Synthesis of novel isoxazoline-fused cyclic β-amino esters by regio- and stereo-selective 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tet.2011.04.005

Isoxazoline-fused 2-aminocyclopentanecarboxylate derivatives were regio- and stereo-selectively synthesized by nitrile oxide 1,3-dipolar cycloaddition to cis- or trans-ethyl-2-aminocyclopent-3-enecarboxylates. The compounds were prepared in enantiomerical

Full text of DOI:10.1016/j.tet.2011.04.005

Tetrahedron 67 (2011) 4079e4085
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of novel isoxazoline-fused cyclic
selective 1,3-dipolar cycloaddition
b-amino esters by regio- and stereo-
a
a
c
a,b,
*
ꢀ
}
ꢀ a
ꢀ
€ €
Melinda Nonn , Lorand Kiss , Eniko Forro , Zoltan Mucsi , Ferenc Fulop
a
€
€
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eotvos u. 6, Hungary
b
€
€
Research Group of Stereochemistry of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eotvos u. 6, Hungary
c Department of Chemical Informatic, University of Szeged, H-6725 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Isoxazoline-fused 2-aminocyclopentanecarboxylate derivatives were regio- and stereo-selectively syn-
thesized by nitrile oxide 1,3-dipolar cycloaddition to cis- or trans-ethyl-2-aminocyclopent-3-ene-
carboxylates. The compounds were prepared in enantiomerically pure form by enzymatic resolution of
Received 24 January 2011
Received in revised form 21 March 2011
Accepted 4 April 2011
the racemic bicyclic b-lactam.
Available online 9 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
examples of this class of compounds.7 A number of cyclic, con-
formationally restricted b-amino acids have been used as building
The 1,3-dipolar cycloaddition of nitrile oxides to alkenes has
become widely used as a highly efficient method for the synthesis of
isoxazolines.1 Nitrile oxides can be generated in situ by either the
base-induced dehydrohalogenation of hydroximoyl chlorides
(methodology of Huisgen2), or the dehydration of primary nitro-
alkane derivatives (methodology of Mukaiyama3). The 1,3-dipolar
cycloaddition of nitrile oxides is a powerful technique to function-
alize olefins since the isoxazoline ring formed may be regarded as
a masked iminoalcohol, hydroxyketone or aminoalcohol.1 A number
blocks for the synthesis of new peptides.8
2. Results and discussion
We recently reported novel isoxazoline-fused cispentacin regio-
and stereo-isomers via a strategy of 1,3-dipolar cycloaddition of
nitrile oxides to protected cis-2-aminocyclopent-3-ene carboxyl-
ates.9 The nitrile oxides were generated from primary nitroalkanes
(RNO2) in the presence of tert-butoxycarbonyl anhydride (Boc2O)
and 4-dimethylaminopyridine (DMAP) according to the method-
ology of Mukaiyama. The cycloadditions to cis-amino esters 1
resulted in three of the four possible regio- and stereo-isomers 2, 3
and 4. Although the cycloaddition was not selective, three
isoxazoline-fused cispentacin derivatives 2, 3 and 4 could be iso-
lated (Scheme 1).
of nitrileoxide cycloadditions tocyclica- org-aminoacid derivatives
have been performed in recent years with the aim of the synthesis of
different biologically active compounds. For example, isoxazole
carboxylic acids, suchasconformationallyconstrainedaspartateand
glutamate analogues have been synthesized via addition to a-amino
cyclopentene esters.4 The derivatives prepared proved to be in-
hibitors of excitatory amino acid transporters with neuroprotective
activity.4 Cycloaddition to
g-amino cyclopentene acids was applied
for the stereoselective synthesis of novel multisubstituted cyclo-
pentene derivatives, which were described as antiviral agents.5
A novel route to isoxazoline/carbocyclic nucleosides involved the
regio-and stereo-selective 1,3-dipolar cycloaddition of nitrile oxides
to 2-azanorbornenes, followed by ring opening and a purine or py-
COOEt
NHR
1
(i) EtNO2 or PrNO2, Boc2O DMAP, THF, 20 °C, 15 h
(ii) chromatography (lit. 9)
rimidine base construction strategy.6 Alicyclic
b
-amino acids have
acquired great interest in recent years because of their pharmaco-
logical potential.7 The naturally occurring
-amino acid cispentacin
X
b
COOEt
COOEt
R'
R'
O
N
O
N
(1R,2S-2-aminocyclopentanecarboxylic acid), an antibiotic and
(1R,2S)-2-amino-4-methylenecyclopentane-carboxylic acid (Ico-
fungipen), a strong antifungal agent, for instance, are important
COOEt
COOEt
N
N
NHR
(35-68%)
NHR
(0%)
O
O
NHR
(6-15%)
NHR
(0-7%)
R'
R'
5
2
3
4
Scheme 1. Synthesis of isoxazoline-fused
b-amino esters from cis-2-amino-
cyclopentenecarboxylates 1 (R¼Boc, COPh; R0¼Me, Et)9.
€ €
* Corresponding author. 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.2011.04.005

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M. Nonn et al. / Tetrahedron 67 (2011) 4079e4085
Since the above procedure was not selective, we continued our
The result of cycloaddition of the nitrile oxide to trans-2-ami-
nocyclopentenecarboxylate 6a,b proved interesting (Scheme 3).
Whereas the addition to the corresponding cis isomer (1) gave the
three isomers 2, 3 and 4 (Scheme 1), under the same experimental
conditions (RNO2, Boc2O and DMAP) the trans counterparts 6a,b
furnished selectively only one cycloadduct isomer (7aed) (Scheme
3). Compounds 7aed could also be prepared by the epimerization
of 4aec at C-5 in the presence of NaOEt in EtOH, 4aec were pre-
pared as very minor isomers by cycloaddition to 1 (Scheme 1).
