Selective nitrile oxide dipolar cycloaddition for the synthesis of highly functionalized β-aminocyclohexanecarboxylate stereoisomers

Article abstract of DOI:10.1016/j.tet.2012.09.085

Highly functionalized β-aminocyclohexanecarboxylate regio- and stereoisomers were synthesized from a bicyclic β-lactam by successive regioselective iodolactonization, stereo- and regioselective nitrile oxide cycloaddition, lactone ring-opening and isoxazoline ring-opening.

Full text of DOI:10.1016/j.tet.2012.09.085

Tetrahedron 68 (2012) 9942e9948
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective nitrile oxide dipolar cycloaddition for the synthesis of highly
functionalized b-aminocyclohexanecarboxylate stereoisomers
,
b
a
a,b,
Melinda Nonn a , Lorand Kiss , Reijo Sillanpaa , Ferenc Fulop
*
ꢀ
€€ c
€ €
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
Department of Chemistry, University of Jyvaskyla, FIN-40351 Jyvaskyla, Finland
b
c
€
€
€
€
€
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a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2012
Received in revised form 28 August 2012
Accepted 17 September 2012
Available online 23 September 2012
Highly functionalized b-aminocyclohexanecarboxylate regio- and stereoisomers were synthesized from
a bicyclic
b-lactam by successive regioselective iodolactonization, stereo- and regioselective nitrile oxide
cycloaddition, lactone ring-opening and isoxazoline ring-opening.
Ó 2012 Published by Elsevier Ltd.
1. Introduction
the hydroxylated cyclohexene amino esters formed and finally the
reductive opening of the isoxazoline ring.
As important bioactive derivatives, highly functionalized cyclic
amino acids have been at the focus of organic and medicinal
chemistry interest during the past ten years. Multifunctionalized
cyclohexane amino acids, such as the antibiotic Oryzoxymycin1 and
the antiviral agents Tamiflu,2 Zanamivir and 2,3-didehydro-2-
deoxy-N-acetylneuraminic acid (DANA)3 (Fig. 1) are important de-
rivatives with high pharmacological potential. Their modified
derivatives3a,d,4 and other functionalized derivatives4c,5 exhibit
strong antiviral, antifungal or antibacterial activities.
Amino acid 2 derived from lactam 1 was subjected to a slightly
modified procedure in comparison with earlier presented
method.11 Iodolactonization procedure by treatment at room
temperature with 1.5 equiv of NaHCO3 and 1.5 equiv of KI, followed
by the addition of 1.5 equiv of I2 in portions during 20 min with
stirring for 24 h, which gave iodolactone 3 in high yield (Scheme 1).
Dehydroiodination with the addition of 2.1 equiv of DBU as base
and stirring at 40 ꢀC for 8 h resulted in unsaturated lactone 4 (91%).
Lactone ring-opening with NaOEt under different reaction condi-
tions furnished hydroxylated amino ester stereoisomers: 5 (74%) at
ꢁ10 ꢀC to 0 ꢀC for 1 h and due to its active methane group its C-1
epimer 6 (76%) at 0 ꢀCe20 ꢀC for 20 h (Scheme 1).11
Hydroxylated aminocarboxylates 5 and 6 were subjected to the
attempted 1,3-dipolar cycloaddition with acetonitrile N-oxide (gener-
ated from nitroethane, di-tert-butoxycarbonylanhydride (Boc2O) and
dimethylaminopyridine (DMAP) in THF). Although the reaction was
tried under different conditions, such as the Huisgen (from aldox-
imes)12 and Mukayama (from primary nitroalkanes)13 methodologies
in different solvents, the required cycloadduct could not be prepared.
The reason is probably the low reactivity due to the sterical and elec-
tronical reasons of the isolated ring double bond in 5 and 6 (Scheme 2).
However, unsaturated cis-lactone 4 (Fig. 1),11 derived from
azetidinone 1, underwent the cycloaddition of the acetonitrile N-
oxide to furnish the isoxazoline-fused aminolactone 7 regio- and
stereoselectively as the sole cycloaddition product, in which the
isoxazoline ring and the carbamate group have cis relative stereo-
chemistry, while the oxygen atom of the isoxazoline ring is closest
to the carbamate (Scheme 2).
