Stereoselectivity of 1,3-dipolar cycloadditions of D-erythrose and D-threose derived nitrones with methyl acrylate

Article abstract of DOI:10.1055/s-2001-18782

1,3-Dipolar cycloadditions between the D-erythrose and D-threose derived nitrones and methyl acrylate proceed in a regiospecific manner to afford the corresponding 3,5-disubstituted diastereomeric isoxazolidines in good yields. The stereoselectivity was dependent on the steric hindrance of the nitrone. The major products were found to have the C-3/C-4′ erythro and C-3/C-5 cis relative configuration. Its formation can be rationalized by less hindered endo attack of the Z-nitrone in an antiperiplanar manner with respect to the largest group of the cyclic acetal.

Full text of DOI:10.1055/s-2001-18782

1
862
LETTER
Stereoselectivity of 1,3-Dipolar Cycloadditions of D-Erythrose and D-Threose
Derived Nitrones with Methyl Acrylate
a
a
a
b
c
d
a
S
J
tereosele
u
ctivity of 1,3
r
-Dipolar
a
C
ycloaddi
j
tions of Deriv
K
ed Nitrones with
M
u
e
thyl
A
cryl
b
ate á , Andrej Kolarovi , Lubor Fišera,* Volker Jäger,* Otakar Humpa, Nada Prónayová, Peter Ertl
a
b
c
d
Department of Organic Chemistry, Slovak University of Technology, SK-812 37 Bratislava, Slovak Republic
Institute of Organic Chemistry, University of Stuttgart, D-70569 Stuttgart, Germany
Department of Organic Chemistry, Masaryk University, CZ-611 37 Brno, Czech Republic
Central Laboratory of Chemical Techniques, Slovak University of Technology, SK-812 37 Bratislava, Slovak Republic
E-mail: fisera@cvt.stuba.sk
Received 31 August 2001
1
´
O
6´
Abstract: 1,3-Dipolar cycloadditions between the D-erythrose and
D-threose derived nitrones and methyl acrylate proceed in a re-
giospecific manner to afford the corresponding 3,5-disubstituted di-
astereomeric isoxazolidines in good yields. The stereoselectivity
was dependent on the steric hindrance of the nitrone. The major
products were found to have the C-3/C-4´ erythro and C-3/C-5 cis
relative configuration. Its formation can be rationalized by less hin-
dered endo attack of the Z-nitrone in an antiperiplanar manner with
respect to the largest group of the cyclic acetal.
OR
2´
5
´
OR
4
2
Bn
methyl acrylate
toluene, 110 °C
4´
3´O
3
N
O
1
3
2N Bn
O
O
4
1
5
O
MeOOC
1a-c
3
,4´-erythro-3,5-cis
a-c
2
O
O
O
O
O
Key words: cycloadditions, nitrones, isoxazolidines, stereoselec-
tivity, heterocycles
OR
N
OR
O
OR
N
+
+
Bn
N
Bn
Bn
O
O
O
The nitrone-olefin 1,3-dipolar cycloaddition is a powerful
reaction in that it can create as many as three new contig-
uous stereogenic centres in a single step. Based on an
MeOOC
MeOOC
MeOOC
3
,4´-threo-3,5-cis
a-c
3,4´-erythro-3,5-trans
3,4´-threo-3,5-trans
1
3
4a-c
5a-c
evaluation of the nitrone cycloaddition, it was felt that the
stereochemistry of these new centers could be controlled
if the reaction system were properly designed. Regio-
and stereoselective nitrone cycloaddition, followed by re-
duction of the N-O bond to produce both an amino and a
HO
1
-5
R
H
N
2
,3
a
b
c
H
HO
OH
Ac
TBDMS
11
hydroxy function, allows the synthesis of many products
4
of potential interest. With our continuing efforts to utilize Scheme 1
5
chiral 1,3-dipolar cycloadditions, and with the goal of de-
veloping a simple route to the synthesis of polyhydroxy-
8
6
When, methyl acrylate was used instead of styrene, selec-
tivity decreased. Only 48% of major diastereomer 2a for
nitrone 1a (Table, entry 1) versus 81% in the case of sty-
lated derivatives of pyrrolizidines, which have been
7
shown to display antiviral activity, via an asymmetric
