Selective syntheses of novel highly functionalized β- aminocyclohexanecarboxylic acids

Article abstract of DOI:10.1016/j.tet.2011.12.065

Highly functionalized β-aminocyclohexanecarboxylate regio- and stereoisomers were synthetized from racemic unsaturated bicyclic β-lactams via enzymatic resolution, selective transformation of the C-C double bond by stereoselective epoxidation, and regiose

Full text of DOI:10.1016/j.tet.2011.12.065

Tetrahedron 68 (2012) 4438e4443
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective syntheses of novel highly functionalized
acids
b-aminocyclohexanecarboxylic
a
a,b,
ꢀ a
€ €
*
ꢀ
}
Lorand Kiss , Eniko Forro , Ferenc Fulop
a
€
€
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eotvos u. 6, Hungary
Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eotvos u. 6, Hungary
b
€
€
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 October 2011
Received in revised form 24 November 2011
Accepted 21 December 2011
Available online 27 December 2011
Highly functionalized
racemic unsaturated bicyclic
double bond by stereoselective epoxidation, and regioselective oxirane ring opening with azide or cy-
anide as nucleophile.
b
-aminocyclohexanecarboxylate regio- and stereoisomers were synthetized from
-lactams via enzymatic resolution, selective transformation of the CeC
b
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Selective functionalization
b-Amino acid
Foldamer building block
Oxirane ring opening
1. Introduction
Stereoselective epoxidation of a functionalized cyclohexene ring
and regioselective oxirane ring opening reactions are efficient and
Highly functionalized cyclic amino acids are an important class
of bioactive compounds of increasing interest that have been
a target of research in organic and medicinal chemistry during the
past 10 years. Highly functionalized cyclic amino acids (e.g., ory-
zoxymycin,1 tamiflu,2 zanamivir and 2,3-didehydro-2-deoxy-N-
acetylneuraminic acid3) exhibit strong antiviral, antifungal or an-
tibacterial activities (Fig. 1). Modified derivatives3b,d,4 and other
multisubstituted cyclohexane amino acids4a,5 have recently been at
the focus of interest in synthetic and medicinal chemistry in view of
their enormous pharmacological potential.
powerful strategies towards the synthesis of multifunctionalized
cyclohexanes.6,7 Stereoselective epoxidation and regioselective
oxirane ring opening were earlier applied successfully for the
synthesis of highly functionalized cyclohexane8 or cyclopentane9
amino acid derivatives.
2. Results and discussion
Our goal in the present work was the synthesis of highly func-
tionalized b-aminocyclohexanecarboxylates, with the focus on the
CO2H
OH
H
OH
O
CO2H
O
O
CO2Et
H
HO
O
CO2H
HO
OH
AcHN
O
AcHN
OH
AcHN
HN
NH2
NH
NH2
OH
Oryzoxymycin
NH2*H3PO4
OH
DANA
Tamiflu
(Oseltamivir)
Zanamivir
Fig. 1. Some highly functionalized bioactive cyclic amino acids.
* Corresponding author. Tel.: þ36 62 545564; fax: þ36 62 545705; e-mail
€ €
address: fulop@pharm.u-szeged.hu (F. Fulop).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.065

L. Kiss et al. / Tetrahedron 68 (2012) 4438e4443
4439
stereoselective epoxidation of the cyclohexene ring CeC double
bond, followed by regioselective oxirane ring opening with azide or
cyanide as nucleophile.
attack. In the presence of AlCl3, most probably due to the ability of Al
to coordinate to the oxirane O-atom and the ester carbonyl O-atom
(C]O group), the conformational equilibrium 3Ae3B is shifted to-
wards 3A. Azide attack on C-4 in the oxirane leads to a favoured ring
opening since it generates a trans-diaxial chair conformation. In
contrast, attack on C-3 would contribute to a trans-diaxial twisted
chair conformation, which explains why the 3-azido derivative is not
formed under the latter conditions (Scheme 2).
Selective introduction of a nitrile function onto the cyclohexane
skeleton in epoxyamino ester 3 was achieved on treatment with
Et2AlCN in toluene at room temperature. As a result of the co-
ordinating ability of Al with the carbonyl O-atom and oxirane O-
atom, the favoured nitrile attack on the preferred conformer 3A
resulted 100% regioselectively in the corresponding 4-cyano-
substituted amino ester 6 in 68% yield (Scheme 1).
In the first part of our investigation, in order to synthetize
multifunctionalized cyclohexanecarboxylic acids,
b-amino-
cyclohexenecarboxylate 2 derived from bicyclic lactam 1 was sub-
jected to epoxidation with m-chloroperbenzoic acid (MCPBA),
which furnished cis-selectively amino ester epoxide 38,9 in 74%
isolated yield. An azido function was introduced onto the ring of the
b
-amino ester with NaN3 in EtOH/H2O in the presence of NH4Cl at
70 ꢀC. The azide attack occurred on both C-3 and C-4, giving the
azido ester regioisomers 4 (31%) and 5 (29%) in approximately 1:1
ratio (1H NMR) (Scheme 1). The structures of 4 and 5 were de-
termined by evaluating their 2D COSYand HSQC spectra besides the
1H NMR and 13C NMR data.
