Stereoselective synthesis of hydroxylated β-aminocyclohexanecarboxylic acids

Article abstract of DOI:10.1016/j.tet.2008.03.068

A simple synthetic approach has been developed for the regio- and diastereoselective synthesis of hydroxylated 2-aminocyclohexanecarboxylic acid stereoisomers from 1,4-cyclohexadiene by the reductive opening of appropriate epoxide intermediates derived from the corresponding bicyclic β-lactams. This method has been extended to the synthesis of these hydroxylated β-amino acids in enantiomerically pure form.

Full text of DOI:10.1016/j.tet.2008.03.068

Tetrahedron 64 (2008) 5036–5043
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of hydroxylated b-aminocyclohexanecarboxylic acids
a
a
a
a,
b
c
a,b,
*
}
´
´
´
´
´
¨ ¨
Lorand Kiss , Eniko Forro , Tamas A. Martinek , Gabor Bernath , Norbert De Kimpe , Ferenc Fulop
a Institute of Pharmaceutical Chemistry, University of Szeged, Eo¨tvo¨s u. 6, H-6720 Szeged, Hungary
b Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, Eo¨tvo¨s u. 6, H-6720 Szeged, Hungary
c Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple synthetic approach has been developed for the regio- and diastereoselective synthesis of hy-
droxylated 2-aminocyclohexanecarboxylic acid stereoisomers from 1,4-cyclohexadiene by the reductive
opening of appropriate epoxide intermediates derived from the corresponding bicyclic b-lactams. This
method has been extended to the synthesis of these hydroxylated b-amino acids in enantiomerically
pure form.
Received 30 January 2008
Received in revised form 4 March 2008
Accepted 19 March 2008
Available online 22 March 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
b-Lactams
b-Amino acids
Epoxidation
Stereoselective synthesis
1. Introduction
oxanorbornene or oxanorbornane skeleton.6 Methyl 2-benzyl-
oxycarbonylamino-5-hydroxy-3-cyclohexenecarboxylate has been
In recent years, conformationally constrained alicyclic b-amino
acids have gained great interest as consequence of their
used as a starting compound for the incorporation of an extra amino
group ontothe cyclohexane skeleton.7 The introduction of a hydroxy
group onto the cyclohexane ring has also been accomplished ste-
reoselectively from cis- and trans-2-aminocyclohexenecarboxylic
acids by iodolactonization or via the corresponding oxazine de-
rivatives.8 Our research group recently developed a new method for
the hydroxylation of trans-2-aminocyclohexenecarboxylic acid by
functionalization of the olefinic bond via an epoxidation reaction.9
Our present aim was to utilize the above procedure involving the
stereodirected epoxidation reaction for the synthesis of different
hydroxylated 2-aminocyclohexanecarboxylic acids. The b-lactam
2 derived from 1,4-cyclohexadiene offered an excellent possibility
for the introduction of a hydroxy function onto the cyclohexane ring
by epoxidation of the olefinic bond.
a
pharmacological potential. These compounds are found in a large
number of natural products, b-lactams or antibiotics (e.g., cis-
pentacin). They are also important building blocks for the synthesis
of peptide oligomers.1 Gellman et al. recently reported the in-
corporation of 3-methoxy- or 3-phenoxy-substituted trans-2-ami-
nocyclopentanecarboxylic acid residues into short 12-helical
b-peptides.2a The presence of a polar side-chain in the peptide
oligomers not only exerts a great influence on the formation of their
secondary structure, but can also have an enormous effect on their
biological activity in an amphiphilic structure.2 Apart from this,
hydroxylated derivatives (taxol, bestatin, and related compounds)
are of considerable interest, all having promising biological prop-
erties as potential therapeutic agents.3 Among the alicyclic
hydroxy-b-amino acids, the natural oryzoxymycin exhibits mod-
erate activity against Xanthomonas oryzae.4 Whilst a number of
methods have been developed for the diastereo- and enantiose-
lective preparation of cyclic b-amino acids, only a few examples
are available for the synthesis of hydroxyl-substituted b-amino-
cyclohexanecarboxylic acids.3e,5 One short approach for the syn-
thesis of hydroxy-functionalized b-aminocyclohexanecarboxylic
acids is the base-induced fragmentation of b-amino esters with an
2. Results and discussion
1,4-Cyclohexadiene (1) was first transformed into ethyl cis-
2-benzyloxycarbonylamino-4-cyclohexenecarboxylate (3a) via b-
lactam derivative 2.11 Chlorosulfonyl isocyanate (CSI) addition to 1
afforded lactam 2, which was subsequently subjected to lactam ring
opening and N-protection reactions forming ester 3a. In the next
step of the strategy, b-amino ester 3a was submitted to epoxidation
of the olefinic bond with m-CPBA in CH2Cl2 (Scheme 1). Epoxida-
tion of a mono-N-protected aminoalkene (carbamate or amide)
with peracids is known to give a high degree of ‘cis selectivity’,10
* Corresponding author. Tel.: þ36 62 545564; fax: þ36 62 545705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fu¨lo¨p).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.068

L. Kiss et al. / Tetrahedron 64 (2008) 5036–5043
5037
O
COOEt
NHZ
COOEt
NHZ
1. CSI, 70 °C, 4 h
1. HCl/EtOH, rt, 1 h
mCPBA, CH2Cl2
O
NH
2 (48%)
2. Na2SO3, H2O
rt, 2 h
2. Z-Cl, TEA, THF
rt, 16 h
rt, 6 h
1
3a (72% two steps)
4a (59%)
Scheme 1. Formation of epoxy amino ester 4a.
presumably via a hydrogen-bonding interaction of the amide and
the peracid in the transition state of the reaction.
The epoxidation of different amino esters or acids with Boc or Z
protection at the nitrogen has been performed (Scheme 2) under
the conditions presented in Table 1.
epoxy ring orientations revealed that the equatorial H-5 exhibits
different distances from H-6ax. For the trans diastereomer, the
distance between H-5 and H-6ax is 2.8 Å, while 2.4 Å is predicted for
cis geometry. Due to the inverse sixth-power dependence of the
NOE intensity on distance, the difference on the NOE intensity scale
is approximately a factor of two, which is not difficult to measure.
As an internal reference, the intensity of the H-2eq H-1ax NOESY
crosspeak was used (d¼2.5 Å). The measured integral value for the
H-5 H-6ax crosspeak was 0.38 relative to the H-2eq H-1ax signal,
which corresponds to a distance of 2.9 Å. These findings strongly
support the cis-epoxy arrangement.
The introduction of a hydroxy group onto the cyclohexane
skeleton of the 2-aminocyclohexanecarboxylic acid moiety was
based on the reductive opening of the oxirane ring of epoxide 4a
(Scheme 3). Opening of the oxirane ring in 4a using NaBH4 in EtOH
at room temperature for 18 h proceeded regioselectively, affording
only 4-hydroxy derivative 6 in 70% yield. When opening of the
oxirane ring of 4a was effected at 70 ꢀC for 12 h, isomerization at
C-1 was observed, resulting in only hydroxy derivative 7 (Scheme
3). Isomerization also occurred when hydroxy derivative 6 was
stirred in EtOH at room temperature in the presence of 1.2 equiv of
NaOEt for 23 h, giving compound 7. The base-mediated partial
isomerization of cis-epoxy amino ester 4a could be accomplished in
refluxing EtOH in the presence of 3 equiv of K2CO3 for 3 days, fur-
nishing a mixture of epoxides 4d/4a in a ratio of 3:1 (Scheme 4).
The opposite regioselectivity observed on the reductive opening
of epoxides 4a and 4d can be analyzed on the basis of their con-
formational arrangement depicted in Figure 2. The formation of
4-hydroxy-substituted cis-amino ester 6 from 4a or 5-hydroxy
substituted trans-amino ester 10 from 4d9 probably involves hy-
COOR
NHR'
COOR
NHR'
COOR
NHR'
see Table 1
epoxidation
+
O
O
3a-c
4a-c
5a-c
Scheme 2. Epoxidation of cis-b-amino esters 3a–c; a: R¼Et, R0¼Z; b: R¼Bn, R0¼Z;
c: R¼Et, R0¼Boc.