The selectivity of formation of 7aed from 6a,b is probably
explained by: steric and H-bonding interactions, as presented in
Fig. 2, i.e, steric repulsion in the transition state (T7) between the
nitrile oxide and the ester group and an H-bonding interaction
between the carbamate and the nitrile oxide (Scheme 3, Fig. 2).4d
The stereoselectivity in the reaction of 1 with the nitrile oxides
(generated from RNO2 and Boc2O; Scheme 1) can probably be
explained analogously. Steric repulsion between the ester moiety
and the nitrile oxide determines the stereochemistry of 2 and 3
(Fig. 2). H-bonding interaction between the nitrile oxide and car-
bamate (cis to eCOOEt) may be neglected in these cases (T2 and
T3). The regioselectivity is probably determined by the electron-
withdrawing effect of the N-atom of the eNHBoc group, favour-
ing attack of the nitrile oxide O-atom on C-4, distant from the
carbamate. These two phenomena lead to the major products 2 and
3 (Scheme 1). Formation of the very minor product 4 is an in-
dication that the H-bonding interaction between the carbamate
and nitrile oxide in transition state can just overcome the ester/
nitrile oxide steric repulsion (Fig. 2). The regioselectivity of the
formation of 4 may also be explained on the basis of H-bonding
interactions. The postulated transition state T5, which would lead
to the fourth possible isomer in this reaction, involves highly
unfavourable steric hindrance not only between the ester and the
nitrile oxide, but also between the carbamate and the alkyl moiety
(R) of the nitrile oxide. This explains why isomer 5 was never
formed (Fig. 3, Scheme 1).
experiments to search for other synthetic routes for the preparation
of isoxazoline-fused cispentacins with higher selectivity. De-
hydration of primary nitroalkanes to generate nitrile oxides may be
accomplished not only with Boc2O and DMAP (Scheme 1), but also
with phenyl isocyanate (PhNCO) and triethylamine (Et3N). Com-
pounds 1a,bwere subjected to1,3-dipolarcycloaddition underthese
conditions, using RNO2, PhNCO, Et3N in THF at 65 ꢀC (Scheme 2).
COOEt
NHR
COOEt
NHR
EtNO2 or PrNO2, PhNCO
O
N
Et3N, THF
65 °C, 15 h
R'
1a: R = Boc
1b: R = COPh
2a: R = Boc; R' = Me; 50%
2b: R = COPh; R' = Me; 38%
2c: R = Boc; R' = Et; 30%
2d: R = COPh; R' = Et; 40%
Scheme 2. Regio- and stereo-selective synthesis of isoxazoline-fused
2aed from cis-2-aminocyclopentenecarboxylates 1a,b.
b-amino esters
The reactions with the nitrile oxides derived from EtNO2 or
PrNO2 in the presence of PhNCO resulted selectively in 2aed, in
which the isoxazoline ring is trans to the carbamate and ester
groups, and the O-atom of the isoxazoline skeleton is farthest from
the carbamate (Scheme 2). The explanation of the unexpected se-
lectivity in this reaction is not yet clear. We are not aware of any
similar example in the literature.
To clarify matters, DFT calculations10 were carried out on the
reaction of 1 and MeNCO by using the G0311 program; the reaction
enthalpies and Gibbs free energies of the transition states (
Gz) and products (
H; G) are listed in Table 1. Surprisingly, from
a kinetic aspect, 4 was predicted to be the main product of the
reaction, due to its lowest activation Gibbs free energy (
Gz).
Compounds 2 and 5 exhibited practically equal
Gz values, but the
D
Hz;
D
D
D
D
D
significantly higher energies (ca. 4 kJ molꢁ1) suggest predicted
concentrations of only a few per cent. The formation of 3 is least
favourable, its formation being practically hindered. A possible
explanation of the lowest-energy transition state of 4 is an in-
termolecular H-bond (HB) between MeNCO and the amide in 1, as
shown in Fig. 1. The same results were obtained at each level of
computation [HF/3-21G, B3LYP/6-31G(d,p) and B3LYP/6-
311þþG(2d,2p)], irrespective of the solvent models applied
[IEFPCM(THF)], and the theoretical model was therefore extended
to a more complex description. It was earlier demonstrated that an
explicit consideration of some selected solvent molecules or other
components in the solvent provided a much more accurate picture
of the mechanism.12 In this particular case, the solvent is THF,
which does not require the exact consideration of any THF mole-
cule. However, excess EtNO2 can be regarded as a cosolvent,
strongly H-bonded to the amide in 1. When the study of the ring
closure mechanism included one explicit EtNO2, the result altered.
The results of calculations at different levels [B3LYP/6-
31þþG(d,p), B3LYP/6-311þþG(d,p) and B3LYP/6-311þþG(2d,2p)]
relating to interpretation of the selectivity agreed well with the
experimental finding that preferred product in the transformation
of 6b was 7b (Table 2, Fig. 4).
These computations furnished eloquent proof that the selec-
tivity
of
nitrile
oxide
addition
to
trans-2-amino-
cyclopentenecarboxylate is largely determined by the H-bonding
effect in the transition state (Fig. 5).
The earlier synthesized isoxazoline-fused cispentacin de-
rivatives (Scheme 1)9 afforded an opportunity for the preparation
of new transpentacin derivatives, regio- and stere-oisomers of 7.
Accordingly, 2aed and 3aed were epimerized at C-5 with NaOEt in
EtOH to give izoxazoline-fused amino esters 8aed and 9aed, in
which the amino and carboxylate functions were trans. Un-
fortunately, the yields were low and a relatively large amount of
starting material was recovered during column chromatography
purification of the products (Scheme 4).