The dipolar cycloaddition of nitrile oxides to unsaturated cyclic
amino acid derivatives has been efficiently applied for the prepa-
ration of substituted cyclic amino acids or amino alcohols6 and for
the selective synthesis of highly functionalized bioactive cyclo-
pentane amino acid derivatives, e.g., Peramivir4c,7 (Fig. 1) and its
analogues.7c,8 Among the large family of
b-amino acids with high
pharmacological potential,1c,9 the highly substituted derivatives are
an interesting class of compounds, which have received consider-
able attention in recent years. Isoxazoline-fused cispentacin stereo-
and regioisomers were recently prepared via a nitrile oxide cyclo-
addition.10 Our current aim was the synthesis of highly function-
alized 2-aminocyclohexanecarboxylate stereoisomers from bicyclic
b-lactam 1 through nitrile oxide cycloaddition.
2. Results and discussion
The synthetic procedure consisted of a modified regio- and
stereoselective iodolactonization and dehydroiodination, lactone
opening, regio- and stereoselective nitrile oxide cycloaddition to
The face of attack of the nitrile oxide on the C]C bond of lactone
4 can be explained by a hydrogen-bonding directing effect,10b,14
from the carbamate, leading to the all-cis derivative 7 (Figs. 2 and 3).
€ €
* Corresponding author. E-mail address: fulop@pharm.u-szeged.hu (F. Fulop).
0040-4020/$ e see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2012.09.085

M. Nonn et al. / Tetrahedron 68 (2012) 9942e9948
9943
CO2H
O
OH
H
O
CO2H
NH2
O
HO
O
CO2Et
OH
AcHN
AcHN
HN
NH2
OH
Oryzoxymycin
NH2*H3PO4
NH
Tamiflu
(Oseltamivir)
Zanamivir
H2N
HN
NH
OH
H
O
CO2H
HO
CO2H
OH
AcHN
OH
DANA
OH
NHAc
Peramivir
Fig. 1. Several bioactive highly functionalized cyclic amino acids.
O
O
KI (1.5 equiv), I2 (1.5 equiv)
O
CO2H
Ref. 11
NaHCO3 (1.5 equiv)
NH
CH2Cl2 , H2O
20 °C, 24 h, 89%
NHBoc
I
NHBoc
1
2
3
DBU (2.1 equiv), THF, 40 °C
8 h, 91%
O
O
NaOEt (1.2 equiv)
EtOH
HO
CO2Et
NaOEt (1.2 equiv)
EtOH, -10 °C
HO
CO2Et
NHBoc
0 °C to 20 °C
20 h, 76%
NHBoc
1 h, 74%
NHBoc
6
5
4
Scheme 1. Synthesis of bicyclic lactone 4 and hydroxylated
b
-amino carboxylates 5 and 6.
4
nitroethane (2 equiv)
Boc2O (3 equiv)
HO
HO
COOEt
NHBoc
nitroethane (2 equiv)
NaOEt
HO
HO
COOEt
NHBoc
DMAP (0.1 equiv)
(1.2 equiv)
Boc2O (3 equiv)
X
THF, 48 h, rt
EtOH, 0 °C
DMAP (0.1 equiv)
THF, rt
O
O
O
N
N
5
O
1 h, 75%
8
NHBoc
COOEt
NHBoc
COOEt
NHBoc
nitroethane (2 equiv)
NaOEt
O
(1.2 equiv)
N
Boc2O (3 equiv)
X
7 (31%)
EtOH, rt, 8 h
47%
DMAP (0.1 equiv)
THF, rt
6
9
Scheme 2. Unsuccessful and successful routes for the synthesis of isoxazoline-fused b-amino carboxylates 8 and 9.

9944
M. Nonn et al. / Tetrahedron 68 (2012) 9942e9948
Fig. 2. Ortep structure of 4.
Next, 7 was subjected to lactone ring-opening with NaOEt.
O
When performed at 0 ꢀC for 1 h, the reaction afforded hydroxylated
isoxazoline-fused aminocyclohexanecarboxylate 8 in 75% yield. In
contrast, at 20 ꢀC for 8 h, epimerization occurred at C-8 to give
hydroxylated amino ester 9, a diastereoisomer of 8, in 47% yield
(Scheme 2). The rather modest yield was probably a result of the
formation of various polymeric materials in the latter reaction.
The reason why isoxazolines 8 and 9 could not be prepared by
the addition of nitrile oxide to the CeC double bond of hydroxyl-
ated amino ester 5 (Fig. 4) or 6 (Fig. 5) is unclear. We initially
R
O
N
O
H
N
H
Boc
H
H
H
H
Fig. 3. H-bonding interaction between nitrile oxide and carbamate.
Fig. 4. Ortep structure of 5.

