β-Cyclodextrin as a scaffold for supramolecular chemistry, to reverse the regioselectivity of nitrile oxide cycloadditions

Article abstract of DOI:10.1021/jo9817321

β-Cyclodextrin has been used as a molecular scaffold, whereby tethering dipolarophiles to the cyclodextrin and then allowing preassociation of the modified cyclodextrins with aromatic nitrile oxides, as host-guest complexes, controls the relative orientations of the dipoles and the dipolarophiles in their cycloadditions. In this manner it has been possible to reverse the usual regioselectivity of cycloadditions of nitrile oxides, as illustrated by reactions with a terminal alkene, a terminal alkyne, and a 1,2-disubstituted alkene. For example, in aqueous solution, 4-tertbutylbenzonitrile oxide reacted with 6(A)-deoxy-6(A)-propynamido-β-cyclodextrin to give the corresponding 4- and 5-substituted isoxazoles, in a 15:1 ratio. With DMF as the solvent, to reduce the extent of host-guest complexation, the product ratio was 1:1.5. The role of complexation in these reactions is also demonstrated by contrasting these results with that of the reaction of the nitrile oxide with methyl propynoate, which afforded only the 5-substituted cycloaddition product. Molecular recognition by the cyclodextrin scaffolds was demonstrated through treatment of 4-tertbutylbenzonitrile oxide with an equimolar mixture of 6(A)-deoxy-6(A)-propynamido-β-cyclodextrin and methyl propynoate, in aqueous solution, which gave only the cycloadducts from reaction of the cyclodextrin dipolarophile.

Full text of DOI:10.1021/jo9817321

J . Org. Chem. 1998, 63, 9069-9075
9069
â-Cyclod extr in a s a Sca ffold for Su p r a m olecu la r Ch em istr y, To
Rever se th e Regioselectivity of Nitr ile Oxid e Cycloa d d ition s
†
,†
‡
§
Adam G. Meyer, Christopher J . Easton,* Stephen F. Lincoln, and Gregory W. Simpson
Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia,
Department of Chemistry, University of Adelaide, Adelaide, SA 5005, Australia, and CSIRO Molecular
Science, Private Bag 10, Clayton South MDC, Clayton, Vic 3169, Australia
Received August 24, 1998
â-Cyclodextrin has been used as a molecular scaffold, whereby tethering dipolarophiles to the
cyclodextrin and then allowing preassociation of the modified cyclodextrins with aromatic nitrile
oxides, as host-guest complexes, controls the relative orientations of the dipoles and the
dipolarophiles in their cycloadditions. In this manner it has been possible to reverse the usual
regioselectivity of cycloadditions of nitrile oxides, as illustrated by reactions with a terminal alkene,
a terminal alkyne, and a 1,2-disubstituted alkene. For example, in aqueous solution, 4-tert-
A
A
butylbenzonitrile oxide reacted with 6 -deoxy-6 -propynamido-â-cyclodextrin to give the corre-
sponding 4- and 5-substituted isoxazoles, in a 15:1 ratio. With DMF as the solvent, to reduce the
extent of host-guest complexation, the product ratio was 1:1.5. The role of complexation in these
reactions is also demonstrated by contrasting these results with that of the reaction of the nitrile
oxide with methyl propynoate, which afforded only the 5-substituted cycloaddition product.
Molecular recognition by the cyclodextrin scaffolds was demonstrated through treatment of 4-tert-
A
A
butylbenzonitrile oxide with an equimolar mixture of 6 -deoxy-6 -propynamido-â-cyclodextrin and
methyl propynoate, in aqueous solution, which gave only the cycloadducts from reaction of the
cyclodextrin dipolarophile.
8
In tr od u ction
such as Diels-Alder reactions and [2 + 2] photochemical
9
cycloadditions are also facilitated by CDs, by virtue of
Cyclodextrins (CDs) are cyclic oligosaccharides consist-
ing of R-1,4-linked D-(+)-glucopyranose units. They are
well-known to form host-guest or inclusion complexes
with a wide variety of hydrophobic species in aqueous
solutions1 and have shown potential for use in areas
aggregation of the starting materials within the CD
annuli, but suggestions that CDs control the regiochemi-
10
cal outcome of nitrile oxide cycloadditions have been
11
discounted.
