some of them, such as
cispentacin
[(−)-(1R,2S)-2-aminocyclopentanecar-
boxylic acid, FR 109615], are biologically active natural
1
6,17
products.
11–13
pounds with smaller fused rings.
As a third
*
Corresponding author. E-mail: lkanerva@utu.fi
resolution method, the enantioselective hydrolysis of
0
957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.028

3
806
Z. Cs. Gyarmati et al. / Tetrahedron: Asymmetry 14 (2003) 3805–3814
6
-azabicyclo[3.2.0]hept-3-en-7-one in water in the pres-
2. Results and discussion
19
ence of a whole-cell preparation (Rhodococcus equi)
or isolated enzymes (lactamases)
20
and the lipase
catalysed hydrolysis of b-lactams (cis-fused with alicy-
cles, ring size 5–8 carbon atoms) by 1 equivalent of
water with diisopropyl ether allows the direct ring
2.1. Enantioselective N-acylation of b-amino esters
Extensive lipase screening for the asymmetric acylation
of 5- and 6-membered alicyclic cis- and trans-b-amino
esters has previously revealed that two lipases, lipase PS
(lipase from Pseudomonas cepacia) and CAL-A (lipase
A from Candida antarctica), display complementary
behavior where CAL-A proved to be more applicable
14
opening of the lactam ring.
Seven-membered and larger rings are present in many
natural products. This gave us a reason to study how
1
8
well the b-amino ester
and N-hydroxymethyl-b-
1
0
18
lactam methods are suitable for the resolution of
compounds containing larger alicyclic rings. Accord-
ingly, the lipase-catalyzed asymmetric N-acylation of
for the cis-isomers. Later, it became clear that CAL-A
is exceptional amongst lipases by catalyzing the N- and
O-acylations of various sterically hindered substances
22–26
7-, 8- and 12-membered alicyclic b-amino acid esters,
in a highly enantioselective manner.
The enzyme
rac-1a–c and rac-(1c+1d) (Scheme 1), and the O-
acylation of the corresponding N-hydroxymethyl-b-lac-
tams, rac-3a–d (Scheme 2), have now been studied.
None of the substrates have been enzymatically
resolved before by these methods, and 1c, 1d, 3c and
works well even for the N-acylation of the secondary
amino groups in proline and pipecolic acid esters.
2
7,28
Previous solvent screening involved simple ethers, such
as diisopropyl and tert-butyl methyl ethers, which were
the most favorable solvents for the enzymatic acylation
18
3
d, including the corresponding free acids and b-lac-
of alicyclic b-amino esters.
tams are new compounds. Gram-scale resolutions were
performed under optimized conditions. One beneficial
feature of the present enzymatic acylation methods is
Encouraged by these findings, we subjected rac-1a–c
(cis isomers) and a mixture of rac-1c and rac-1d
(cis:trans 1:2) to acylation with a CAL-A preparation
in the presence of 2,2,2-trifluoroethyl butanoate in
2
1
that the water activity can be expected to stay con-
stant throughout the reaction.
Scheme 1.
Scheme 2.

Z. Cs. Gyarmati et al. / Tetrahedron: Asymmetry 14 (2003) 3805–3814
3807
Table 1. Enantioselectivity of the CAL-A preparation for the acylation of rac-1a–c (0.1 M) and rac-[1c+1d, (1:2)] (0.1 M)
with 2,2,2-trifluoroethyl butanoate (0.2 M) in diisopropyl ether (2 ml) at room temperature
Entry
Compounds
Enzyme content (mg/ml)
Time (h)
Conversion (%)
E
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c+1d
1c+1d
10
20
25
50
75
5
10
20
40
75
50
50
50
1
1
1
1
1
1
1
1
1
28
48
49
48
46
24
33
34
18
17
>200
>200
>200
>200
>200
130±7
170±7
>200
>200
>200
>200
–
10
11
12
13
1
a
24
48
24
50
–
50/8
a
116±13/7±1
a
Temperature 47°C.
diisopropyl ether (Scheme 1). Excellent enantioselectiv-
ity in the terms of E values is obvious for the present
cis-amino esters (Table 1, entries 1–11 and 13), while the
trans-isomer 1d in the cis/trans-mixture (entry 13) reacts
with negligible enantioselectivity. The reactivity
2.2. Enantioselective O-acylation of N-hydroxymethyl-
b-lactams
For a second synthetic approach to the enantiomers of
alicyclic b-amino acids, N-hydroxymethyl-b-lactams
rac-3a–d were subjected to lipase-catalyzed acylation in
dry acetone (Scheme 2). As concerns enzymatic enan-
tioselectivity and suppression of the enzymatic hydroly-
sis (caused by the water adsorbed on the seemingly dry
enzyme preparation) of new ester product 4 back to 3,
acetone has previously been shown to be the most
(
reflected by the conversion reached after a certain time)
of the cis-isomers decreased considerably with increas-
ing size of the alicyclic ring. Thus, conversions of 48%
for 1a (entry 2) and 34% for 1b (entry 8) were reached
after 1 h when 20 mg/ml of the enzyme preparation was
used, whereas there was no reaction in the case of the
mixture of 1c and 1d as substrate (entry 12) after 2 days
at room temperature, even though the enzyme content
was high (50 mg/ml of the enzyme preparation). In the
case of the mixture of 1c and 1d, the replacement of
diisopropyl ether with acetone, acetonitrile, toluene or
diethyl ether as solvent did not improve the reactivity.
When lipase PS, lipase AK (lipase from Pseudomonas
fluorescens), CAL-B (lipase B from Candida antarctica)
or PPL (porcine pancreatic lipase) was used in place of
CAL-A in diisopropyl ether, negligible reactivity (con-
version 0–7% after 1 day) with practically no enantiose-
lectivity was observed. When 2,2,2-trifluoroethyl
chloroacetate was used with lipase PS in diisopropyl
ether, a chemical reaction strongly disturbed the enzy-
matic acylation. For the cis-substrate 1c (entry 11) and
the cis/trans-mixture of 1c and 1d (entry 13), raising the
temperature (47°C) was necessary for acylation to pro-
ceed.
10
appropriate solvent for b-lactam substrates. Vinyl
esters were expected to be excellent as achiral acyl
donors because the vinyl alcohols produced (another
product of enzymatic acylation) were unstable and thus
decomposed with the formation of acetaldehyde.
Accordingly, the reverse enzymatic reactions of (1R,(n+
4
)S)-4a–c (n=3, 4 and 8) and (1S,12S)-4d with the
released vinyl alcohol and the consequent racemization
were avoided.
1
0–13
As expected on the basis of the earlier studies,
lipases PS (Table 2, entries 1–6) and AK (entry 7)
smoothly catalyzed the formation of (1R,7S)-4a with
vinyl esters in dry acetone with the combination of
lipase PS and vinyl butanoate (entry 5) being the most
enantioselective. For appropriate reactivity, 50 mg/ml of
the enzyme preparation was chosen for further studies.