As a result of the conformational equilibrium of 3A (with NHBoc
equatorial and CO2Et axial) and 3B (with CO2Et equatorial and NHBoc
axial),8d the oxirane ring opens via the trans-diaxial chair confor-
mation at both C-3 and C-4, leading to azido esters 4 and 5 (Scheme
2). Oxirane ring opening of 3 with NaN3 was accomplished by car-
rying out the reaction in toluene at room temperature with 1 equiv of
AlCl3 as additive. Interestingly, the reaction proceeded 100% regio-
selectively, with the azide attack occurring on C-4, yielding azido
aminocyclohexanecarboxylate 4 as the sole product (Scheme 1). This
regioselectivity of the oxirane ring opening may be explained by the
diaxial chair conformation being favoured during the nucleophile
In order to synthetize other novel highly functionalized b-ami-
nocyclohexanecarboxylate stereoisomers, we investigated the
transformation through selective epoxidation and oxirane ring
opening of bicyclic b-lactam 7, a regioisomer of 1. Epoxyamino ester
9 prepared from lactam 7 via N-Boc ester 8 was regioselectively
transformed on treatment with NaN3/NH4Cl in EtOH/H2O at 70 ꢀC
to 5-azido-substituted aminocyclohexanecarboxylate 10 in 67%
yield (Scheme 3). The 100% regioselectivity of this transformation is
a result of the shifted conformational equilibrium from 9B to 9A, in
which NHBoc has an axial arrangement8c,d and whose oxirane ring
opening at C-5 led through the trans-diaxial chair conformation to
O
CO2Et NaN3, AlCl3
CO2Et
MCPBA, CH2Cl2
PhMe
NH
0 °C, 5 h
20 °C, 8 h
68%
NHBoc
3 (74%)
NHBoc
O
2
1
NaN3, NH4Cl
EtOH/H2O
70 °C, 4 h
100%
Et2AlCN, toluene
rt, 15 h
selective
CO2Et
CO2Et
CO2Et
NC
NHBoc
HO
N3
NHBoc
N3
NHBoc
OH
6 (68%)
100% selective
OH
1:1
5 (29%)
4 (31%)
Scheme 1.
CO2Et
OH
H
CO2Et
H
H
Nu
attack on C-3
Nu
OH CO2R
NHBoc
O 1
H
4
H
attack on C-4
NHBoc
H
NHBoc
2
3
H
H
unfavoured
ring opening
favoured
H
H
H
ring opening
Nu
H
H
3A
Nu
4:
Nu = N3
6: Nu = CN
H
NHBoc
OH
OH
H
Nu
Nu
CO2Et
O
NHBoc
NHBoc
H
3
H
attack on C-3
attack on C-4
H
H
2
H
4
CO2Et
H
CO2Et
favoured
unfavoured
H
1
H
ring opening
ring opening
Nu
H
Nu
5: Nu = N3
3B
Scheme 2.

4440
L. Kiss et al. / Tetrahedron 68 (2012) 4438e4443
NC
HO
CO2Et
O
HO
NC
CO2Et
N3
CO2Et
+
NH
NHBoc
12 (18%)
NHBoc
13 (45%)
HO
NHBoc
(32%)
7
14
Et2AlCN
toluene
rt, 15 h
NaOEt, EtOH
20 h, 20 °C
MCPBA
CH2Cl2
CO2Et
N3
CO2Et
HO
CO2Et
CO2Et
NaN3, AlCl3
+
O
0 °C, 5 h
NHBoc
toluene
HO
NHBoc
N3
NHBoc
NHBoc
(71%)
8
20 °C, 8 h
9
10
(36%)
11
(35%)
NaN3, NH4Cl, EtOH/H2O
70 °C, 4 h, 67%
Scheme 3.
azido ester 10. Azide attack on C-4 in 9A under these conditions
would generate an unfavoured trans-diaxial twisted chair confor-
mation (Scheme 4).
On change of the oxirane ring opening reaction conditions to
NaN3/AlCl3/toluene (considering the coordinating capability of Al,
with an increased contribution of 9B), due to the conformational
equilibrium 9Ae9B, the azide attack on both C-4 and C-5 is fav-
oured, and azido esters 10 and 11 were formed in approximately
1:1 ratio (1H NMR) (Schemes 3 and 4).
In the presence of Et2AlCN, both conformational arrangements
9A and 9B contribute, while nitrile attack can occur on C-4 and C-5,
affording the nitrile-substituted b-aminocyclohexanecarboxylates
12 and 13 in 1:2.5 ratio (Scheme 3). A new azido ester stereoisomer
14 could be prepared from 10 by epimerization with NaOEt in EtOH
(Scheme 3).
Epoxyamino ester 15 derived from lactam 7, in which the car-
boxylate and amino moieties are in a trans relationship, offered
a possibility for the synthesis of other novel multifunctionalized
aminocyclohexanecarboxylic ester isomers.
b-
Opening of the oxirane ring in amino ester 15 with either NaN3/
NH4Cl/EtOH or Et2AlCN as nucleophile afforded amino-
cyclohexanecarboxylic ester 16 or 17 100% regioselectively with the
N3 or CN group in position-4 (Scheme 5). Since the diequatorial
(carboxylate and carbamate) arrangement predominates as the
favoured conformation of 15, attack of the nucleophile through the
trans-diaxial chair conformation will be preferred on C-4 (Scheme
6). It is noteworthy that the oxirane ring opening of 15 in the
NaN3/AlCl3/toluene system gave, as expected, azido ester 16, which
could also be prepared by epimerization at C-1 from the earlier
synthetized cis-amino ester 11 (Scheme 5).
Nu
CO2Et
NHBoc
Nu
NHBoc
OH
CO2Et
O
NHBoc
2
EtO2C
1
attack
attack
OH
O
H
H
H
H
H
on C-4
on C-5
H
4
5
3
H
H
H
H
H
H
3
4
H
5
favoured
NHBoc
EtO2C
favoured
ring
H
H
ring
2
1
H
H
H
H
H
H
opening
opening
Nu
Nu
9A
9B
10:
12:
Nu = N3
Nu = CN
11:
13:
Nu = N3
Nu = CN
Nu
unfavoured
ring
attack
opening
on C-4
OH NHBoc
H
EtO2C
H
Nu
Scheme 4.