M. Nonn et al. / Tetrahedron 68 (2012) 9942e9948
9945
Fig. 5. Ortep structure of 6.
assumed that it might be due to a difference length of the CeC
double bond in the structures of 4 (Fig. 1) and 5 and 6. We supposed
that the rigidity in the structure of lactone 4 would lead to a longer
(C3eC4 C]C) bond distance than that in 5 (C23eC24 in ORTEP,
Fig. 4) or 6. Unfortunately, X-ray studies did not support this as-
trans-lactone 1311 by applying the modified iodolactonization and
dehydroiodination presented in Scheme 1. Cycloaddition to hy-
droxylated ester 14 again failed, leading to no isoxazoline-fused
products. However, the addition of the nitrile oxide derived from
nitroethane to lactone 13 (Scheme 4) resulted regio- and stereo-
selectively in isoxazoline 15, in which (as a result of the H-bonding)
the isoxazoline ring is cis to the carbamate, while the oxygen atom
of the heterocycle is closest to this group (NHBoc).10b,14
On the treatment of 15 with NaOEt, lactone ring-opening
resulted in the corresponding hydroxylated ester 16, isoxazoline
ring-opening with NaBH4/NiCl2 gave the corresponding highly
functionalized amino ester 17 (Scheme 4).
ꢁ
sumption. The CeC double bond distance in 4 was 1.3230 A, while
ꢁ
that in 5 was 1.325 A, i.e., no relevant difference. Thus, the differ-
ence in reactivity of the CeC double bond in these two types of
molecules appears to be attributable to stereochemical reasons: our
experimental results indicated that the rigid ring framework in 4
results in a much higher reactivity of the CeC olefinic bond than in
5 or 6, without such a constrained system.
Next, in order to synthesize the desired multisubstituted
b
-
In conclusion, three highly functionalized cyclohexane b-amino
amino esters, the isoxazoline-fused esters 8 and 9 were submitted
to reductive ring-opening. Catalytic hydrogenation over Pd/C in
MeOH with drops of HCl at 10 bar led to the desired ring-opened
products (10 and 11) in rather low isolated yields. With NaBH4 in
the presence of NiCl2, the stereochemistry of the new stereocentre
could not be determined, but it most probably corresponded with
the earlier experiments where the H attack occurred from the same
side as the carbamate (with the formation of a new stereocentre at
1C distance from C-4) (Scheme 3).4c,7,15
ester stereoisomers were prepared by regio- and stereoselective
cycloaddition of nitrile oxides to unsaturated bicyclic amino lac-
tones, followed by reductive opening of the isoxazoline ring. These
multifunctionalized cyclic aminocarboxylates with multiple ster-
eocenters may be regarded as promising b-amino acid analogues of
bioactive compounds, e.g., Tamiflu and Zanamivir.
3. Experimental
3.1. General
The successful synthetic procedures presented above were next
attempted for the synthesis of other novel highly substituted b-
aminocyclohexanecarboxylates. Hydroxylated cyclohexene amino
ester 14, a stereoisomer of 5 and 6, was synthesized from 1 via
The chemicals were purchased from Aldrich. Melting points
were determined with a Kofler apparatus. NMR spectra were
recorded on Bruker DRX 400 and 500 MHz spectrometers. Chem-
ical 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. Mass spectra were recorded on a Fin-
nigan MAT 95S spectrometer. Elemental analyses were performed
with a PerkineElmer CHNS-2400 Ser II Elemental Analyzer.
HO
HO
COOEt
NHBoc
NaBH4 (2 equiv)
NiCl2 (2 equiv)
Boc2O (2 equiv)
HO
BocHN
CO2Et
NHBoc
O
N
EtOH/THF
OH
8
rt, 6 h
10 (58%)
3.2. General procedure for iodolactonization
HO
BocHN
CO2Et
NHBoc
COOEt
NHBoc
NaBH4 (2 equiv)
NiCl2 (2 equiv)
Boc2O (2 equiv)
To a solution of N-Boc-protected amino acid (36 mmol, 2) in
CH2Cl2 (150 mL), H2O (200 mL) was added, followed by NaHCO3
(1.5 equiv) and KI (1.5 equiv). To this mixture, I2 (1.5 equiv) was
added in portions during 20 min. After stirring for 24 h at room
temperature, the mixture was taken up in CH2Cl2 (300 mL), and
washed with saturated aqueous Na2SO3 solution. The organic layer
OH
O
EtOH/THF
N
rt, 6 h
9
11 (78%)
Scheme 3. Synthesis of highly functionalized b-amino carboxylates 10 and 11.