In the cases of substrates rac-3b–d, the acylation reac-
tions with vinyl butanoate tended to stop at an early
stage (entries 9, 11 and 15). It is well known that
aldehydes form hemiacetals under both acidic (with this
reaction continuing to form an acetal) and basic condi-
tions. The formation of hemiacetal esters in appreciable
yields was previously observed when sterically hindered
secondary alcohols were treated with lipase PS or CAL-
Successful gram-scale resolutions of 1a–c with CAL-A
in diisopropyl ether were performed as described in
Section 5. For substrates 1a and 1b, 10 or 20 mg/ml of
the enzyme preparation was taken as optimal enzyme
contents. For the acylation of 1b, high enzyme contents
tended to halt the reactivity (entries 9 and 10). Aggrega-
tion of the enzyme preparation under the given reaction
conditions was taken as an explanation. As shown later,
29
B and vinyl acetate in organic solvents. However,
side-products were not detected by the GC method with
the present primary alcohols. Any drop in e.e. for the
separated substrates 3 due to the decomposition of free
hemiacetals (if present) during the work-up when com-
paring the e.e. with the resolved mixture was not
(
1S,2R)-1a–c and (1R,2R)-1d are the more reactive
enantiomers in the racemates.

3
808
Z. Cs. Gyarmati et al. / Tetrahedron: Asymmetry 14 (2003) 3805–3814
Table 2. Enzymatic acylation of rac-3a–d with acyl donors (0.2 M) in acetone (2 ml) at room temperature
Entry
Compounds
Acyl donor
Enzyme content (mg/ml)
Time (h)
Conversion (%)
E
1
2
3
4
5
6
7
8
9
3a (0.1 M)
3a (0.1 M)
3a (0.1 M)
3a (0.1 M)
3a (0.1 M)
3a (0.1 M)
3a (0.1 M)
3b (0.1 M)
3b (0.1 M)
3c (0.05 M)
3c (0.05 M)
3c (0.05 M)
3d (0.1 M)
3d (0.1 M)
3d (0.1 M)
3d (0.05 M)
3d (0.05 M)
3d (0.05 M)
MeCO CHꢀCH
Lipase PS (50)
Lipase PS (10)
Lipase PS (30)
Lipase PS (40)
Lipase PS (50)
Lipase PS (75)
Lipase AK (50)
Lipase PS (50)
Lipase PS (50)
Lipase PS (50)
Lipase PS (25)
CAL-B (2.5)
Lipase PS (50)
Lipase PS-C (50)
Lipase PS (50)
PPL (25)
CAL-B (2.5)
CAL-B (2.5)
1
1
1
1
1
1
1
2
2
3
3
1
2
2
2
2
2
2
48
17
36
40
45
48
46
32
50±10
>200
>200
>200
>200
>200
82±9
27±1
–
83±10
–
3±1
5±1
10±2
–
2
2
PrCO CHꢀCH
2
2
2
2
2
2
2
PrCO CHꢀCH
2
PrCO CHꢀCH
2
PrCO CHꢀCH
2
PrCO CHꢀCH
2
PrCO CHꢀCH
2
PrCO CH CF
2
2
3
b
PrCO CHꢀCH
30
2
2
10
11
12
13
14
15
16
17
18
PrCO CH CF
48
30
2
2
3
a
b
PrCO CHꢀCH
2
2
PrCO CHꢀCH
62
39
49
2
2
PrCO CH CF
2
2
3
a
PrCO CH CF
3
2
2
b
PrCO CHꢀCH
23
2
2
PrCO CHꢀCH
11
54
40
18±2
26±2
15±5
2
2
PrCO CHꢀCH
2
2
PrCO (CH ) CH
2
2 3
3
a
0
.4 M.
b
Reaction ceases.
detected. However the present observations do not
exclude the possibility of the inactivation of lipase PS
by unstable hemiacetal formation. It is worth emphasiz-
ing that vinyl esters are commonly accepted by lipase
Gram-scale resolutions with lipase PS, vinyl butanoate
(rac-3a) and 2,2,2-trifluoroethyl butanoate (rac-3b and
3c) in acetone were performed as described in Section 5.
The results are shown in Table 3. In accordance with
the relatively low enantioselectivity of lipase PS for
rac-3b and rac-3c (Table 2, entries 8 and 10) the
resolution products (1S,8R)-3b, (1R,8S)-4b, (1S,12R)-
3c and (1R,12S)-4c were not enantiopure at 50% con-
version. For the resolution of the trans-b-lactam
analogue 3d, CAL-B-catalyzed acylation with vinyl
butanoate in acetone was the most appropriate (Table
2, entry 17).
3
0
PS. Another possibility is that the enzymatic reaction
between the produced (1R,(n+4)S)-4 and the less reac-
tive primary alcohol (1S,(n+1)R)-3 becomes increas-
ingly important in the reaction mixture at longer
reaction times: If true, a drop in e.e. is expected for
both resolution products. As the e.e. values in the
resolution mixture remained practically unchanged for
hours after the reaction had stopped and because the
change of the vinyl ester to 2,2,2-trifluoroethyl
butanoate as acyl donor (entries 8, 10 and 13) allowed
us to complete the resolutions, the possibility was not
studied further. The same reactions with CAL-B and
PPL proceeded without difficulty, but with low selectiv-
ity (entries 12, 16 and 17).
3. Absolute configuration
The less reactive enantiomers of 1a and 1b were
obtained from the gram-scale resolutions by CAL-A as
Table 3. Acylation results for rac-1 with CAL-A (10–50 mg/ml of the preparation) in diisopropyl ether and for rac-3 with
lipase PS (50 mg/ml of the preparation) in dry acetone, using 2,2,2-trifluoroethyl butanoate (vinyl butanoate in the case of
rac-3a) at room temperature
Ee1
or 3
(%) (configuration)
Ee2 or 4 (%) (configuration)
Substrate
Time (h)
Conversion (%)
rac-1a
rac-1b
rac-1c
rac-3a
rac-3b
rac-3c
1.8
4
24
2
24
10
2.5
3
50
50
49
49
52
50
50
51
98 (1R,2S)
99 (1R,2S)
96 (1R,2S)
93 (1S,7R)
90 (1S,8R)
90 (1S,12R)
85 (1R,12R)
96 (1S,8R)
97 (1S,2R)
95 (1S,2R)
99 (1S,2R)
97 (1R,7S)
82 (1R,8S)
a
c
–
–
b
c
rac-3d
d
rac-5
92 (1R,8S)
a
Temperature 47°C.
CAL-B as enzyme.
b
c
Determination of e.e. was not possible in the resolution mixture.
Acylation of N-hydroxymethyl-9-azabicyclo[6.2.0]dec-4-en-10-one 5 with vinyl butanoate and lipase PS in diisopropyl ether, temperature −15°C;
d
Ref. 13.

Z. Cs. Gyarmati et al. / Tetrahedron: Asymmetry 14 (2003) 3805–3814
3809
shown in Section 5. In order to confirm the absolute
configurations, the amino esters were subjected to
hydrolysis in 18% HCl, followed by treatment of the acid
hydrochlorides obtained with a basic Amberlite IRA 904
strate alcohol (E between >200 and 27, Table 2) and the
results in Table 3 clearly indicate that Method 1 is by far
the more favorable enzymatic kinetic resolution method
for the preparation of normal-, medium- and large-ring
alicyclic b-amino esters (or b-amino acids) with the cis
configuration.
2
5
resin. The specific rotations, [h] =−4.6 (c 0.5, H O) for
D
2
2
5
the free acid produced from ester 1a and [h] =+11.0 (c
D
0
.5, H O) for that produced from 1b, are in accordance
2
14 25
with the literature values, [h] =−7.2 (c 0.5, H O) and
The b-lactam method with CAL-B acting as the catalyst
and vinyl butanoate as the acyl donor, is usable for the
gram-scale resolution of the trans-b-amino ester precur-
sor 3d.