1
,3-dipolar cycloaddition we have recently published the
8
rene as dipolarophile was deemed unacceptable. The use-
preparation of new D-erythrose-1a and D-threose-6a de-
fulness of the chiral 1,3-dipolar cycloaddition depends on
the diastereoselectivity achieved, since the major diastere-
oisomers 2a will be used subsequently for the synthesis of
pyrrolizidines 11.11 In light of these differences; we un-
dertook a systematic study of the possibility to influence
the selectivity of the cycloaddition. Our objective was the
study of diastereoselectivity of cycloadditions stemming
from the nitrone part. In the case of the cycloadditions
with styrene we have found, that the stereoselectivity of
the cycloaddition was influenced by the steric hindrance
of both the N- and C-substituent of the nitrone, i.e. the se-
lectivity increases as the nitrogen substituent of the nitro-
rived nitrones and the stereoselectivity of their cycloaddi-
tions to styrene. We now report the stereoselectivity of
the cycloaddition of chiral sugar-derived nitrones 1a–c,
8
6
a and 6b with methyl acrylate.
The results are presented in the Table. In all cases the re-
actions were highly regiospecific, leading to the formation
of diastereomeric isoxazolidines 2–5 (Scheme 1) and 7–
1
0 (Scheme 2) as a mixture of three or four diastereoiso-
9
mers in a good overall yield. Purification by flash chro-
matography allowed the isolation of the pure major
diastereoisomers 2a–c, 7a and 7b, while the isolation and/
or characterization of minor isomers was possible only for
8
ne becomes bulkier. The best diastereoselectivity was
1
0
some of them.
achieved with the N-benzyl nitrones 1a and 6a. Therefore,
in addition to the parent chiral sugar-derived nitrones 1a
and 6a, the hydroxy group protected nitrones 1b, 1c and
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
437-2096,E;2001,0,12,1862,1865,ftx,en;D20201ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
1
©
6
b have also been prepared and used for the improvement
of the selectivity of the cycloaddition.

LETTER
Stereoselectivity of 1,3-Dipolar Cycloadditions of Derived Nitrones with Methyl Acrylate
1863
Table 1,3-Dipolar Cycloaddition of Nitrones 1a–c, 6a and 6b to Methyl Acrylate
Entry
Nitrone
1a
Yield (%)
erythro-cis
threo-cis
erythro-trans threo-trans
erythro: threo
77:23
cis:trans
1
2
3
4
5
85
77
82
68
65
48
73
87
62
96
18
3
29
24
6
5
-
66:34
76:24
92:8
1b
97:3
1c
5
2
8
-
93:7
6a
11
1
19
3
81:19
73:27
97:3
6b
99:1
1
´
6´
and 6a adopts the most favorable conformation around the
C-1 C-2 bond having dihedral angle between the protons
H-1 and H-2 close to 180°. From this point of view, the
front side attack of the dipolarophile leads to the erythro
isoxazolidines, while the backside approach to the threo
products (Scheme 3). As has been already mentioned, the
nitrone 1a imposes only the moderate selectivity in its re-
action with methyl acrylate (Table, entry 1). Conforma-
tional consideration indicates that an increase of the size
of the hydroxyl-protecting group resulted in an increase of
the induced stereoselectivity. The more bulky protection
of the free hydroxy group of the nitrone can effectively
hinder the approach of the alkene from the backside. The
front side attack is then favored and leads to the major
erythro-cis product 7a (Scheme 3). The results obtained
using -hydroxy protected nitrones 1b, 1c and 6b support
this hypothesis. Indeed, even the use of the acetyl protect-
ing group improves the selectivity of the nitrone 1b (Ta-