O
HO
N3
CO2Et
CO2Et
NH
NHBoc
NHBoc
7
14
11
MCPBA, CH2Cl2
0 °C, 5 h
NaOEt, EtOH
20 °C,
16 h
NaN3, NH4Cl
EtOH/H2O
HO
NC
COOEt
CO2Et
HO
N3
CO2Et
Et2AlCN, toluene
20 °C, 15 h
O
70 °C, 4 h
NHBoc
(62%)
NHBoc
NHBoc
17
15 (63%)
16 (87%)
Scheme 5.

L. Kiss et al. / Tetrahedron 68 (2012) 4438e4443
4441
H
NHBoc
H
1
NHBoc
OH
O
O
H
H
H
4
H
H
EtO2C
EtO2C
H
H
3
H
H
5
NHBoc favoured
ring opening
H
2
H
CO2Et
H
H
Nu
Nu
15B
15
15A
16: Nu = N3
17:
Nu = CN
Scheme 6.
The synthetic procedures for the synthesis of azido or nitrile-
substituted 2-aminocyclohexanecarboxylate regio- and stereoiso-
mers were extended to the preparation of these multi-
functionalized cyclohexanes in enantiomerically pure form. The
3. Experimental
3.1. General
syntheses were accomplished by starting from enantiopure
aminocyclohexenecarboxylic acid (þ)-18. For this purpose, the ra-
cemic bicyclic -lactam 1 was first subjected to enzymatic resolu-
b
-
The epoxidation reactions were performed according to the
earlier-published procedures.8c,d
b
tion with CAL-B in t-BuOMe to yield optically pure amino acid
(þ)-18. This was converted by esterification with EtOH/SOCl2 via
(þ)-19, followed by N-Boc protection, to (þ)-2. The amino ester was
then functionalized by selective epoxidation, followed by oxirane
ring opening. On treatment with NaN3/NH4Cl in EtOH/H2O, epox-
yamino ester (þ)-3 afforded enantiomerically pure azido ester
stereoisomers (ꢁ)-4 and (þ)-5 in 38% and 34% yields, respectively
(Scheme 7).
3.2. General procedure for the azidolysis of epoxyamino
esters
Method A: To a solution of epoxiamino ester (2 mmol) in EtOH
(20 mL), NaN3 (4 mmol), H2O (1 mL) and NH4Cl (40 mg) were
added. The mixture was then stirred at 70 ꢀC for 4 h and concen-
trated at reduced pressure. The residue was taken up in EtOAc
(25 mL) and washed with water (2ꢂ15 mL). The organic layer was
next dried (Na2SO4) and concentrated. The residue was purified by
column chromatography on silica gel (n-hexane/acetone 4:1).
Method B: To a solution of epoxyamino ester (2 mmol) in dry
toluene (20 mL), NaN3 (4 mmol) and AlCl3 (2 mmol) were added
and the mixture was stirred at 20 ꢀC for 8 h. It was then diluted
with CH2Cl2 (25 mL) and washed with water (2ꢂ15 mL). The or-
ganic layer was next dried (Na2SO4) and concentrated. The residue
was purified by column chromatography on silica gel (n-hexane/
acetone 4:1).
When subjected to reaction with Et2AlCN, epoxyamino ester
enantiomer (þ)-3 underwent regioselective oxirane ring opening
to give the 4-cyano-substituted
59% yield (Scheme 7).
b
-amino ester enantiomer (ꢁ)-6 in
In conclusion,
a series of highly functionalized b-amino-
cyclohexanecarboxylate stereo- and regioisomers containing new
stereogenic centres were efficiently synthetized by diaster-
eoselective epoxidation and regioselective oxirane ring opening
with azide or cyanide as nucleophile. Since these substituents may
be regarded as masked amines or carboxylates, the synthesis might
furnish orthogonally protected diaminocyclohexanecarboxylates or
aminocyclohexanedicarboxylates, respectively. In view of the con-
siderable importance of multifunctionalized cyclic amino acid de-
rivatives, the compounds synthetized in this work may be of value
as precursors for potentially pharmacologically active products.
3.3. General procedure for oxirane ring opening with nitrile
To a solution of epoxyamino ester (2 mmol) in dry toluene
(15 mL), a 50% solution of Et2AlCN (2.2 mmol) in toluene was added
and the mixture was stirred at 20 ꢀC for 15 h. Water (5 mL) was
1R
O
CO2H
O
CAL-B, tBuOMe
+
NH
NH
NH2
2S
(+)-18
(-)-1
rac-1
SOCl2, EtOH
70 °C, 1 h
1R
1R
CO2Et
CO2Et
Boc2O, TEA
THF, 0 °C, 8 h
NH2HCl
NHBoc
2S
2S
(+)-2 (87%)
(+)-19 (89%)
MCPBA, CH2Cl2, 0 °C, 5 h
1R
3S
Et2AlCN
toluene
1R
3R
CO2Et
2R
NHBoc
CO2Et
1R
1R
3S
CO2Et
CO2Et
NaN3, NH4Cl
4S
HO
2R
NHBoc
OH
(-)-4 (38%)
4R
N3
4S
NC
2R
NHBoc
+
2R
NHBoc
OH
(-)-6 (59%)
4S
O
rt, 15 h
EtOH/H2O
70 °C, 4 h
3R
N3
(+)-3 (67%)
(+)-5 (34%)
Scheme 7.

4442
L. Kiss et al. / Tetrahedron 68 (2012) 4438e4443
then added and the mixture was extracted with CH2Cl2 (2ꢂ15 mL).