Table 1
Epoxidation reaction of cis-b-amino esters 3a–c
Entry
R
R0
Alkene
Reaction conditions
Yield (%)
Epoxide
1
2
3
4
5
6
7
Et
Et
Et
Et
Bn
Et
Et
Z
Z
Z
Z
Z
BOC
BOC
3a
3a
3a
3a
3b
3c
3c
m-CPBA, CH2Cl2
Peracetic acid
59
51
64
49
65
57
58
4a
4a
4a
4a
4b
4c
4c
Dimethyldioxirane
m-CPBA, [BMIM][PF6]
m-CPBA, CH2Cl2
m-CPBA, CH2Cl2
Dimethyldioxirane
The epoxidations were performed in non-polar or polar solvents
(e.g., CH2Cl2, MeCN or the ionic liquid 1-butyl-3-methylimidazolium
hexafluorophosphate), using different oxidizing agents, such as
m-chloroperbenzoic acid, peracetic acid or dimethyldioxirane. In all
cases, the reaction resulted diastereoselectively in cis-epoxides 4a–c
as single diastereoisomers, in moderate yields.
The stereoselectivity of the epoxidation reactions was de-
termined from the spectroscopic and GC analyses of the crude
products. The stereochemical analysis is presented for epoxide 4a
and the structural assignment can be transferred to 4b and 4c. First,
the conformation of the cyclohexane ring was determined.
The non-overlapping H-6 signal at 2.35 ppm exhibited a scalar
coupling of 7.8 Hz together with a weak NOE interaction with H-1 at
2.58 ppm, which indicated their trans-diaxial (anti-periplanar)
orientation. Due to considerable overlap, the HSQC spectrum was
utilized to estimate the coupling constants around H-3; it revealed
that the highest 3J(H-3,H-2) was approximately 5.5 Hz, suggesting
an equatorial position for H-2. A strong NOE crosspeak was ob-
served in DMSO between the NH at 6.23 ppm and H-6ax at
2.35 ppm. These findings supported a twist conformation with
an axial substituent at position 2 and an equatorial substituent at
position 1 (Fig. 1). However, such a conformation can accommodate
both cis and trans arrangements of the epoxy ring with an axial
oxygen. The structure refinement at the HF/3-21 G level for the two
dride attack from the sterically less hindered side (6-Heq and 3-Heq
,
approach a for 4a and approach b for 4d in Fig. 2) of the cyclohexane
skeleton. Since the opening of the oxirane ring by hydride occurs
faster than the isomerization at C-1, it is concluded that the same
approach is valid for the formation of hydroxy derivative 7.
Alkaline hydrolysis of the ester group in compounds 6 and 7 and
deprotection of the amino groups by catalytic hydrogenation
afforded 2-amino-4-hydroxycyclohexanecarboxylic acids 8 and 9
(Scheme 3).
For 2-amino-4-hydroxy ester 6, position 4 for the hydroxy group
is proven unequivocally from the COSY spectrum. Unfortunately,
broadened signals were obtained, possibly due to the conforma-
tional flexibility of 6, which prevented a complete conformational
assignment by NMR spectroscopy. Nevertheless, a weak NOE
interaction was detected between H-4 and H-2, indicating the cis
arrangement of the hydroxy group relative to the protected amino
group. For 2-amino-4-hydroxy ester 7, the COSY crosspeak pattern
indicated that the hydroxy group occupies position 4. The confor-
mation of the cyclohexane scaffold is chair with scalar coupling
constant values above 12 Hz for 3J(H-1ax,H-2ax), 3J(H-2ax,H-3ax),
and 3J(H-1ax,H-6ax), pointing to a trans-diequatorial arrangement of
the protected amino and carboxylic groups. The rigid chair con-
formation is corroborated by the mutual NOEs observed between
H-2ax, H-4ax, and H-6ax. The NOEs to H-4ax and the large coupling
between H-3ax and H-4ax prove the equatorial orientation of the
hydroxy group. For 2-amino-4-hydroxy acid 9, the COSY spectrum
indicates that the hydroxy group is in position 4. The conformation
is chair with scalar couplings of 3J(H-1ax,H-2ax)¼11 Hz and
R
HN
H6ax
H
O
H2eq
H3eq
H6eq
R'OOC
H
H3ax
H1ax
Figure 1. Proposed stereostructure of epoxides 4a–c.

5038
L. Kiss et al. / Tetrahedron 64 (2008) 5036–5043
COOEt
COOH
NH2
NaBH4, EtOH
1. NaOH, MeOH/H2O, rt, 5 h
2. H2, Pd/C, MeOH, rt, 2 h
rt, 18 h
HO
NHZ
6 (70%)
HO
HO
8 (87%)
COOEt
NHZ
O
NaOEt, EtOH, rt
23 h, 84%
COOH
NH2
COOEt
NaBH4, EtOH
70 °C, 12 h
1. NaOH, MeOH/H2O, rt, 5 h
2. H2, Pd/C, MeOH, rt, 2 h
HO
NHZ
7 (56%)
Scheme 3. Formation of 4-hydroxylated amino esters 6 and 7 and amino acids 8 and 9.
9 (85%)
cyclohexane skeleton cis relative to the protected amino group in
the C-2 carbamate.
COOEt
NHZ
COOEt
NHZ
COOEt
NHZ
K2CO3
EtOH, Δ
O
O
O
+
It was expected that introduction of a hydroxy group trans rel-
ative to the amino group in C-2 on the cyclohexanecarboxylic
amino ester moiety would be possible without changing the re-
action conditions or the oxidizing agent, but starting from the Boc-
protected lactam 11. In lactam 11, the N-substituted imide moiety
would not exert the cis stereodirecting effect observed earlier in the
transition state of the epoxidation reaction. For this reason Boc-
protected lactam 11 was treated with m-chloroperbenzoic acid at
0 ꢀC for 5 h (Scheme 5). In this case, due to the presence of the bulky
Boc group, trans-epoxide 12 was formed exclusively (yield 67%).
Interestingly, when the reaction was performed at room tempera-
ture for 12 h, a mixture of trans- and cis-epoxides 12 and 12a was
detected in a 2:1 ratio (Scheme 5). The COSY connectivity pattern
accounts for the formation of the epoxy ring in the indicated po-
sition for both 12 and 12a. The scalar couplings do not readily allow
the stereochemical assignment. Nevertheless, quantitative analysis
of the NOESY crosspeak intensities of H-2–H-3eq and H-2–H-3eq
revealed intensity ratios of 1.26 and 1.89 for 12 and 12a, re-
spectively. The ab initio modeling of the rigid ring systems led
to calculated NOE intensities of 1.28 and 1.99 for the trans and cis
orientations of the epoxy ring relative to the lactam ring, re-
spectively. The stereochemical assignment (12: trans, 12a: cis) is
supported by the significant downfield shifts (Dd ca. þ0.35 ppm)
observed for H-3ax and H-6ax in 12, caused by the shielding effect of
the vicinal epoxy oxygen in the axial position. The latter ring
opening of 12 unequivocally proved its stereochemistry.
4a
4d (62%)
4a
Scheme 4. Isomerization of the epoxy amino ester 4a to 4d.
3J(H-1ax,H-6ax)¼12 Hz, pointing to a trans-diequatorial arrange-
ment of the amino and carboxylic groups. H-4 exhibits two large
couplings (around 12 Hz), which proves the equatorial position of
the hydroxy group cis to the amino group. The all-equatorial ori-
entation of the substituents is supported by the NOE interactions
observed in the H-2ax–H-4ax–H-6ax triangle. For 2-amino-4-hy-
droxy acid 8, the connectivity pattern proves position 4 for the
hydroxy group. The highest scalar coupling around H-1 is estimated
as less than 4 Hz, showing its equatorial arrangement, while H-2 is
axial because 3J(H-2ax,H-3ax)¼10.6 Hz. The cis orientation of the
hydroxy group relative to the amino substituent is strongly sup-
ported by a strong NOE interaction between H-2ax and H-4ax. The
conformation of the cyclohexane scaffold cannot be determined,
due to the unclear spatial arrangement around H-5 and H-6. The
most likely explanation is a conformational equilibrium between
twist and chair forms.
The method presented above indicated that the presence of a
mono-protected amino group (carbamate) on the cycloalkene
skeleton always gave rise to cis selectivity during epoxidation,
which resulted, after reductive opening of the oxirane ring, in a
hydroxy derivative with the hydroxy functionality on the
NHZ
2
a
b
O
1
2
COOEt
NHZ
2
4
H
5
1
HO
COOEt
NHZ
NHZ
6
4
6
3
5
4
EtOOC
3
H
5
H
HO
1
EtOOC
2
O
1
6
a
H
b
9
10
4d
approach b favored
4a
(approach a favored)
Figure 2. Reductive opening of the oxirane ring in cis-amino ester 4a and trans-amino ester 4d.