ble, entry 2). The strong preference for the erythro-cis
products 2c and 7b provided more sterically demanding
O-tert-butyldimethylsilyl group. The induced selectivity
increased from 77:23 to 93:7 and also the growth of the
simple selectivity was observed (66:34 versus 92:8) in the
cycloaddition of the nitrones 1a and 1c, respectively (en-
tries 1 and 3). These results concur with AM1 calculations
O
OR
2´
5
´
OR
4
2
Bn
methyl acrylate
4´
3
N
O
3´O
1
3
2N Bn
O
O
toluene, 110 °C
4
1
5
O
MeOOC
6
a,b
3
,4´-erythro-3,5-cis
7a,b
O
O
O
O
OR
OR
O
OR
N
O
N
O
Bn
+
+
N
Bn
Bn
O
O
MeOOC
MeOOC
MeOOC
3
,4´-threo-3,5-cis
a,b
3,4´-erythro-3,5-trans
3,4´-threo-3,5-trans
8
9a,b
10a,b
6
-10
R
a
b
H
TBDMS
Scheme 2
The regiochemistry of the cycloadducts 2–5 and 7–10
were readily deduced from resonance positions and spin
multiplicity of protons H-3, H-4 and H-5 and the relative
stereochemistry of these adducts was indicated from NOE
studies. The major adduct formed has the same configura-
12
of the rotation barrier. Activation energy of the possible
isomerization for the nitrone 1a has been calculated to be
1
0
3
6 kcal/mol, while for the silylated nitrone 1c it is 60 65
kcal/mol. The higher energy barrier in the O-protected ni-
trone 1c is fully in accord with the aforementioned higher
simple selectivity.
8
tion of stereogenic centres as with styrene meaning an
erythro relationship between the existing centre C-4’ on
the sugar moiety and the hydrogen at C-3, and 3,5-cis con-
figuration between isoxazolidine centres. While the con-
figuration on C-3 and C-5 was confirmed by NOE
measurement of cycloadducts, relationship between stere-
ocentres at C-3 and C-4’ was confirmed by conversion
into rigid pyrrolizidine 11. The cis relationship of sub-
stituents at C-3 and C-5 in 2a was assigned on the basis of
NOEDS. The composition of diastereoisomers was deter-
The analysis of the product configuration in D-threo ni-
trones 6a and 6b indicates that the major cycloadduct 7
arises from the cycloaddition that has occurred on the
more sterically accessible face of the nitrone (Scheme 3).
This conclusion, that steric factors are important for the
orientation of the nitrone, is also supported by the fact,
that cycloaddition of D-threo nitrone 6b proceeds with the
best anti-facial (99:1) and endo-facial (97:3) preference in
this series (entry 5, Table).
1
1
8
mined analogously to previously from peak integration
of C-4 in quantitative C NMR analysis.
1
3
The cycloadditions of nitrones are thus rationalized by
anti approach with respect to the alkyl group of the hetero-
cyclic acetal to afford the major erythro pair 7a, 9a. The
endo transition state results in the formation cis diastere-
oisomer 7a, while the exo transition state gives the corre-
Decline of the stereoselectivity in the cycloaddition of the
nitrones 1a and 6a with methyl acrylate compelled us to
focus on the nitrone reactive conformations, that can lead
to the prediction of this stereoselectivity. The MM2
1
2
calculations suggest that sugar moiety of D-nitrones 1a
Synlett 2001, No. 12, 1862–1865 ISSN 0936-5214 © Thieme Stuttgart · New York

1
864
J. Kubá et al.
LETTER
COOMe
(6) (a) Denmark, S. E.; Hurd, R. A.; Sacha, H. J. J. Org. Chem.
1997, 62, 1668. (b) McGaig, A. E.; Meldrum, K. P.;
OR
OR
Wightman, R. H. Tetrahedron 1998, 54, 9429. (c) Hall, A.;
Meldrum, K. P.; Therond, P. R.; Wightman, R. H. Synlett
1997, 123. (d) Müller, R.; Leibold, T.; Pätzel, M.; Jäger, V.
Angew. Chem., Int. Ed. Engl. 1994, 1295. (e) Broggini, G.;
Zecchi, G. Synthesis 1999, 905.