The organic layer was dried (Na2SO4) and concentrated under re-
duced pressure. The crude product was purified by column chro-
matography on silica gel (n-hexane/EtOAc 3:1).
(m, 1H, CH2), 1.80e1.89 (m, 1H, CH2), 2.08e2.15 (m, 1H, CH2),
2.40e2.43 (m, 1H, CH2), 2.93e2.99 (m, 1H, H-1), 2.40e2.46 (m, 1H,
H-2), 3.61e3.68 (m, 1H, H-5), 3.80e3.96 (m, 1H, H-4), 4.19e4.27
(m, 2H, OCH2), 5.56 (br s, 1H, NeH); 13C NMR (400 MHz, DMSO):
d
¼14.9, 29.0, 35.7, 39.9, 42.3, 48.6, 60.9, 63.1, 71.5, 78.7, 155.6, 173.3.
3.3.1. Ethyl (1R
*
,2R
*
,3R
*
,4S
*
)-2-(tert-butoxycarbonylamino)-3,4-
MS: (ESI) m/z¼351 (Mþ23). IR (KBr): nmax 1525, 1659, 1720, 2102,
2983, 3357, 3376. Anal. Calcd for C14H24N4O5: C, 51.21; H, 7.37; N,
17.06. Found: C, 50.90; H, 7.01; N, 16.89.
epoxycyclohexanecarboxylate [(ꢃ)-3]. White solid; mp 87e90 ꢀC;
yield: 74%. 1H NMR (400 MHz, CDCl3):
d¼1.29 (t, 3H, CH3,
J¼7.20 Hz), 1.46 (s, 9H, CH3), 1.50e1.56 (m, 1H, CH2), 1.74e1.80 (m,
2H, CH2), 2.12e2.21 (m,1H, CH2), 2.45e2.50 (m,1H, H-1), 3.29e3.38
(m, 2H, H-3 and H-4), 4.11e4.20 (m, 2H, OCH2), 5.52e5.56 (m, 1H,
3.3.7. Ethyl (1R
5-hydroxycyclohexanecarboxylate [(ꢃ)-11]. White solid; mp
134e136 ꢀC, yield: 35%. 1H NMR (400 MHz, DMSO):
*
,2S
*
,4S
*
,5S )-4-azido-2-(tert-butoxycarbonylamino)-
*
H-2), 5.63 (br s, 1H, NeH); 13C NMR (400 MHz, DMSO):
d
¼14.8, 17.3,
d¼1.20 (t, 3H,
24.0, 29.0, 43.4, 45.9, 53.7, 54.0, 60.6, 78.9,155.7,172.7. IR (KBr): nmax
1161, 1514, 1718, 1731, 2954, 2981, 3357. Anal. Calcd for C14H23NO5:
C, 58.93; H, 8.12; N, 4.91. Found: C, 58.70; H, 7.82; N, 4.65.
CH3, J¼7.4 Hz), 1.36 (s, 9H, t-Bu), 1.73e2.04 (m, 4H, CH2), 2.68e2.80
(m, 1H, H-1), 3.34e3.42 (m, 1H, H-5), 3.84e4.01 (m, 2H, OCH2),
4.04e4.09 (m, 1H, H-4), 4.16e4.21 (m, 1H, H-2), 5.17 (br s,1H, OeH),
7.00 (br s, 1H, NeH); 13C NMR (400 MHz, DMSO):
d¼14.8, 29.0, 31.9,
* * * *
3.3.2. Ethyl (1R ,2R ,3R ,4R )-4-azido-2-(tert-butoxycarbonylamino)-
32.0, 44.3, 48.4, 60.7, 63.1, 73.2, 78.7,155.8,172.4. MS: (ESI) m/z¼351
(Mþ23). IR (KBr): nmax 1522, 1700, 1717, 2102, 2975, 3353. Anal.
Calcd for C14H24N4O5: C, 51.21; H, 7.37; N, 17.06. Found: C, 50.86; H,
7.04; N, 17.30.
3-hydroxycyclohexane carboxylate [(ꢃ)-4]. White solid; mp
89e90 ꢀC; yield: 31% or 68% (see Scheme 1). 1H NMR (400 MHz,
DMSO):
d
¼1.18 (t, 3H, CH3, J¼7.20 Hz), 1.47 (s, 9H, CH3), 1.49e1.57 (m,
1H, CH2), 1.70e1.78 (m, 2H, CH2), 2.50e2.57 (m, 2H, CH2 and H-1),
3.48e3.54 (m, 1H, H-3), 3.59e3.66 (m, 1H, H-4), 3.98e4.12 (m, 2H,
OCH2), 4.30e4.38 (m, 1H, H-2), 5.29 (br s, 1H, OeH), 6.53 (br s, 1H,
3.3.8. Ethyl (1R
cyano-4-hydroxycyclohexanecarboxylate [(ꢃ)-12]. White solid; mp
136e138 ꢀC; yield: 18%. 1H NMR (400 MHz, CDCl3):
*
,2S
*
,4R
*
,5S
*
)-2-(tert-butoxycarbonylamino)-5-
NeH); 13C NMR (400 MHz, DMSO):
d¼14.8, 21.0, 29.0, 29.1, 45.1, 53.9,
d
¼1.24 (t, 3H,
60.6, 61.5, 73.9, 78.5,156.5, 172.8. MS: (ESI) m/z¼351 (Mþ23). IR (KBr):
nmax: 1532, 1700, 1720, 2109, 2982, 3368, 3458. Anal. Calcd for
C14H24N4O5: C, 51.21; H, 7.37; N,17.06. Found: C, 51.40; H, 7.08; N,16.86.
