Highly Stereoselective [3+2] Cycloadditions of Nitrile Oxides to Methyl 4-O-Acryloyl-6-deoxy-2,3-O-(t-butyldimethylsilyl)-α-D-glucopyranoside

Article abstract of DOI:10.1055/s-2003-41404

The [3+2] cycloadditions of benzonitrile oxide or pivalonitrile oxide to methyl 4-O-acryloyl-6-deoxy-2,3-di-O-(t-butyldimethylsilyl)-α -D-glucopyranoside provided the respective adducts, each as virtually a single diastereomer. By reductive removal of the

Full text of DOI:10.1055/s-2003-41404

LETTER
1865
Highly Stereoselective [3+2] Cycloadditions of Nitrile Oxides to Methyl 4-O-
Acryloyl-6-deoxy-2,3-O-(t-butyldimethylsilyl)-a-D-glucopyranoside
[3+2]
C
ycloadd
e
itions of
N
t
itrile
O
x
s
ide
s
to
a
u
D
-Glucose
D
o
erivative Tamai, Shingo Asano, Kiichiro Totani, Ken-ichi Takao, Kin-ichi Tadano*
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
Fax +81(45)5661571; E-mail: tadano@applc.keio.ac.jp
Received 26 June 2003
oxide was prepared by dehydrogenation of benzaldehyde
Abstract: The [3+2] cycloadditions of benzonitrile oxide or pivalo-
nitrile oxide to methyl 4-O-acryloyl-6-deoxy-2,3-di-O-(t-butyl-
dimethylsilyl)-a-D-glucopyranoside provided the respective
adducts, each as virtually a single diastereomer. By reductive
oxime with chloramine-T.4 The [3+2] cycloaddition
proceeded with high regio- and diastereoselectivity at
room temperature to provide the expected adduct 3R5,6 as
removal of the carbohydrate template from each adduct, the virtually a single adduct (dr = 99:1) in 96% yield.7,8 Anal-
respective (R)-enriched D2-isoxazoline derivative was obtained.
ogously, the [3+2] cycloaddition of 2 with pivalonitrile
oxide (CH2Cl2, r.t., 6 h) proceeded stereoselectively to
provide the adduct 4R9 (90%, dr = 99:1). The (R)-config-
uration for the newly introduced chiral carbon in both 3R
and 4R was assigned by comparison of the optical rota-
tions of the oxazoline methanols 5R10 and 6R11 derived
from 3R and 4R, respectively, with the known
compounds. Thus, removal of the carbohydrate template
from 3R or 4R was conducted by treatment with lithium
triethylborohydride to provide essentially enantiopure
(R)-3-phenyl-D2-isoxazoline-5-methanol (5R) or (R)-3-t-
butyl-D2-isoxazoline-5-methanol (6R). In both cases, the
chiral template 1 was recovered efficiently. The
enantiomeric homogeneity of 5R and 6R was further con-
firmed by chiral HPLC analysis of the methyl ether 7R12
and the benzoyl ester 8R13 prepared from 5R and 6R,
respectively.