D
2
+
17.8 (c 0.4, H O) for the (1R,2S) acids. As a conse-
2
25
quence of the slight differences between our [h]D values
and the literature values, the enantiopurity was con-
firmed by transforming the free acids back to the amino
esters and determining the e.e.=96% for the reproduced
1
a and 1b (as compared with e.e.=98 and 99% for the
5. Experimental
resolved products) by the GC method. Accordingly, the
N-acylations by CAL-A had proceeded at the stereogenic
5.1. Materials and methods
18
(
2R) center, as expected on the basis of previous work.
There is every reason to presume that the same enantio-
preference will hold for the CAL-A-catalyzed N-
acylation of 1c. It is therefore concluded that the more
reactive enantiomer of rac-1a–c has the (1S,2R) absolute
configuration and for the same reasoning the (1R,2R)
enantiomer reacts in the case of rac-1d.
Chlorosulfonyl isocyanate, cycloalkenes, propylene
oxide, vinyl and methyl butanoates and 2,2,2-trifl-
uoroethanol were products of Aldrich or Fluka. All sol-
vents were of the highest analytical grade and were dried
over molecular sieves (3 A) before use. Pseudomonas
,
cepacia lipase (lipase PS) was from Amano Europe, while
lipases A (CAL-A, Chirazyme L5, lyo.) and B (CAL-B,
Chirazyme L2, cf. C2, lyo) from Candida antarctica were
products of Roche. Before use, lipases PS and CAL-A
were adsorbed on celite by dissolving the enzyme (5 g)
and sucrose (3 g) in a tris–HCl buffer (250 ml, 20 mM, pH
Opposite enantiodiscrimination has previously been
reported for the acylation of alicyclic b-amino esters and
for the acylation of the corresponding N-hydroxymethyl-
1
0,18
b-lactams with lipases.
This is also true for the present
31
work, where the separated unreacted enantiomers of rac-
7.8), followed by the addition of celite (17 g). The mix-
ture was dried by allowing the water to evaporate. The
final lipase content in the enzyme preparation was 20%
(w/w). Most of the enzymatic reactions were performed
at room temperature (23–24°C). 2,2,2-Trifluoroethyl
butanoate was prepared from butyric acid by using
thionyl chloride and 2,2,2-trifluoroethanol.
3
1
b and rac-3d were first transformed to the amino esters
b and 1d by treatment with MeOH/HCl and NH , after
3
which the positions of the peaks in the GC chro-
matograms were compared with those for the CAL-A-
catalyzed acylations of the amino esters. This result
justifies the conclusion concerning the absolute configu-
rations of (1S,8R) for the unreacted enantiomer of rac-3b
and (1R,12R) for rac-3d. In general, the (1R,(n+4)S)
enantiomers (n=3, 4 and 8) are more reactive for the
lipase-catalyzed acylation of racemic cis isomers 3a–c.
In a typical small-scale experiment, one of the substrates
rac-1a–c and (1c+1d) (0.2 mmol) in diisopropyl ether (2
ml), or one of the substrates rac-3a–d (0.1–0.2 mmol) in
dry acetone (2 ml), was added to a lipase preparation (20–
150 mg, corresponding to 4–30 mg of a lipase) or to a
commercial lipase (5–100 mg), followed by the addition
of an achiral acyl donor (2 equivalents to the substrate).
The progress of the reactions and the e.e. values were fol-
lowed by taking samples (0.1 ml) at intervals and analyz-
ing them by gas chromatography. For good baseline
separation, the unreacted amino (substrates 1) and
hydroxy (substrates 3) groups in the sample were deriva-
tized with acetic anhydride in the presence of pyridine
containing 1% 4-N,N-dimethylaminopyridine (DMAP)
before injection. The GC was equipped with a Chrom-
pack CP-Chirasil-DEX CB or Chrompack CP-Chirasil-
4. Conclusions
The present work extends the usability of known enzy-
matic kinetic resolution methods (method 1 and 2) for the
preparation of medium- (8-membered) and large-ring
(
12-membered) alicyclic b-amino acid derivatives in addi-
10,18
tion to normal-ring (5- to 7-membered) analogues.
In
method 1, the N-acylation of alicyclic b-amino esters rac-
1a–c (cis-isomers) with 2,2,2-trifluoroethyl butanoate has
been studied (Scheme 1). The reactions in diisopropyl
ether proceeded with excellent enantioselectivity (usually
E>200, Table 1) in the presence of CAL-A, allowing the
enantioseparation as a one-pot acylation at 50% conver-
sion (Table 3). The alicyclic ring size did not exert any
effect on the enantioselectivity and an amide product 2
with a (1S,2R) configuration. In accordance with the pre-
L
-Valine column. HPLC equipped with a Sumichiral
OA-4900 (46 mm×0.25 m, u=210 nm) column was used
3d
to obtain the e.e. value. Conversions were calculated
from the e.e. values c=ee /(ee +ee ) except in the cases of
S
S
P
1
8
vious results, the method works poorly (E=7) for the
resolution of trans isomer 1d. In method 2 (Scheme 2), the
corresponding N-hydroxymethyl-b-lactams rac-3a–c
have been enantioselectively O-acylated with vinyl and
3c and 3d as substrates, where hexadecane served as an
internal standard in the GC method. Preparative chro-
matographic separations were performed by column
chromatography on Merck Kieselgel 60 (0.063–0.200
mm). TLC was carried out with Merck Kieselgel 60F
2
,2,2-trifluoroethyl butanoates in dry acetone with lipase
2
54
PS acting as the catalyst. The enantioselectivity of lipase
PS is highly dependent on the molecular size of the sub-
sheets. Spots were visualized with 5% ethanolic phospho-
molybdic acid solution and heating.

3
810
Z. Cs. Gyarmati et al. / Tetrahedron: Asymmetry 14 (2003) 3805–3814
+
Elemental analyses were carried out with a Perkin–
(1), 208 (1) [M] :181 (1), 180 (1), 169 (1), 168 (1), 167
1
13
1
Elmer 2400 CHNS instrument. The H and C NMR
spectra were recorded on a Brucker 400 spectrometer
(8), 166 (63), 164 (1); H NMR (CDCl ) l (ppm):
3
1.16–1.97 (20H, m, 10×CH2
CHCO), 3.42–3.46 (1H, m, CHNH), 5.97 (1H, bs, NH
C NMR (CDCl ) l (ppm): 23.23, 23.32, 24.27, 25.08,
25.27, 25.75, 27.83, 28.06, 28.43, 35.07, 54.32, 55.22,
172.55.
6
), 2.84–2.88 (1H, m,
1
13
operating at 400 and 100 MHz, respectively. H and
C
6
3
6
6
);
1
spectra were referenced internally to TMS as internal
standard. MS spectra were taken on a VG 7070E mass
spectrometer. Melting points were determined by the
hot plate method and are uncorrected. Optical rota-
tions were determined with a JASCO Model DIP-360
3
5
.2.4.
trans-2-Aminocyclododecanecarboxylic
Yield: 74%. Mp: 261–262°C. Anal. calcd for
C H NO : C, 68.68; H, 11.08; N, 6.16. Found: C,
8.93; H, 10.92; N, 6.08%. HRMS M found (M
calcd): 227.18887 (227.18853); MS: m/z (relative inten-
sity)=227 (2), [M] : 210 (3), 198 (1), 185 (1), 184 (4),
83 (1), 170 (2), 169 (1), 168 (4), 167 (1), 166 (2); H
NMR (D O in the presence of KOH) l (ppm): 1.28–
acid.