O
O
O
O
Boc2O, 20% DMAP
CH2Cl2, rt, 13 h
mCPBA, CH2Cl2
+ O
O
NBoc
NH
NBoc
NBoc
rt, 12 h
2
11 (86%)
12a
12
mCPBA, CH2Cl2
0 °C, 5 h
O
O
NBoc
12 (67%)
Scheme 5. Epoxidation of the Boc-protected b-lactam 11.

L. Kiss et al. / Tetrahedron 64 (2008) 5036–5043
5039
COOEt
COOEt
NHBoc
COOH
NaBH4, EtOH
rt, 7 h
18% HCl, Δ
O
O
4 h
HO
NHBoc
16 (72%)
HO
NH2HCl
18 (48%)
14 (51%)
NaOEt, EtOH
rt, 16 h
HO
COOEt
+
O
COOEt
NHBoc
HO
COOEt
NHBoc
NaOEt, EtOH
0 °C, 5 h
NaBH4, EtOH
O
NBoc
rt, 7 h
O
NH
12
13 (71%)
15 (14% from 13)
O
17 (65%)
22%
18%
NaBH4, EtOH, rt, 19 h
Scheme 6. Formation of hydroxylated amino esters 15 and 16 and amino acid 18.
Opening of the lactam ring in 12 in the presence of 1.2 equiv of
NaOEt in EtOH at room temperature for 16 h led to isomerization at
C-1, giving epoxy ester 14 in 51% yield (Scheme 6). Isomerization at
C-1 was avoided by carrying out the reaction at 0 ꢀC for 5 h,
resulting in epoxy ester 13 (71% yield). Subsequently, reductive
opening of the oxirane ring of 14 with NaBH4 in EtOH at room
temperature for 7 h afforded 4-hydroxylated amino ester 16
regioselectively in 72% yield. Reductive oxirane ring opening for
epoxide 13 was performed under similar conditions as for 14 but
the corresponding hydroxylated amino ester 15 was formed only in
low yield (18%). The main product of this reaction was oxazinone
derivative 17, formed in good yield, which probably involves attack
of the carbonyl oxygen at C-4 of the oxirane ring (Scheme 6). For 13,
the conformation of the cyclohexane scaffold is the same as that for
4a. A small coupling is measured between H-1ax and H-2eq (3.1 Hz),
while a large coupling (9.2 Hz) and a weak NOE are observed
between H-1ax and H-6ax. The NOE intensities for H-5eq–H-6eq and
H-5eq–H-6ax are the same, which indicates that H-5eq bisects the
dihedral. H-4 exhibits a larger NOE toward H-3eq than H-3ax. These
observations are in good accord with the trans orientation of the
epoxy ring relative to the protected amino group.
which is possible only with a trans arrangement relative to the
protected amino group.
The regioselectivity of the oxirane ring opening in 13 and 14 can
be modeled analogously to that presented for epoxides 4a and 4d.
The stereochemistry of the opening of the epoxide in 13 is
governed by the axial arrangement of H-6ax, which does not favor
attack according to approach a (Fig. 3). With the favored approach b,
formation of 5-hydroxy-substituted ester 15 was observed (Fig. 3).
In the case of epoxide 14, hydride attack at position 5 is favored
from the less hindered face (6-Heq, approach a in Fig. 3), furnishing
hydroxylated ester 16.
According to this modeling, the formation of oxazinone de-
rivative 17 can be readily understood. While the NHBoc and ester
groups in trans-amino epoxide 14 are presumably equatorially
oriented, in cis-derivative 13 the axial NHBoc (through its carbonyl
oxygen) attacks the oxirane ring at C-4, forming the bicyclic 17
(Fig. 4).
It was expected that formation of oxazinone derivative 17 could
be avoided by opening of the oxirane ring in lactam 12. For this
reason lactam 12 was treated with NaBH4 in EtOH at room tem-
perature (Scheme 6). After stirring for 19 h at room temperature,
the formation of epoxide 13 (22%) and 5-hydroxylated ester 15
(18%) was observed, together with a large amount of unreacted
material. Simultaneous hydrolysis of the ester and deprotection of
the amino group of 18 by treatment with 18% HCl under reflux for
4 h led to (r-1,t-2,c-4)-2-amino-4-hydroxycyclohexanecarboxylic
acid hydrochloride 18 (Scheme 6). Unfortunately, not only was
hydroxylated ester 15 formed in only low yield (Scheme 6), but its
hydrolysis and deprotection under the same conditions as for 16
failed, instead giving a complex mixture, probably involving
For 2-N-Boc-amino-4-hydroxy ester 16, the COSY connectivity
pattern unequivocally proves position 4 for the hydroxyl group.
The trans-diequatorial arrangement of the protected amino and
carboxyl groups is indicated by the large vicinal coupling (11.5 Hz)
between the trans-diaxial H-1ax and H-2ax. The scalar couplings
and the NOE interactions H-1ax–H-3ax and H-1ax–H-5ax show that
the cyclohexane ring attains a stable chair conformation. Only one
large vicinal coupling (>11 Hz) was observed around H-3ax
,
strongly supporting the axial orientation of the hydroxyl group,
a
b
NHBoc
a
b
2
1
5
H
HO
COOEt
NHBoc
1
1
COOEt
NHBoc
H
EtOOC
6
6
3
3
H
5
4
4
4
EtOOC
5
NHBoc
O
HO
1
2
15
O
2
16
2
cis-amino ester 13
approach a favored
trans-amino ester 14
approach a favored
Figure 3. Reductive opening of the oxirane ring in cis-amino ester 13 and trans-amino ester 14.
O
HN
2
OtBu
H
HO
COOEt
1
1
COOEt
NHBoc
H
H
EtOOC
5
4
6
3
4
3
H
5
4
6
NHBoc
EtOOC
O
NH
HO
H
O
2
16
O
1
2
O
17
trans-amino ester 14
cis-amino ester 13
Figure 4. Reductive opening of the oxirane ring of trans-amino ester 14 and opening of the oxirane ring mediated by the Boc group in cis-amino ester 13.

5040
L. Kiss et al. / Tetrahedron 64 (2008) 5036–5043
different elimination reactions. For 15, the scalar coupling pattern
indicates that the hydroxyl group occupies position 5. The highest
coupling constant is estimated as <5 Hz around H-1, showing its
equatorial position, while a single large coupling is measured for
H-2 (9.4 Hz), pointing to its axial orientation. These findings prove
the cis arrangement of the protected amino and carboxylic groups.
3J(H-5ax,H-6ax)¼9.6 Hz suggests an equatorial orientation for
the hydroxyl group, which supports trans stereochemistry relative
to the protected amino group. For 18, the COSY spectrum un-
equivocally proves position 4 for the hydroxyl group. The scalar
couplings point to a stable chair conformation with a trans-
diequatorial orientation of the amino and carboxyl groups (3J(H-
4. Experimental
4.1. General
Melting points were determined with a Kofler apparatus. NMR
spectra were recorded on a Bruker DRX 400 spectrometer. Chem-
ical shifts are given in parts per million relative to TMS as internal
standard with CDCl3 or D2O or DMSO as solvents. The reagents and
solvents were used as received from the supplier. Optical rotations
were measured with a Perkin–Elmer 341 polarimeter.
