Design and synthesis of novel oxa-bridged isoxazolidines and 1,3-aminoalcohols

Article abstract of DOI:10.1016/j.tetlet.2005.03.021

An expedient intramolecular olefin-nitrone cycloaddition (INC) route is reported for the synthesis of a series of novel oxa-bridged isoxazolidines and 1,3-aminoalcohols starting from D-(+)-mannose-derived nitrones.

Full text of DOI:10.1016/j.tetlet.2005.03.021

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3037–3040
Design and synthesis of novel oxa-bridged isoxazolidines and
1,3-aminoalcohols
Krishna P. Kaliappan,* Prasanta Das and Nirmal Kumar
Department of Chemistry, Indian Institute of Technology—Bombay, Powai, Mumbai 400 076, India
Received 17 January 2005; revised 25 January 2005; accepted 3 March 2005
Available online 19 March 2005
Dedicated to Professor G. S. R. Subba Rao, Indian Institute of Science, Bangalore, India
Abstract—An expedient intramolecular olefin–nitrone cycloaddition (INC) route is reported for the synthesis of a series of novel
oxa-bridged isoxazolidines and 1,3-aminoalcohols starting from D-(+)-mannose-derived nitrones.
Ó 2005 Elsevier Ltd. All rights reserved.
Optically pure 1,2- and 1,3-aminoalcohols have found
wide applications as chiral ligands in asymmetric synthe-
sis.1 These ligands have primarily been used in enantio-
selective additions of dialkylzinc to a,b-unsaturated
ketones2 and for the enantioselective reduction of prochiral
ketones.1a,3 Though 1,2-aminoalcohols can be readily
obtained by the reduction of commercially available
naturally occurring amino acids, 1,3-aminoalcohols usu-
ally need to be generated from isoxazolidines by N–O
bond cleavage. There are many reports of the synthesis
of isoxazolidines from various olefinic aldehydes. These
isoxazolidines (obtained from 1,3-dipolar cycloaddition
reactions)4 have long been regarded as important key
intermediates for the synthesis of a wide variety of natural
and unnatural products, particularly alkaloids,5 amino
acids6 and amino sugars.7 The more demanding non-
racemic isoxazolidines can be prepared using chiral pool
derived precursors for intramolecular olefin–nitrone
cycloaddition.8 Sugar templates have also been used ele-
gantly in INC9 to generate enantiomerically pure hetero-
cycles such as tetrahydropyrans, pyrans and oxepanes.
new types of oxa-bridged bicyclic chiral 1,3-aminoalco-
hols and isoxazolidines. We chose D-(+)-mannose as a
suitable starting material as it has the appropriate
stereochemistry to provide the desired tricyclic isoxazol-
idines by INC (Scheme 1). In addition, the acetonide
group directs the formation of one of the possible diaste-
reomers and also offers an opportunity for temporarily
appending a range of noncarbohydrate ligands. To
the best of our knowledge, this is the first successful
approach to oxa-bridged tricyclic isoxazolidines via
intramolecular nitrone cycloaddition (INC) and to
their corresponding optically active chiral 1,3-
aminoalcohols.
According to our retrosynthetic analysis, as shown in
Scheme 2, the isoxazolidine 2, the key intermediate for
the 1,3-aminoalcohol, can be prepared from naturally
occurring, easily available and optically pure
D-(+)-mannose in a few steps.
Our synthesis (Scheme 3) starts with the addition of an
excess of vinylmagnesium bromide in THF to D-(+)-
mannose diacetonide 4 to afford a mixture of two diaste-
reomers 510 in 90% yield. Selective oxidation of this dia-
stereomeric allylic alcohol was carried out with MnO2 in
CH2Cl2 to provide an allylic ketone, which spontane-
ously underwent cyclization to give the lactol 6 in 92%
yield. Under mild acidic condition (PPTS in methanol),
O-methylation of the alcohol as well as deprotection of
more exposed 5,6-O-isopropylidene group was accom-
plished to afford the diol 7 in 88% yield. Though the lac-
tol 6 was obtained as a mixture of diastereomers, we
In view of the importance of 1,3-aminoalcohols in asym-
metric synthesis and in continuation of our interest in
utilizing carbohydrates in natural product synthesis,
we became interested in designing and synthesizing
Keywords: Sugars; INC; Isoxazolidines; Aminoalcohols; Asymmetric
synthesis.