9946
M. Nonn et al. / Tetrahedron 68 (2012) 9942e9948
O
O
O
nitroethane (2 equiv)
Boc2O (3 equiv)
O
CO2H
see
scheme 1
DMAP (0.1 equiv)
NHBoc
15 (32%)
NHBoc
NHBoc
THF, 48 h, rt
12
O
N
13
NaOEt (1.2 equiv)
EtOH, rt, 1 h
see scheme 1
nitroethane (2 equiv)
HO
CO2Et
HO
CO2Et
NHBoc
HO
BocHN
CO2Et
NHBoc
OH
17 (87%)
NaBH4 (2 equiv)
NiCl2 (2 equiv)
Boc2O (3 equiv)
X
NHBoc
O
16 (88%)
DMAP (0.1 equiv)
Boc2O (2 equiv)
14
THF, rt
N
EtOH/THF, rt
6 h
Scheme 4. Synthesis of highly functionalized
b
-amino carboxylate 17.
was then dried (Na2SO4) and concentrated under reduced pressure,
Calcd for C14H20N2O5: C, 56.75; H, 6.80; N, 9.45. Found: C, 56.50; H,
6.99; N, 9.11.
giving 3.11
3.5.2. tert-Butyl-(3-methyl-9-oxo-5,10-dioxa-4-azatricyclo[6.2.1.02,6
]
3.3. General procedure for dehydroiodination
undec-3-en-7-yl)-carbamoate (15). A yellowish-white solid; yield
32% (1.18 g); mp: 147e148 ꢀC; Rf¼0.38 (n-hexaneeEtOAc 1:2); 1H
To a solution of iodolactone (12 mmol, 3) in THF (60 mL), DBU
(2.1 equiv) was added and the mixture was stirred at 40 ꢀC for 8 h.
The solution was then concentrated under reduced pressure and
the residue was taken up in EtOAc (140 mL). The organic layer was
washed with H2O (3ꢂ70 mL), dried (Na2SO4) and concentrated
under vacuum. The residue was crystallized from n-hexaneeEtOAc,
giving 4 (a similar procedure for 13).11
NMR (400 MHz, CDCl3):
d
¼1.50 (s, 9H, CH3), 2.11 (s, 3H, CH3), 2.17,
(d, 1H, H-8, J¼12.6 Hz), 2.26e2.35 (m, 1H, CH2), 2.92e3.00 (m, 1H,
CH2), 3.52 (d, 1H, H-7, J¼9.1 Hz), 4.30e4.39 (m, 1H, H-2), 4.70 (d, 1H,
H-6, J¼5.3 Hz), 4.91 (t, 1H, H-1, J¼8.2 Hz), 5.42 (br s, 1H, NeH). 13C
NMR (100 MHz, DMSO):
d
¼12.4, 27.3, 29.0, 43.3, 53.8, 75.9, 119.1,
122.7, 140.6, 153.4, 156.5, 177.3. Anal. Calcd for C14H20N2O5: C,
56.75; H, 6.80; N, 9.45. Found: C, 56.52; H, 6.63; N, 9.27.
3.4. General procedure for lactone ring-opening reactions
3.6. General procedure for the synthesis of hydroxylated
isoxazoline-fused
pounds 8, 9 and 16
b-amino carboxylates. Synthesis of com-
To a solution of lactone 4 (10.5 mmol) in EtOH (15 mL), NaOEt
(12.6 mmol) was added and the mixture was stirred at ꢁ10 ꢀC for
1 h. The mixture was concentrated under reduced pressure and the
residue was then diluted with CHCl3 (50 mL), washed with H2O
(3ꢂ20 mL), dried (Na2SO4) and concentrated under reduced pres-
To a solution of isoxazoline-fused lactones (7 or 15) (2.66 mmol)
in EtOH (10 mL), NaOEt (15 mmol) was added and the mixture was
stirred at 22 ꢀC for the time indicated in the text. The mixture was
concentrated under reduced pressure, and the residue was then
diluted with CHCl3 (30 mL), washed with H2O (3ꢂ15 mL), dried
(Na2SO4) and concentrated under reduced pressure. The crude
residue was purified by column chromatography on silica gel (n-
hexaneeEtOAc), giving diastereoisomers 8 and 9 in 1:3 ratio or 16.
When the reaction mixture was stirred at 0 ꢀC for 1 h, only the all-
cis diastereoisomer (8) was detected. The product was purified by
crystallization (n-hexaneeEtOAc).
sure. The product
5 was purified by crystallization (n-hex-
aneeEtOAc). When the reaction was carried out at 20 ꢀC under the
same reaction conditions the epimerized diastereomer 6 was
obtained.
3.5. General procedure for synthesis of isoxazoline-fused
lactones
To a solution of lactone (4 or 15) (12.55 mmol) in THF (20 mL),
EtNO2 (25.1 mmol), Boc2O (37.6 mmol) and DMAP (1.3 mmol) were
added and the mixture was stirred at 22 ꢀC for 48 h. The reaction
mixture was then diluted with EtOAc (75 mL) and extracted with
H2O (3ꢂ20 mL), dried (Na2SO4) and concentrated under reduced
pressure. The crude residue was purified by column chromatogra-
phy on silica gel (n-hexaneeEtOAc), giving 7 and 15.