CH3, J¼7.20 Hz), 1.42 (s, 9H, CH3), 1.80e1.89 (m, 2H, CH2), 2.18e2.24
(m, 1H, CH2), 2.42e2.55 (m, 1H, CH2), 2.71e2.79 (m, 1H, H-1),
2.98e3.03 (m, 1H, H-5), 3.91e3.99 (m, 2H, H-2 and H-4), 4.20e4.28
(m, 2H, OCH2), 5.52 (br s, 1H, NeH); 13C NMR (400 MHz, CDCl3):
3.3.3. Ethyl (1R
4-hydroxycyclohexanecarboxylate
88e90 ꢀC; yield: 29%. 1H NMR (400 MHz, DMSO):
*
,2R
*
,3S
*
,4S
*
)-3-azido-2-(tert-butoxycarbonylamino)-
[(ꢃ)-5]. White solid; mp
¼1.19 (t, 3H, CH3,
d
¼14.5, 28.7, 34.1, 36.5, 36.7, 42.5, 58.4, 61.7, 69.6, 80.2, 121.6, 158.2,
170.6. MS: (ESI) m/z¼335 (Mþ23). IR (KBr): nmax 1525, 1683, 1716,
2252, 2977, 3358, 3452. Anal. Calcd for C15H24N2O5: C, 57.68; H,
7.74; N, 8.97. Found: C, 57.40; H, 7.98; N, 8.65.
d
J¼7.20 Hz), 1.46 (s, 9H, CH3), 1.52e1.81 (m, 4H, CH2), 2.95e3.00 (m,
1H, H-1), 3.25e3.45 (m, 2H, H-2 and H-4), 3.61e3.68 (m, 1H, H-3),
4.08e4.16 (m, 2H, OCH2), 5.36 (br s, 1H, OeH), 6.98 (br s, 1H, NeH);
3.3.9. Ethyl (1R
cyano-5-hydroxycyclohexanecarboxylate [(ꢃ)-13]. White solid; mp
172e174 ꢀC; yield: 45%. 1H NMR (400 MHz, DMSO):
*
,2S
*
,4R
*
,5S
*
)-2-(tert-butoxycarbonylamino)-4-
13C NMR (400 MHz, DMSO):
d¼14.9, 23.7, 29.1, 30.1, 43.9, 52.9, 60.8,
66.9, 72.9, 78.9,155.8,173.4. MS: (ESI) m/z¼351 (Mþ23). IR(KBr): nmax
1515, 1693, 1725, 2099, 2934, 2981, 3378. Anal. Calcd for C14H24N4O5:
C, 51.21; H, 7.37; N, 17.06. Found: C, 50.92; H, 7.02; N, 16.88.
d¼1.18 (t, 3H,
CH3, J¼7.15 Hz), 1.39 (s, 9H, CH3), 1.61e1.90 (m, 4H, CH2), 2.63e2.74
(m, 1H, H-1), 2.83e2.90 (m, 1H, H-4), 3.52e3.60 (m, 1H, H-5),
3.95e4.02 (m, 2H, OCH2), 4.15e4.21 (m, 1H, H-2), 5.50 (br s, 1H,
3.3.4. Ethyl (1R
cyano-3-hydroxycyclohexanecarboxylate [(ꢃ)-6]. White solid; mp
185e187 ꢀC; yield: 68%. 1H NMR (400 MHz, DMSO):
CH3, J¼7.15 Hz), 1.40 (s, 9H, CH3), 1.45e1.60 (m, 3H, CH2), 1.81e1.90
(m, 1H, CH2), 2.58e2.63 (m, 1H, H-1), 2.92e2.99 (m, 1H, H-4),
3.58e3.63 (m, 1H, H-3), 3.95e4.01 (m, 2H, OCH2), 4.36e4.41 (m,1H,
H-2), 5.52 (br s, 1H, OeH), 6.62 (br s, 1H, NeH); 13C NMR (400 MHz,
*
,2R
*
,3S
*
,4S
*
)-2-(tert-butoxycarbonylamino)-4-
OeH), 7.01 (br s, 1H, NeH); 13C NMR (400 MHz, CDCl3):
d
¼14.8,
29.0, 31.7, 32.5, 33.8, 44.2, 43.0, 60.7, 69.3, 78.4, 122.8, 156.0, 172.3.
MS: (ESI) m/z¼335 (Mþ23). IR (KBr): nmax 1521, 1701, 1710, 2252,
2975, 3348, 3479. Anal. Calcd for C15H24N2O5: C, 57.68; H, 7.74; N,
8.97. Found: C, 57.96; H, 7.50; N, 8.69.
d¼1.18 (t, 3H,
3.3.10. Ethyl (1S
*
,2S
*
,4R
*
,5S )-2-(tert-butoxycarbonylamino)-3,4-
*
DMSO):
d
¼14.8, 20.8, 27.0, 29.1, 31.5, 44.9, 52.9, 60.7, 70.3, 78.6,
epoxycyclohexanecarboxylate [(ꢃ)-15]. White solid; mp 96e98 ꢀC;
122.9, 158.0, 172.5. MS: (ESI) m/z¼335 (Mþ23). IR (KBr): nmax 1532,
1700, 1718, 2246, 2981, 3363, 3456. Anal. Calcd for C15H24N2O5: C,
57.68; H, 7.74; N, 8.97. Found: C, 57.42; H, 7.52; N, 8.67.