*
Corresponding author. Tel.: +91 22 25767177; fax: +91 22 25723480;
e-mail: kpk@iitb.ac.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.021

3038
K. P. Kaliappan et al. / Tetrahedron Letters 46 (2005) 3037–3040
O
O
O
O
O
O
OH
D-(+)-Mannose
O
O
O
N
R
NH
R
1
2
Scheme 1.
O
O
O
O
O
O
O
O
O
O
OH
NH
R
O
O
D-(+)-Mannose
O
N
R
O
2
1
3
Scheme 2.
OH
O
HO
H
MeO
MeO
O
O
OH
OH
O
O
O
O
a
c
b
d
O
O
O
O
O
H
O
O
H
H
H
H
O
O
O
OH
O
O
O
O
OH
6
4
5
7
3
Scheme 3. Reagents and conditions: (a) CH2@CHMgBr, THF, 0 °C–rt, 12 h, 90%; (b) MnO2, CH2Cl2, rt, 12 h, 92%; (c) PPTS, MeOH, rt, 10 h, 88%;
(d) silica gel supported NaIO4, CH2Cl2, rt, 2 h, 87%.
were gratified to find that the methanolysis of 6 to 7 was
highly stereoselective as anticipated. The stereochemis-
try of the quaternary carbon was tentatively assigned
as shown in Scheme 3 since the OMe group is expected
to approach the substrate from the least hindered b-face.
The requisite aldehyde 3 for the key INC, was subse-
quently obtained by cleaving the diol 7 with silica gel
supported NaIO4 in 87% yield. The aldehyde 3, thus
obtained, was sufficiently pure to proceed to the next
step.
isoxazolidine 8a12 in 70% yield13 prompted us to proceed
to cleave the N–O bond and extend this route to a range
of novel isoxazolidines and 1,3-aminoalcohols. Though
there are several methods (reductive and oxidative cleav-
age)14 reported for the cleavage of N–O bonds, in our
hands, our acid sensitive isoxazolidines were reductively
cleaved by reacting with Mo(CO)615 and water to afford
1,3-aminoalcohols with complete retention of configur-
ation of the stereocentres (Scheme 4).
11
After successfully synthesizing chiral 1,3-aminoalcohol16
9a in diastereomerically pure form, we extended this
methodology to the synthesis of a series of N-substituted
isoxazolidines by using different N-arylhydroxylamines
followed by reductive cleavage to afford a range of
N-substituted chiral 1,3-aminoalcohols. In all cases,
the N-monosubstituted hydroxylamines were prepared17
by reduction of the corresponding substituted nitrobenz-
ene with zinc and ammonium chloride (Table 1).
With abundant quantities of aldehyde 3, we were suit-
ably placed for the execution of the key intramolecular
nitrone olefin cycloaddition reaction. To check the feasi-
bility of this key INC, initially an equimolar mixture of
aldehyde 3 and N-phenylhydroxylamine in toluene was
refluxed in the presence of a catalytic amount of dibutyl-
tin oxide (2 mol %) for several hours using a Dean–
Stark apparatus. The successful formation of the desired
O O
MeO
OH
O
O
O
O
a
O
b
O
O
O
O
NH
H
N
O
H
O
3
8a
9a
Scheme 4. Reagents and conditions: (a) PhNHOH, Bu2SnO, toluene, reflux, 4 h, 70%; (b) Mo(CO)6, CH3CN–H2O, reflux, 2–3 h, 85%.

K. P. Kaliappan et al. / Tetrahedron Letters 46 (2005) 3037–3040
3039
Table 1.