3.6.1. Ethyl (3aS*,4S*,6R*,7R*,7aS*)-7-(tert-butoxycarbonylamino)-4-
hydroxy-3-methyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazole-6-
carboxylate (8). A white solid, yield 75% (670 mg); mp: 123e124 ꢀC;
Rf¼0.30 (n-hexaneeEtOAc 1:3); 1H NMR (400 MHz, CDCl3):
¼1.26
d
(t, 3H, CH3, J¼7.1 Hz), 1.44 (s, 9H, CH3), 1.68 (t, 1H, H-6, J¼12.8 Hz),
2.02 (s, 3H, CH3), 2.02e2.10 (m, 1H, CH2), 2.41e2.56 (m, 1H, CH2),
3.17e3.30 (m, 1H, H-7), 3.38 (d, 1H, H-3a, J¼9.3 Hz), 3.44e3.54 (m,
1H, H-7a), 4.09e4.22 (m, 2H, OCH2), 4.24e4.32 (m, 1H, H-4), 4.91
(br s, 1H, NeH), 5.08 (br s, 1H, OeH). 13C NMR (100 MHz, CDCl3):
3.5.1. tert-Butyl-(1S*,2S*,6S*,7R*,8R*)-(3-methyl-9-oxo-5,10-dioxa-
4-azatricyclo-[6.2.1.02,6]undec-3-en-7-yl)-carbamoate
(7). A
yellowish-white solid; yield 31% (1.15 g); mp: 160e161 ꢀC; Rf¼0.32
d
¼12.3, 14.6, 28.7, 32.6, 39.8, 52.7, 56.7, 58.8, 61.4, 64.7, 80.6, 155.7,
(n-hexaneeEtOAc 1:2); 1H NMR (500 MHz, DMSO):
d
¼1.39 (s, 9H,
157.2, 173.9. Anal. Calcd for C16H26N2O6: C, 56.13; H, 7.65; N, 8.18.
Found: C, 55.90; H, 7.96; N, 8.40.
CH3), 1.69 (d, 1H, H-8, J¼12.0 Hz), 1.92 (s, 3H, CH3), 2.38e2.45 (m,
1H, CH2), 2.59e2.64 (m, 1H, CH2), 3.49e3.56 (m, 1H, H-7), 3.86 (d,
1H, H-2, J¼10.0 Hz), 4.66e4.73 (m,1H, H-6), 5.02e5.07 (m,1H, H-1),
3.6.2. Ethyl (3aS*,4S*,6S*,7R*,7aS*)-7-(tert-butoxycarbonylamino)-4-
hydroxy-3-methyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazole-6-
carboxylate (9). A white solid, yield 47% (220 mg); mp: 140e141 ꢀC;
7.38 (d, 1H, NeH, J¼7.4 Hz). 13C NMR (100 MHz, DMSO):
¼11.0,
d
28.2, 31.2, 40.8, 53.9, 54.9, 59.8, 75.3, 78.4, 79.3, 155.3, 174.8. Anal.

M. Nonn et al. / Tetrahedron 68 (2012) 9942e9948
9947
Rf¼0.58 (n-hexaneeEtOAc 1:3); 1H NMR (400 MHz, CDCl3):
d
¼1.26
1.61e1.78 (m, 3H, CH2, H-1), 2.27e2.37 (m, 1H, H-4), 2.73e2.82 (m,
1H, CH), 3.51e3.60 (m, 1H, H-5), 4.06e4.19 (m, 3H, OCH2, H-2), 4.23
(br s, 1H, NeH), 4.29e4.32 (m, 1H, H-3), 4.88 (br s, 1H, NeH). 13C
(t, 3H, CH3, J¼7.2 Hz), 1.43 (s, 9H, CH3), 1.54e1.76 (m, 2H, CH2),
1.99e2.08 (m, 4H, CH3, H-6), 3.18e3.30 (m, 1H, H-3a), 3.38 (d, 1H,
H-7, J¼8.9 Hz), 3.43e3.54 (m, 1H, H-7a), 4.09e4.20 (m, 2H, OCH2),
4.23e4.29 (m, 1H, H-4), 4.90 (br s, 1H, NeH), 5.08 (br s, 1H, OeH).