−
1
digital polarimeter. [h] values are given in units of 10
D
2
deg cm /g. The determination of E was based on the
equation E=ln[1−ee )/(1−ee /ee )]/ln[(1−ee )/(1+ee /
13
25
2
S
S
P
S
S
+
+
6
ee )] with c=ee /(ee +ee ), as derived from the original
equations of Chen et al., using linear regression, with
P
S
S
P
3
2
+
E as the slope of the line ln[(1−c)(1−ee )] vs. ln[(1−c)(1+
S
1
1
ee )].
S
2
1
.75 (20H, m, 10×CH2
6 ), 2.66–2.70 (1H, m, CH6 CO),
5
.2. Preparation of b-lactams and b-amino acids
13
3
.25–3.29 (1H, m, CHNH). C NMR (D O in the
6
2
presence of KOH) l (ppm): 19.68, 22.90 (2 overlapping
Alicyclic b-lactams were prepared by the cycloaddition
of chlorosulfonyl isocyanate to the corresponding
cycloalkenes and thereafter transformed to b-amino
signals), 23.23, 23.63, 23.72, 24.70, 24.95, 26.88, 29.75,
5
0.07, 51.67, 183.33.
5
,7–14
acids.
For the synthesis of 13-azabicyclo[10.2.0]-
tetradecan-14-one as a new compound, a mixture of
cis- and trans-cyclododecene (cis:trans=2:1) gave a
mixture of isomers (cis:trans=45%:55%) which were
separated by column chromatography on silica gel with
diethyl ether:ethyl acetate (4:1). The products were
recrystallized from ethyl acetate and hydrolyzed to the
corresponding b-amino acids. The other b-lactams and
5.3. Preparation of methyl b-aminocycloalkanecarboxyl-
ates 1a–c
Distilled thionyl chloride (1.1 ml, 14 mmol) was added
dropwise to a solution of a racemic 2-aminocycloalka-
necarboxylic acid (12.7 mmol) in methanol (40 ml) at
−5°C. The reaction mixture was first stirred at −5°C
(0.5 h), then at room temperature (1 h) and then finally
refluxed (2 h). The solvent was evaporated off and the
resulting semisolid product was crystallized from
1
3,14
b-amino acids were described earlier.
5
6
7
6
.2.1. cis-13-Azabicyclo[10.2.0]tetradecan-14-one. Yield:
0%. Mp: 147–148°C. Anal. calcd for C H NO: C,
diethyl ether. NH gas was bubbled into a solution of a
13
23
3
4.59; H, 11.07; N, 6.69. Found: C, 74.25; H, 10.94; N,
b-amino ester hydrochloride (12 mmol) in chloroform
(20 ml) for 0.5 h. The reaction mixture was extracted
with distilled water (3×10 ml) and the organic layer
dried over sodium sulfate and concentrated in vacuo.
+
+
.66%. HRMS M found (M calcd): 209.17822
(
209.17796); MS: m/z (relative intensity)=210 (2), 209
+
1
(
1), 208 (1) [M] : 168 (1), 167 (8), 166 (57); H NMR
(
3
(
2
5
CDCl ) l (ppm): 1.26–1.84 (20H, m, 10×CH
6
2), 3.11–
NH), 5.87
3
.16 (1H, m, CH
6 CO), 3.65–3.69 (1H, m, CH
6
5
.3.1. Methyl cis-2-aminocycloheptanecarboxylate 1a.
1
3
1H, bs, N H6 ); C NMR (CDCl ) l (ppm): 22.44, 23.03,
3
Yield: 93%. Anal. calcd for C H NO : C, 63.13; H,
9
17
2
3.41, 25.11, 28.83, 27.92, 28.05, 28.32, 28.42, 29.42,
3.43, 54.41, 171.89.
1
0.01; N, 8.18. Found: C, 63.06; H, 10.04; N, 8.15%.
+ +
HRMS M found (M calcd): 171.12600 (171.12593);
MS: m/z (relative intensity)=171 (3), [M] : 156 (3), 142
+
5
7
6
6
.2.2. cis-2-Aminocyclododecanecarboxylic acid. Yield:
1
(
3), 140 (2), 128 (4), 114 (13), 97 (5); H NMR (CDCl )
3
2%. Mp: 239–241°C. Anal. calcd for C H NO : C,
1
3
25
2
l (ppm): 1.38–1.90 (10H, m, 5×CH2
CHCO), 3.39–3.46 (1H, m, CHNH), 3.69 (3H, m,
COOCH3); C NMR (CDCl ) l (ppm): 23.59, 24.52,
6.82, 28.53, 36.06, 50.47, 51.44, 51.82, 175.89
6 ), 2.65–2.69 (1H, m,
8.68; H, 11.08; N, 6.16. Found: C, 68.47; H, 10.95; N,
6
6
+
+
.14%. HRMS M found (M calcd): 227.18857
13
6
3
(
(
(
227.18853); MS: m/z (relative intensity)=228 (1), 227
2), 226 (1), [M] : 211 (1), 210 (3), 198 (1), 192 (1), 185
1), 184 (5), 182 (1), 180 (1), 170 (2), 169 (1), 168 (5),
67 (1), 166 (2);); H NMR (D O in the presence of
2
+
1
1
5.3.2. Methyl cis-2-aminocyclooctanecarboxylate 1b.
2
KOH) l (ppm): 1.34–1.80 (20H, m, 10×CH
6
), 2.62–2.64
NH). C NMR
Yield: 85%. Anal. calcd for C H NO : C, 64.83; H,
2
10 19
2
13
(
1H, m, CH
6
CO), 3.45–3.47 (1H, m, CH
6
10.34; N, 7.56. Found: C, 64.63; H, 10.30; N, 7.55%.
+ +
(
D O in the presence of KOH) l (ppm): 20.44, 21.86,
HRMS M found (M calculated for): 185.14169
2
2
1.95, 22.21, 23.04 (2 overlapping signals), 24.54, 25.55
(185.14158); MS: m/z (relative intensity)=186 (21), 185
(7), 184 (26); [M] 169 (4), 168 (5), 155 (5), 154 (35), 153
+
(
2 overlapping signals), 30.85, 48.17, 51.91, 183.95.
(
10), 138 (4), 137 (39), 136 (5), 126 (19), 125 (18),
1
5
.2.3.
trans-13-Azabicyclo[10.2.0]tetradecan-14-one.
112(13), 111 (7), 110 (7), 109 (24); H NMR (CDCl ) l
3
Yield: 63%. Mp: 126–127°C. Anal. calcd for C H NO:
(ppm): 1.33–1.87 (12H, m, 6×CH2
CHCO), 3.31–3.35 (1H, m, CH
COOCH
25.63, 26.59, 28.00, 33.86, 46.66, 51.37, 51.55, 176.45.
6
), 2.76–2.79 (1H, m,
NH), 3.69 (3H, m,
13
23
C, 74.59; H, 11.07; N, 6.69. Found: C, 74.13; H, 10.97;
6
6
+
+
13
N, 6.65%. HRMS M found (M calcd): 209.17814
209.17796); MS: m/z (relative intensity)=210 (2), 209
6 3); C NMR (CDCl ) l (ppm): 23.21, 23.65,
3
(

Z. Cs. Gyarmati et al. / Tetrahedron: Asymmetry 14 (2003) 3805–3814
3811
2
2
5
.3.3. Methyl cis-2-aminocyclododecanecarboxylate 1c.
chloride (0.21 g, 0.94 mmol, mp 143–145°C; [h] =+33.4
D
Yield: 60%. Mp: 54–57°C. Anal. calcd for C H NO : C,
(c 1, H O); e.e.=99%) was obtained as white crystals.