RNHOH
O O
O
O
O O
Bu2SnO
Mo(CO)6
O
O
OH
OMe
Toluene
CH3CN : H2O
O
O
O
O
O
reflux, 4 h
N
NH
R
R
3
8b-e
9b-e
Entry
R
Yield (%)
8
9
a
b
70
85
65
74
90
91
c
d
e
71
71
89
93
Cl
Cl
4. For reviews on 1,3-dipolar cycloadditions, see: (a) Goth-
elf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863–909;
(b) Gothelf, K. V.; Jorgensen, K. A. Chem. Commun.
2000, 1449–1458, and references cited therein.
5. (a) Schiehser, G. A.; White, J. D.; Matsumoto, G.;
Pezzanite, J. O.; Clardy, J. Tetrahedron Lett. 1986, 27,
5587–5590; (b) McCaig, A. E.; Wightman, R. H. Tetra-
hedron Lett. 1993, 34, 3939–3942; (c) Goti, A.; Cardona,
F.; Brandi, A.; Picasso, S.; Vogel, P. Tetrahedron: Asym-
metry 1996, 7, 1659–1674.
In conclusion, this paper illustrates the potential of com-
mercially available sugars as starting materials for the
synthesis of a wide range of tricyclic oxa-bridged chiral
isoxazolidines and bicyclic oxa-bridged chiral 1,3-
aminoalcohols via intramolecular nitrone cycloaddition
reactions. The utility of these aminoalcohols and isoxaz-
olidines in various asymmetric reactions is currently
being studied in our laboratory and the results will be re-
ported elsewhere.
6. (a) Kiers, D.; Moffat, D.; Overton, K. J. Chem. Soc.,
Chem. Commun. 1988, 654–655; (b) Kiers, D.; Moffat, D.;
Overton, K.; Tomanek, R. J. Chem. Soc., Perkin Trans. 1
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7. (a) Vasella, A.; Voeffray, R. J. Chem. Soc., Chem.
Commun. 1981, 97–98; (b) Vasella, A.; Voeffray, R. Helv.
Chim. Acta 1982, 65, 1134–1144.
8. (a) For intramolecular nitrone–olefin cyclizations, see:
Wade, P. A. Intramolecular 1,3-Dipolar Cycloadditions.
In Comprehensive Organic Synthesis; Trost, B. M., Flem-
ing, I., Eds.1991; Pergamon: Oxford; Vol. 4, p 1111; (b)
Frederickson, M. Tetrahedron 1997, 53, 403–425.
9. (a) Bhattacharjya, A.; Chattopadhyay, P.; McPhail, A. T.;
McPhail, D. R. (Corrigendum: J. Chem. Soc., Chem.
Commun. 1990, 1508–1509) (Corrigendum: J. Chem. Soc.,
Chem. Commun. 1991, 136); (b) Shing, T. K. M.; Fung,
W.-C.; Wong, C. H. J. Chem. Soc., Chem. Commun. 1994,
449–450.
Acknowledgements
We thank DAE. Young Scientist Research Grant from
BRNS, Mumbai for financial support. Two of us
(P.D. and N.K.) thank CSIR for fellowships. We also
thank SAIF, IIT—Bombay for providing spectroscopic
facilities.
References and notes
1. (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev.
1996, 96, 835–875; (b) Itsuno, S.; Watanabe, K.; Ito, K.;
El-Shehawy, A. A.; Sarhan, A. A. Angew. Chem., Int. Ed.
1997, 36, 109–110; (c) Shibata, T.; Takahashi, T.; Konishi,
T.; Soai, K. Angew. Chem., Int. Ed. 1997, 36, 2458–2460;
(d) Shibahara, S.; Kondo, S.; Maeda, K.; Umezawa, H.;
Ohno, M. J. Am. Chem. Soc. 1972, 94, 4353–4354; (e)
Knapp, S. Chem. Rev. 1995, 95, 1859–1876.
2. (a) de Oliveria, L. F.; Costa, V. E. U. Tetrahedron:
Asymmetry 2004, 15, 2583–2590; (b) Dimitrov, V.; Dobri-
kov, G.; Genov, M. Tetrahedron: Asymmetry 2001, 12,
1323–1329; (c) Cicchi, S.; Crea, S.; Goti, A.; Brandi, A.
Tetrahedron: Asymmetry 1997, 8, 293–301.