H
O
O
COOMe
≡
8
a,b
O
H
O
N
erythro-cis
N
Bn
Bn
O
6
a,b
O
(
7) (a) Taylor, D. L.; Nash, R.; Fellows, L. E.; Kang, M. S.;
Syms, A. S. Antiviral Chem. Chemother. 1992, 3, 273.
(b) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. V. J.
Tetrahedron: Asymmetry 2000, 11, 1645.
8) Kubán, J.; Blanáriková, I.; Fišera, L.; Jarošková, L.; Fengler-
Veith, M.; Jäger, V.; Kozíšek, J.; Humpa, O.; Langer, V.
Tetrahedron 1999, 55, 9501.
9) Typical experimental procedure: To a stirred solution of
nitrone (4.0 mmol) in toluene (12 mL) was added methyl
acrylate (4.6 mmol) and the reaction mixture was heated at
reflux for 4 h. The solvent was evaporated in a rotary
evaporator and the dark brown oil thus obtained was purified
by flash chromatography (silica gel, hexanes–ethyl acetate
90:10).
OR
MeOOC
O
O
O
H
O
7a,b
threo-cis
N
≡
Bn
N
H
(
(
O
O
Bn
MeOOC
RO
Scheme 3
sponding trans isomer 9a. On the other hand, the
corresponding syn orientation in the transition state is re-
sponsible for the formation of the threo products. The C–
COOMe functionalized isoxazolidine 2a represents sub-
unit with potential for the cleavage and recyclization to
form a pyrrolizidine 11. This opens a new route to the ste-
reocontrolled formation of polyhydroxysubtituted pyr-
rolizidines, which is described in the subsequent paper.11
(10) Selected data: Methyl (3S,5R,2’R,4’S,5’R)-2-N-benzyl-3-
5-hydroxy-2-methyl-1,3-dioxan-4-yl)isoxazolidine-5-
carboxylate (2a): Colorless solid, mp 118-120 °C; yield
(
1
4
3%; [ ] = –54.2 (CH Cl , c 0.21); H NMR (500 MHz,
D 2 2
CDCl ): = 7.36–7.31 (m, 5 H, NCH Ph), 5.17 (s, 1 H, OH),
3
2
4
.66 (dd, 1 H, J4b,5 = 8.8 Hz, J4a,5 = 8.7 Hz, H-5), 4.61 (q, 1
H, J2’,CH3 = 5.1 Hz, H-2’), 4.32 (d, 1 H, J = 12.4 Hz,
NCH Ph), 4.05 (dd, 1 H, J = 10.3 Hz, J5’,6’e = 4.7 Hz,
2
6’a,6’e
Acknowledgement
H-6’e), 3.82 (s, 3 H, COOCH ), 3.80 (d, 1 H, J = 12.4 Hz,
3
The authors are grateful to the Slovak Grant Agency (No. 1/7314/
NCH Ph), 3.51 (dd, 1 H, 3.33 J3,4’ = 9.5 Hz, J3,4a = 7.0 Hz,
2
2
0) and Volkswagen-Stiftung for financial support.
H-3), 3.33 (dd, 1 H, J6’a,6’e = 10.3 Hz, J5’,6’a = 10.1 Hz,
H-6’a), 3.28 (ddd, 1 H, J5’,6’a = 10.1 Hz, J4’,5’ = 8.2 Hz, J5’,6’e
=
4.7 Hz, H-5’), 3.14 (dd, 1 H, J3,4’ = 9.5 Hz, J4’,5’ = 8.2 Hz,
H-4’), 2.85 (dd, 1 H, J4a,4b = 13.3 Hz, J4b,5 = 8.8 Hz, H-4b),
.69 (ddd, 1 H, J4a,4b = 13.3 Hz, J4a,5 = 8.7 Hz, J = 7.0 Hz,
References
2
3,4a
(
1) (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley-Interscience: New York, 1984, Chap.