yield: 63%. 1H NMR (400 MHz, CDCl3):
d
¼1.29 (t, 3H, CH3,
J¼7.20 Hz), 1.46 (s, 9H, CH3), 1.90e1.99 (m, 1H, CH2), 2.21e2.26 (m,
2H, CH2), 2.33e2.42 (m, 1H, CH2), 2.68e2.74 (m, 1H, H-1),
3.20e3.23 (m, 1H, H-4), 3.28e3.32 (m, 1H, H-5), 4.03e4.09 (m, 1H,
H-2), 4.14e4.23 (m, 2H, OCH2), 5.14 (br s, 1H, NeH); 13C NMR
3.3.5. Ethyl (1R
*
,2S
*
,4R
*
,5S )-2-(tert-butoxycarbonylamino)-4,5-
*
epoxycyclohexanecarboxylate [(ꢃ)-9]. Colourless oil; yield: 71%. 1H
(400 MHz, CDCl3):
d¼15.5, 24.4, 28.7, 29.1, 41.7, 46.4, 51.6, 52.1, 61.3,
NMR (400 MHz, CDCl3):
d
¼1.30 (t, 3H, CH3, J¼7.20 Hz), 1.44 (s, 9H,
79.8, 156.8, 173.5. IR (KBr): nmax 1161, 1514, 1716, 1731, 2954, 2981,
3350. Anal. Calcd for C14H23NO5: C, 58.93; H, 8.12; N, 4.91. Found: C,
58.70; H, 7.84; N, 4.55.
CH3), 2.08e2.31 (m, 3H, CH2), 2.45e2.53 (m, 1H, CH2), 2.60e2.67
(m, 1H, H-1), 3.20e3.23 (m, 2H, H-4 and H-5), 4.06e4.11 (m, 1H, H-
2), 4.13e4.26 (m, 2H, OCH2), 5.53 (br s, 1H, NeH); 13C NMR
(400 MHz, DMSO):
d
¼14.7, 24.1, 29.0, 29.5, 46.1, 48.2, 51.1, 52.2,
3.3.11. Ethyl (1S
5-hydroxycyclohexanecarboxylate [(ꢃ)-16]. Colourless oil; yield: 87%.
1H NMR (400 MHz, CDCl3):
*
,2S
*
,4S
*
,5S
*
)-4-azido-2-(tert-butoxycarbonylamino)-
60.8, 79.0, 155.0, 173.1. IR (KBr): nmax 1161, 1515, 1718, 1731, 2954,
2981, 3358. Anal. Calcd for C14H23NO5: C, 58.93; H, 8.12; N, 4.91.
Found: C, 58.72; H, 7.89; N, 4.59.
d
¼1.29 (t, 3H, CH3, J¼7.20 Hz),1.47 (s, 9H,
CH3), 1.80e1.88 (m, 1H, CH2), 1.98e2.06 (m, 2H, CH2), 2.21e2.28 (m,
1H, CH2), 2.80e2.88 (m, 1H, H-1), 3.35e3.70 (m, 1H, H-2), 3.82e3.89
(m, 1H, H-4), 4.09e4.14 (m, 1H, H-5), 4.14e4.23 (m, 2H, OCH2), 4.67
3.3.6. Ethyl (1R
*
,2S
*
,4R
*
,5R )-5-azido-2-(tert-butoxycarbonylamino)-
*
4-hydroxycyclohexanecarboxylate [(ꢃ)-10]. White solid; mp
(br s, 1H, NeH); 13C NMR (400 MHz, DMSO):
d¼14.9, 29.0, 31.3, 31.6,
68e70 ꢀC; yield: 36% or 67% (see Scheme 3). 1H NMR (400 MHz,
43.7, 46.8, 60.8, 62.3, 66.7, 78.5, 155.6, 174.0. MS: (ESI) m/z¼351
(Mþ23). IR (KBr): nmax 1528,1700,1719, 2105, 2934, 2980, 3374. Anal.
CDCl3):
d
¼1.33 (t, 3H, CH3, J¼7.20 Hz), 1.46 (s, 9H, CH3), 1.63e1.70

L. Kiss et al. / Tetrahedron 68 (2012) 4438e4443
4443
ꢀ
ꢀ
Calcd for C14H24N4O5: C, 51.21; H, 7.37; N, 17.06. Found: C, 50.89; H,
7.01; N, 16.88.
Bolyai Janos Fellowships for L.K. and E.F. We also thank TAMOP-
4.2.1/B-09/1/KONV-2010-0005.
3.3.12. Ethyl (1S
cyano-5-hydroxycyclohexanecarboxylate [(ꢃ)-17]. Colourless oil;
yield: 62%. 1H NMR (400 MHz, DMSO):
*
,2S
*
,4R
*
,5S
*
)-2-(tert-butoxycarbonylamino)-4-
References and notes
d¼1.18 (t, 3H, CH3,
J¼7.15 Hz), 1.36 (s, 9H, CH3), 1.62e2.00 (m, 4H, CH2), 2.65e2.70 (m,
1H, H-1), 2.98e3.03 (m,1H, H-4), 3.70e3.76 (m,1H, H-2), 3.89e3.94
(m, 1H, H-5), 4.01e4.12 (m, 2H, OCH2), 5.45 (br s, 1H, OeH), 6.51 (br
€ €
ꢀ
€ €
€ €
1. (a) Kiss, L.; Fulop, F. Synlett 2010, 1302; (b) Palko, M.; Kiss, L.; Fulop, F. Curr. Med.