Ethyl cis-2-(tert-butoxycarbonylamino)-4-cyclohexenecarboxy-
late 3c was prepared according to a known procedure.8a Gram-scale
resolution of 7-azabicyclo[4.2.0]oct-3-en-8-one, (ꢁ)-2: crystalline
1
ax,H-2ax)¼11.5 Hz). No large coupling was observed for H-4, while
i
both H-3ax and H-5ax exhibit two large couplings (>12 Hz), which
proves the axial orientation for the hydroxyl group (trans to the
amino group).
racemic 2 (6 g, 48.8 mmol) was dissolved in Pr2O (180 mL). Lip-
olase (5.4 g, 30 mg mLꢂ1) and H2O (0.43 mL, 24.4 mmol) were
added and the mixture was shaken in an incubator shaker at 65 ꢀC
for 51 h. The reaction was stopped by filtering off the enzyme at 49%
conversion. The solvent was evaporated off and the residue (ꢂ)-2
crystallized out [2.76 g, 46%; [a]2D5 ꢂ26.8 (c 0.4, CHCl3); mp 150–
153 ꢀC (recrystallized from iPr2O); ee 95%]. The enzyme was filtered
off and washed with distilled H2O (3ꢃ30 mL), and the H2O was
evaporated off in vacuo, yielding crystalline b-amino acid (ꢂ)-19
[2.92 g, 44%; [a]2D5 ꢂ38.6 (c 0.33, H2O); mp 232–234 ꢀC [recrystal-
lized from H2O/Me2CO]; ee 99%]. The 1H NMR data for (ꢂ)-2 and
(ꢂ)-19 are similar to those in the literature.13
Epoxidation and reductive oxirane ring opening were also per-
formed for enantiomerically enriched substances (Scheme 7). The
gram-scale resolution of (ꢁ)-2 was performed with H2O (0.5 equiv)
in the presence of Lipolase [lipase B from Candida antarctica,
produced by submerged fermentation of a genetically modified
Aspergillus oryzae microorganism and adsorbed on a macroporous
resin, was from Sigma–Aldrich (Catalog no. L4777); 30 mg mLꢂ1] in
iPr2O at 65 ꢀC, using a slightly modified literature procedure.13 The
enantioselective (E>200) ring cleavage resulted in (ꢂ)-19 (ee¼99%,
yield¼44%) and (ꢂ)-2 (ee¼95%, yield¼46%), which could be easily
separated.
4.1.1. Ethyl cis-2-(benzyloxycarbonylamino)-4-cyclohexenecarb-
oxylate (3a)
A solution of lactam 211 (6 g, 48.8 mmol) was treated with HCl/
EtOH (25 mL) at 0 ꢀC for 30 min. The mixture was treated with Et2O
(100 mL), the crystals formed were filtered off, and the crude
product was crystallized from EtOH/Et2O (1:1) to give ethyl cis-2-
amino-4-cyclohexenecarboxylate hydrochloride.
O
NH
rac-2
Lipolase, iPr2O, 70 °C
Yield: 8.4 g, 84%; a white solid; mp 93–95 ꢀC. 1H NMR (CDCl3,
400 MHz): d 1.28 (t, J¼7.1 Hz, 3H, CH3), 2.40–2.73 (m, 4H, CH2),
3.21–3.24 (m, 1H, H-1), 3.82–3.87 (m, 1H, H-2), 4.20–4.26 (m, 2H,
OCH2), 5.59–5.64 (m, 1H, H-5), 5.72–5.76 (m, 1H, H-4), 8.52 (br s,
3H, N–H). Anal. Calcd for C9H16ClNO2 (205.7): C, 52.56; H, 7.84; N,
6.81. Found: C, 52.91; H, 7.46; N, 6.49.
To a solution of ethyl 2-amino-4-cyclohexenecarboxylate hy-
drochloride (6 g, 29.23 mmol) and Et3N (9 mL, 89 mmol) in THF
(160 mL), benzyl chloroformate (7.5 g, 44 mmol) was added at 0 ꢀC.
After stirring for 16 h, the mixture was taken up in EtOAc (200 mL),
washed with H2O (3ꢃ100 mL), dried (Na2SO4), concentrated under
reduced pressure, and the residue was crystallized from n-hexane.
Yield: 7.6 g, 86%; a white solid; mp 59–60 ꢀC. 1H NMR (400 MHz,
CDCl3): d 1.24 (t, J¼7.10 Hz, 3H, CH3), 2.18–2.23 (m, 1H, CH2), 2.31–
2.40 (m, 2H, CH2), 2.49–2.54 (m, 1H, CH2), 2.80–2.81 (m, 1H, H-1),
4.12–4.16 (m, 2H, OCH2), 4.25–4.28 (m, 1H, H-2), 5.08 (s, 2H, OCH2),
5.41–5.45 (br s 1H, N–H), 5.58–5.62 (m, 1H, H-5), 5.64–5.68 (m, 1H,
H-4), 7.28–7.36 (m, 5H, Ar–H). IR (KBr): nmax 3346, 2972, 2926,1726,
1716, 1539. Anal. Calcd for C17H21O4N (303.3): C, 67.31; H, 6.98; N,
4.62. Found: C, 67.01; H, 6.59; N, 4.22.
O
1R
2S
COOH
NH2
1S
HN
6R
(-)-2
(-)-19
see
SOCl2, EtOH, 70 °C, 4 h
and see Scheme 1
Scheme 5
1R
1R
COOEt
NHZ
O
5S
COOH
NH2
1S
6R
3S
O
4R
see Scheme 3
HO
O
4R
BocN
4S
2S
2S
(-)-4a
(-)-12
(-)-8
see
Scheme 6
see Scheme 6
see Scheme 3
1R
1S
1S
COOH
COOH
HO
5R
COOEt
HO
NH2*HCl
HO
NH2
2R
NHBoc
4S
2S
4S
2R
(-)-18
(+)-9
(+)-15
Scheme 7. Synthesis of the corresponding chiral hydroxylated compounds 8, 9, 15,
and 18.
4.1.2. Benzyl cis-2-(benzyloxycarbonylamino)-4-cyclohexenecarb-
oxylate (3b)
3. Conclusion
To a solution of cis-2-amino-4-cyclohexenecarboxylic acid12
(11 g, 78 mmol) in 2 M NaOH (45 mL), benzyl chloroformate
(13.5 mL, 78 mmol) and 2 M NaOH (45 mL) were added simulta-
neously dropwise at ꢂ10 ꢀC over a period of 30 min. The mixture
was stirred at 0 ꢀC for 6 h. HCl (10%) was then added until pH 3 was
attained. The mixture was extracted with EtOAc (3ꢃ70 mL) and the
organic layer was washed with H2O, dried (Na2SO4), and concen-
trated, giving a white solid with mp 135–136 ꢀC (n-hexane). This
compound (8 g, 29.1 mmol) was dissolved in THF (130 mL), and
DBU (6.6 mL, 43.6 mmol) and benzyl bromide (4.8 mL, 40 mmol)
In summary, a novel and simple approach to hydroxy-function-
alized b-aminocyclohexanecarboxylic acid derivatives has been in-
vestigated, starting from the readily available 1,4-cyclohexadiene,
based on diastereoselective epoxidation reactions with opposite
diastereoselectivity and hydroxylation involving regioselective
opening of the oxirane ring. Racemic and enantiomerically enriched
b-amino-hydroxycarboxylic acids could be synthesized by this
route.

L. Kiss et al. / Tetrahedron 64 (2008) 5036–5043
5041
were then added. The mixture was stirred under reflux for 2 h and
10% HCl was added dropwise until neutral pH was attained. It was
next diluted with EtOAc (250 mL), washed with brine, dried
(Na2SO4), concentrated under reduced pressure, and the residue
was crystallized from n-hexane.
H-5), 4.07–4.16 (m, 3H, H-2 and OCH2), 5.07 (s, 2H, OCH2), 5.40 (br s,
1H, NH), 7.30–7.34 (m, 5H, Ar–H). 13C NMR (CDCl3): 20.6, 24.6, 29.2,
41.8, 47.2, 51.8, 52.2, 61.6, 67.3, 128.7, 129.1, 137.1, 156.0, 173.6. IR
(KBr): nmax 3312, 2982, 2917, 1721, 1687, 1544. Anal. Calcd for
C17H21NO5 (319.3): C, 63.94; H, 6.63; N, 4.39. Found: C, 63.66; H,
Yield: 21.6 g, 76%; a white solid; mp 69–70 ꢀC. 1H NMR
(400 MHz, CDCl3,): d 2.14–2.21 (m,1H, CH2), 2.33–2.40 (m, 2H, CH2),
2.51–2.59 (m,1H, CH2), 2.86–2.90 (m,1H, H-1), 4.28–4.31 (m,1H, H-
2), 5.02–5.16 (m, 4H, OCH2), 5.39 (br s, 1H, N–H), 5.58–5.63 (m, 1H,
H-5), 5.65–5.70 (m, 1H, H-4), 7.28–7.38 (m, 10H, Ar–H). IR (KBr):
6.31; N, 4.18.
4.3. General procedure for reductive opening of epoxides 4a,
14, and 21
n
max 3347, 3033, 2922, 1710, 1683, 1532. Anal. Calcd for C22H23NO4
To a solution of epoxide (3.2 mmol) in EtOH (15 mL), NaBH4
(6.3 mmol) was added in several portions. The mixture was stirred
at the temperature and for the time indicated, saturated NH4Cl/H2O
(1 mL) was then added, and most of the solvent was evaporated off.