Whereas the reactions reported to date
,2
have involved the self-assembly of reagents, our interest
in modified CDs is toward the controlled assembly of
starting materials to manipulate the outcome of chemical
2
,3
such as drug delivery and chromatographic separa-
tions.4 Furthermore, they have been found to enhance
the rates of organic transformations and control the
distribution of products. In this context, the CD annulus
serves as a reaction vessel and has been used in various
12
reactions.
(4) (a) Hinze, W. L.; Riehl, T. E.; Armstrong, D. W.; DeMond, W.;
5
,6
processes, including the saponification of esters and the
Alak, A.; Ward, T. Anal. Chem. 1985, 57, 237-242. (b) Armstrong, D.
W.; Ward, T. J .; Armstrong, R. D.; Beesley, T. E. Science 1986, 232,
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1
132-1135. (c) Szejtli, J .; Zsadon, B.; Cserhati, T. In Ordered Media
in Chemical Separations; Hinze, W. L., Armstrong, D. W., Eds.;
American Chemical Society: Washington, DC, 1987; pp 200-217. (d)
Menges, R. A.; Armstrong, D. W. In Chiral Separations by Liquid
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1992, 92, 1457-1470.
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5231-5234.
†
Australian National University.
University of Adelaide.
CSIRO Molecular Science.
‡
§
(1) (a) Bender, M. L.; Komiyama, M. Cyclodextrin Chemistry;
Springer-Verlag: Berlin, 1978. (b) Atwood, J . L., Davies, J . E. D.,
MacNicol, D. D., Eds.; Inclusion Compounds; Academic Press: London,
984; Vol. 3. (c) Duch eˆ ne, D., Ed.; Cyclodextrins and their Industrial
Uses; Editions de Sant e´ : Paris, 1987. (d) Clarke, R. J .; Coates, J . H.;
Lincoln, S. F. Adv. Carbohydr. Chem. Biochem. 1988, 46, 205-249.
e) Szejtli, J .; Osa, T. Cyclodextrins. In Comprehensive Supramolecular
1
(
Chemistry; Lehn, J .-M., Atwood, J . L., Davies, J . E. D., MacNicol, D.
D., V o¨ gtle, F., Eds.; Pergamon: New York, 1996; Vol. 3. (f) Easton, C.
J .; Lincoln, S. F. Chem. Soc. Rev. 1996, 25, 163-170. (g) For a summary
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1
357. (h) Lincoln, S. F.; Easton, C. J . In Structural Diversity and
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Dekker: New York, 1998; pp 473-511.
(2) (a) Szejtli, J . Cyclodextrins and their Inclusion Complexes;
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ogy; Kluwer Academic Publishers: Dordrecht, The Netherlands, 1988.
(3) (a) Szejtli, J . In Inclusion Compounds; Atwood, J . L., Davies, J .
E. D., MacNicol, D. D., Eds.; Academic Press: London, 1984; Vol. 3,
pp 349-368. (b) Duch eˆ ne, D., Ed.; New Trends in Cyclodextrins and
Derivatives; Editions de Sant e´ : Paris, 1991. (c) Duchene, D.; Wouessid-
jewe, D. J . Coord. Chem. 1992, 27, 223-236. (d) Easton, C. J .; Coates,
J . H.; Lincoln, S. F.; van Eyk, S. J .; Singh, P.; Williams, M. L.; Stile,
M. A. US Pat. 5 324 750 A, 1994.
1
0.1021/jo9817321 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/10/1998

9
070 J . Org. Chem., Vol. 63, No. 24, 1998
Meyer et al.
F igu r e 2. The relative orientation of the dipole and dipolaro-
phile in the host-guest complex.
F igu r e 1. Structure of â-CD and its representation as a
truncated cone.