The lowest D
Gz was computed for 2 (Fig. 1), but the value for 3 was
very close, in agreement with experiment, where 3 was also
detected in a significant amount beside the main component (2).
For 4 and 5, the
D
Gz values were in all cases higher than those
The 100% regio- and stereo-selective synthesis of 2a and 2c
(Scheme 2) and 7a and 7c (Scheme 3) was extended to their
preparation in enantiomerically pure form. The starting material
calculated in vacuo, because the nitro compound occupied the re-
active zone to some extent and hinders the attack of MeNCO (Fig.1).
Table 1
Enthalpy (in kJ molꢁ1) and Gibbs free energy (in kJ molꢁ1) of the transformation of 1b to 2be5b in vacuo, with implicit solvent and with explicit solvent model
In vacuo
Hz
In implicit solvent (THF)
Hz Gz
With explicit cosolvent
Hz Gz
D
D
Gz
D
H
DG
D
D
DH
D
G
D
D
DH
DG
2b
3b
4b
5b
55.8
75.1
49.8
54.9
114.1
128.3
109.5
113.7
ꢁ169.5
ꢁ159.1
ꢁ164.1
ꢁ166.7
ꢁ104.3
ꢁ97.2
59.1
79.3
54.2
58.2
118.2
132.5
113.8
117.9
ꢁ165.7
ꢁ154.1
ꢁ160.3
ꢁ161.9
ꢁ100.0
ꢁ92.0
ꢁ98.1
ꢁ96.3
67.3
70.1
75.8
95.4
126.1
129.3
135.5
153.9
ꢁ164.1
ꢁ153.4
ꢁ160.2
ꢁ161.3
ꢁ100.1
ꢁ92.0
ꢁ97.7
ꢁ96.5
ꢁ101.5
ꢁ100.9

M. Nonn et al. / Tetrahedron 67 (2011) 4079e4085
olven model:
4081
in vacuo or implicit s
t
R
N
N
H
R
R
O
N
N
R
O
O
Boc
N
BocHN
EtOOC
EtOOC
O
BocHN
EtOOC
BocHN
EtOOC
T4
T5
T2
T3
explicit solvent model:
R
R
R
N
N
R
O
N
N
O
O
O
O
O
BocN
BocN
R
H
H
N
COOEt
O
COOEt
O
N
R
O
Boc
H
H
N
O
O
BocN
EtOOC
EtOOC
O
N
N
R
R
T2'
T4'
T3'
T5'
Fig. 1. Transition states T2, T3 and T4 in the formation of cycloadducts 2e5; steric repulsions between eCOOEt and nitrile oxides in T2 and T3, and between eNHBoc and nitrile
oxide and eCOOEt and nitrile oxide in T5 and hydrogen bonding interaction between eNHBoc and nitrile oxide in T4.
nitroethane or nitropropane,
COOEt
COOEt
NHR
DMAP
R'
O
N
O
N
COOEt
X
Boc2O, THF, 20 °C
20 h
N
NHR
O
NHR
9
R'
R'
5'
8
R'
R'
nitroethane or nitropropane,
DMAP
COOEt
COOEt
NHR
COOEt
NaOEt
N
N
Boc2O, THF, 20 °C
20 h, (27-46%)
EtOH, 20 °C, 12 h
( 31-39%)
O
O
NHR
NHR
: R = Boc
7a
: R = Boc; R' = Me
6a
6b: R = COPh
4a
: R = Boc; R' = Me
7b: R = COPh; R' = Me
7c: R = Boc; R' = Et
7d: R = COPh; R' = Et
4b: R = COPh; R' = Me
4c: R = COPh; R' = Et
Scheme 3. Regio- and stereo-selective synthesis of isoxazoline-fused
b-amino esters 7aed from trans-2-aminocyclopentenecarboxylates 6a,b.
the racemic bicyclic lactam 10 was subjected to enzymatic ring
opening reaction with Lipolase in i-Pr2O,13 which afforded the de-
sired amino acid enantiomer (þ)-11 in excellent enantiomeric ex-
cess (ee >99%).14 Compound (þ)-11 was then transformed by
known procedures to the corresponding protected amino ester
(þ)-1a.15 Compound (þ)-1a was next submitted to nitrile oxide
(generated from EtNO2 or PrNO2 and PhNCO and Et3N) cycloaddi-
tion, which resulted in the enantiomerically pure isoxazoline-fused
cispentacin derivatives (ꢁ)-2a and (ꢁ)-2c in yield of 53% and
40% (Scheme 5).
H
N
O
Boc
N
R
EtOOC
T7
Compounds (ꢁ)-2a and (ꢁ)-2c were epimerized in the presence
of NaOEt in EtOH to the enantiomerically pure isoxazoline-fused
transpentacin derivatives (þ)-8a and (þ)-8c (Scheme 5).
Fig. 2. Transition state T7 stabilized by hydrogen bonding interactions during for-
mation of cycloadducts 7aed.
N
N
R
H
O
N
R
N
R
O
O
Boc
N
R
BocHN
EtOOC
EtOOC
O
BocHN
EtOOC
BocHN
EtOOC
T4
T5
T2
T3
Fig. 3. Transition states T2, T3 and T4 in the formation of cycloadducts 2e5; steric repulsions between eCOOEt and nitrile oxides in T2 T3 and between eNHBoc and the nitrile
oxide and between eCOOEt and the nitrile oxide in T5 and H-bonding interaction between eNHBoc and the nitrile oxide in T4.