The residue was taken up in EtOAc (25 mL), washed with H2O, dried
(Na2SO4), and concentrated. The crude oily product was chroma-
tographed over silica gel (n-hexane/EtOAc 1:2).
(365.4): C, 72.31; H, 6.34; N, 3.83. Found: C, 72.80; H, 6.57; N, 3.70.
4.2. General procedure for epoxidation of amino esters 3a, 3b,
and 3c or b-lactam 13 with m-chloroperbenzoic acid
To a solution of amino ester 3a, 3b, 3c or b-lactam 13 (36 mmol)
in CH2Cl2 (200 mL), m-CPBA (43 mmol) was added at 0 ꢀC. After
stirring for 5 h, further CH2Cl2 (150 mL) was added and the mixture
was washed with saturated aqueous NaHCO3 (3ꢃ150 mL). The or-
ganic layer was dried (Na2SO4) and concentrated under reduced
pressure. The crude product was chromatographed over silica gel
(n-hexane/EtOAc 3:1).
4.3.1. Ethyl (1R
*
,2S
*
,4S )-2-(benzyloxycarbonylamino)-4-
*
hydroxycyclohexanecarboxylate (6)
Yield: 720 mg, 70%; a white solid; mp 50–53 ꢀC. 1H NMR
(400 MHz, DMSO): d 1.14 (t, J¼7.2 Hz, 3H, CH3), 1.41–1.63 (m, 3H,
H3, H6), 1.69–1.80 (m, 2H, H5), 1.85–1.95 (m, 1H, H6), 2.68–2.75 (m,
1H, H1), 3.63–3.72 (m, 1H, H4), 3.77–3.89 (m, 1H, H2), 4.00 (q,
J¼7.2 Hz, 1H, CH2), 4.97–5.20 (m, 2H, OCH2), 6.89 (d, J¼8.4 Hz, 1H,
NH), 7.27–7.39 (m, 5H, Ar). 13C NMR (100 MHz, DMSO): d 14.8, 21.8,
31.5, 37.3, 44.1, 48.3, 60.5, 66.1, 67.0, 128.5, 128.6, 129.1, 138.0, 155.9,
4.2.1. Ethyl (1R
epoxycyclohexanecarboxylate (4a)
*
,2S
*
,4R
*
,5S )-2-(benzyloxycarbonylamino)-4,5-
*
Yield: 6.8 g, 59%; a white solid; mp 64–65 ꢀC. 1H NMR (400 MHz,
DMSO): d 1.15 (t, J¼7.1 Hz, 3H, CH3), 2.03–2.19 (m, 3H, H3, H6eq),
2.35 (dd, J¼7.8, 15.7 Hz, 1H, H6ax), 2.58 (td, J¼7.0, 3.2 Hz, 1H, H1),
3.14–3.19 (m, 2H, H4, H5), 3.88–3.96 (m, 1H, H2), 4.01 (q, J¼7.1 Hz,
2H, CH2), 4.99 (s, 2H, OCH2), 6.23 (d, J¼9.0 Hz, 1H, NH), 7.25–7.38
(m, 5H, Ar). 13C NMR (100 MHz, DMSO): d 14.2, 23.9, 28.4, 39.7, 46.2,
51.2, 51.9, 60.4, 65.7, 128.0, 128.7, 129.2, 137.8, 155.4, 172.8. IR (KBr):
173.5. IR (KBr): n
3396, 2941, 1724, 1716, 1513. Anal. Calcd for
max
C17H23NO5 (321.4): C, 63.54; H, 7.21; N, 4.36. Found: C, 63.13; H,
7.01; N, 4.02.
4.3.2. Ethyl (1S
*
,2S
*
,4S )-2-(benzyloxycarbonylamino)-4-
*
hydroxycyclohexanecarboxylate (7)
n
3418, 2993, 2952, 1733, 1726, 1511. Anal. Calcd for C17H21NO5
Yield: 575 mg, 56%; a white solid; mp 52–55 ꢀC. 1H NMR
(400 MHz, DMSO): d 1.01–1.07 (m, 1H, H5ax), 1.09 (t, J¼7.1 Hz, 3H,
CH3), 1.19 (q, J¼11.8 Hz, 1H, H3ax), 1.38 (dq, J¼4.0, 13.2 Hz, 1H, H6ax),
1.71–1.85 (m, 2H, H5eq, H6eq), 1.88–1.98 (m, 1H, H3eq), 2.19 (dt,
J¼3.4, 11.6 Hz, 1H, H1), 3.37–3.49 (m, 1H, H4), 3.57 (dq, J¼3.9,
10.8 Hz, 1H, H2), 3.97 (q, J¼7.1 Hz, 2H, OCH2), 4.71 (d, J¼4.5 Hz, 1H,
OH), 4.97 (br s, 2H, OCH2), 7.25–7.38 (m, 6H, NH, Ar). 13C NMR
(100 MHz, DMSO): d 14.8, 26.4, 34.3, 42.5, 48.9, 50.7, 60.6, 65.9, 67.9,
max
(319.3): C, 63.94; H, 6.63; N, 4.39. Found: C, 63.57; H, 6.36; N, 4.01.
4.2.2. Benzyl (1R ,2S ,4R ,5S )-2-(benzyloxycarbonylamino)-4,5-
epoxycyclohexanecarboxylate (4b)
*
*
*
*
Yield: 8.9 g, 65%; a white solid; mp 69–70 ꢀC. 1H NMR (400 MHz,
CDCl3): d 2.11 (ddd, J¼3.2, 5.9, 15.6 Hz, 1H, H6eq), 2.16–2.27 (m, 2H,
H3), 2.53 (td, J¼6.6, 3.1 Hz 1H, H1), 2.65 (dd, J¼7.6, 15.6 Hz, 1H,
H6ax), 3.16–3.22 (m, 2H, H4, H5), 4.11–4.19 (m, 1H, H2), 5.00–5.17
(m, 4H, 2ꢃOCH2), 5.77 (d, J¼9.9 Hz, 1H, NH), 7.27–7.40 (m, 10H, Ar).
13C NMR (100 MHz, CDCl3): d 25.1, 29.7, 41.1, 46.7, 51.5, 52.2, 67.3,
67.4, 128.66, 128.69, 128.9, 129.0, 129.1, 129.2, 136.5, 137.2, 156.3,
173.2. IR (KBr): nmax 3436, 3007, 2947, 1724, 1719, 1507. Anal. Calcd
for C22H23NO5 (381.4): C, 69.28; H, 6.08; N, 3.67. Found: C, 68.93; H,
5.79; N, 3.32.
128.4, 128.6, 129.2, 138.1, 156.0, 174.4. IR (KBr): n
3339, 2938,
max
1722, 1712, 1544. Anal. Calcd for C17H23NO5 (321.4): C, 63.55; H,
7.21; N, 4.36. Found: C, 63.19; H, 7.10; N, 4.08.
4.4. General procedure for alkaline hydrolysis and
deprotection of esters 6 and 7
To a solution of amino ester 6 or 7 (1.92 g, 6 mmol) in MeOH
(40 mL), NaOH (0.72 g, 18 mmol) in H2O (12 mL) was added. After
stirring for 5 h, 10% HCl was added at 0 ꢀC until pH 5, after which
the mixture was extracted with CHCl3 (3ꢃ70 mL). The combined
organic layers were dried (Na2SO4) and concentrated, and the
products were used without further purification.