ꢀ
Chem. 2005, 12, 3063; (c) Kiss, L.; Forro, E.; Fulop, F. Synthesis of carbocyclic
b
-
amino acids In; Hughes, A. B., Ed. . Amino Acids, Peptides and Proteins in Organic
Chemistry; Wiley: Weinheim, 2009; Vol. 1, p 367.
s, 1H, NeH); 13C NMR (400 MHz, DMSO):
d¼14.9, 29.1, 32.7, 32.8,
2. (a) Karpf, M.; Trussardi, R. Angew. Chem., Int. Ed. 2009, 48, 5760; (b) Satoh, N.;
Akiba, T.; Yokoshima, S.; Fukuyama, T. Tetrahedron 2009, 65, 3239; (c) Ishikawa,
H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304; (d) Ishikawa, H.;
Suzuki, T.; Orita, H.; Uchimaru, T.; Hayashi, Y. Chem.dEur. J. 2010, 16, 12616; (e)
Ko, J. S.; Keum, J. E.; Ko, S. Y. J. Org. Chem. 2010, 75, 7006; (f) Mohan, S.; McA-
tamney, S.; Haselhorst, T.; von Itzstein, M.; Pinto, B. M. J. Med. Chem. 2010, 53,
7377; (g) Kamimura, A.; Nakano, T. J. Org. Chem. 2010, 75, 3133; (h) Nie, L. D.; Shi,
X.-X.; Ko, K. H.; Lu, W.-D. J. Org. Chem. 2009, 74, 3970; (i) Osato, H.; Jones, I. L.;
Chen, A.; Chai, C. L. L. Org. Lett. 2010, 12, 60; (j) Sullivan, B.; Carrera, I.; Drouin, M.;
Hudlicky, T. Angew. Chem., Int. Ed. 2009, 48, 4229; (k) Trost, B. M.; Zhang, T.
Angew. Chem., Int. Ed. 2008, 47, 3759; (l) Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew.
Chem., Int. Ed. 2010, 49, 4656.
3. (a) Calveras, J.; Nagai, Y.; Sultana, I.; Ueda, Y.; Higashi, T.; Shoji, M.; Sugai, T.
Tetrahedron 2010, 66, 4284; (b) Honda, T.; Kubo, S.; Masuda, T.; Arai, M.; Ko-
bayashi, Y.; Yamashita, M. Bioorg. Med. Chem. Lett. 2009, 19, 2938; (c) Soule, J.-F.;
Mathieu, A.; Norsikian, S.; Beau, J.-M. Org. Lett. 2010, 12, 5322; (d) Wena, W.-H.;
Wang, S.-Y.; Tsai, K.-C.; Cheng, Y.-S. E.; Yang, A.-S.; Fang, J.-M.; Wong, C.-H. Bi-
oorg. Med. Chem. 2010, 18, 4074; (e) Xu, G.; Kiefel, M. J.; Wilson, J. C.; Andrew, P.
W.; Oggioni, M. R.; Taylor, G. L. J. Am. Chem. Soc. 2011, 133, 1718.
33.2, 43.5, 47.6, 60.9, 64.7, 78.7, 121.7, 158.0, 173.8. MS: (ESI) m/
z¼335 (Mþ23). IR (KBr): nmax 1528, 1716, 1720, 2244, 2937, 2980,
3376. Anal. Calcd for C15H24N2O5: C, 57.68; H, 7.74; N, 8.97. Found: C,
57.41; H, 7.49; N, 8.65.
3.4. Characterization of the enantiomers
The ee values for 4 and 5 were determined by using HPLC on
a Chiralpak IA 5
m
column (0.4 cmꢂ1 cm), for 4 (enantiomer, ee 98%)
[mobile phase: n-hexane/2-propanol (95:5); flow rate
0.5 mL minꢁ1; detection at 205 nm; retention time (min): 46.65
(antipode: 44.75)]; for 5 (enantiomer, ee 98%) [mobile phase: n-
hexane/2-propanol (90:10); flow rate 0.5 mL minꢁ1; detection at
205 nm; retention time (min): 15.59 (antipode: 19.85)].
The ee value for 6 (99%) was determined by using GC on
a Chromopack Chiralsil-Dex CB column (25 m) after derivatization
with hexanoic anhydride in the presence of pyridine containing
10% DMAP [190 ꢀC; 140 kPa; retention time (min): 30.89].
4. (a) Lu, W. J.; Chen, Y. L.; Ma, W. P.; Zhang, X. Y.; Luan, F.; Liu, M. C.; Chen, X. G.;
Hu, Z. D. Eur. J. Med. Chem. 2008, 43, 569; (b) Watson, K. G.; Cameron, R.; Fenton,
R. J.; Gower, D.; Hamilton, S.; Jin, B.; Krippner, G. Y.; Luttick, A.; McConnell, D.;
MacDonald, S. J. F.; Mason, A. M.; Nguyen, V.; Tucker, S. P.; Wu, W.-Y. Bioorg. Med.
Chem. Lett. 2004, 14, 1589; (c) Li, J.; Zheng, M.; Tang, W.; He, P.-L.; Zhu, W.; Li, T.;
Zuo, J.-P.; Liu, H.; Jiang, H. Bioorg. Med. Chem. Lett. 2006, 16, 5009; (d) Masuda, T.;
Yoshida, S.; Arai, M.; Kaneko, S.; Yamashita, M.; Honda, T. Chem. Pharm. Bull.
2003, 51, 1386; (e) Lew, W.; Wu, H.; Chen, X.; Graves, B. J.; Escarpe, P. A.; Mac-
Arthur, H. L.; Mendel, D. B.; Kim, C. U. Bioorg. Med. Chem. Lett. 2000, 10, 1257; (f)
Kipassa, N. T.; Okamura, H.; Kina, K.; Hamada, T.; Iwagawa, T. Org. Lett. 2008, 10,
815; (g) Weiwer, M.; Chen, C.-C.; Kemp, M. M.; Linhardt, R. J. Eur. J. Org. Chem.
2009, 2611; (h) Wyatt, P. G.; Coomber, B. A.; Evans, D. N.; Jack, T. I.; Fulton, H. E.;
Wonacott, A. J.; Colman, P.; Varghese, J. Bioorg. Med. Chem. Lett. 2001, 11, 669.