NMR (100 MHz, CDCl3):
d¼13.9, 22.6, 28.3, 28.3, 31.7, 42.3, 48.2,
51.9, 60.1, 65.0, 70.2, 77.0, 80.3, 92.2, 115.4, 121.0, 161.3. Anal. Calcd
for C21H38N2O8 C, 56.48; H, 8.58; N, 6.27. Found: C, 56.40; H, 8.68;
N, 6.22.
13C NMR (100 MHz, CDCl3):
d¼12.4, 14.6, 32.6, 38.9, 52.7, 56.7, 61.4,
64.8, 80.3, 90.9, 113.2, 153.1, 157.1, 165.8. Anal. Calcd for C16H26N2O6:
C, 56.13; H, 7.65; N, 8.18. Found: C, 55.92; H, 7.87; N, 8.32.
Acknowledgements
3.6.3. Ethyl (3aS*,4R*,6S*,7R*,7aS*)-7-(tert-butoxycarbonylamino)-
4-hydroxy-3-methyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazole-6-
carboxylate (16). A white solid, yield 88% (790 mg); mp 118e119 ꢀC;
We are grateful to the Hungarian Research Foundation (OTKA
No. NK81371 and KI00530) for financial support and acknowledge
the receipt of a Bolyai Janos Fellowship for L.K.
Rf¼0.29 (n-hexaneeEtOAc 1:3); 1H NMR (400 MHz, CDCl3):
¼1.30
d
ꢀ
(t, 3H, CH3, J¼7.1 Hz), 1.46 (s, 9H, CH3), 1.89e2.00 (m, 2H, CH2), 2.09
(s, 3H, CH3), 2.65e2.75 (m, 1H, H-6), 2.89e3.05 (m, 1H, H-7),
3.09e3.17 (m, 1H, H-3a), 3.77e3.85 (m, 1H, H-7a), 4.11e4.29 (m, 2H,
OCH2), 4.45e4.57 (m, 1H, H-4), 4.61 (dd, 1H, NeH, J¼3.1 Hz), 5.00
References and notes
(d, 1H, OeH, J¼9.2 Hz). 13C NMR (100 MHz, CDCl3):
d
¼13.4, 14.4,
€ € ꢀ € €
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Amino Acids; Hughes, A. B., Ed.; Amino Acids, Peptides and Proteins in Organic
Chemistry; Wiley: Weinheim, 2009; Vol. 1, p 367; (d) Fulop, F. Chem. Rev. 2001,
ꢀ
€ €
b
-
28.6, 33.6, 42.5, 49.7, 56.8, 61.7, 67.9, 80.2, 81.2, 155.5, 161.4, 174.6.
Anal. Calcd for C16H26N2O6: C, 56.13; H, 7.65; N, 8.18. Found: C,
56.32; H, 7.46; N, 8.39.
€ €
101, 2181.
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2010, 16, 12616; (b) Ko, J. S.; Keum, J. E.; Ko, S. Y. J. Org. Chem. 2010, 75, 7006; (c)
Karpf, M.; Trussardi, R. Angew. Chem., Int. Ed. 2009, 48, 5760; (d) Satoh, N.;
Akiba, T.; Yokoshima, S.; Fukuyama, T. Tetrahedron 2009, 65, 3239; (e) Ishikawa,
H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304; (f) Sullivan, B.;
Carrera, I.; Drouin, M.; Hudlicky, T. Angew. Chem., Int. Ed. 2009, 48, 4229; (g)
Trost, B. M.; Zhang, T. Angew. Chem., Int. Ed. 2008, 47, 3759; (h) Zhu, S.; Yu, S.;
Wang, Y.; Ma, D. Angew. Chem., Int. Ed. 2010, 49, 4656; (i) Mohan, S.; McA-
tamney, S.; Haselhorst, T.; von Itzstein, M.; Pinto, B. M. J. Med. Chem. 2010, 53,
7377; (j) Kamimura, A.; Nakano, T. J. Org. Chem. 2010, 75, 3133; (k) Nie, L. D.;
Shi, X.-X.; Ko, K. H.; Lu, W.-D. J. Org. Chem. 2009, 74, 3970; (l) Osato, H.; Jones, I.
L.; Chen, A.; Chai, C. L. L. Org. Lett. 2010, 12, 60.
3. (a) Wena, W.-H.; Wang, S.-Y.; Tsai, K.-C.; Cheng, Y.-S. E.; Yang, A.-S.; Fang, J.-M.;
Wong, C.-H. Bioorg. Med. Chem. 2010, 18, 4074; (b) Xu, G.; Kiefel, M. J.; Wilson, J.
C.; Andrew, P. W.; Oggioni, M. R.; Taylor, G. L. J. Am. Chem. Soc. 2011, 133, 1718;
(c) Calveras, J.; Nagai, Y.; Sultana, I.; Ueda, Y.; Higashi, T.; Shoji, M.; Sugai, T.