4.2.3. Ethyl (1R
*
,2S
*
,4R
*
,5S )-2-(tert-butoxycarbonylamino)-4,5-
*
epoxycyclohexanecarboxylate (4c)
Yield: 5.8 g, 57%; a white solid; mp 58–60 ꢀC. 1H NMR (400 MHz,
t
CDCl3): d 1.27 (t, J¼7.10 Hz, 3H, CH3), 1.41 (s, 9H, Bu), 2.09 (ddd,
J¼3.2, 6.2, 15.7 Hz, 1H, H6), 2.15–2.20 (m, 2H, H3), 2.46 (ddd, J¼3.2,
6.3, 7.4 Hz, 1H, H1), 2.62 (dd, J¼7.5, 15.7 Hz, 1H, CH2), 3.17–3.20 (m,
2H, H4, H5), 4.01–4.10 (m, 1H, H2), 4.14 (q, J¼7.10 Hz, 2H, OCH2),
5.50 (d, J¼9.8 Hz, 1H, NH). 13C NMR (100 MHz, CDCl3): d 14.8, 25.3,
29.0 (3C), 29.8, 41.1, 46.0, 51.6, 52.3, 61.4, 79.8, 155.8, 173.5. IR (KBr):
A
mixture of a solution of benzyloxycarbonylamino acid
obtained above (440 mg, 1.5 mmol) in MeOH (15 mL) and 10% Pd/C
(80 mg) was stirred under H2 at atmospheric pressure for 2 h. The
Pd/C was filtered off and the filtrate was concentrated under re-
duced pressure. The residue was crystallized from MeOH/Et2O
(1:1).
n
3433, 2979, 1723, 1720, 1499. Anal. Calcd for C14H23NO5
(285.3): C, 58.93; H, 8.12; N, 4.91. Found: C, 58.63; H, 7.83; N, 4.72.
max
4.2.4. Ethyl (1S ,2S ,4R ,5S )-2-(benzyloxycarbonylamino)-4,5-
*
*
*
*
4.4.1. (1R
*
,2S
*
,4S )-2-Amino-4-hydroxycyclohexanecarboxylic
*
epoxycyclohexanecarboxylate (4d)
acid (8)
Yield: 7.1 g, 62%; a white solid; mp 55–58 ꢀC. 1H NMR (400 MHz,
CDCl3): d 1.22 (t, J¼7.10 Hz, 3H, CH3), 1.90–1.97 (m, 1H, CH2), 2.09–
2.32 (m, 3H, CH2), 2.62–2.69 (m,1H, H-1), 3.16–3.27 (m, 2H, H-4 and
Yield: 207 mg, 87%; white crystals; mp 222–225 ꢀC. 1H NMR
(400 MHz, DMSO): d 1.14–1.28 (m, 2H, H5eq, H6ax), 1.41 (q,
J¼10.8 Hz, 1H, H3ax), 1.50–1.58 (m, 1H, H5ax), 1.90 (d, J¼11.8 Hz, 1H,

5042
L. Kiss et al. / Tetrahedron 64 (2008) 5036–5043
H3eq), 2.05–2.15 (m, 1H, H6eq), 2.18–2.23 (m, 1H, H1), 3.13 (td, J¼4.0,
15.5 Hz, 1H, H3eq), 1.94 (dd, J¼5.5, 15.7 Hz, 1H, H6eq), 2.02 (dd,
J¼5.8, 15.5 Hz, 1H, H3ax), 2.22 (ddd, J¼2.6, 8.9, 15.7 Hz, 1H, H6ax),
2.51–2.57 (m, 1H, H1), 3.10 (t, J¼3.7 Hz, 1H, H4), 3.13–3.16 (m, 1H,
H5), 3.81–3.88 (m, 1H, H2), 3.99–4.11 (m, 4H, 2ꢃOCH2), 6.88 (d,
J¼8.0 Hz, 1H, NH). 13C NMR (100 MHz, CDCl3): d 14.2, 22.9, 28.5
(3C), 30.0, 39.4, 44.3, 50.6, 51.5, 60.4, 60.7,153.4,172.7. IR (KBr): nmax
3270, 2925, 1737, 1680. Anal. Calcd for C14H23NO5 (285.3): C, 58.93;
H, 8.12; N, 4.91. Found: C, 58.57; H, 7.88; N, 4.60.
10.3 Hz, H2), 3.43–3.52 (m, 1H, H4). 13C NMR (100 MHz, DMSO):
d 23.6, 31.9, 37.3, 41.6, 48.9, 67.2, 176.0. IR (KBr): n
3132, 3117,
max
1598, 1455. Anal. Calcd for C7H13NO3 (159.2): C, 52.82; H, 8.23; N,
8.80. Found: C, 52.44; H, 8.02; N, 8.48.
4.4.2. (1S
*
,2S
*
,4S )-2-Amino-4-hydroxycyclohexanecarboxylic
*
acid (9)
Yield: 203 mg, 85%; white crystals; mp 256–258 ꢀC. 1H NMR
(400 MHz, D2O): d 1.22–1.48 (m, 3H, H3ax, H5ax, H6ax), 2.00 (d,
J¼11.7 Hz, 1H, H5eq), 2.10–2.22 (m, 2H, H1, H6eq), 2.24–2.31 (m, 1H,
H3eq), 3.30 (dt, J¼3.9, 11.5 Hz, 1H, H2), 3.66–3.74 (m, 1H, H4). 13C
NMR (100 MHz, D2O): d 26.4, 33.5, 37.9, 47.8, 50.7, 67.9, 180.3. IR
(KBr): nmax 3146, 2935, 1584, 1519. Anal. Calcd for C7H13NO3 (159.2):
C, 52.82; H, 8.23; N, 8.80. Found: C, 52.47; H, 8.03; N, 8.55.
4.5.2. Ethyl (1S
*
,2S
*
,4S
*
,5R )-2-(tert-butoxycarbonylamino)-4,5-
*
epoxycyclohexanecarboxylate (14)
Yield: 1.45 g, 51%; a white solid; mp 90–91 ꢀC. 1H NMR
(400 MHz, CDCl3): d 1.23 (t, 3H, CH3),1.41 (s, 9H, CH3), 2.22–2.54 (m,
5H, H-1, CH2), 3.13–3.21 (m, 2H, H-4, H-5), 3.82–3.85 (m, 1H, H-2),
4.13–4.16 (m, 2H, OCH2), 4.65 (br s, 1H, NH). IR (KBr): n
3363,
max
2990, 1728, 1681. Anal. Calcd for C14H23NO5 (285.3): C, 58.93; H,
8.12; N, 4.91. Found: C, 58.62; H, 8.01; N, 4.63.
4.4.3. 7-(tert-Butoxycarbonyl)azabicyclo[4.2.0]oct-3-en-8-one (11)
A solution of b-lactam 2 (6 g, 48.8 mmol), 4-dimethylamino-
pyridine (DMAP) (1.19 g, 9.7 mmol), and Boc2O (15.5 g, 73.2 mmol)
in CH2Cl2 (100 mL) was stirred at room temperature for 13 h. The
mixture was then diluted with CH2Cl2 (140 mL) and washed with
H2O (3ꢃ150 mL). The organic layer was dried (Na2SO4) and the
residue was purified by column chromatography (silica gel, n-
hexane/EtOAc 2:1).
4.5.3. Ethyl (1R
*
,2S
*
,5S )-2-(tert-butoxycarbonylamino)-4-
*
hydroxycyclohexanecarboxylate (15)
Yield: 560 mg, 18%; a white solid; mp 101–103 ꢀC. 1H NMR
(400 MHz, CDCl3): d 1.28 (t, J¼7.1 Hz, 3H, CH3), 1.39–1.45 (m, 10H,
H4ax, tBu), 1.64 (ddd, J¼4.5, 9.5, 13.8 Hz, 1H, H6ax), 1.74–1.88 (m, 2H,
H3), 1.88–1.96 (m, 1H, H4eq), 2.25 (td, J¼4.3, 13.8 Hz, 1H, H6eq),
2.98 (q, J¼4.6 Hz, 1H, H1), 3.68–3.92 (m, 2H, H2, H5ax), 4.16 (q,
J¼7.2 Hz, 2H, OCH2), 5.3 (br s, 1H, NH). 13C NMR (100 MHz, CDCl3):
d 14.9, 27.5, 29.1 (3C), 33.3, 35.8, 49.5, 61.3, 67.0, 156.0, 170.1. IR
Yield: 9.3 g, 86%; a white solid; mp 63–64 ꢀC. 1H NMR (400 MHz,
CDCl3): d 1.52 (s, 9H, CH3), 2.12–2.18 (m, 2H, CH2), 2.45–2.53 (m, 1H,
CH2), 2.75–2.83 (m, 1H, CH2), 3.36–3.41 (m, 1H, H-1), 4.23–4.28 (m,
1H, H-2), 5.75–5.79 (m, 1H, CH), 5.84–5.90 (m, 1H, CH). IR (KBr):
nmax 1798, 1720, 1343. Anal. Calcd for C12H17NO3 (223.3): C, 64.55;
H, 7.67; N, 6.27. Found: C, 64.19; H, 8.01; N, 6.01.
(KBr): n
3364, 3207, 2973, 1724, 1684, 1519. Anal. Calcd for
max
C14H25NO5 (287.4): C, 58.52; H, 8.77; N, 4.87. Found: C, 58.29; H,
8.46; N, 4.51.