Sch em e 2
Sch em e 1
Nitrile oxides (1,3-dipoles) undergo efficient [3 + 2]
cycloadditions with alkynes and alkenes (dipolarophiles),
to generate isoxazoles and 4,5-dihydroisoxazoles, respec-
tively.13 With unsymmetrical dipolarophiles there exists
the possibility of regioisomeric mixtures of products;
however, it is generally found that the regioselectivity is
determined by steric effects and the more encumbered
end of the dipolarophile becomes attached to the oxygen
of the nitrile oxide. For example, terminal alkynes and
alkenes afford almost exclusively 5-substituted isoxazoles
complex formed between the modified CD and an aro-
matic nitrile oxide was expected to predetermine the
relative orientation of reaction of those species (Figure
2). With terminal dipolarophiles it was anticipated that
this would result in a reversal of the usual regioselec-
tivity, with alkynes and alkenes giving 4-substituted
isoxazoles. Similarly, we aimed to control the regiose-
lectivity of cycloadditions involving 1,2-disubstituted
alkenes.
1
and dihydroisoxazoles 2, respectively (Scheme 1).
We envisaged that CDs could be used as molecular
scaffolds to control the assembly of reactants in nitrile
oxide cycloadditions.14 With the dipolarophile tethered
to â-cyclodextrin (â-CD) (3) (Figure 1), the host-guest
Resu lts
(
8) (a) Rideout, D. C.; Breslow, R. J . Am. Chem. Soc. 1980, 102,
7
1
816-7817. (b) Sternbach, D. D.; Rossana, D. M. J . Am. Chem. Soc.
The means used to tether dipolarophiles to â-CD (3)
982, 104, 5853-5854. (c) Schneider, H.-J .; Sangwan, N. K. J . Chem.
Soc., Chem. Commun. 1986, 1787-1789; Angew. Chem., Int. Ed. Engl.
1
Perkin Trans. 2 1989, 1223-1227. (e) Wernick, D. L.; Yazbek, A.; Levy,
J . J . Chem. Soc., Chem. Commun. 1990, 956-957. (f) Hunt, I.; J ohnson,
C. D. J . Chem. Soc., Perkin Trans. 2 1991, 1051-1056.
are shown in Scheme 2 and involved treatment of the
987, 26, 896-897. (d) Sangwan, N. K.; Schneider, H.-J . J . Chem. Soc.,
15
16
amino-substituted â-CD 4 with the acid chlorides 5
and 7a ,b, under basic aqueous conditions, to give the
corresponding amides 6 and 8a ,b, in yields of 71, 79, and
7%, respectively. 4-tert-Butylbenzonitrile oxide (11a ),
-phenylbenzonitrile oxide (11b), and benzonitrile oxide
(
9) For examples, see: (a) Tamaki, T.; Kokubu, T. J . Inclusion
7
4
Phenom. 1984, 2, 815-822. (b) Tamaki, T.; Kokubu, T.; Ichimura, K.
Tetrahedron 1987, 43, 1485-1494. (c) Moorthey, J . N.; Venkatesan,
K.; Weiss, R. G. J . Org. Chem. 1992, 57, 3292-3297. (d) Herrmann,
W.; Wehrle, S.; Wenz, G. J . Chem. Soc., Chem. Commun. 1997, 1709-
(11c) were selected as the dipoles, since benzene deriva-
tives are known to form thermodynamically stable inclu-
sion complexes with CDs.1 In particular, the nitrile oxide
11a was chosen because tert-butylbenzene derivatives are
1
710. (e) Nozaki, T.; Maeda, M.; Maeda, Y.; Kitano, H. J . Chem. Soc.,
Perkin Trans. 2 1997, 1217-1220. (f) Maafi, M.; Aaron, J .-J .; Lion, C.
J . Inclusion Phenom. 1998, 30, 227-241.
(10) (a) Rama Rao, K.; Bhanumathi, N.; Srinivasan, T. N.; Sattur,
17
known to form very stable CD inclusion complexes.
P. B. Tetrahedron Lett. 1990, 31, 899-902. (b) Rama Rao, K.;
Bhanumathi, N.; Sattur, P. B. Tetrahedron Lett. 1990, 31, 3201-3204.