4082
M. Nonn et al. / Tetrahedron 67 (2011) 4079e4085
Table 2
O
O
1R
1S
5R
Enthalpy (in kJ molꢁ1) and Gibbs free energy (in kJ molꢁ1) of the transformation of
COOH
Lipolase
6b to 7b, 8b, 9b and 50b
+
2S
NH2
(+)-11
NH
iPr2O, 70 °C
NH
rac-10
6b/TS
Hs
6b/products
(-)-10
D
D
Gs
DH
DG
1. SOCl2, EtOH, 70 °C, 3 h
7b
8b
9b
50b
47.76
65.32
76.83
55.36
102.21
119.90
130.31
113.99
ꢁ170.02
ꢁ154.35
ꢁ152.22
ꢁ163.44
ꢁ106.24
ꢁ92.50
ꢁ90.46
ꢁ100.12
2. Boc2O, Et3N, THF, 0 °C to 20 °C
1R
COOEt
2S
NHBoc
(+)-1a
see Scheme 2
6aR
5R
4S
NHBoc
6aR
5R
4S
NHBoc
COOEt
COOEt
O
N
O
N
3aR
3aR
(-)-2c (40%)
(-)-2a (53%)
NaOEt, EtOH, 20 °C
12 h, 25%
NaOEt, EtOH, 20 °C
12 h, 22%
6aR
5S
6aR
5S
4S
NHBoc
COOEt
COOEt
O
N
O
N
4S
NHBoc
3aR
3aR
(+)-8a
(+)-8c
Fig. 4. Energy diagram for the transformation of 6b to 7b.
Scheme 5. Synthesis of the isoxazoline-fused
(ꢁ)-2c, (þ)-8a and (þ)-8c.
b-amino ester enantiomers (ꢁ)-2a,
5S
3aR
see
COOEt
6R
Scheme 3
N
6aS
O
NHBoc
(+)-7a (52%)
1R
1S
COOEt
COOEt
NaOEt, EtOH
2S
NHBoc
(+)-1a
2S
NHBoc
(+)-6a
20 °C, 12 h, 58%
5S
3aR
COOEt
6R
see
Scheme 3
N
6aS
O
NHBoc
(+)-7c (34%)
Fig. 5. H-bonding stabilization of TS 7b in the formation of 7b.
Scheme 6. Synthesis of the isoxazoline-fused
(þ)-7c.
b
-amino ester enantiomers (þ)-7a and
COOEt
O
N
NaOEt, EtOH
20 °C, 12 h
2a-d
In conclusion, isoxazoline-fused cispentacin derivatives were
synthesized regio- and stereo-selectively via the 1,3-dipolar cy-
cloaddition of nitrile oxides to cis- and trans-ethyl 2-amino-3-
cyclopentenecarboxylates. This synthetic pathway was also applied
for the preparation of these compounds in enantiomerically pure
form.
NHR
R'
8a: R = Boc; R' = Me; 75%
8b: R = COPh; R' = Me; 37%
8c: R = Boc; R' = Et; 30%
8d: R = COPh; R' = Et; 45%
R'
COOEt
3. Experimental
3.1. General
NaOEt, EtOH
3a-d
N
20 °C, 12 h
O
NHR
9a: R = Boc; R' = Me; 20%
9b: R = COPh; R' = Me; 30%
9c: R = Boc; R' = Et; 28%
9d: R = COPh; R' = Et; 10%
The chemicals were purchased from Aldrich. Melting points
were determined with a Kofler apparatus. NMR spectra were
recorded on a Bruker DRX 400 spectrometer. Chemical shifts are
given in parts per million relative to TMS as internal standard, with
CDCl3 or DMSO as solvent. The solvents were used as received from
the supplier. Optical rotations were measured with a PerkineElmer
341 polarimeter. Mass spectra were recorded on a Finnigan MAT
95S spectrometer. Elemental analyses were performed with a Per-
kineElmer CHNS-2400 Ser II Elemental Analyzer.
Scheme 4. Synthesis of isoxazoline-fused
rization of 2aed and 3aed.
b-amino esters 8aed and 9aed by epime-
Boc-protected amino ester (þ)-1a was isomerized to its trans de-
rivative (þ)-6a, which was then subjected to nitrile oxide (gener-
ated from EtNO2 or PrNO2 and Boc2O and Et3N) cycloaddition,
giving the enantiomerically enriched isoxazoline-fused cispentacin
derivatives (þ)-7a and (þ)-7c in yield of 52% and 34% (Scheme 6).
The ee values for (ꢁ)-2a, (þ)-14a and (þ)-7a were determined
by GC on a Chromopack Chiralsil-Dex CB column (25 m) [190 ꢀC;

M. Nonn et al. / Tetrahedron 67 (2011) 4079e4085
4083
140 kPa; retention times (min): (ꢁ)-2a: 19.82 (antipode: 20.02);
(þ)-7a: 16.99 (antipode: 15.79); (þ)-8a: 19.46 (antipode: 20.01)],
83.0, 128.4, 129.0, 132.1, 135.0, 157.7, 167.1, 173.3; MS: (ESI) m/z¼317
(Mþ1). Anal. Calcd for C17H20N2O4: C, 64.54; H, 6.37; N, 8.86.