14
27
2
2
6
5
9.66; H, 11.27; N, 5.80. Found: C, 69.85; H, 11.30; N,
.80%. HRMS M found (M calcd): 241.20430
Anal. calcd for C H ClNO : C, 54.17; H, 9.09; N, 6.32.
10
20
2
+
+
1
Found: C, 54.00; H, 9.12; N, 6.31%. H NMR (D O) l
2
(
(
241.20418); MS: m/z (relative intensity)=242 (1), 241
2), 240 (1); [M] : 224 (4), 211 (1), 210 (7), 199 (1), 198 (5),
(ppm): 1.53–1.95 (12H, m, 6×CH2
6
), 3.12–3.16 (1H, m,
), 3.79–3.84 (1H, m,
+
CH
6
CO), 3.77 (3H, s, COOCH
6
3
1
13
1
92 (3), 184 (2), 170 (3), 169 (1), 168 (6). H NMR
CH
6
NH); C NMR (D O) l (ppm): 23.89, 25.30, 26.08,
2
(
CDCl ) l (ppm): 1.23–1.72 (20H, m, 10×CH
6
2), 2.60–2.62
NH), 3.70 (3H, s,
); C NMR (CDCl ) l (ppm): 20.99, 22.11,
26.83, 27.19, 29.37, 43.48, 52.19, 53.07, 175.21.
3
(
1H, m, CH6 CO), 3.10–3.12 (1H, m, CH6
13
22
COOCH
6
(1S,2R)-2b (0.25 g, 0.98 mmol, [h] =+41.7 (c 1, CHCl );
3
3
D
3
2
4
2.14, 22.45, 23.53, 23.69, 24.47, 25.61, 25.68, 31.25,
6.04, 47.32, 52.00, 176.69.
e.e.=95%) was obtained as a yellow oil after column
chromatography. Anal. calcd for C H NO : C, 65.85;
14
25
3
H, 9.87; N, 5.49. Found: C, 66.00; H, 9.89; N, 5.50%.
+
+
5
.4. Gram-scale resolution of 2-aminocycloalkane-
HRMS M found (M calcd): 255.18401 (255.18344);
+
carboxylates
MS: m/z (relative intensity)=256 (3), 255 (15), [M] : 224
(
7), 212 (2), 195(4), 185 (10), 184 (54), 182 (4), 169 (3), 168
5
.4.1. Methyl cis-2-aminocycloheptanecarboxylate rac-
a. rac-1a (0.85 g, 5.0 mmol) and 2,2,2-trifluoroethyl
(13), 156 (3), 154 (5), 153 (4), 152 (4), 142 (6), 140 (3), 137
1
(9), 136 (11), 128 (3), 127 (3), 126 (10), 125 (5), 124 (3), 115
1
butanoate (1.5 ml, 10.0 mmol) in diisopropyl ether (50
ml) were added to the CAL-A preparation (1.0 g). The
mixture was stirred for 1.8 h at room temperature. The
reaction was stopped by filtering off the enzyme at 50%
conversion, with 98% e.e. for (1R,2S)-1a and 97% e.e. for
(4), 114 (39), 113 (14), 112 (7), 110 (3). H NMR (CDCl )
3
l (ppm): 0.94 (3H, t, J=7 Hz, CH CH CH
6
3), 1.50–2.01
6 ), 1.67 (2H, m, CH CH6 CH ), 2.22 (2H,
2 2
2
2
(12H, m, 6×CH2
t, J=7 Hz, CH
3
6
CH CH ), 2.84–2.89 (1H, m, CH
6
CO),
NH), 6.40
(1H, bs, N H6 ); C NMR (CDCl ) l (ppm): 13.46, 19.40,
2
2
3
3.69 (3H, s, COOCH6 ), 4.43–4.49 (1H, m, CH6
3
13
(
1S,2R)-2a. The temperature was lowered to 0°C and
3
gaseous hydrogen chloride bubbled through the solution
for 30 min. After evaporation, the residue was dissolved
in diethyl ether (20 ml) after which (1R,2S)-1a was
allowed to precipitate as a white hydrochloride salt (0.40
24.88, 25.11, 25.79, 26.39, 30.93, 35.80, 37.85, 46.33,
49.16, 51.75, 173.47, 174.95.
5.4.3. Methyl cis-2-aminocyclododecanecarboxylate rac-
1c. rac-1c (0.17 g, 0.70 mmol) and 2,2,2-trifluoroethyl
butanoate (0.27 g, 0.25 ml, 1.6 mmol) in diisopropyl ether
(8 ml) were added to the CAL-A preparation (0.4 g). The
mixture was stirred for 24 h at 47°C. The reaction was
stopped by filtering off the enzyme at 49% conversion,
with 96% e.e. for (1R,2S)-1c and 99% e.e. for (1S,2R)-2c.
The work-up followed the above procedure. (1R,2S)-
Methyl 2-aminocyclododecanecarboxylate hydrochlo-
2
2
g, 1.9 mmol, mp 146–148°C; [h] =+12.2 (c 1, H O);
e.e.=99%). Anal. calcd for C H ClNO : C, 52.05; H,
8
D
2
9
18
2
1
.74; N, 6.74. Found: C, 51.98; H, 8.75; N, 6.73%. H
NMR (D O) l (ppm): 1.30–1.96 (10H, m, 5×CH
6
2), 3.02–
NH), 3.65
2
3
.05 (1H, m, CH
6
CO), 3.53–5.57 (1H, m, CH
6
1
3
(3H, s, COOCH
6
3); C NMR (D O) l (ppm): 23.95,
2
25.44, 26.95, 27.00, 30.77, 45.77, 53.40, 53.47, 176.13.
2
1
(
1S,2R)-2a was obtained as a yellow oil after column
ride (0.097 g, 0.35 mmol, mp 174–175°C; [h] =+33.4 (c
D
chromatography involving elution with dichloro-
1, MeOH); e.e.=97%) was obtained as white crystals.
2
2
methane:ethyl acetate (1:1) (0.51 g, 2.1 mmol, [h] =
Anal. calcd for C H ClNO : C, 60.52; H, 10.16; N, 5.04.
D
14 28
2
1
+
11.9 (c 1, CHCl ); e.e.=98%). Anal. calcd for
Found: C, 60.39; H, 10.14; N, 5.04%. H NMR (D O) l
3
2
C H NO : C, 64.70; H, 9.61; N, 5.80. Found: C, 64.52;
(ppm): 1.32–1.88 (20H, m, 10×CH2
CHCO), 3.65–3.68 (1H, m, CH
COOCH6 3); C NMR (D O) l (ppm): 21. 10, 21.26,
2
6
), 2.89–2.93 (1H, m,
NH), 3.75 (3H, s,
13
23
3
+
+
H, 9.59; N, 5.81%. HRMS M found (M calcd):
41.16793 (241.16779); MS: m/z (relative intensity)=242
6
6
13
2
+
(
4), 241 (16), [M] : 210 (10), 198 (3), 182 (4), 171 (10), 170
59), 154 (19), 140 (8), 139 (10), 138 (10), 123 (13), 122
21.55, 21.99, 22.67, 23.13, 23.68, 24.19, 25.48, 25.95,
47.68, 50.65, 53.10, 176.22.