10. Boggelen, M. P.; Dommelen, B. F. G. A.; Jiang, S.; Singh,
G. Tetrahedron 1997, 53, 16897–16910.
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2622–2624.
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dron: Asymmetry 1995, 6, 1295–1300; (b) Walts, A. E.;
Roush, W. R. T. Tetrahedron 1985, 41, 3463–3478.
13. All compounds reported here were duly characterized.
Selected data: Compound 8a: Rf = 0.53 [ethyl acetate–
3. Li, X.; Yeung, C.-h.; Chan, A. S. C.; Yang, T.-K.
Tetrahedron: Asymmetry 1999, 10, 759–763.
25
hexanes (3:7)]; ½aꢀD +127.61 (c 1.05, CHCl3); IR (film)

3040
K. P. Kaliappan et al. / Tetrahedron Letters 46 (2005) 3037–3040
house, M. B.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1
1989, 2415–2424.
2930, 2859, 1596, 1489, 1382, 1265, 1200, 1158, 1092 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 7.32–7.25 (2H, m), 7.05–
6.93 (3H, m), 4.78–4.70 (2H, m), 4.55–4.51 (2H, m), 4.35
(1H, dd, J = 8.7, 3.3 Hz), 3.89 (1H, dd, J = 8.7, 7.8 Hz),
3.55 (3H, s), 3.49 (1H, dt, J = 7.2, 3.0 Hz), 1.55 (3H, s),
1.39 (3H, s); 13C NMR (75 MHz, CDCl3): d 150.6, 129.1,
121.8, 118.6, 114.7, 110.8, 78.2, 75.0, 68.1, 65.8, 52.8, 48.6,
26.0, 25.1; LRMS (EI) (M+Na)+ 342.1690; HRMS (EI)
calcd for C17H21NO5Na (M+Na)+ m/z 342.1317. Found
m/z 342.1315. Compound 8c: Rf = 0.40 [ethyl acetate–
15. Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; Sarlo, F. D.
Tetrahedron Lett. 1990, 31, 3351–3354.
16. All compounds reported here were duly characterized.
Selected data: Compound 9a: Rf = 0.64 [ethyl acetate–
25
hexanes (1:4)]; mp 139–141 °C; ½aꢀD +19.84 (c 1.26,
CHCl3); IR (KBr) 3541, 3400, 2920, 2859, 1600, 1508,
1382, 1266, 1200, 1091 cmꢁ1
;
1H NMR (300 MHz,
CDCl3): d 7.22–7.16 (2H, m), 6.74 (1H, t, J = 7.2 Hz),
6.67 (2H, d, J = 8.1 Hz) 4.73–4.65 (2H, m), 4.52 (1H, d,
J = 8.4 Hz), 4.17 (1H, d, J = 4.8 Hz), 4.00 (1H, dd,
J = 12.0, 4.5 Hz), 3.91 (1H, dd, J = 12.0, 3.6 Hz), 3.59
(3H, s), 2.99–2.94 (1H, m), 1.61 (3H, s), 1.39 (3H, s); 13C
NMR (75 MHz, CDCl3): d 129.5, 118.7, 118.3, 113.9,
112.1, 77.9, 77.6, 74.6, 59.3, 53.9, 52.8, 41.7, 26.1, 25.2.
Compound 9c: Rf = 0.56 [ethyl acetate–hexanes (1:4)]; mp
25
hexanes (1:4)]; ½aꢀD +122.77 (c 1.01, CHCl3); IR (film)
2925, 2859, 1609, 1449, 1366, 1258, 1200, 1158, 1092 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 7.19–7.14 (1H, m), 6.87
(1H, s), 6.83–6.76 (2H, m), 4.78–4.73 (2H, m), 4.54–4.50
(2H, m), 4.34 (1H, dd, J = 8.7, 3.3 Hz), 3.88 (1H, dd,
J = 8.7, 7.7 Hz), 3.55 (3H, s), 3.51–3.45 (1H, m), 2.33 (3H,
s), 1.55 (3H, s), 1.39 (3H, s); 13C NMR (75 MHz, CDCl3):
d 150.3, 139.1, 129.0, 123.0, 118.7, 115.5, 112.0, 110.8,
78.3, 78.1, 75.1, 68.1, 66.0, 52.8, 48.5, 26.0, 25.1, 21.7;
LRMS (EI) (M+Na)+ 356.1599; HRMS (EI) calcd for
C18H24NO5 (M+H)+ m/z 334.1654. Found m/z 334.1662.