Key words: asymmetric synthesis, [3+2] cycloadditions, nitrile
oxides, D-glucose, chiral auxiliary
The development of asymmetric synthesis for practical
access to chiral building blocks is one of the current topics
in organic synthesis. The design and preparation of
effective chiral auxiliaries using carbohydrates as tem-
plates is one of the promising approaches to this subject.1
We have studied the utility of chiral templates prepared
from a variety of hexopyranoside derivatives. Several
carbohydrate derivatives serve as good to excellent chiral
templates for providing chiral nonracemic building
blocks.2 Among the D-glucopyranoside-derived tem-
plates, methyl 6-deoxy-2,3-di-O-(t-butyldimethylsilyl)-a-
D-glucopyranoside (1) (Figure 1) serves as an extremely
effective chiral template for the diastereoselective a-alky-
lation of the 4-O-propionyl ester.2f In this letter, we report
highly diastereoselective [3+2] cycloadditions3 of nitrile
oxides to the 4-O-acryloyl derivative 2,2e which was pre-
pared from 1 (CH2=CHCOCl, Et3N, CH2Cl2, r.t., 2 h;
98%). As a result, two chiral D2-isoxazoline derivatives
were prepared in a highly enantioenriched form from the
respective cycloaddition products. These D2-isoxazolines
are expected to be versatile synthetic intermediates of
functionalized heterocyclic compounds and a-hydroxy-g-
carbonyl esters.3
O
O
R C N O
CH2Cl2, rt
O
O
Xc
Xc
O
O
N
N
2
3R, 4R
3S, 4S
R
R
3: R = Ph, 4: R = C(CH3)3
O
R
LiB(Et)3H
THF, rt
O
O
O
N
+
1
OH
N
TBSO
O
TBSO
R
OMe
5R : R = Ph (99%), 1 (98%)
6R : R = C(CH3)3 (89%), 1 (92%)
3R, 4R
O
C(CH3)3
Ph
BzCl, DMAP
CH2Cl2, rt
Xc
NaH, MeI
DMF, rt
O
O
HO
TBSO
O
TBSO
5R
6R
OMe
OBz
N
N
(80%)
(97%)
TBSO
TBSO
O
O
OMe
OMe
7R
8R
The carbohydrate template 1
2
Scheme 1
Figure 1
We explain the observed stereochemical outcome
adopting a plausible transition-state model as shown in
Scheme 2. In the present non-Lewis acid-mediated cyclo-
addition, the acryloyl part is apt to exist in s-cis
conformation.14 Then the nitrile oxide approaches from
the less-hindered side (from re-face at the a-carbon of the
First, we conducted the [3+2] cycloaddition of 2 using
benzonitrile oxide as a 1,3-dipole (Scheme 1). The nitrile
SYNLETT 2003, No. 12, pp 1865–1867
2
9
.0
9
.2
0
0
3
Advanced online publication: 28.08.2003
DOI: 10.1055/s-2003-41404; Art ID: U12303ST.pdf
© Georg Thieme Verlag Stuttgart · New York

1866
T. Tamai et al.
LETTER
2001, 481. (d) Totani, K.; Nagatsuka, T.; Yamaguchi, S.;
Takao, K.; Ohba, S.; Tadano, K. J. Org. Chem. 2001, 66,
5965. (e) Nagatsuka, T.; Yamaguchi, S.; Totani, K.; Takao,
K.; Tadano, K. J. Carbohydr. Chem. 2001, 20, 519.
(f) Totani, K.; Asano, S.; Takao, K.; Tadano, K. Synlett
2001, 1772.
R
C
N
O
O
3R or 4R
O
s-cis
O
O
Si
TBSO
(3) (a) For a recent review on [3+2] cycloadditions, see: Gothelf,
K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863. (b) For a
recent paper on the sugar-based stereoselective [3+2]
cycloadditions of nitrile oxide, see:Desroses, M.; Chéry, F.;
Tatibouët, A.; De Lucchi, O.; Rollin, P. Tetrahedron:
Asymmetry 2002, 13, 2535.
OMe
Scheme 2 A plausible transition-state mechanism for the [3+2] cy-
cloaddition
(4) (a) Hassner, A.; Rai, K. M. L. Synthesis 1989, 57. (b) Rai,
K. M. L.; Hassner, A. Indian J. Chem., Sect. B 1997, 36, 242.
(5) All new compounds gave spectroscopic data (1H, 13C NMR,
IR, and HRMS) in agreement with the structures depicted.
Yields refer to purified sample by chromatography on silica
gel.
(6) The [3+2] Cycloaddition of 2 using Benzonitrile Oxide in
CH2Cl2; Preparation of Methyl 6-deoxy-4-O-[(5R)-3-
phenyl-D2-isoxazoline-5-carbonyl]-2,3-di-O-t-
enoate moiety), thus avoiding the steric hindrance occur-
ring from the C-3 TBS group. As a result, the R adduct 3R
or 4R was obtained exclusively.