Found: C, 64.38; H, 6.27; N, 8.75.
while ee for (ꢁ)-2c was determined by GC on a CP-Chiralsil
L-Val
column (25 m) [190 ꢀC; 100 kPa; retention time (min): 17.61 (an-
tipode: 17.86)]. The ee value for (þ)-7c was determined by HPLC on
3.3.3. Ethyl (3aR
*
,5S
*
,6R
*
,6aS )-6-(tert-butoxycarbonylamino)-3-ethyl-
*
a ChiralcelR OD 5
m
column (0.46 cmꢂ25 cm) [mobile phase: n-
4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate (7c). A
hexane/2-propanol (95:5); flow rate 5 mL minꢁ1; detection at
205 nm; retention time (min): 25.06 (antipode: 32.39)], and ee for
white solid; yield: 215 mg, 22%; mp 105e106 ꢀC; Rf¼0.36 (n-hexane/
EtOAc 2:1); 1H NMR (400 MHz, DMSO):
d¼1.07 (t, 3H, CH3, J¼7.4 Hz),
(þ)-8c was determined by HPLC on a Chiral Pak IA 5
m
column
1.17 (t, 3H, CH3, J¼7.2 Hz), 1.39 (s, 9H, CH3), 1.85e2.03 (m, 2H, CH2),
2.15e2.27 (m, 1H, CH2), 2.29e2.37 (m, 1H, CH2), 2.38e2.47 (m, 1H, H-
5), 3.71 (m, 1H, H-3a), 3.97e4.13 (m, 3H, OCH2 and H-6), 4.71e4.76
(m, 1H, H-6a), 6.74 (br s, 1H, NeH);13 C NMR (100 MHz, CDCl3):
(0.4 cmꢂ1 cm) [mobile phase: n-heaxane/2-PrOH (90:10); flow
rate 5 mL minꢁ1; detection at 205 nm; retention time (min): 21.86
(antipode: 18.46)].
d
¼11.4, 14.9, 19.5, 29.0, 30.9, 45.8, 52.3, 60.3, 61.0, 78.8, 83.1, 155.8,
3.2. Computational methods
161.9,173.4; MS: (ESI) m/z¼227 (Mþ1). Anal. Calcd for C16H26N2O5: C,
58.88; H, 8.03; N, 8.58. Found: C, 58.62; H, 7.92; N, 8.44.
All computations were carried out with the Gaussian03 program
package (G03),10,11 using standard convergence criteria, at B3LYP/6-
31G(d,p), B3LYP/6-311þþG(d,p) and B3LYP/6-311þþG(2d,2 p)
levels of theory. The vibrational frequencies were computed at the
same levels of theory as used for geometry optimization in order to
confirm all structures as residing at minima on their potential en-
ergy hypersurfaces. Thermodynamic functions U, H, G and S were
computed at 298.15 K, using the quantum chemical, rather than the
conventional, thermodynamic reference state.
3.3.4. Ethyl (3aR
*
,5S
*
,6R
*
,6aS )-6-benzamido-3-ethyl-4,5,6,6a-tetra-
*
hydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
(7d). A white
solid; yield: 436 mg, 44%; mp 127e129 ꢀC; Rf¼0.15 (n-hexane/
EtOAc 2:1); 1H NMR (400 MHz, CDCl3):
d¼1.19, (t, 3H, CH3,
J¼7.1 Hz), 1.26 (t, 3H, CH3, J¼7.1 Hz), 2.06e2.12 (m, 1H, CH2),
2.23e2.37 (m, 2H, CH2), 2.44e2.63 (m, 2H, CH2 and H-5), 3.77 (m,
1H, H-3a), 4.12e4.21 (m, 2H, OCH2), 4.80e4.87 (m, 1H, H-6),
4.98e5.03 (m, 1H, H-6a), 6.75 (b rs, 1H, NeH), 7.44e7.49 (m, 2H,
AreH), 7.51e7.56 (m, 1H, AreH), 7.77e7.85 (m, 2H, AreH); 13C NMR
3.3. General procedure for the synthesis of isoxazoline-fused-
(100 MHz, CDCl3):
d
¼11.1, 14.4, 19.9, 30.7, 47.1, 52.4, 59.0, 61.6, 83.5,
b-aminocyclopentanecarboxylates
127.5, 129.0, 132.1, 134.5, 162.3, 167.5, 172.6; MS: (ESI) m/z¼331
(Mþ1). Anal. Calcd for C18H22N2O4: C, 65.44; H, 6.71; N, 8.48.
Found: C, 65.23; H, 6.63; N, 8.29.
Method A: To a solution of amino ester 1a or 1b (3.92 mmol) in
THF (15 ml), RNO2 (2 equiv), PhNCO (2 equiv) and Et3N (2 equiv)
were added and the mixture was stirred under reflux for 15 h. The
reaction mixture was then diluted with EtOAc (50 ml), washed with
H2O (3ꢂ15 ml), dried (Na2SO4), and concentrated under reduced
pressure. The crude residue was purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc), giving 2aed.9
3.4. General procedure for the synthesis of isoxazoline-fused-
b-amino esters 8aed and 9aed by epimerization of 2aed and
3aed
To
a solution of isoxazoline-fused b-aminocyclopentane-
Method B: To a solution of amino ester 6a or 6b (3 mmol) in THF
(20 mL), RNO2 (3.2 mmol), DMAP (0.6 mmol, 20 mol %) and Boc2O
(9 mmol, 3 equiv) were added and the mixture was stirred at 20 ꢀC
for 15 h. The reaction mixture was then diluted with H2O (50 mL)
and extracted with EtOAc (3ꢂ15 mL). The combined organic layer
was washed with 5% HCl (15 mL) and brine (2ꢂ20 mL), dried
(Na2SO4) and concentrated under reduced pressure. The crude
residue was purified by column chromatography on silica gel (n-
hexane/EtOAc), giving 7aed.
carboxylate 2aed and 3aed (1 mmol) in EtOH (10 ml), NaOEt
(1.2 mmol) was added and the mixture was stirred at room temper-
ature for 12 h. The mixture was then concentrated under reduced
pressure, and the residue was then diluted with CHCl3 (30 ml),
washed with H2O (3ꢂ10 ml), dried (Na2SO4) and concentrated under
reduced pressure. The crude residue was purified by crystallization
(n-hexane/EtOAc)orcolumnchromatographyonsilicagel (n-hexane/
EtOAc 5:1).