Tetrahedron 2010, 66, 4284; (d) Honda, T.; Kubo, S.; Masuda, T.; Arai, M.; Ko-
bayashi, Y.; Yamashita, M. Bioorg. Med. Chem. Lett. 2009, 19, 2938; (e) Soule, J.-F.;
Mathieu, A.; Norsikian, S.; Beau, J.-M. Org. Lett. 2010, 12, 5322.
3.7. General procedure for isoxazoline ring-opening. Synthe-
sis of compounds 10, 11 and 17
To a solution of 8 or 9 or 15 (1.16 mmol) in 8 mL of EtOH/THF
(3:1), NiCl2 (2.32 mmol) and Boc2O (2.32 mmol) were added. After
stirring for 10 min, NaBH4 (2.32 mmol) was added in portions, the
reaction mixture was stirred at room temperature for 6 h and the
reaction was then quenched with H2O (5 mL). The reaction mixture
was filtered through a silica pad and the filtrate was evaporated in
vacuo. The crude residue was diluted with H2O (30 mL), washed
with EtOAc (3ꢂ15 mL), dried over Na2SO4 and concentrated under
reduced pressure. The residue was then purified by column chro-
matography on silica gel (n-hexaneeEtOAc), giving 10, 11 or 17.
4. (a) 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; (b)
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; (c) 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; (d) Masuda, T.; Yoshida, S.; Arai, M.; Kaneko, S.; Yamashita, M.; Honda, T.
Chem. Pharm. Bull. 2003, 51, 1386; (e) 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; (f) Lew, W.; Wu, H.; Chen, X.; Graves, B. J.; Escarpe, P.
A.; MacArthur, H. L.; Mendel, D. B.; Kim, C. U. Bioorg. Med. Chem. Lett. 2000, 10,
1257; (g) Kipassa, N. T.; Okamura, H.; Kina, K.; Hamada, T.; Iwagawa, T. Org. Lett.
2008, 10, 815; (h) Weiwer, M.; Chen, C.-C.; Kemp, M. M.; Linhardt, R. J. Eur. J.
Org. Chem. 2009, 2611.
3.7.1. Ethyl (1R*,2R*,3S*,4S*,5S*)-2-(tert-butoxycarbonylamino)-4-
(1-(tert-butoxycarbonyl)ethyl)-3,5-dihydroxycyclohexanecarboxylate
(10). A white solid, yield 58% (300 mg); mp 70e71 ꢀC; Rf¼0.29 (n-
hexaneeEtOAc 1:3); 1H NMR (400 MHz, CDCl3):
d
¼1.25e1.32 (m,
3H, CH3), 1.37 (d, 3H, CH3, J¼7.0 Hz), 1.47 (s, 9H, CH3), 1.49 (s, 9H,
CH3), 2.32e2.40 (m, 1H, CH2), 2.76e2.83 (m, 1H, CH2), 3.81e4.00
(m, 3H, H-4, H-1, CH), 4.1e4.3 (m, 4H, OCH2, H-2, H-5), 4.34e4.41
(m, 1H, H-3), 4.60e4.69 (m, 1H, NeH), 4.95 (br s, 1H, NeH). 13C NMR
(100 MHz, CDCl3):
d
¼14.4, 18.7, 28.7, 28.8, 30.1, 39.5, 44.6, 52.1, 61.6,
63.0, 67.0, 70.7, 80.1, 80.6, 157.7, 173.6, 174.1. (ESI) m/z¼469 (MþNa).
Anal. Calcd for C21H38N2O8: C, 56.48; H, 8.58; N, 6.27. Found: C,
56.30; H, 8.38; N, 6.40.
5. (a) Roberts, S.; Chittapragada, M.; Pendem, K.; Leavitt, B. J.; Mahler, J. W.; Ham,
Y. W. Tetrahedron Lett. 2010, 51, 1779; (b) Rassu, G.; Auzzas, L.; Pinna, L.; Zam-
brano, V.; Zanardi, F.; Battistini, L.; Marzocchi, L.; Acquotti, D.; Casiraghi, G. J.
ꢀ
ꢀ
ꢀ
Org. Chem. 2002, 67, 5338; (c) Fernandez, F.; Estevez, A. M.; Estevez, J. C.;
ꢀ
3.7.2. Ethyl (1S*,2R*,3S*,4S*,5S*)-2-(tert-butoxycarbonylamino)-4-
(1-(tert-butoxycarbonylamino)ethyl)-3,5-dihydroxycyclohexanecarbo-
xylate (11). A white solid, yield 78% (400 mg); mp: 72e73 ꢀC;
Rf¼0.23 (n-hexaneeEtOAc 1:2); 1H NMR (400 MHz, CDCl3):
Estevez, R. J. Tetrahedron: Asymmetry 2009, 20, 892.