13
H-4a), 1.27 (d, 3 H, J2’,CH3 = 5.1 Hz, 2’-CH ); C NMR (125
MHz, CDCl3): = 172.7 (COOCH ), 135.4, 129.4, 128.8,
3
3
9, 83. (b) Gothelf, K. V.; Jorgensen, K. V. Chem. Rev. 1988,
128.2 (NCH Ph), 99.1 (C-2’), 77.7 (C-4’), 77.5 (C-5), 69.8
2
98, 863.
(
(
C-6’), 68.4 (C-3), 66.0 (C-5’), 62.4 (NCH Ph), 52.6
COOCH ), 33.3 (C-4), 20.4 (2’-CH ); C H NO (337.37)
2
(2) Frederickson, M. Tetrahedron 1997, 53, 403.
3
3
17 23
6
(
3) (a) Baggiolini, E. G.; Iacobelli, J. A.; Hennesy, B. M.;
Batcho, A. D.; Sereno, J. F.; Uskovic, M. R. J. Org. Chem.
calcd C 60.52, H 6.87, N 4.15; found: C 60.33, H 7.01, N
.24. Methyl (3S,5S,2’R,4’S,5’R)-2-N-benzyl-3-(5-
4
1
986, 51, 3098. (b) Brandi, A.; Cicchi, S.; Goti, A.;
Pietrusiewicz, K. M. Tetrahedron: Asymmetry 1991, 2,
063. (c) Saito, S.; Ishikawa, T.; Kishimoto, N.; Kohara, T.;
hydroxy-2-methyl-1,3-dioxan-4-yl)isoxazolidine-5-
carboxylate (4a): Colorless solid, mp 136-137 °C; yield
1
1
24%; [ ] = –26.3 (CH Cl , c 0.24); H NMR (300 MHz,
D
2
2
Moriwake, T. Synlett 1994, 282. (d) Kametani, T.; Chu, S.
D.; Honda, T. Heterocycles 1987, 25, 241. (e) Merino, P.;
Castillo, E.; Franco, S.; Merchan, F. L.; Tejero, T. J. Org.
Chem. 1998, 63, 2371. (f) Bernet, B.; Vasella, A. Helv.
Chim. Acta. 1979, 62, 2411.
CDCl ): = 7.40-7.28 (m, 5 H, NCH Ph), 5.00 (s, 1 H, OH),
3
2
4
1
.85 (dd, 1 H, J4b,5 = 10.0 Hz, J4a,5 = 5.6 Hz, H-5), 4.60 (q,
H, J2’,CH3 = 5.1 Hz, H-2’), 4.12 (d, 1 H, J = 12.4 Hz,
NCH Ph), 4.03 (dd, 1 H, J
H-6’e), 3.79 (s, 3 H, COOCH ), 3.77 (d, 1 H, J = 12.4 Hz,
NCH Ph), 3.45-3.27 (m, 4 H, H-3, H-4’, H-5’, H-6’a), 2.79
= 10.3 Hz, J5’,6’e = 4.7 Hz,
2
6’a,6’e
3
(4) (a) Torssell, K. B. G. Nitrile Oxides, Nitrones, and
Nitronates; VCH Publishers Inc.: New York, 1988.
2
(
1
dd, 1 H, J4a,4b = 13.6 Hz, J4b,5 = 10.0 Hz, H-4b), 2.64 (ddd,
H, J4a,4b = 13.6 Hz, J4a,5 = 5.6 Hz, J = 1.7 Hz, H-4a), 1.26
(
b) Grünanger, P.; Vita-Finzi, P. Isoxazoles. Part One., In
3,4a
The Chemistry of Heterocyclic Compounds; Taylor, E. C.;
Weissberger, E., Eds.; Wiley: New York, 1991.