3.4.1. Ethyl
(3aR
*
,4S
*
,5S
*
,6aR )-4-(tert-butoxycarbonylamino)-3-
*
3.3.1. Ethyl (3aR
*
,5S
*
,6R
*
,6aS
*
)-6-(tert-butoxycarbonylamino)-3-meth-
methyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxyl-
yl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
ate (8a). A white solid; yield: 234 mg, 75%; mp 92e94 ꢀC; Rf¼0.63
(7a). A white solid; yield: 431 mg, 46%; mp 63e65 ꢀC; Rf¼0.25 (n-
(n-hexane/EtOAc 1:2); 1H NMR (400 MHz, CDCl3):
d
¼1.28 (t, 3H,
hexane/EtOAc 2:1); 1H NMR (400 MHz, CDCl3):
d¼1.28 (t, 3H, CH3,
CH3, J¼7.1 Hz), 1.48 (s, 9H, CH3), 2.11 (s, 3H, CH3), 2.25e2.34 (m, 1H
CH2), 2.42e2.50 (m, 1H, CH2), 2.82e2.91 (m, 1H, H-5), 3.49e3.57
(m, 1H, H-3a), 4.10e4.22 (m, OCH2), 4.34e4.40 (m, 1H, H-4), 4.82
(br s, 1H, NeH), 5.06e5.13 (m, 1H, H-6a); 13C NMR (100 MHz,
J¼7.1 Hz), 1.46 (s, 9H, CH3), 1.97e1.99 (s, 3H, CH3), 2.00e2.05 (m, 1H,
CH2), 2.13e2.26 (m, 1H, CH2), 2.38e2.48 (m, 1H, H-5), 3.63 (m, 1H, H-
3a), 4.11e4.34 (m, 3H, H-6 and OCH2), 4.89e4.94 (m, 1H, H-6a), 5.21
(br s, 1H, NeH); 13C NMR (100 MHz, DMSO):
d¼11.5, 14.8, 29.0, 30.7,
CDCl3):
d
¼12.2, 14.5, 28.7, 36.8, 49.7, 58.1, 61.6, 63.3, 83.9, 98.0,
36.8, 45.7, 53.6, 60.4, 61.2, 83.9, 157.6, 172.7, 173.4; MS: (ESI) m/z¼335
(MþNa). Anal. Calcd for C15H24N2O5: C, 57.68; H, 7.74; N, 8.97. Found:
C, 57.41; H, 7.58; N, 8.82.
106.9, 155.2, 172.1; MS: (ESI) m/z¼313 (Mþ1). Anal. Calcd for
C15H24N2O5: C, 57.68; H, 7.74; N, 8.97. Found: C, 57.43; H, 7.61;
N, 8.90.
3.3.2. Ethyl (3aR
*
,5S
*
,6R
*
,6aS
*
)-6-benzamido-3-methyl-4,5,6,6a-tet-
3.4.2. Ethyl (3aR
*
,4S
*
,5S
*
,6aR )-4-benzamido-3-methyl-4,5,6,6a-tet-
*
rahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate (7b). A white
rahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate (8b). A white
solid; yield: 398 mg, 42%; mp 172e174 ꢀC; Rf¼0.15 (n-hexane/EtOAc
solid; yield: 117 mg, 37%; mp 142e144 ꢀC; Rf¼0.3 (n-hexane/EtOAc
2:1); 1H NMR (400 MHz, CDCl3):
d
¼1.16 (t, 3H, CH3, J¼7.1 Hz),
1:1); 1H NMR (400 MHz, CDCl3):
d
¼1.22e1.3 (t, 3H, CH3, J¼7.1 Hz),
1.98e2.00 (s, 3H, CH3), 2.03e2.10 (m, 1H, CH2), 2.24e2.34 (m, 1H,
CH2), 2.51e2.59 (m, 1H, H-5), 3.69 (m, 1H, H-3a), 4.10e4.17 (m, 2H,
OCH2), 4.77e4.84 (m, 1H, H-6), 4.97e5.01 (m, 1H, H-6a), 6.70 (br s,
1H, NeH), 7.41e7.53 (m, 3H, AreH), 7.77e7.81 (m, 2H, AreH); 13C
2.16 (s, 3H, CH3), 2.26e2.36 (m, 1H, CH2), 2.50e2.61 (m, 1H, CH2),
3.05e3.13 (m, 1H, H-5), 3.69e3.76 (m, 1H, H-3a), 4.12e4.20 (m, 2H,
OCH2), 4.72e4.79 (m, 1H, H-4), 5.12e5.21 (m, 1H, H-6a), 6.47e6.69
(br s, 1H, NeH), 7.43e7.50 (m, 2H, AreH), 7.52e7.58 (m, 1H, AreH),
NMR (100 MHz, DMSO):
d
¼11.6, 14.9, 30.8, 45.1, 53.9, 59.3, 61.0,
7.76e7.80 (m, 2H, AreH); 13C NMR (100 MHz, CDCl3):
d¼12.3, 14.5,

4084
M. Nonn et al. / Tetrahedron 67 (2011) 4079e4085
30.1, 36.9, 49.4, 57.5, 61.7, 63.0,126.3,127.3,129.1,132.4,134.3,156.3,
172.1; MS: (ESI) m/z¼317 (Mþ1). Anal. Calcd for C17H20N2O4: C,
64.54; H, 6.37; N, 8.86. Found: C, 64.41; H, 6.21; N, 8.70.