However, it is not feasible to determine the equilibrium
constants for formation of the inclusion complexes of the
nitrile oxides 11a -c with the CDs 6 and 8a ,b since the
contributing species react with each other in the complex.
The nitrile oxides 11a -c were generated for the cycload-
ditions in situ, through reaction of triethylamine with
the hydroximinoyl chlorides 10a -c, which were prepared
from the appropriate aldehydes 9a -c by treatment with
(
c) Rama Rao, K. Pure Appl. Chem. 1992, 64, 1141-1145.
(
11) Easton, C. J .; Hughes, C. M. M.; Tiekink, E. R. T.; Savage, G.
P.; Simpson, G. W. Tetrahedron Lett. 1995, 36, 629-632.
12) Easton, C. J .; Harper, J . B.; Lincoln, S. F. New J . Chem. 1998,
2, in press.
13) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565-
98. (b) Bianchi, G.; Gandolfi, R.; Gr u¨ nanger P. In The Chemistry of
(
2
(
5
Functional Groups; Patai, S., Rappoport, Z., Eds.; J ohn Wiley & Sons:
New York, 1983; Suppl. C, Part 2, pp 752-773. (c) Caramella, P.;
Gr u¨ nanger P. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
J ohn Wiley & Sons: New York, 1984; Vol. 1, pp 291-392. (d)
Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410-416. (e) Torssell, K.
B. G. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis:
Novel Strategies in Synthesis; VCH Publishers: New York, 1988. (f)
Kanemasa, S.; Tsuge, O. Heterocycles 1990, 30, 719-736. (g) Easton,
C. J .; Hughes, C. M. M.; Savage, G. P.; Simpson, G. W. Adv. Heterocycl.
Chem. 1994, 60, 261-327.
(15) (a) Brown, S. E.; Coates, J . H.; Coghlan, D. R.; Easton, C. J .;
van Eyk, S. J .; J anowski, W.; Lepore, A.; Lincoln, S. F.; Luo, Y.; May,
B. L.; Schiesser, D. S.; Wang, P.; Williams, M. L. Aust. J . Chem. 1993,
46, 953-958. (b) Melton, L. D., Slessor, K. N. Carbohydr. Res. 1971,
18, 29-37.
(16) Balfour, W. J .; Greig, C. C.; Visaisouk, S. J . Org. Chem. 1974,
39, 725-726.
(17) Matsui, Y.; Nishioka, T.; Fujita, T. Top. Curr. Chem. 1985, 128,
61-89.
(
14) For a preliminary report of the reaction of compounds 8a and
1a , see: Meyer, A. G.; Easton, C. J .; Lincoln, S. F.; Simpson, G. W.
J . Chem. Soc., Chem. Commun. 1997, 1517-1518.
1

â-Cyclodextrin as a Scaffold
Sch em e 3
J . Org. Chem., Vol. 63, No. 24, 1998 9071
Sch em e 5
Sch em e 4
Ta ble 1. Resu lts of Rea ction s of th e CDs 6 a n d 8a ,b
w ith th e Nitr ile Oxid es 11a -c
nitrile
oxide
ratio of
regioisomers
yield
(%)
a
b
dipolarophile
solvent
6
6
6
6
6
6
8
8
8
8
8
8
11a
11a
11b
11b
11c
11c
11a
11a
11c
11c
11a
11a
H2O
DMF
H2O
DMF
H2O
DMF
H2O
DMF
H2O
DMF
H2O
DMF
12a :13a , 15:1
12a :13a , 1:1.5
12b:13b, 5:1
12b:13b, 1:5
12c:13c, 1:2
12c:13c, 1:10
14a :15a , 2.3:1
14a :15a , 1:4c
15b
71
86
100
93
100
87
100
87
97
82
100
64
c
a
a
a
a
b
b
15b
14c:15c, 3:1
14c:15c, 1:15
hydroxylamine hydrochloride and N-chlorosuccinimide
(
a
1
2
Determined through H NMR analysis (500 MHz, [ H6]DMSO)
Scheme 3).18 Cycloaddition reactions were conducted in
b
of the crude reaction mixtures. Total isolated yield of regioiso-
aqueous solution to allow host-guest dipolarophile-
dipole complexes to form. The role of the CD cavity was
investigated by repeating the cycloadditions in DMF
instead of water, since DMF generally reduces the
thermodynamic stability of CD host-guest complexes,19
and by comparing reactions of the CD dipolarophiles 6
and 8a ,b with those of methyl propynoate (16) and
propenamide (18).
mers. c Reference 14.