(
1
(
12), 114 (34), 112 (14), 97 (14), 95 (30). H NMR
2
2
(CDCl ) l (ppm): 0.93 (3H, t, J=7 Hz, CH CH CH
6
3),
(1S,2R)-2c (0.093 g, 0.30 mmol, [h] =+28.6 (c 1,
3
2
2
D
1
CH
COOCH
.41–1.99 (12H, m, 6×CH ), 2.11 (2H, t, J=7 Hz,
CHCl ); e.e.=99%) was obtained as a yellow oil after
2
3
6
CH CH ), 2.89–2.93 (1H, m, CH
6
CO), 3.70 (3H, s,
NH), 6.17 (1H, bs,
); C NMR (CDCl ) l (ppm): 13.59, 19.15, 24.45,
column chromatography. Anal. calcd for C H NO : C,
2
2
3
18 33
3
6
), 4.23–4.30 (1H, m, CH
6
69.41; H, 10.68; N, 4.50. Found: C, 69.54; H, 10.73; N,
3
1
3
+ +
NH
6
5.49%. HRMS M found (M calcd): 311.24634
3
2
1
5.04, 26.92, 27.17, 32.47, 38.83, 47.45, 50.43, 51.48,
71.63, 175.07.
(311.24604); MS: m/z (relative intensity)=312 (2), 311
+
(7); [M] : 281(1), 280 (3), 279 (1), 268 (2), 251 (1), 242 (1),
2
41 (5), 240 (20), 238 (4), 225 (2), 224 (6), 212 (1), 211 (1),
5
.4.2. Methyl cis-2-aminocyclooctanecarboxylate rac-1b.
210 (6), 198 (4), 196 (2), 182 (3), 180 (1), 170 (3), 169 (2),
168 (7), 164 (1). H NMR (CDCl ) l (ppm): 0.96 (3H, t,
1
rac-1b (0.37 g, 2.0 mmol) and 2,2,2-trifluoroethyl
butanoate (0.60 ml, 5.0 mmol) in diisopropyl ether (20
ml) were added to the CAL-A preparation (0.20 g). The
mixture was stirred for 4 h at room temperature. The
reaction was stopped by filtering off the enzyme at 50%
conversion, with 99% e.e. for (1R,2S)-1b and 95% e.e. for
3
J=7 Hz, CH CH CH ), 1.34–0.74 (22H, m, 10×CH
6
6
2,
CH CH6 CH ), 2.22 (2H, t, J=7 Hz, C H6 CH CH ), 2.59–
2 3 2
2
2
3
2
2
3
2.61 (1H, m, CH
6
CO), 3.69 (3H, s, COOCH
6
3), 4.36–4.39
13
(1H, m, CHNH), 6.57 (1H, bs, NH
6
6 ); C NMR (CDCl )
3
l (ppm): 13.54, 18.17, 21.73, 23.06, 23.28, 23.42, 25.08,
25.22, 26.58, 30.28, 35.81, 38.45, 46.50, 46.92, 51.66,
173.18, 174.74.
(
(
1S,2R)-2b. The work-up followed the above procedure.
1R,2S)-Methyl 2-aminocyclooctanecarboxylate hydro-

3
812
Z. Cs. Gyarmati et al. / Tetrahedron: Asymmetry 14 (2003) 3805–3814
5.5. Preparation of N-hydroxymethyl-b-lactams 3a–d
24.35, 24.63, 25.33, 25.66, 27.81, 27.93, 28.04, 32.62,
4.32, 57.02, 63.46, 171.97.
5
A b-lactam (30 mmol) was dissolved in tetrahydrofuran
(
(
60 ml). Paraformaldehyde (1.08 g, 36 mmol), K CO
2 3
0.42 g, 3 mmol) and distilled water (3 ml) were added.
5.6. Gram scale resolution of N-hydroxymethyl-b-lac-
tams rac-3a–d
The solution was sonicated for 8 h. The solvent was
evaporated off and the residue dissolved in diethyl ether
(
50 ml). The solution was dried over sodium sulfate for
2 h. The solvent was evaporated off and recrystalliza-
1
5.6.1. cis-8-Hydroxymethyl-8-azabicyclo[5.2.0]nonan-9-
one 3a. After rac-3a (0.80 g, 4.7 mmol) was dissolved in
dry acetone (47 ml), lipase PS preparation (2.4 g) and
vinyl butanoate (2.16 g, 18.9 mmol, 2.40 ml) were
added. The mixture was stirred for 2 h at room temper-
ature. The enzyme was filtered off at 49% conversion,
with 93% e.e. for the unreacted 3a and 97% e.e. for the
produced 4a. The acetone was evaporated off and the
residue chromatographed on silica, with elution with
dichloromethane:acetone (4:1), affording (1S,7R)-3a
tion from diisopropyl ether afforded colorless crystals
of 3a–d.
5
.5.1. cis-8-Hydroxymethyl-8-azabicyclo[5.2.0]nonan-9-
one 3a. Yield: 75%. Mp: 73–75°C. Anal. calcd for
C H NO : C, 63.88; H, 8.93; N, 8.28. Found: C, 64.09;
9
15
2
+
+
H, 8.89; N, 8.26%. HRMS M found (M calcd):
1
1
9
1
3
4
69.11102 (169.11028); MS: m/z (relative intensity)=
+
71 (1), 170 (4), 169 (2), [M] : 152 (6), 151 (5), 124 (1),
1
22
7 (7), 96 (96) 95 (13); H NMR (CDCl ) l (ppm):
(0.41 g, 2.4 mmol; [h] =−26.2 (c 1, CHCl ); e.e.=97%)
3
D
3
2
2
.20–2.09 (10H, m, 5×CH2
.50 (1H, bs, OH), 3.86–3.96 (1H, m, CH
.48 (1H, m, CH OH), 4.68–4.83 (1H, m, CH
6
), 3.28–3.39 (1H, m, CH
6
CO),
and (1R,7S)-4a (0.59 g, 2.4 mmol, [h] =−52.3 (c 1,
CHCl ); e.e.=97%), both as colorless oils.
D
6
NH), 4.35–
3
13
6
6
2OH);
C
2
NMR (CDCl ) l (ppm): 24.59, 24.97, 27.90, 29.53,
(1R,7S)-4a: Anal. calcd for C H NO : C, 65.25; H,
3
13 21
3
3
1.35, 54.25, 55.71, 62.35, 170.63.
8.84; N, 5.85. Found: C, 65.06; H, 8.86; N, 5.84%.
+ +
HRMS M found (M calcd): 239.152680 (239.15214);
+
5
.5.2. cis-9-Hydroxymethyl-9-azabicyclo[6.2.0]decan-10-
MS: m/z (relative intensity)=239 (2); [M] : 169 (1), 168
one 3b. Yield: 80%. Mp: 67–69°C. Anal. calcd for
(3), 153 (4), 152 (35), 151 (7), 144 (10), 124 (4), 101 (10),
1
C H NO : C, 65.54; H, 9.35; N, 7.64. Found: C,
97 (8), 96 (100). H NMR (CDCl ) l (ppm): 0.95 (3H,
1
0
17
2
3
+
+
6
1
1
1
5.23; H, 9.32; N, 7.66%. HRMS M found (M calcd):
t, J=8 Hz, CH CH CH ), 1.33–2.04 (10H, m, 5×CH
6
6
2),
1.61–1.70 (2H, m, CH CH6 CH ) 2.31 (2H, t, J=8 Hz,
2 2
2
2
3
83.12595 (183.12593); MS: m/z (relative intensity)=
3
+
85 (1), 184 (5), 183 (4), [M] : 166 (8), 138 (2), 124 (2),
CH
6
CH CH ), 3.31–3.36 (1H, m, CH
6
CO), 3.81–3.86
NH), 5.06 (1H, d, J=6 Hz, NCH2O), 5.18
2O); C NMR (CDCl ) l (ppm):
2
2
3
1
10 (65); H NMR (CDCl ) l (ppm): 1.94–2.08 (12H,
(1H, m, CH
6
6
3
13
m, 6×CH
OH), 3.70–3.81 (1H, m, CH
CH OH), 4.65–4.81 (1H, m, CH
6
), 3.02–3.13 (1H, m, CH
6
CO), 3.55 (1H, bs,
(1H, d, J=6 Hz, NCH
6
2
3
6
NH), 4.39–4.51 (1H, m,
13.62, 18.22, 24.60, 25.03, 27.95, 29.42, 31.39, 35.89,
54.90, 57.35, 62.71, 170.51, 173.62.