5.08 (br s, 1H, NeH); 13C NMR (100 MHz, CDCl3):
28.7, 30.1, 31.1, 52.4, 61.5, 63.4, 117.5, 119.5, 124.4, 155.4, 162.3; MS:
(ESI) m/z¼349 (MþNa). Anal. Calcd for C16H26N2O5: C, 58.88; H,
8.03; N, 8.58. Found: C, 58.73; H, 7.85; N, 8.31.
d
¼11.0, 14.5, 20.2,
3.4.3. Ethyl
(3aR
*
,4S
*
,5S
*
,6aR )-4-(tert-butoxycarbonylamino)-3-
*
ethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
3.4.8. Ethyl (3aS
*
,5S
*
,6R
*
,6aR )-6-benzamido-3-ethyl-4,5,6,6a-tetra-
*
(8c). A white solid; yield: 98 mg, 30%; mp 119e121 ꢀC; Rf¼0.42 (n-
hydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
(9d). A white
hexane/EtOAc 2:1); 1H NMR (400 MHz, DMSO):
d
¼1.07 (t, 3H, CH3,
solid; yield: 33 mg, 10%; mp 192e194 ꢀC; Rf¼0.39 (n-hexane/EtOAc
J¼7.47 Hz),1.14 (t, 3H, CH3, J¼7.1 Hz),1.38 (s, 9H, CH3),1.87e1.96 (m,
1H, CH2), 2.23e2.46 (m, 3H, CH2), 2.48e2.51 (m, 1H, H-5),
2.72e2.79 (m, 1H, H-3a), 3.45 (dd, 1H, H-4, J¼5.0 and 5.1 Hz),
3.96e4.06 (m, 2H, OCH2), 4.10e4.17 (m, 1H, H-6a), 4.89e4.96 (br s,
1:1) and 1H NMR (400 MHz, DMSO):
d¼1.05 (t, 3H, CH3, J¼7.2 Hz),
1.10 (t, 3H, CH3, J¼7.2 Hz),1.94e2.05 (m,1H, CH2), 2.21e2.43 (m, 3H,
CH2), 2.90e2.98 (m, 1H, H-5), 3.72e3.80 (m, 1H, H-3a), 3.92e4.05
(m, 2H, OCH2), 4.40e4.47 (m, 1H, H-6), 4.92 (dd,1H, H-6a, J¼4.8 and
7.7 Hz), 7.44e7.57 (m, 3H, AreH), 7.83 (d, 2H, AreH, J¼7.5 Hz), 8.65
1H, NeH); 13C NMR (100 MHz, CDCl3):
d¼11.3, 14.8, 20.2, 29.0, 36.7,
49.7, 58.5, 61.2, 61.7, 79.1, 83.9, 155.7, 160.7, 172.7; MS: (ESI)
m/z¼327 (Mþ1). Anal. Calcd for C16H26N2O5: C, 58.88; H, 8.03; N,
8.58. Found: C, 58.71; H, 7.85; N, 8.30.
(br s, 1H, NeH); 13C NMR (100 MHz, DMSO):
d¼11.3, 14.7, 19.9, 30.9,
48.7, 52.4, 61.2, 61.9, 89.1, 128.1, 129.2, 132.2, 135.1, 162.7, 167.1,
172.7; MS: (ESI) m/z¼331 (Mþ1). Anal. Calcd for C18H22N2O4: C,
65.44; H, 6.71; N, 8.48. Found: C, 65.20; H, 6.56; N, 8.28.
3.4.4. Ethyl (3aR
*
,4S
*
,5S
*
,6aR )-4-benzamido-3-ethyl-4,5,6,6a-tetra-
*
hydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
(8d). A white
solid; yield: 149 mg, 45%; mp 136e137 ꢀC; Rf¼0.46 (n-hexane/
EtOAc 1:1); 1H NMR (400 MHz, DMSO):
d¼1.05 (t, 3H, CH3,
3.5. Characterization of the enantiomers
J¼7.15 Hz), 1.07 (t, 3H, CH3, J¼7.2 Hz), 1.93e2.01 (m, 1H, CH2),
2.23e2.34 (m, 1H, CH2), 2.36e2.53 (m, 2H, CH2), 2.91e2.99 (m, 1H,
H-5), 3.63 (dd, 1H, H-3a, J¼5.0 and 5.1 Hz), 3.93e4.01 (m, 2H,
OCH2), 4.57e4.64 (m, 1H, H-4), 4.95e5.02 (m, 1H, H-6a), 7.42e7.54
(m, 3H, AreH), 7.77e7.81 (m, 2H, AreH), 8.66 (br s, 1H, NeH); 13C
The 1H NMR spectra of the enantiomeric substances were the
same as those of the corresponding racemic compounds.
3.5.1. Ethyl (1S,2S)-2-(tert-butoxycarbonylamino)cyclopent-3-ene-
NMR (100 MHz, DMSO):
d
¼11.4, 14.7, 20.3, 36.9, 49.6, 57.4, 61.2,
carboxylate [(þ)-6a]. A white solid; yield: 58%; mp¼58e60 ꢀC;
61.5, 84.1, 128.1, 129.2, 132.3, 134.0, 136.5, 158.0, 171.8; MS: (ESI) m/
z¼331 (Mþ1). Anal. Calcd for C18H22N2O4: C, 65.44; H, 6.71; N, 8.48.
Found: C, 65.21; H, 6.80; N, 8.30.
½
a 2D5
ꢃ
þ121.7 (c 0.38, EtOH).