Sch em e 6
The results of the cycloaddition reactions of the CD
derivatives 6 and 8a ,b (Schemes 4 and 5) are sum-
marized in Table 1.14 The reactions of methyl propynoate
(
16) and propenamide (18) with the nitrile oxide 11a , in
either water or DMF, gave the 5-substituted isoxazoles
7 and 19, respectively (Scheme 6). Each of the cycload-
1
dition products 12a -c, 13a -c, 14a ,c, 15a -c, 17, and 19
was isolated as an individual component and fully
characterized. The isoxazoles 12a -c and 13a -c were
with typical literature values.20 The phenyl proton
resonances for the 4-substituted isoxazole 12a , at δ 7.58
and 7.47, were upfield relative to those of the regioisomer
1
most readily distinguished on the basis of their H NMR
spectra. The 4-substituted isoxazoles 12a -c showed
resonances for their C-5 protons at δ 9.27, 9.30, and 9.29,
respectively, while the 5-substituted regioisomers 13a -c
exhibited resonances for their C-4 protons at δ 7.58, 7.66,
and 7.61, respectively. These data are in good agreement
1
3a , at δ 7.82 and 7.54. This relative shielding of the
phenyl protons of the 4-substituted isoxazole 12a is
consistent with the inclusion of that aromatic group
21
within the â-CD cavity, as depicted in Scheme 4. The
substitution pattern of the isoxazoles 14a ,c and 15a -c
(
18) Liu, K.-C.; Shelton, B. R.; Howe, R. K. J . Org. Chem. 1980, 45,
1
was also determined on the basis of their H NMR
3
916-3918.
(
19) (a) Siegel, B.; Breslow, R. J . Am. Chem. Soc. 1975, 97, 6869-
6
3
4
870. (b) Eftink, M. R.; Harrison, J . C. Bioorg. Chem. 1981, 10, 388-
98. (c) Gerasimowicz, W. V.; Wojcik, J . F. Bioorg. Chem. 1982, 11,
20-427.
(20) Gr u¨ nanger, P.; Vita-Finzi, P. Isoxazoles: The Chemistry of
Heterocyclic Compounds; Taylor, E. C., Ed.; J ohn Wiley & Sons: New
York, 1991; Vol. 49, Part 1, pp 1-647.

9
072 J . Org. Chem., Vol. 63, No. 24, 1998
Meyer et al.
spectra. The isoxazoles 15a -c showed resonances for
their C-5 protons at δ 5.09, 5.10, and 5.14, respectively,
while the regioisomer 14a displayed a resonance for its
C-4 proton at ca. δ 4.40. Although the latter resonance
was masked by CD proton resonances in the 1D spec-
trum, it was readily identified using a 2D COSY experi-
conclusion is supported by the observation that changing
the solvent to DMF altered the product ratio by a factor
of 25, in favor of the 5-substituted isoxazole 13b. In
water, the effect of the CD annulus of the propynamide
6 is even less pronounced in the reaction with benzoni-
trile oxide (11c), which afforded the 4- and 5-substituted
regioisomers 12c and 13c in a ratio of 1:2. This indicates
a lower thermodynamic stability of the complex of the
1
1
ment, through a H- H correlation with the resonances
of the C-5 protons at δ 4.66 and 4.60. The chemical shift
values for the C-4 and C-5 protons of the isoxazoles 14a
and 15a -c, respectively, agree with those reported for
1
7
nitrile oxide 11c with the CD 6, as would be expected.
Even so, preassociation of the dipole 11c and the dipo-
larophile 6 must be a contributing factor in this reaction,
since the corresponding reaction in DMF shows an even
greater preference for production of the 5-substituted
regioisomer 13c.