1
3
6
6
2OH); C NMR
2
(CDCl ) l (ppm): 21.60, 25.60, 25.94, 25.96, 27.32,
3
2
9.01, 53.62, 56.42, 62.72, 171.00.
5
.6.2. cis-9-Hydroxymethyl-9-azabicyclo[6.2.0]decan-10-
5
.5.3. cis-13-Hydroxymethyl-13-azabicyclo[10.2.0]tetra-
one 3b. After rac-3b (0.36 g, 2.0 mmol) was dissolved in
dry acetone (20 ml), lipase PS preparation (1.0 g) and
2,2,2-trifluoroethyl butanoate (1.35 g, 7.9 mmol, 1.20
ml) were added and the mixture stirred for 24 h at
room temperature. The enzyme was filtered off at 52%
conversion, with 90% e.e. for the unreacted 3b and 82%
e.e. for the produced 4b. The work-up carried out as
previously described, afforded (1S,8R)-3b (0.17 g, 0.93
decan-14-one 3c. Yield: 77%. Mp: 126–128°C. Anal.
calcd for C H NO : C, 70.25; H, 10.53; N, 5.85.
1
4
25
2
+
Found: C, 70.04; H, 10.55; N, 5.86%. HRMS M found
+
(
M calcd): 239.18904 (239.18853); MS: m/z (relative
+
intensity)=240 (1), 239 (1), [M] : 222 (5), 210 (2), 208
1
(
2), 194 (3), 180 (2), 168 (3), 167 (25), 166 (74); H
NMR (CDCl ) l (ppm): 1.29–1.79 (20H, m, 10×CH
6
2),
NH),
2OH),
3
2
2
3
3
4
.09–3.14 (1H, m, CH
.85 (1H, lb, OH), 4.49 (1H, d, J=11 Hz, CH
6
CO), 3.78–3.84 (1H, m, CH
6
mmol, [h] =−38.8 (c 1, CHCl ); e.e.=91%) and
D
3
2
2
6
(1R,8S)-4b (0.20 g, 0.79 mmol, [h] =−39.9 (c 1,
D
13
.77 (2H, d, J=11 Hz, CH2
6
OH); C NMR (CDCl ) l
CHCl ); e.e.=82%) as colorless oils.
3
3
(
ppm): 21.83, 22.73, 23.07, 24.57, 24.63, 26.01, 26.23,
2
7.50, 27.60, 27.96, 54.00, 56.39, 67.34, 170.96.
(1R,8S)-4b: Anal. calcd for C H NO : C, 66.37; H,
1
4
23
3
9
.15; N, 5.53. Found: C, 66.54; H, 9.17; N, 5.52%.
+ +
5
.5.4.
trans-13-Hydroxymethyl-13-azabicyclo[10.2.0]-
HRMS M found (M calcd): 253.166840 (253.16779);
+
tetradecan-14-one 3d. Yield: 83%. Mp: 92–93°C. Anal.
MS: m/z (relative intensity)=254 (1), 253 (5); [M] : 182
calcd for C H NO : C, 70.25; H, 10.53; N, 5.85.
(4), 183 (1), 167 (3), 166 (31), 138 (4), 124 (2), 111 (7),
1
4
25
2
+
1
Found: C, 70.28; H, 10.51; N, 5.86%. MS M found
110 (75), 109 (7). H NMR (CDCl ) l (ppm): 0.95 (3H,
3
+
(
M
calcd): 239.18809 (239.18853); MS: m/z (relative
t, J=8 Hz, CH CH CH ), 1.25–2.12 (14H, m, 7×CH
6
6
2),
2
2
3
6
+
intensity)=240 (1), [M] : 222 (4), 210 (2), 194 (2), 180
2.31 (2H, t, J=8 Hz, CH
CH CH ), 3.05–3.10 (1H, m,
2
2
3
1
(
(
2), 168 (4), 167 (25), 166 (78); H NMR (CDCl ) l
CH
Hz, NCH
6
CO), 3.66–3.71 (1H, m, CH
6
NH), 5.08 (1H, d, J=6
3
1
3
ppm): 1.12–2.05 (20H, m, 10×CH
CO), 3.56–3.60 (1H, m, CHNH), 4.10 (1H, lb, OH),
.48 (1H, d, J=11 Hz, CH OH), 4.81 (1H, d, J=11
6
2), 2.84–2.89 (1H, m,
6
O), 5.15 (1H, d, J=6 Hz, NCH
6
2O);
C
2
CH
4
6
6
NMR (CDCl ) l (ppm): 13.57, 18.20, 21.57, 25.62,
3
6
25.82, 25.97, 27.35, 28.94, 35.87, 54.21, 58.02, 62.08,
170.86, 173.52.
2
1
3
Hz, CH6 2OH); C NMR (CDCl ) l (ppm): 23.27, 23.34,
3

Z. Cs. Gyarmati et al. / Tetrahedron: Asymmetry 14 (2003) 3805–3814
3813
5
.6.3. cis-13-Hydroxymethyl-13-azabicyclo[10.2.0]tetra-
(1H, m, CH
(1H, d, J=6 Hz, NCH6 2O); C NMR (CDCl ) l
3
6
NH), 5.09 (1H, d, J=6 Hz, NCH
6
2O), 5.16
13
decan-14-one 3c. After rac-3c (0.30 g, 1.3 mmol) was
dissolved in dry acetone (25 ml), lipase PS preparation
(ppm):13.53, 18.24, 22.68, 22.97, 23.07, 23.92, 25.04,
25.22, 27.35, 29.30, 31.88, 32.08, 35.96, 54.65, 58.40,
62.64, 171.27, 173.39.
(
1.25 g), 2,2,2-trifluoroethyl butanoate (0.85 g, 5.0
mmol, 0.75 ml) and hexadecane (56 mg) were added
and the mixture stirred for 10 h at room temperature.
The enzyme was filtered off at 50% conversion, with
9
0% e.e. for the unreacted 3c; for 4c e.e. determination
Acknowledgements
was not possible in the resolution mixture. The work-
up as previously described, afforded (1S,12R)-3c (0.15
22
g, 0.63 mmol, mp 128–130°C; [h] =−30.2 (c 1,
Z.C.G. is grateful for the grant from the Center of
International Mobility (CIMO) in Finland. We also
thank OTKA grant T030647, OTKA grant T034422
and grant ETT 556/2000 in Hungary.
D
CHCl ); e.e.=93%) and (1R,12S)-4c (0.17 g, 0.55
3
2
2
mmol, mp 72–74°C; [h] =−24.5 (c 1, CHCl ); e.e.=
4%), both as white crystals. The value of the e.e. was
D
3
4c
9
obtained by the GC method using NH OH/MeOH
2
followed by MeOH/HCl treatments and preparing the
acetamide of the amino ester.