3.5.2. Ethyl (3aR,4S,5R,6aR)-4-(tert-butoxycarbonylamino)-3-methyl-
4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
3.4.5. Ethyl
(3aS
*
*
,5S ,6R
*
,6aR
*
)-6-(tert-butoxycarbonylamino)-3-
[(ꢁ)-2a]. A white solid; yield: 53%; mp 80e82 ꢀC; ½a D25
ꢁ8.3 (c 0.4,
ꢃ
methyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxyl-
EtOH).
ate (9a). A white solid; yield: 62 mg, 20%; mp 113e115 ꢀC; Rf¼0.47
(n-hexane/EtOAc 1:2); 1H NMR (400 MHz, CDCl3):
d¼1.26 (t, 3H,
3.5.3. Ethyl (3aR,4S,5R,6aR)-4-(tert-butoxycarbonylamino)-3-ethyl-
4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
CH3, J¼7.2 Hz), 1.44 (s, 9H, CH3), 1.97e1.98 (s, 3H, CH3), 2.03e2.12
(m, 1H, CH2), 2.24e2.34 (m, 1H, CH2), 3.08e3.20 (m, 1H, H-5),
3.54e3.62 (m, 1H, H-3a), 3.93e4.04 (m, 1H, H-6), 4.11e4.18 (m, 2H,
OCH2), 4.83 (br s, 1H, NeH), 5.00e5.10 (m, 1H, H-6a); 13C NMR
[(ꢁ)-2c]. A white solid; yield: 40%; mp 105e107 ꢀC; ½a D25
ꢁ2 (c 0.1,
ꢃ
EtOH).
(100 MHz, CDCl3):
d
¼11.8,14.5, 28.7, 28.8, 30.8, 53.7, 59.9, 61.5, 63.6,
3.5.4. Ethyl (3aR,4S,5S,6aR)-4-(tert-butoxycarbonylamino)-3-methyl-
4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
101.3, 139.9, 155.4, 157.8; MS: (ESI) m/z¼335 (MþNa). Anal. Calcd
for C15H24N2O5: C, 57.68; H, 7.74; N, 8.97. Found: C, 57.41; H, 7.63; N,
8.92.
[(þ)-8a]. A white solid; yield: 22%; mp 90e93 ꢀC; ½a D25
þ20 (c 0.28,
ꢃ
EtOH).
3.4.6. Ethyl (3aS
*
,5S
*
,6R
*
,6aR
*
)-6-benzamido-3-methyl-4,5,6,6a-tet-
3.5.5. Ethyl (3aR,4S,5S,6aR)-4-(tert-butoxycarbonylamino)-3-ethyl-
4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
rahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate (9b). A white
solid; yield: 95 mg, 30%; mp 181e183 ꢀC; Rf¼0.23 (n-hexane/EtOAc
[(þ)-8c]. A white solid; yield: 25%; mp 119e121 ꢀC; ½a D25
þ20
ꢃ
1:1); 1H NMR (400 MHz, CDCl3):
d¼1.23 (t, 3H, CH3, J¼7.2 Hz), 1.42
(c 0.37, EtOH).
(s, 3H, CH3), 2.05e2.12 (m, 1H, CH2), 2.44e2.55 (m, 1H, CH2),
3.49e3.58 (m, 1H, H-5), 3.71e3.79 (m, 1H, H-3a), 4.13e4.20 (m, 2H,
OCH2), 4.21e4.29 (m, 1H, H-6), 5.40 (dd, 1H, H-6a, J¼5.0 and
5.2 Hz), 6.65 (br s, 1H, NeH), 7.44e7.49 (m, 2H, AreH), 7.52e7.57
(m, 1H, AreH), 7.76e7.80 (m, 2H, AreH); 13C NMR (100 MHz,
3.5.6. Ethyl (3aR,5S,6R,6aS)-6-(tert-butoxycarbonylamino)-3-methyl-
4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
[(þ)-7a]. Yellow oil; yield: 52%; ½a D25
þ105 (c 0.39, EtOH).
ꢃ
CDCl3):
d
¼11.86,14.52, 27.56, 31.29, 47.26, 53.91, 61.59, 63.88, 88.26,
3.5.7. Ethyl (3aR,5S,6R,6aS)-6-(tert-butoxycarbonylamino)-3-ethyl-
4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
122.64, 126.92, 127.33, 129.05, 132.20, 148.00, 182.23; MS: (ESI)
m/z¼317 (Mþ1). Anal. Calcd for C17H20N2O4: C, 64.54; H, 6.37; N,
8.86. Found: C, 64.39; H, 6.25; N, 8.69.
[(þ)-7c]. A white solid; yield: 34%; mp 105e107 ꢀC; ½a D25
þ136 (c
ꢃ
0.30, EtOH).
3.4.7. Ethyl
(3aS
*
*
,5S ,6R
*
,6aR )-6-(tert-butoxycarbonylamino)-3-
*
ethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-5-carboxylate
(9c). A white solid; yield: 75 mg, 23%; mp 113e115 ꢀC; Rf¼0.61
Acknowledgements
(n-hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3):
d
¼1.21 (t, 3H,
CH3, J¼7.5 Hz), 1.26e1.32 (t, 3H, CH3, J¼7.4 Hz), 1.47 (s, 9H, CH3),
2.03e2.14 (m, 1H, CH2), 2.24e2.38 (m, 2H, CH2), 2.44e2.55 (m, 1H,
CH2), 3.11e3.25 (m, 1H, H-5), 3.62e3.70 (m, 1H, H-3a), 4.95e4.07
(m, 1H, H-6), 4.14e4.20 (m, 2H, OCH2), 4.82e4.93 (m, 1H, H-6a),
We are grateful to the Hungarian Research Foundation (OTKA
ꢀ
No. T81371) and TAMOP-4.2.1/B-09/1/KONV-2010-0005 for finan-
ꢀ
cial support and acknowledge the receipt of Bolyai Janos Fellowship
for L.K. and E.F.

M. Nonn et al. / Tetrahedron 67 (2011) 4079e4085
4085
Tetrahedron Lett. 2008, 49, 7368; (c) Rua, F.; Boussert, S.; Parella, T.; Diez-Perez,
I.; Branchadell, V.; Giralt, E.; Ortuno, R. M. Org. Lett. 2007, 9, 3643; (d) D’Elia, V.;
Zwicknagl, H.; Reiser, O. J. Org. Chem. 2008, 73, 3262; (e) Fulop, F.; Martinek, T.
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