13
(
d, 3 H, J2’,CH3 = 5.1, 2’-CH3); C NMR (75 MHz, CDCl ):
3
=
170.8 (COOCH ), 134.7, 129.2, 128.8, 128.2 (NCH Ph),
3 2
(
5) (a) Fišera, L.; Al-Timari, U. A. R.; Ertl, P. In Cycloadditions
in Carbohydrate Chemistry; ACS Monograph., American
Chemical Society: Washington, 1992, 158. (b) Al-Timari,
U. A. R.; Fišera, L.; Ertl, P.; Goljer, I.; Prónayová, N.
Monatsh. Chem. 1992, 123, 999. (c) Kubán, J.;
9
6
2
9.0 (C-2’), 78.3 (C-4’), 75.5 (C-5), 69.7 (C-6’), 67.6 (C-3),
6.1 (C-5’), 60.9 (NCH Ph), 52.5 (COOCH ), 33.6 (C-4),
0.4 (2’-CH ). Methyl (3S,5R,2’R,4’S,5’R)-2-N-benzyl-3-
2
3
3
(
5-acetoxy-2-methyl-1,3-dioxan-4-yl)isoxazolidine-5-
carboxylate (2b): Colorless solid, mp 74-75 °C; yield 62%;
[
Blanáriková, I.; Fišera, L.; Prónayová, N. Chem. Pap. 1997,
1
] = -37.1 (CH Cl , c 0.23); H NMR (300 MHz, CDCl ):
D 2 2 3
5
1, 378. (d) Kubán, J.; Blanáriková, I.; Fengler-Veith, M.;
Jäger, V.; Fiera, L. Chem. Pap. 1998, 52, 780.
e) Blanáriková, I.; Dugovi, B.; Fiera, L.; Hametner, C.
ARKIVOC 2001, 2, 1091.
=
7.43-7.36 (m, 5 H, NCH Ph), 4.71 (dd, 1 H, J = 8.3
2 4a,5
Hz, J4b,5 = 7.7 Hz, H-5), 4.66 (q, 1 H, J2’,CH3 = 5.1 Hz, H-2’),
.34 (d, 1 H, J = 12.4 Hz, NCH Ph), 4.00 (d, 1 H, J = 12.4
(
4
2
Hz, NCH Ph), 3.92 (dd, 1 H, J
= 10.1 Hz, J5’,6’e = 4.0 Hz,
2
6’a,6’e
H-6’e), 3.83 (s, 3 H, COOCH ), 3.61-3.43 (m, 3 H, H-3, H-
3
Synlett 2001, No. 12, 1862–1865 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Stereoselectivity of 1,3-Dipolar Cycloadditions of Derived Nitrones with Methyl Acrylate
1865
4’, H-5’), 3.34 (dd, 1 H, J6’a,6’e = 10.1 Hz, J5’,6’a = 9.0 Hz,
H-5’, H-6’a, H-6’e), 3.72 (s, 3 H, COOCH ), 3.69 (ddd, 1 H,
3
H-6’a), 2.94 (ddd, 1 H, J4a,4b = 12.1 Hz, J4b,5 = J3,4b = 7.7 Hz,
J3,4’ = 8.5 Hz, J3,4a = 7.8 Hz, J3,4b = 5.0 Hz, H-3), 2.94 (ddd,
1 H, J4a,4b = 13.1 Hz, J4b,5 = 8.6 Hz, J3,4b = 5.0 Hz, H-4b), 2.59
H-4b), 2.51 (ddd, 1 H, J4a,4b = 12.1 Hz, J4a,5 = 8.3 Hz, J3,4a
=
4
=
.1 Hz, H-4a), 1.79 (d, 3 H, OCOCH ), 1.37 (d, 3 H, J
(ddd, 1 H, J4a,4b = 13.1 Hz, J3,4a = J = 7.8 Hz, H-4a), 1.33
3
2’,CH3
4a,5
13
1
3
5.1, 2’-CH3); C NMR (75 MHz, CDCl ): = 172.6 and
(d, 3 H, J2’,CH3 = 5.1 Hz, 2’-CH ); C NMR (125 MHz,
3
3
1
70.0 (COOCH and OCOCH ), 136.4, 129.3, 128.6, 128.4
CDCl ): = 171.8 (COOCH ), 136.3, 129.4, 128.7, 127.9
3
3
3
3
(
NCH Ph), 98.7 (C-2’), 80.4 (C-4’), 77.3 (C-5), 70.9 (C-6’),
(NCH Ph), 99.3 (C-2’), 80.5 (C-4’), 78.2 (C-5), 71.9 (C-6'),
2
2
6
4.2 (C-3), 63.5 (C-5’), 61.8 (NCH Ph), 52.4 (COOCH ),
64.7 (C-3), 62.3 (C-5’), 60.8 (NCH Ph), 53.1 (COOCH ),
2
3
2
3
3
2.5 (C-4), 20.5 and 20.4 (2’-CH and OCOCH );
33.5 (C-4), 20.5 (2’-CH ); C H NO (337.37) calcd C
3
3
3
17 23
6
C H NO (379.41) calcd C 60.15, H 6.64, N 3.69; found: C
60.52, H 6.87, N 4.15; found: C 60.17, H 6.79, N 3.99.