References
1R,12S)-4c: Anal. calcd for C H NO : C, 69.86; H,
1. Enantioselective Synthesis of i-Amino Acids; Juaristi, E.,
Ed.; Wiley-VHC: New York, 1997.
2. Gademann, K.; Hintermann, T.; Schreiber, J. V. Curr.
Med. Chem. 1999, 6, 905–925.
1
8
31
3
0.10; N, 4.53. Found: C, 69.99; H, 10.12; N, 4.54%.
+ +
+
(
2
(
1), 239 (2), 238 (6), 224 (6), 223(6), 222 (40), 221(4),
20 (5), 211 (1), 210 (3), 209 (2), 208 (4), 204 (3), 197
1), 196 (3), 195 (3) 194 (10), 193 (6), 192 (5), 180 (5),
3. Ojima, I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6,
927–954.
4. Scarborough, R. M. Curr. Med. Chem. 1999, 6, 971–981.
5. F u¨ l o¨ p, F. Chem. Rev. 2001, 101, 2181–2204.
6. Park, K.; Kurth, M. J. Tetrahedron 2002, 58, 8629–8659.
7. Nativ, E.; Rona, P. Isr. J. Chem. 1972, 10, 55–58.
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9. Singh, R.; Cooper, R. D. G. Tetrahedron 1994, 50,
12049–12064.
10. Csom o´ s, P.; Kanerva, L. T.; Bern a´ th, G.; F u¨ l o¨ p, F.
Tetrahedron: Asymmetry 1996, 7, 1789–1796.
1
1
78 (5), 168 (8), 167 (13), 166 (100), 165 (7), 164 (6). H
NMR (CDCl ) l (ppm): 0.95 (3H, t, J=7 Hz,
3
CH CH CH
CH CH
3
5
NCH
2
2
6
3),
1.26–1.76
(22H,
m,
10×CH2
6
,
2
2
6
CH ), 2.30 (2H, t, J=7 Hz, CH
6
CH CH ),
2
2
3
2
2
3
.13–3.16 (1H, m, CH
6
CO), 3.67–3.70 (1H, m, CH
6
NH),
.07 (1H, d, J=6 Hz, NCH
6
O), 5.14 (1H, d, J=6 Hz,
2
1
3
6
2O); C NMR (CDCl ) l (ppm): 13.56, 18.23,
3
1.79, 22.66, 22.75, 23.10, 24.51, 25.87, 27.40, 27.57,
9.33, 31.90, 35.90, 54.25, 57.18, 62.30, 170.87, 173.48.
11. K a´ m a´ n, J.; Forr o´ , E.; F u¨ l o¨ p, F. Tetrahedron: Asymmetry
5
.6.4.
trans-13-Hydroxymethyl-13-azabicyclo[10.2.0]-
2000, 11, 1593–1600.
tetradecan-14-one 3d. After rac-3d (0.30 g, 1.3 mmol)
was dissolved in dry acetone (25 ml), CAL-B (63 mg),
vinyl butanoate (0.57 g, 5.0 mmol, 0.64 ml) and hexade-
cane (56 mg) were added and the mixture stirred for 2.5
h at room temperature. The enzyme was filtered off at
12. F u¨ l o¨ p, F.; Palk o´ , M.; K a´ m a´ n, J.; L a´ z a´ r, L.; Sillanp a¨ a¨ , R.
Tetrahedron: Asymmetry 2000, 11, 4179–4187.
´
13. Forr o´ , E.; Arva, J.; F u¨ l o¨ p, F. Tetrahedron: Asymmetry
2001, 12, 643–649.
14. Forr o´ , E.; F u¨ l o¨ p, F. Org. Lett. 2003, 5, 1209–1212.
15. Martinek, T. M.; T o´ th, G. K.; Vass, E.; Holl o´ si, M.;
F u¨ l o¨ p, F. Angew. Chem., Int. Ed. 2002, 41, 1718–1721.
16. Oki, T.; Hirano, M.; Tomatsu, K.; Numata, K.; Kamei,
H. J. Antibiot. 1989, 42, 1756–1762.
17. Iwamato, T.; Tsujii, E.; Ezaki, M.; Fujie, A.; Hashimoto,
S.; Okuhara, M.; Kohsaka, M.; Imanaka, H.; Kawabata,
K.; Inamato, Y.; Sakane, K. J. Antibiot. 1990, 43, 1–7.
18. Kanerva, L. T.; Csom o´ s, P.; Sundholm, O.; Bern a´ th, G.;
F u¨ l o¨ p, F. Tetrahedron: Asymmetry 1996, 7, 1705–1716.
19. Evans, C.; McCague, R.; Roberts, S. M.; Sutherland, A.
G.; Wisdom, R. J. Chem. Soc., Perkin Trans. 1 1991,
2276–2277.
20. Taylor, S. J. M.; McCague, R.; Wisdom, R.; Lee, C.;
Dickson, K.; Ruecroft, G.; O’Brien, F.; Littlechild, J.;
Bevan, J.; Roberts, S. M.; Evans, C. T. Tetrahedron:
Asymmetry 1993, 4, 1117–1128.
21. Halling, P. J. Enzyme Microb. Technol. 1994, 16, 178–
206.
5
0% conversion, with 85% e.e. for the unreacted 3d; for
d e.e. determination was not possible in the resolution
4
mixture. The work-up as above afforded (1R,12R)-3d
2
2
(
0.12 g, 0.50 mmol, mp 93–94°C; [h] =−146.6 (c 1,
D
CHCl ); e.e.=91%) as white crystals and (1S,12S)-4d
3
22
(
0.19 g, 0.61 mmol, [h] =54.4 (c 1, CHCl ); e.e.=91%)
D 3
4d
as a colorless oil. The value of e.e. was obtained by
the GC method using NH OH/MeOH followed by
MeOH/HCl treatments and preparing the acetamide of
the amino ester.
2
(
1
1S,12S)-4d: Anal. calcd for C H NO : C, 69.86; H,
18
31
3
0.10; N, 4.53. Found: C, 70.00; H, 10.14; N, 4.54%.
+
+
HRMS M found (M calcd): 309.23056 (309.23039);
MS: m/z (relative intensity)=309 (1); [M] : 281 (1), 264
+
(
2
1), 239 (2), 238 (4), 224 (2), 223(8), 222 (41), 221(1),
20 (1), 211 (1), 210 (1), 209 (1), 208 (1), 204 (1), 196
(
(
(
(
1), 195 (2) 194 (8), 193 (1), 192 (1), 180 (2), 169 (2), 168
2), 167 (14), 166 (100), 165 (2). H NMR (CDCl ) l
ppm): 0.95 (3H, t, J=7 Hz, CH CH CH
22H, m, 10×CH
1
22. Liljeblad, A.; Kanerva, L. T. Tetrahedron: Asymmetry
1999, 10, 4405–4415.
23. Virsu, P.; Liljeblad, A.; Kanerva, A.; Kanerva, L. T.
3
6
3), 1.21–1.68
CH ), 2.31 (2H, t, J=7 Hz,
2
2
6
, CH CH
6
2
2
2
3
CH6 CH CH ), 2.88–2.91 (1H, m, CH6 CO), 3.46–3.48
Tetrahedron: Asymmetry 2001, 12, 2447–2455.
2 2 3

3
814
Z. Cs. Gyarmati et al. / Tetrahedron: Asymmetry 14 (2003) 3805–3814
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6
2
2
2
2
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