4.4.4. (1R
*
,3S
*
,4R
*
*
,6S )-3,4-Epoxy-7-tert-butoxycarbonyl-
4.5.4. Ethyl (1S
*
,2S
*
,4R )-2-(tert-butoxycarbonylamino)-4-
*
azabicyclo[4.2.0]octan-8-one (12a)
hydroxycyclohexanecarboxylate (16)
Yield: 5.7 g, 67%; a white solid; mp 105–106 ꢀC. 1H NMR
(400 MHz, CDCl3): d 1.53 (s, 9H, tBu), 2.03–2.13 (m, 2H, H3eq, H6eq),
2.63 (dd, J¼3.3,16.0 Hz,1H, H6ax), 2.94 (dd, J¼3.2,16.7 Hz,1H, H3ax),
3.13 (t, J¼7.1 Hz, 1H, H1), 3.19 (t, J¼3.8 Hz, 1H, H4), 3.23 (t, J¼3.7 Hz,
1H, H5), 4.02 (t, J¼6.4 Hz,1H, H2). 13C NMR (100 MHz, CDCl3): d 21.6,
22.7, 28.8 (3C), 43.6, 48.2, 50.7, 51.3, 83.4, 148.5, 168.2. IR (KBr): nmax
2977, 1804, 1701, 1335. Anal. Calcd for C12H17NO4 (239.3): C, 60.24;
H, 7.16; N, 5.85. Found: C, 59.89; H, 6.90; N, 5.55.
Yield: 410 mg, 72%; a white solid; mp 120–121 ꢀC. 1H NMR
(400 MHz, DMSO): d 1.16 (t, J¼7.1 Hz, 3H, CH3), 1.24–1.41 (m, 11H,
tBu, H3ax, H5ax), 1.49–1.58 (m, 2H, H5eq, H6eq), 1.69 (td, J¼4.0,
13.5 Hz, 1H, H3eq), 1.83 (dq, J¼4.3, 12.9 Hz, 1H, H6eq), 2.23 (dt, J¼3.6,
11.2 Hz, 1H, H1), 3.83–3.94 (m, 2H, H2, H4), 3.95–4.10 (m, 2H,
OCH2), 4.48 (d, J¼2.9 Hz, 1H, OH), 6.66 (d, J¼9.6 Hz, 1H, NH). 13C
NMR (100 MHz, DMSO): d 14.4, 22.9, 28.7 (3C), 31.1, 39.3, 46.2, 49.2,
60.0, 64.5, 77.6, 152.9, 173.9. IR (KBr): nmax 3528, 3354, 2986, 1708,
1686. Anal. Calcd for C14H25NO5 (287.4): C, 58.52; H, 8.77; N, 4.87.
Found: C, 58.20; H, 8.42; N, 4.54.
4.4.5. (1R
*
,3R
*
,4S
*
,6S )-3,4-Epoxy-7-tert-butoxycarbonyl-
*
azabicyclo[4.2.0]octan-8-one (12)
Yield: 2.6 g, 30%; a white solid; mp 106–108 ꢀC. 1H NMR
4.5.5. (1S
*
,2S
*
,4R )-2-Amino-4-hydroxycyclohexanecarboxylic
*
t
(400 MHz, CDCl3): d 1.52 (s, 9H, Bu), 2.14 (ddd, J¼1.5, 6.8, 15.3 Hz,
acid hydrochloride (18)
1H, H3eq), 2.19–2.35 (m, 2H, H6ax, H6eq), 2.60 (ddd, J¼4.0, 7.0,
15.3 Hz, 1H, H3ax), 3.19 (dt, J¼1.6, 4.0 Hz, 1H, H4), 3.22–3.30 (m, 2H,
H5, H1), 4.00 (q, J¼6.8 Hz, 1H, H2). 13C NMR (100 MHz, CDCl3):
d 21.3, 26.6, 28.9 (3C), 44.1, 47.9, 49.1, 49.7, 84.0, 148.5, 168.0. IR
(KBr): nmax 2973, 1810, 1705, 1303. Anal. Calcd for C12H17NO4
(239.3): C, 60.24; H, 7.16; N, 5.85. Found: C, 59.87; H, 6.97; N, 5.62.
Ester 16 (786 mg, 1.5 mmol) in 18% HCl solution (6 mL) was
heated under reflux for 4 h. The reaction mixture was next con-
centrated under reduced pressure and crystallized from EtOH/Et2O
(1:1).
Yield: 140 mg, 48%; white crystals; mp 199–202 ꢀC. 1H NMR
(400 MHz, D2O): d 1.53–1.77 (m, 3H, H3ax, H5ax, H6ax), 1.82 (qd,
J¼2.8, 13.6 Hz, 1H, H5eq), 1.96 (dd, J¼4.1, 12.0 Hz, 1H, H6eq), 2.11 (d,
J¼13.6 Hz, 1H, H3eq), 2.26 (dt, J¼3.8, 11.3 Hz, 1H, H1), 3.54 (dt, J¼4.0,
12.0 Hz, 1H, H2), 4.19–4.24 (m, 1H, H4eq). 13C NMR (100 MHz, D2O):
4.5. General procedure for ring opening reaction of lactam 12
To a solution of 2-azetidinone 12 (2.4 g, 10 mmol) in anhydrous
EtOH (50 mL), NaOEt (1.2 equiv) was added and the mixture was
stirred for the time and at the temperature indicated. It was then
diluted with EtOAc (100 mL), washed with H2O, dried (Na2SO4), and
concentrated. The crude oily product was chromatographed over
silica gel (n-hexane/EtOAc 2:1).
d 23.4, 30.9, 35.7, 48.4 (2C), 65.6, 180.6. IR (KBr): n
1716, 1503. Anal. Calcd for C7H14ClNO3 (195.6): C, 42.97; H, 7.21; N,
7.16. Found: C, 42.63; H, 7.01; N, 6.82.
3323, 2932,
max
4.5.6. Ethyl (1R
*
,5S
*
,6R
*
,8R )-8-hydroxy-3-oxo-2-oxa-4-
*
azabicyclo[3.3.1]nonane-6-carboxylate (17)
Yield: 268 mg, 65%; a white solid; mp 138–141 ꢀC 1H NMR
(400 MHz, DMSO): d 1.20 (t, J¼7.1 Hz, 3H, CH3), 1.65–1.80 (m, 3H,
H3, H6ax, H6eq), 2.12 (d, J¼13.2 Hz, 1H, H3), 2.76 (ddd, J¼1.3, 5.0,
12.2 Hz, 1H, H1), 3.73–3.78 (m, 1H, H2), 3.87–3.92 (m, 1H, H5),
4.00–4.14 (m, 2H, OCH2), 4.21–4.27 (m, 1H, H4), 5.21 (d, J¼3.8 Hz,
4.5.1. Ethyl (1R
*
,2S
*
,4S
*
,5R )-2-(tert-butoxycarbonylamino)-4,5-
*
epoxycyclohexanecarboxylate (13)
Yield: 2 g, 71%; a white solid; mp 96–98 ꢀC. 1H NMR (400 MHz,
CDCl3): d 1.20 (t, J¼7.1 Hz, 3H, CH3), 1.37 (s, 9H, tBu), 1.87 (td, J¼4.7,

L. Kiss et al. / Tetrahedron 64 (2008) 5036–5043
5043
1H, OH), 7.41 (d, J¼4.5 Hz, 1H, NH). 13C NMR (100 MHz, DMSO):
4.6.11. Ethyl 1S,2R,5R-2-(tert-butoxycarbonylamino)-4-hydroxy-
cyclohexanecarboxylate [(þ)-15]
d 14.8, 24.5, 26.7, 42.8, 47.2, 61.1, 66.5, 74.8, 153.3, 173.2. IR (KBr):
n
3270, 2957, 1737, 1678. Anal. Calcd for C10H15NO5 (229.2): C,
Yield: 16%; mp 101–103 ꢀC; [a]D25 þ14.5 (c 0.5, CHCl3).
max
52.40; H, 6.60; N, 6.11. Found: C, 52.04; H, 6.26; N, 5.89.
4.6.12. Ethyl 1R,2R,4S-2-(tert-butoxycarbonylamino)-4-hydroxy-
cyclohexanecarboxylate [(ꢂ)-16]
4.6. Synthesis of the enantiomers
Yield: 62%; mp 119–121 ꢀC; [a]D25 ꢂ10.8 (c 0.33, CHCl3).
For preparation of the optically active compounds, the same
procedures were used as for the racemic substances. The NMR
spectra of the enantiomers were identical with those of the cor-
responding racemic compounds.