We considered that the presence of a bulky substituent at
C-2 is not necessary to realize the observed high stereo-
selectivity. Thus, we next explored the role of the C-2 sub-
stituent in the [3+2] cycloaddition using a new chiral
template 9. The template 9 was prepared from tri-O-
acetyl-D-glucal.15 The [3+2] cycloaddition of 9 with
benzonitrile oxide proceeded smoothly at room tempera-
ture (Scheme 3) to provide the cycloadduct with a lower
dr of 77:23 in favor of the formation of 10R.16 The new
stereogenic carbon in the major adduct 10R possessed the
same R-configuration as that of the cycloadduct 3R.
Owing to the significant loss of the stereoselectivity in the
case of 9, the presence of the C-2 bulky substituent is
important and has a complementary effect on the stereo-
selectivity in the [3+2] cycloaddition of 2.
butyldimethylsilyl-a-D-glucopyranoside (3R). To a cooled
(0 °C) stirred solution of 2 (211 mg, 0.459 mmol) in CH2Cl2
(4 mL) was added benzonitrile oxide (274 mg, 2.28 mmol).
The mixture was stirred at r.t. for 4 h, then diluted with
EtOAc (20 mL), and washed with sat. aq NH4Cl (10 mL
× 3). The organic layer was dried over anhyd Na2SO4 and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc–hexane = 1:40) to
give 262 mg (96%) of 3R as colorless oil. Compound 3R:
TLC, Rf 0.47 (EtOAc–hexane = 1:6); IR(neat): 3100–2800,
1750, 1600 cm–1; 1H NMR (300 MHz, CDCl3) d: 0.10, 0.11,
0.12 (total 12 H, 3s), 0.85, 0.93 (each 9 H, each s), 1.10 (3 H,
d, J = 6.6 Hz), 3.37 (3 H, s), 3.52 (1 H, dd, J = 11.2, 16.8 Hz),
3.67 (1 H, dd, J = 3.7, 9.2 Hz), 3.80 (1 H, dd, J = 6.3, 16.8
Hz), 3.83 (1 H, m), 4.01 (1 H, t, J = 9.2 Hz), 4.62 (1 H, d,
J = 3.7 Hz), 4.74 (1 H, dd, J = 9.2, 9.9 Hz), 5.14 (1 H, dd,
J = 6.3, 11.2 Hz), 7.40–7.70 (5 H, m); 13C NMR (75 MHz,
CDCl3) d: –4.49, –4.39, –3.39, –3.06, 17.32, 17.88, 18.41,
25.87 × 3, 26.12 × 3, 38.00, 54.92, 65.16, 71.62, 74.45,
78.12, 78.58, 100.06, 126.94 × 2, 128.77 × 2, 130.53 × 2,
156.37, 169.40; HRMS: m/z calcd for C28H46NO6Si2 (M+ –
OCH3): 548.2864, found 548.2872.
O
O
O
O
N
TBSO
O
10R
Ph C N O
Ph
CH2Cl2, rt, 4 h
O
O
O
O
TBSO
O
O
TBSO
N
9
10S
Ph
(7) The [3+2] cycloaddition was best achieved in CH2Cl2 (96%).
In benzene, the cycloaddition provided 3R in 92% yield, and
the dr of the adducts was 99:1.
Scheme 3
(8) We also conducted the Lewis acid (2 equiv)-mediated
cycloaddition of 2 with benzonitrile oxide. The results are as
follows: 1) BF3·OEt2/CH2Cl2/–78 °C/6 h (97% recovery of
2), 2) ZnI2/CH2Cl2/–78 °C/6 h (90% recovery of 2), 3)
Yb(OTf)3/CH2Cl2/–78 °C/6 h (27% of the adduct, dr = ca
6:1, 47% recovery of 2), 4) MgBr2/CH2Cl2/–78 °C to r.t./6 h
(49% of the adduct, dr = ca 7:1, 47% recovery of 2).