19
25
7
59.87, H 6.23, N 3.95. Methyl (3S,5R,2’R,4’S,5’R)-2-N-
Methyl (3R,5S,2’S,4’R,5’R)-2-N-benzyl-3-(5-tert-
benzyl-3-(5-tert-butyldimethylsilyloxy-2-methyl-1,3-
dioxan-4-yl)isoxazolidine-5-carboxylate (2c): Colorless
solid, mp 66-68 °C; yield 78%; [ ] = -69.7 (CH Cl , c
butyldimethylsilyloxy-2-methyl-1,3-dioxan-4-yl)isoxazo-
lidine-5-carboxylate (7b): Colorless oil; yield 65%; [ ] =
D
1
+40.0 (CH Cl , c 0.19); H NMR (500 MHz, CDCl ):
=
D
2
2
2
2
3
1
0
.23); H NMR (300 MHz, CDCl ): = 7.32-7.14 (m, 5 H,
7.46-7.29 (m, 5 H, NCH Ph), 4.72 (dd, 1 H, J = 8.4 Hz,
3
2 4a,5
NCH Ph), 4.57-4.51 (m, 2 H, H-5, H-2’), 4.19 (d, 1 H, J =
J4b,5 = 7.8 Hz, H-5), 4.73 (q, 1 H, J2’,CH3 = 5.1 Hz, H-2’), 4.21
2
1
4
3
3.2 Hz, NCH Ph), 3.86 (dd, 1 H, J6’a,6’e = 10.2 Hz, J5’,6’e
=
(d, 1 H, JCH2a,CH2b = 13.2 Hz, NCH Ph), 4.06-4.04 (m, 2 H,
2
2
.5 Hz, H-6’e), 3.85 (d, 1 H, J = 13.2 Hz, NCH Ph), 3.68 (s,
H-6'e and NCH Ph), 3.78 (d, 1 H, J
= 12.1 Hz, H-6’a),
2
2
6’a,6’e
H, COOCH ), 3.43 (dd, 1 H, J = 8.1 Hz, J3,4b = 4.1 Hz,
3.79-3.77 (m, 1 H, H-5’), 3.76 (s, 3 H, COOCH ), 3.62 (ddd,
3
3,4a
3
H-3), 3.39-3.36 (m, 1 H, H-4’), 3.32 (ddd, 1 H, J4’,5’ = J5’,6’a
9.3 Hz, J5’,6’e = 4.5 Hz, H-5’), 3.19 (dd, 1 H, J6’a,6’e = 10.2
Hz, J5’,6’a = 9.3 Hz, H-6’a), 2.70 (dd, 1 H, J4a,4b = 12.3 Hz,
J4b,5 = 9.0 Hz, J3,4b = 4.1 Hz, H-4b), 2.64 (ddd, 1 H, J4a,4b
2.3 Hz, J3,4a = 8.1 Hz, J4a,5 = 7.3 Hz, H-4a), 1.21 (d, 3 H,
J2’,CH3 = 5.1 Hz, 2’-CH ), 0.67 (s, 9 H, OSiC(CH ) ), -0.01
1 H, J3,4’ = 8.7 Hz, J3,4b = 7.9 Hz, J3,4a = 4.9 Hz, H-3), 3.52
(d, 1 H, J3,4’ = 8.7 Hz, H-4’), 2.95 (ddd, 1 H, J4a,4b = 13.0 Hz,
J3,4b = 7.9 Hz, J4b,5 = 7.8 Hz, H-4b), 2.39 (s, 1 H, OH), 2.21
(ddd, 1 H, J4a,4b = 13.0 Hz, J4a,5 = 8.4 Hz, J3,4a = 4.9 Hz,
=
=
1
H-4a), 1.36 (d, 3 H, J2’,CH3 = 5.1 Hz, 2’-CH ), 0.92 (s, 9 H,
3
OSiC(CH ) ), 0.14 and 0.08 (2 s, 2 3 H, OSi(CH ) );