Compound 8d: Rf = 0.60 [ethyl acetate–hexanes (1:4)];
25
164–165 °C; ½aꢀD +16.07 (c 1.12, CHCl3); IR (KBr) 3558,
3409, 2986, 2950, 2920, 2854, 1611, 1474, 1265, 1200,
1092 cmꢁ1 1H NMR (300 MHz, CDCl3): d 7.09 (1H, t,
;
J = 7.8 Hz), 6.60 (1H, d, J = 7.2 Hz), 6.54–6.51 (2H, m),
4.73–4.64 (2H, m), 4.50 (1H, d, J = 8.8 Hz), 4.17 (1H, dd,
J = 4.8, 1.2 Hz), 4.00 (1H, dd, J = 12.0, 4.5 Hz), 3.94 (1H,
dd, J = 12.3, 4.0 Hz), 3.60 (3H, s), 2.99–2.94 (1H, m), 2.28
(3H, s), 1.61 (3H, s), 1.39 (3H, s); 13C NMR (75 MHz,
CDCl3): d 139.4, 129.4, 119.6, 118.7, 115.2, 112.1, 111.0,
77.9, 77.6, 74.6, 59.4, 54.3, 52.8, 41.7, 29.8, 26.2, 25.2, 21.7.
Compound 9d: Rf = 0.33 [ethyl acetate–hexanes (1:4)]; mp
25
½aꢀD +123.01 (c 1.26, CHCl3); IR (film) 2920, 2859, 1585,
1
1493, 1377, 1258, 1159, 1097 cmꢁ1; H NMR (300 MHz,
CDCl3):
d 7.23 (2H, d, J = 9.0 Hz), 6.95 (2H, d,
J = 9.0 Hz), 4.77–4.69 (2H, m), 4.50–4.45 (2H, m), 4.34
(1H, dd, J = 8.7, 3.0 Hz), 3.86 (1H, dd, J = 8.7, 7.8 Hz),
3.55 (3H, s), 3.52–3.46 (1H, m), 1.55 (3H, s), 1.39 (3H, s);
13C NMR (75 MHz, CDCl3): d 149.1, 129.0, 127.0, 118.7,
116.0, 110.8, 78.2, 78.0, 75.0, 68.2, 66.0, 52.9, 48.6, 26.0,
25.1; LRMS (EI) (M+Na)+ 376.1233; HRMS (EI) calcd
for C17H21NO5Cl (M+H)+ m/z 354.1108. Found m/z
354.1113.
25
125–126 °C; ½aꢀD +16.83 (c 1.01, CHCl3); IR (KBr) 3562,
1
3409, 2920, 2859, 1598, 1505, 1265, 1097 cmꢁ1; H NMR
(300 MHz, CDCl3): d 7.16 (2H, d, J = 8.4 Hz), 6.66 (2H, d,
J = 8.4 Hz), 4.74–4.65 (2H, m), 4.46 (1H, d, J = 8.4 Hz),
4.16 (1H, d, J = 4.8 Hz), 4.05 (1H, dd, J = 12.0, 3.6 Hz),
3.94 (1H, dd, J = 12.0, 3.0 Hz), 3.6 (3H, s), 2.97–2.92 (1H,
m), 1.59 (3H, s), 1.39 (3H, s); 13C NMR (75 MHz, CDCl3):
d 144.5, 129.5, 123.7, 118.8, 115.5, 112.1, 74.5, 59.3, 54.9,
52.9, 41.5, 32.0, 29.8, 26.2, 25.2.
14. For hydrogenation with palladium on carbon, see: (a)
Ihara, M.; Takahashi, M.; Fukumoto, K.; Kametani, T. J.
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(e) Lathbury, D. C.; Shaw, R. W.; Bates, P. A.; Hurst-
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