(9) Compound 4R: TLC, Rf 0.54 (EtOAc–hexane = 1:6);
IR(neat): 3100–2800, 1750, 1600 cm–1: 1H NMR (300 MHz,
CDCl3) d: 0.07, 0.09, 0.10 (total 12 H, 3s), 0.83, 0.92 (each
9 H, each s), 1.10 (3 H, d, J = 6.2 Hz), 1.22 (9 H, s), 3.14 (1
H, dd, J = 11.0, 16.9 Hz), 3.36 (3 H, s), 3.38 (1 H, dd, J = 5.9,
16.9 Hz), 3.65 (1 H, dd, J = 3.3, 9.2 Hz), 3.82 (1 H, dq, J =
6.2, 9.2 Hz), 3.98 (1 H, t, J = 9.2 Hz), 4.62 (1 H, d, J = 3.3
Hz), 4.70 (1 H, t, J = 9.2 Hz), 4.94 (1 H, dd, J = 5.9, 11.0 Hz);
13C NMR (75 MHz, CDCl3) d: –4.49, –4.43, –3.39, –3.06,
17.30, 17.86, 18.42, 25.86 × 3, 26.14 × 3, 28.05 × 3, 32.80,
37.54, 54.92, 65.19, 71.60, 74.45, 77.81, 77.89, 100.06,
165.83, 169.88; HRMS m/z calcd for C26H50NO6Si2 (M+ –
OCH3): 528.3177, found 528.3147.
In summary, we have found novel and highly diastereo-
selective [3+2] cycloadditions realized on a D-glucose-
derived chiral template. By removal of the chiral tem-
plates, essentially enantiopure chiral isoxazoline deriva-
tives are prepared.
References and Notes
(1) (a) Cintas, P. Tetrahedron 1991, 47, 6079. (b) Seyden-
Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; Wiley: New York, 1995. (c) Kunz, H. Angew.
Chem., Int. Ed. Engl. 1993, 32, 336. (d) Rück, K.; Kunz, H.
Chiral Auxiliaries in Cycloadditions; Wiley: New York,
1995. (e) Hultin, P. G.; Earle, M. A.; Sudharshan, M.
Tetrahedron 1997, 53, 14823.
(2) (a) Totani, K.; Nagatsuka, T.; Takao, K.; Ohba, S.; Tadano,
K. Org. Lett. 1999, 1, 1447. (b) Munakata, R.; Totani, K.;
Takao, K.; Tadano, K. Synlett 2000, 979. (c) Nagatuska, T.;
Yamaguchi, S.; Totani, K.; Takao, K.; Tadano, K. Synlett
Synlett 2003, No. 12, 1865–1867 © Thieme Stuttgart · New York

LETTER
[3+2] Cycloadditions of Nitrile Oxides to a D-Glucose Derivative
1867
(10) (a) Compound 5R: TLC, Rf 0.19 (EtOAc–hexane = 1:1);
IR(neat): 3500(br), 3100–2800 cm–1; [a]D22 –170 (c 1.01,
CHCl3); 1H NMR (300 MHz, CDCl3) d 3.28 (1 H, dd, J =
7.9, 16.5 Hz), 3.39 (1 H, dd, J = 10.4, 16.5 Hz), 3.68 (1 H,
dd, J = 4.3, 12.2 Hz), 3.87 (1 H, dd, J = 3.1, 12.2 Hz), 4.87
(1 H, dddd, J = 3.1, 4.3, 7.9, 10.4 Hz), 7.37–7.68 (5 H, m);
13C NMR (75 MHz, CDCl3) d: 36.29, 63.63, 81.21, 126.68 ×
2, 128.69 × 2, 130.17 × 2, 157.08; HRMS m/z calcd for
C10H11NO2 (M+): 177.0790, found 177.0790. (b) Curran and
co-workers reported the preparation of 5R from a 95:5
mixture of the [3+2] cycloaddition of the acryloyl amide of
Oppolzer’s chiral sultam with benzonitrile oxide. They
obtained the cycloadduct in a dr of 95:5, from which 5R
possessing [a]D25 –161 (c 1.0, CHCl3) was prepared: Curran,
D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron
Lett. 1988, 29, 3555. (c) On the other hand, Akiyama and
Ozaki reported the preparation of 5S, which relied on the
[3+2] cycloaddition of the acryloyl ester of optically active
cyclitol (L-chiro-inositol) with benzonitrile oxide. By this
chiral auxiliary-based methodology, they obtained a 95:5
mixture of the cycloadduct. From the major cycloadduct, 5S
possessing [a]D25 +172 (c 1.0, CHCl3) was prepared:
Akiyama, T.; Okada, K.; Ozaki, S. Tetrahedron Lett. 1992,
33, 5766.