6. (a) Conti, P.; Caligiuri, A.; Pinto, A.; Roda, G.; Tamborini, L.; Nielsen, B.; Madsen,
U.; Frydenvang, K.; Colombo, A.; De Micheli, C. Eur. J. Med. Chem. 2007, 42, 1059;
(b) Mineno, T.; Miller, M. J. J. Org. Chem. 2003, 68, 6591; (c) Park, K.-H.; Olm-
stead, M. M.; Kurt, M. J. J. Org. Chem. 1998, 63, 113; (d) Park, K.-H.; Kurt, M. J. J.
Org. Chem. 2000, 65, 3520; (e) Quadrelli, P.; Piccanello, A.; Martinez, N.-V.;
Bovio, B.; Mella, M.; Caramella, P. Tetrahedron 2006, 62, 7370; (f) Pinto, A.;
Conti, P.; De Amici, M.; Tamborini, L.; Grazioso, G.; Colleoni, S.; Mennini, T.;
Gobbi, M.; De Micheli, C. Tetrahedron: Asymmetry 2008, 19, 867; (g) Quadrelli,
P.; Piccanello, A.; Mella, M.; Corsaro, A.; Pistara, V. Tetrahedron 2008, 64, 3541;
(h) Quadrelli, P.; Bovio, B.; Piccinini, A.; Caramella, P.; De Sarlo, F.; Machetti, F.
Tetrahedron 2009, 65, 10679; (i) Roda, G.; Conti, P.; De Amici, M.; He, J.; Pola-
varapu, P. L.; De Micheli, C. Tetrahedron: Asymmetry 2004, 15, 3079.
7. (a) Chand, P.; Kotian, P. L.; Dehghani, A.; El-Kattan, Y.; Lin, T.-H.; Hutchison, T. L.;
Babu, Y. S.; Bantia, S.; Elliott, A. J.; Montgomery, J. A. J. Med. Chem. 2001, 44,
4379; (b) Chand, P.; Babu, Y. S.; Bantia, S.; Rowland, S.; Dehghani, A.; Kotian, P.
L.; Hutchison, T. L.; Ali, S.; Brouillette, W.; El-Kattan, Y.; Lin, T.-H. J. Med. Chem.
2004, 47, 1919; (c) Yi, X.; Guo, Z.; Chu, F. M. Bioorg. Med. Chem. 2003, 11, 1465;
(d) Oakley, A. J.; Barrett, S.; Peat, T. S.; Newman, J.; Streltsov, V. A.; Waddington,
L.; Saito, T.; Tashiro, M.; McKimm-Breschkin, J. L. J. Med. Chem. 2010, 53, 6421;
(e) Chand, P.; Bantia, S.; Kotian, P. L.; El-Kattan, Y.; Lin, T.-H.; Babu, Y. S. Bioorg.
Med. Chem. Lett. 2005, 13, 4071.
d
¼1.21e1.35 (m, 6H, CH3), 1.41e1.47 (m, 18H, CH3), 1.50e1.62 (m,
3H, CH2, H-1), 2.27e2.37 (m, 1H, H-4), 2.72e2.78 (m, 1H, CH), 3.82
(br s, 1H, NeH), 3.89e3.95 (m, 1H, H-5), 4.06e4.25 (m, 3H, OCH2, H-
2), 4.30e4.37 (m, 1H, H-3), 4.61 (br s, 1H, NeH). 13C NMR (100 MHz,
CDCl3):
d
¼13.9, 22.6, 28.1, 28.3, 31.7, 42.3, 48.2, 51.9, 60.1, 65.1, 72.4,
77.0, 80.6, 92.2, 115.4, 121.0, 161.3. Anal. Calcd for C21H38N2O8 C,
56.48; H, 8.58; N, 6.27. Found: C, 56.36; H, 8.68; N, 6.30.
3.7.3. Ethyl (1S*,2R*,3S*,4S*,5R*)-2-(tert-butoxycarbonylamino)-4-
(1-(tert-butoxycarbonylamino)ethyl)-3,5-dihydroxycyclohex-
anecarboxylate (17). A white solid, yield 87% (450 mg); mp:
75e76 ꢀC; Rf¼0.63 (n-hexaneeEtOAc 1:5); 1H NMR (400 MHz,
CDCl3):
d¼1.21e1.31 (m, 6H, CH3), 1.43e1.46 (m, 18H, CH3),

9948
M. Nonn et al. / Tetrahedron 68 (2012) 9942e9948
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