3
3 3
3 3
3 2
1
3
13
and -0.02 (2 s, 2 3 H, OSi(CH ) ); C NMR (75 MHz,
C NMR (125 MHz, CDCl ): = 171.7 (COOCH ), 137.1,
3
2
3
3
CDCl ): = 172.9 (COOCH ), 137.0, 129.1, 128.4, 127.4
128.9, 128.3, 127.4 (NCH Ph), 99.1 (C-2’), 78.8 (C-4’), 74.8
3
3
2
(
NCH Ph), 98.7 (C-2’), 82.3 (C-4’), 77.4 (C-5), 71.0 (C-6’),
(C-5), 71.4 (C-6’), 63.4 (C-3), 62.3 (C-5’), 60.7 (NCH Ph),
2
2
6
3.7 (C-3), 63.5 (C-5’), 63.0 (NCH Ph), 52.2 (COOCH ),
52.3 (COOCH ), 33.6 (C-4), 26.0 (OSiC(CH ) ), 21.0 (2’-
2
3
3
3 3
3
2.4 (C-4), 25.5 (OSiC(CH ) ), 20.4 (2’-CH ), 17.6
CH ), 17.3 (OSiC(CH ) ), -4.0 and -4.2 (OSi(CH ) ).
3
3
3
3 3 3 3 2
(
OSiC(CH ) ), -4.4 and -5.0 (OSi(CH ) ); C H NO Si
(11) Kubán, J.; Kolarovi , A.; Fišera, L.; Jäger, V.; Humpa, O.;
Prónayová, N. Synlett 2001, 1866.
3
3
3 2
23 37
6
(
451.63) calcd.: C 61.17, H 8.26, N 3.10; found: C 60.79, H
.23, N 3.17. Methyl (3R,5S,2’S,4’R,5’R)-2-N-benzyl-3-
5-hydroxy-2-methyl-1,3-dioxan-4-yl)isoxazolidine-5-
carboxylate (7a): Colorless solid, mp 87-88 °C; yield 47%;
8
(
(12) The quantum-chemical calculations (AM1 and MM2) were
carried out with MOPAC version 6 (on Silicon Graphics
Oxygen 2). Geometry optimization and calculation of
electronic parameters of reactants, products and transition
states was done by semi-empirical methods (AM1
parameters), in all cases using the PRECISE keyword.
Transition states were identified by performing force field
calculations.
1
[
] = +71.2 (CH Cl , c 0.26); H NMR (500 MHz, CDCl ):
D
2
2
3
=
7.48-7.37 (m, 5 H, NCH Ph), 4.70 (q, 1 H, J
= 5.1
2
2’,CH3
Hz, H-2’), 4.56 (dd, 1 H, J4b,5 = 8.6 Hz, J4a,5 = 7.8 Hz, H-5),
.25 (d, 1 H, JCH2a,CH2b = 13.2 Hz, NCH Ph), 4.01 (d, 1 H,
4
2
JCH2a,CH2b = 13.2 Hz, NCH Ph), 3.98-3.85 (m, 4 H, H-4’.
2
Synlett 2001, No. 12, 1862–1865 ISSN 0936-5214 © Thieme Stuttgart · New York