2
0
analogous compounds. The acid 14c is probably pro-
duced through hydrolysis of the corresponding ester, due
to the proximity of CD hydroxyl groups.5 The C-4 proton
resonance of the isoxazole 14c is also masked by CD
proton resonances but there is no resonance in the range
δ 5.3-4.9 which would be expected for the C-5 proton of
the regioisomeric cycloadduct. The isoxazoles 14a ,c and
The effect of the CD 6, to reverse the usual regiose-
lectivity of reactions of nitrile oxides with terminal
alkynes, is substantially greater than that observed in
our preliminary work14 with the propenamido-â-CD 8a ,
which serves as an example of a terminal alkene.
Whereas the cycloaddition of the nitrile oxide 11a and
propenamide (18) in either water or DMF gave the
5-substituted isoxazoline 19, reaction of the CD 8a with
the nitrile oxide 11a gave mainly the 4-substituted
isoxazole 14a in water and mainly the 5-substituted
isoxazole 15a in DMF. Furthermore, benzonitrile oxide
(11c) reacted with the CD 8a to give only the 5-substi-
tuted isoxazole 15b in both water and DMF. Again, this
indicates the relatively low thermodynamic stability of
CD complexes of the dipole 11c.
The CD moiety differentiates the reactive centers of
the fumaric acid derivative 8b. In the reaction of the
dipolarophile 8b with 4-tert-butylbenzonitrile oxide (11a ),
in water it functions as a binding site to favor production
of the isoxazole 14c. By contrast, in the corresponding
reaction in DMF, it disfavors the formation of the
isoxazole 14c, presumably through a steric effect. The
regioisomer 15c is by far the predominant product in that
case. Similar steric effects would also be expected in the
reactions of the propynamide 6 and the propenamide 8a ,
where the bulk of the CD would disfavor formation of
the 4-substituted isoxazoles 12a -c and 14a . Therefore,
the extent to which these products form in the reactions
of the CDs 6 and 8a with the nitrile oxides 11a -c in
water is even more remarkable.
1
5a -c appear to be single compounds, on the basis of
their physical and spectroscopic properties, but they
probably exist as diastereomers. Presumably, there is
insufficient interaction between the chiral centers of the
substituents and those of the CD annuli for the diaster-
eomers to be distinguished. The 4-substituted isoxazoles
1
2a -c and 14a were readily soluble in water whereas
the 5-substituted regioisomers 13a -c and 15a dissolved
only sparingly. This difference is consistent with in-
tramolecular complexation of the phenyl substituent
within the annuli of the CDs 12a -c and 14a . The
isoxazoles 17 and 19 were also identified as 5-substituted
1
regioisomers on the basis of their H NMR spectra.
Discu ssion
The results shown in Table 1 establish that â-CD (3)
is an effective template to control the regioselectivity of
nitrile oxide cycloaddition reactions, as illustrated in
Figure 2. The effect is most clearly demonstrated in the
reactions of the propynamido-â-CD 6 with 4-tert-butyl-
benzonitrile oxide (11a ). In aqueous solution, the 4- and
5
-substituted isoxazoles 12a and 13a formed in a 15:1
ratio. The predominance of the 4-substituted regioisomer
2a can be attributed to the reaction of a preassociated
1
complex of the dipole 11a and the dipolarophile 6
because, when DMF was used instead of water as the
solvent, to reduce the extent of host-guest complexation,
the product ratio decreased to 1:1.5. It follows that the
small amount of the isoxazole 13a formed in the reaction
in water most probably results from noncomplexed nitrile
oxide 11a . The effect of the host-guest complex in these
reactions is also demonstrated by contrasting these
results with that of the reaction of the nitrile oxide 11a
with methyl propynoate (16), which afforded only the
Overall, the results shown in Table 1 demonstrate the
effect of the CD annulus, to control the regioselectivity
of nitrile oxide cycloadditions, through host-guest com-
plex formation as illustrated in Figure 2. It follows that
molecular recognition should occur between dipoles and
dipolarophiles by virtue of their ability to form host-
guest complexes. Accordingly, treatment of the nitrile
oxide 11a , in aqueous solution, with equimolar amounts
of the dipolarophiles 6 and 16, afforded only the cycload-
ducts 12a and 13a , from reaction of the CD 6.