6S (dr of the cycloadduct = 91:9) possessing [a]D20 +121 (c
1.68, CHCl3). See ref.10
(12) Retention times of racemic 7: tR(S) = 17.1 min and tR (R) =
19.7 min (DAICEL Chiralcel OD-H, 2-propanol–hexane =
1:8).
(13) Retention times of racemic 8: tR (S) = 22.0 min and tR (R) =
25.2 min (DAICEL Chiralcel OJ-H, 2-propanol–hexane =
1:15).
(14) Curran, D. P.; Kim, B. H.; Piyasena, H. P.; Loncharich, R. J.;
Houk, K. N. J. Org. Chem. 1987, 52, 2137.
(15) The new template 9 was prepared from known compound 11
as shown below (Scheme 4). Compound 11 was prepared
from tri-O-acetyl-D-glucal according to the reported
procedure:Giuliano, R. M.; Jordan, A. D.; Gauthier, A. D.;
Hoogsteen, K. J. Org. Chem. 1993, 58, 4979.
R
Ph
O
b)-d)
e)
O
O
HO
O
PO
TBSO
13: R = OH
14: R = OTs
15: R = I
11: P = H
12: P = TBS
a)
O
f)
O
O
HO
TBSO
O
TBSO
(11) Compound 6R: TLC, Rf 0.45 (EtOAc); IR(neat): 3480 (br),
3100–2800 cm–1: [a]D22 –120 (c 0.88, CHCl3); 1H NMR (300
MHz, CDCl3) d 1.21 (9 H, s), 2.88 (1 H, dd, J = 7.4, 16.7 Hz),
3.02 (1 H, dd, J = 10.4, 16.7 Hz), 3.55 (1 H, dd, J = 4.8, 12.0
Hz), 3.76 (1 H, m), 4.67 (1 H, dddd, J = 3.3, 4.8, 7.4, 10.4
Hz); 13C NMR (75 MHz, CDCl3) d: 3 × 28.03, 33.03, 35.69,
63.76, 80.09, 166.59; HRMS m/z calcd for C8H15NO2 (M+):
157.1103, found 157.1105. Curran and co-workers reported
16
9
Scheme 4 Reagent and conditions: a) NaH/TBSCl/THF, reflux (11
→ 12, 89%), b) H2/Pd(OH)2 on C/EtOH (12 → 13, 99%), c) TsCl/
Et3N/DMAP/CH2Cl2 (13 → 14, quant.), d) NaI/2-butanone, reflux
(14 → 15, 94%), e) Raney Ni W4/EtOH (15 → 16, 91%), f)
CH2=CHCOCl/Et3N/CH2Cl2 (16 → 9, 79%).
25
the preparation of both 6R and 6S (each er = 95:5; [a]D
–127 (c 1.0, CHCl3) for 6R and [a]D25 +124 (c 1.0, CHCl3)
for 6S by the chiral auxiliary methodology. Using the same
methodology, Akiyama and Ozaki obtained enantioenriched
(16) The dr of the cycloadduct 10 was precisely determined by
the chiral HPLC analysis after converting the adduct into the
isoxazoline derivative 7.
Synlett 2003, No. 12, 1865–1867 © Thieme Stuttgart · New York