5. (a) Rassu, G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Zanardi, F.; Battistini, L.; Mar-
3.4.1. Ethyl (1R,2S)-2-aminocyclohex-3-enecarboxylate hydrochlo-
ride [(þ)-19]. White solid; mp 155e159 ꢀC; yield: 89%. [
a
]
25 þ108 (c
D
0.38, EtOH).
3.4.2. Ethyl (1R,2S)-2-(tert-butoxycarbonylamino)cyclohex-3-
enecarboxylate [(þ)-2]. White solid; mp 64e65 ꢀC (n-hexane);
ꢀ
25
zocchi, L.; Acquotti, D.; Casiraghi, G. J. Org. Chem. 2002, 67, 5338; (b) Fernandez,
yield: 87%. [
a
]
þ178 (c 0.35, EtOH).
D
ꢀ
ꢀ
ꢀ
F.; Estevez, A. M.; Estevez, J. C.; Estevez, R. J. Tetrahedron: Asymmetry 2009, 20,
892; (c) Roberts, S.; Chittapragada, M.; Pendem, K.; Leavitt, B. J.; Mahler, J. W.;
Ham, Y. W. Tetrahedron Lett. 2010, 51, 1779; (d) Udumula, V.; Chittapragada, M.;
Marble, J. B.; Dayton, D. L.; Ham, Y. W. Bioorg. Med. Chem. Lett. 2011, 21, 4713.
6. (a) Busscher, G. F.; Groothuys, S.; Gelder, R.; Rutjes, F. P. J. T.; van Delft, F. L. J. Org.
Chem. 2004, 69, 4477; (b) Di Bussolo, V.; Checchia, L.; Romano, M. R.; Favero, L.;
Pineschi, M.; Crotti, P. Tetrahedron 2010, 66, 689; (c) Monceaux, C. J.; Carlier, P. R.
Org. Lett. 2010, 12, 620; (d) Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem.
Rev. 2004, 104, 2857; (e) D’Antona, N.; Morrone, R.; Bovicelli, P.; Gambera, G.;
3.4.3. Ethyl (1R,2R,3R,4S)-2-(tert-butoxycarbonylamino)-3,4-
epoxycyclohexanecarboxylate [(þ)-3]. A white solid; mp 85e87 ꢀC
(n-hexane); yield: 67%. [
a]
25 þ40 (c 0.7, EtOH).
D
3.4.4. Ethyl (1R,2R,3R,4R)-4-azido-2-(tert-butoxycarbonylamino)-3-
hydroxycyclohexanecarboxylate [(ꢁ)-4]. White solid; mp 84e86 ꢀC
ꢀ
ꢀ
Kubac, D.; Martínkova, L. Tetrahedron: Asymmetry 2010, 21, 2448; (f) Fringuelli, F.;
Pizzo, F.; Rucci, M.; Vaccaro, L. J. Org. Chem. 2003, 68, 7041; (g) Hodgson, D. M.;
Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52, 14361.
25
(n-hexane); yield: 38%. [
a
]
ꢁ29 (c 2.2, EtOH).
D
7. (a) 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; (b) Serrano, P.; Llebaria, A.;
Delgado, A. J. Org. Chem. 2005, 70, 7829; (c) Sureshkumar, D.; Maity, S.; Chan-
drashekaran, S. J. Org. Chem. 2006, 71, 1653; (d) Ouchi, H.; Mihara, Y.; Watanabe,
H.; Takahata, H. Tetrahedron Lett. 2004, 45, 7053; (e) Tan, Q.; Hayashi, M. Org. Lett.
2009, 11, 3314; (f) Tokuda, O.; Aikawa, T.; Ikemoto, T.; Kurimoto, I. Tetrahedron
Lett. 2010, 51, 2832.
3.4.5. Ethyl (1R,2R,3S,4S)-3-azido-2-(tert-butoxycarbonylamino)-4-
hydroxycyclohexanecarboxylate [(þ)-5]. A white solid; mp
90e92 ꢀC (n-hexane); yield: 34%. [
a
]
25 þ1.8 (c 1.3, EtOH).
D
3.4.6. Ethyl (1R,2R,3S,4S)-2-(tert-butoxycarbonylamino)-4-cyano-3-
8. (a) Brouillette, W. J.; Saeed, A.; Abuelyaman, A.; Hutchison, T. L.; Wolkowicz, P.
E.; McMillino, J. B. J. Org. Chem. 1994, 59, 4297; (b) Masesane, I. B.; Steel, P. G.
Tetrahedron Lett. 2004, 45, 5007; (c) Kiss, L.; Forro, E.; Martinek, T. A.; Bernath, G.;
hydroxycyclohexanecarboxylate
[(ꢁ)-6]. White
solid;
mp
183e186 ꢀC (n-hexane); yield: 59%. [
a
]
25 ꢁ55.7 (c 1.1, EtOH).
D
ꢀ
ꢀ
€ €
ꢀ
€ €
De Kimpe, N.; Fulop, F. Tetrahedron 2008, 64, 5036; (d) Kiss, L.; Forro, E.; Fulop, F.
Tetrahedron Lett. 2006, 47, 285; (e) Reina, J. J.; Bernardi, A. Tetrahedron 2011, 67,
5770.
Acknowledgements
9. (a) Giorgi, G.; Guideri, L.; Ponticelli, F. Tetrahedron 2011, 67, 1463; (b) Kiss, L.;
We are grateful to the Hungarian Research Foundation (OTKA
No. T81371) for financial support and acknowledge the receipt of
ꢀ
€€
€ €
ꢀ
Forro, E.; Sillanpaa, R.; Fulop, F. J. Org. Chem. 2007, 72, 8786; (c) Kiss, L.; Forro, E.;
€ €
Fulop, F. Synthesis 2010, 153.