4.6.13. 1R,2R,4S-2-Amino-4-hydroxycyclohexanecarboxylic acid
hydrochloride [(ꢂ)-18]
Yield: 41%; mp 197–200 ꢀC; [a]D25 ꢂ13 (c 0.3, H2O); ee¼92%.
Acknowledgements
4.6.1. Ethyl 1R,2S-2-(benzyloxycarbonylamino)-4-cyclohexene-
carboxylate [(ꢂ)-3a]
We are grateful to the Hungarian Research Foundation (OTKA
No. F67970 and T049407) and the National Research and De-
velopment Office, Hungary (GVOP-311-2004-05-0255/3.0) for
financial support.
Yield: 82%; mp 58–60 ꢀC; [a]D25 ꢂ12.5 (c 0.57, CHCl3).
4.6.2. Ethyl 1R,2S,4R,5S-2-(benzyloxycarbonylamino)-4,5-
epoxycyclohexanecarboxylate [(ꢂ)-4a]
Yield: 51%; mp 62–64 ꢀC; [a]D25 ꢂ7.1 (c 1.72, CHCl3).
References and notes
1. (a) Epand, R. F.; Raguse, T. L.; Gellman, S. H.; Epand, R. M. Biochemistry 2004, 43,
9527; (b) Hayen, A.; Schmitt, M. A.; Ngassa, F. N.; Thomasson, K. A.; Gellmann,
S. H. Angew. Chem., Int. Ed. 2004, 43, 505; (c) Huck, B. R.; Fisk, J. D.; Gusei, I. A.;
Carlson, H. A.; Gellmann, S. H. J. Am. Chem. Soc. 2003, 125, 9035; (d) Raguse, T. L.;
Lai, J. R.; Gellman, S. H. J. Am. Chem. Soc. 2003, 125, 5592; (e) Wang, X.; Espinosa,
J. F.; Gellman, S. H. J. Am. Chem. Soc. 2000, 122, 4821; (f) Bailey, S.; Davies, S. G.;
Smith, A. D.; Withey, J. M. Chem. Commun. 2002, 2910; (g) Langer, O.; Kaehling,
H.; Zierler-Gould, K.; Bats, J. W.; Mulzer, J. J. Org. Chem. 2002, 67, 6878; (h)
4.6.3. Ethyl 1R,2S,4S-2-(benzyloxycarbonylamino)-4-
hydroxycyclohexanecarboxylate [(ꢂ)-6]
Yield: 63%; mp 52–54 ꢀC; [a]D25 ꢂ12.5 (c 0.53, CHCl3).
4.6.4. Ethyl 1S,2S,4S-2-(benzyloxycarbonylamino)-4-
hydroxycyclohexanecarboxylate [(þ)-7]
Yield: 49%; mp 51–53 ꢀC; [a]D25 þ6.8 (c 0.41, CHCl3).
´
´
¨ ¨
Martinek, T. A.; Toth, G. K.; Vass, E.; Hollosi, M.; Fulop, F. Angew. Chem., Int. Ed.
2002, 41, 1717; (i) Hete´nyi, A.; Mandity, I.; Martinek, T. A.; Fu¨ lo¨p, F. J. Am. Chem.
Soc. 2005, 127, 547.
4.6.5. 1R,2S,4S-2-Amino-4-hydroxycyclohexanecarboxylic
acid [(ꢂ)-8]
2. (a) Woll, M. G.; Fisk, J. D.; LePlae, P. R.; Gellman, S. H. J. Am. Chem. Soc. 2002, 124,
12447; (b) Cheng, R. P.; DeGrado, W. F.; Gellman, S. H. Chem. Rev. 2001, 101,
3219; (c) Langenhan, J. M.; Gellman, S. H. J. Org. Chem. 2003, 68, 6440; (d)
Porter, E. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11516; (e)
Yield: 87%; mp 220–224 ꢀC; [a]D25 ꢂ20.5 (c 0.5, H2O); ee¼96%.
´
Fu¨lo¨p, F.; Martinek, T. A.; Toth, G. K. Chem. Soc. Rev. 2006, 35, 323.
3. (a) Enantioselective Synthesis of b-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New
York, NY, 2005; (b) Gademann, K.; Hintermann, T.; Schreiber, J. V. Curr. Med.
Chem. 1999, 6, 905; (c) Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A. Curr.
Med. Chem. 1999, 6, 955; (d) Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6,
4.6.6. 1S,2S,4S-2-Amino-4-hydroxycyclohexanecarboxylic
acid [(þ)-9]
Yield: 78%; mp 254–257 ꢀC; [a]D25 þ18.5 (c 1.2, H2O); ee¼97%.
´
¨ ¨
983; (e) Palko, M.; Kiss, L.; Fulop, F. Curr. Med. Chem. 2005, 12, 3063.
4. (a) Hashimoto, T.; Takahasi, S.; Naganawa, H.; Takita, T.; Maeda, K.; Umezawa,
H. J. Antibiot. 1972, 6, 350; (b) Hashimoto, T.; Kondo, S.; Naganawa, H.; Takita, T.
J. Antibiot. 1974, 27, 86; (c) Bunnage, M. E.; Ganesh, T.; Masesane, I. B.; Orton, D.;
Steel, P. G. Org. Lett. 2003, 5, 239.
4.6.7. 1S,6R-7-Benzyloxycarbonylazabicyclo[4.2.0]oct-3-en-8-one
[(ꢂ)-11]
Yield: 77%; mp 62–65 ꢀC; [a]D25 ꢂ81 (c 1.05, CHCl3).
5. Fu¨lo¨p, F. Chem. Rev. 2001, 101, 2181.
6. (a) Couche, E.; Deschatrettes, R.; Poumellec, K.; Bortolussi, M.; Mandville, G.;
Bloch, R. Synlett 1999, 87; (b) Masesane, I. B.; Steel, P. G. Synlett 2003, 735.
7. Apella, H. D.; LePlae, P. R.; Raguse, T. L.; Gellman, S. H. J. Org. Chem. 2000, 65,
4766.
4.6.8. 1S,3S,4R,6R-3,4-Epoxy-7-benzyloxycarbonyl-
azabicyclo[4.2.0]octan-8-one [(ꢂ)-12]
Yield: 61%; mp 104–107 ꢀC; [a]D25 ꢂ34.5 (c 0.75, CHCl3).
´
´
8. (a) Fu¨lo¨p, F.; Palko, M.; Forro, E.; Dervarics, M.; Martinek, T. A.; Sillanpaa, R. Eur.
J. Org. Chem. 2005, 3214; (b) Szakonyi, Z.; Gyo´nfalvi, S.; Forro´ , E.; Hete´nyi, A.; De
Kimpe, N.; Fu¨lo¨p, F. Eur. J. Org. Chem. 2005, 4017.
4.6.9. Ethyl 1S,2R,4R,5S-2-(tert-butoxycarbonylamino)-4,5-
epoxycyclohexanecarboxylate [(þ)-13]
9. Kiss, L.; Forro´, E.; Fu¨lo¨p, F. Tetrahedron Lett. 2006, 47, 2855.
Yield: 66%; mp 95–97 ꢀC; [a]D25 þ19.5 (c 0.55, CHCl3); ee¼93%.
10. (a) Rotella, D. P. Tetrahedron Lett. 1989, 30, 1913; (b) Wipf, P.; Wang, X. Tetra-
hedron Lett. 2000, 41, 8747; (c) O’Brien, P.; Childs, A. C.; Ensor, G. J.; Hill, C. L.;
Kirby, J. P.; Dearden, M. J.; Oxenford, S. J.; Rosser, C. M. Org. Lett. 2003, 5, 4955;
´
(d) Masesane, I. B.; Steel, P. G. Tetrahedron Lett. 2004, 45, 5007; (e) Kiss, L.; Forro,
4.6.10. Ethyl 1R,2R,4R,5S-2-(tert-butoxycarbonylamino)-4,5-
epoxycyclohexanecarboxylate [(ꢂ)-14]
Yield: 44%; mp 90–92 ꢀC; [a]D25 ꢂ17.4 (c 0.75, CHCl3); ee¼92–
93%.
E.; Sillanpa¨a¨, R.; Fu¨lo¨p, F. J. Org. Chem. 2007, 72, 8786.
11. Singh, R.; Cooper, R. D. G. Tetrahedron 1994, 50, 12049.
12. Berna´th, G.; Sta´jer, G.; Szabo´, A.; Fu¨lo¨p, F. Tetrahedron 1985, 41, 1353.
13. Forro´, E.; Fu¨lo¨p, F. Tetrahedron: Asymmetry 2004, 15, 2875.