5
-substituted cycloaddition product 17.
Cycloaddition of the propynamido-â-CD 6 with 4-phe-
nylbenzonitrile oxide (11b) in aqueous solution furnished
a 5:1 ratio of the 4- and 5-substituted isoxazoles 12b and
Con clu sion s
1
1
3b. This preference for the 4-substituted regioisomer
2b is less pronounced than that observed in the corre-
Earlier studies have demonstrated the use of CDs in
the self-assembly of reactants for cycloaddition reac-
tions.8 The results described above constitute controlled-
assembly of reactants through the use of â-CD (3) as a
molecular scaffold. They show it is possible to manipu-
late the regioselectivity of nitrile oxide cycloadditions
with terminal alkynes and alkenes, and 1,2-disubstituted
alkenes. This has been achieved by predetermining the
orientation of reaction of the dipoles and dipolarophiles,
sponding reaction of the nitrile oxide 11a ; however, it is
still an obvious effect of host-guest complexation. This
,9
(
21) (a) Lehmann, J .; Kleinpeter, E.; Krechl, J . J . Inclusion Phenom.
1
991, 10, 233-239. (b) For a review, see: Inoue, Y. Annu. Rep. NMR
Spectrosc. 1993, 27, 59-101. (b) Ndou, T. T.; Mukundan, S., J r.;
Warner, I. M. J . Inclusion Phenom. 1993, 15, 9-25. (c) Chen, Z.;
Bradshaw, J . S.; Yi, G.; Pyo, D.; Black, D. R.; Zimmerman, S. S.; Lee,
M. L.; Tong, W.; D’Souza, V. T. J . Org. Chem. 1996, 61, 8949-8955.

â-Cyclodextrin as a Scaffold
J . Org. Chem., Vol. 63, No. 24, 1998 9073
through appropriate design of their host-guest com-
plexes, and exemplifies the utility of CDs in the construc-
tion of templates to control the geometry of organic
transformations.
NO35‚6H
2
O: C, 41.70; H, 6.61; N, 1.08. Found: C, 41.59; H,
6
.30; N, 1.19.
A
A
(
E)-6 -Deoxy-6 -(3-eth oxyca r bon ylp r op en a m id o)-â-cy-
1
clod extr in (8b): yield 214 mg (77%); H NMR δ 8.43 (br s,
1
5
4
H, NH), 7.09 (d, J ) 15.0 Hz, 1H), 6.53 (d, J ) 15.0 Hz, 1H),
.81-5.68 (m, 14H), 4.87-4.81 (m, 7H), 4.54-4.44 (m, 6H),
.17 (q, J ) 5.5 Hz, 2H, OCH
CH
2
CH
3
), 3.72-3.28 (m, 42H), 1.23
Exp er im en ta l Section
1
3
(t, J ) 7.0 Hz, 3H, OCH
2
3
); C NMR δ 165.2 and 163.1
Gen er a l Meth od s. Proton nuclear magnetic resonance
(CdO), 137.5 (dCH), 128.4 (dCH), 102.2-101.7 (C-1), 83.4 and
1
3
81.6-81.4 (C-4), 73.0-72.0 and 69.3 (C-2, C-3, and C-5), 60.7
(
NMR) spectra were recorded at 500 MHz, and C NMR
2
(OCH CH ), 59.9-59.6 (C-6), 14.1 (OCH CH ); ESI-MS m/z
spectra were recorded at 75 MHz, using [ H
solvent and the internal reference.
6
]DMSO as the
C NMR spectra were
2
3
2
3
1
3
1259 (M ). Anal. Calcd for C H NO ‚5H O: C, 42.70; H,
+
48 77
37
2
assigned with the aid of attached proton test NMR experi-
ments. Electrospray ionization mass spectra (ESI-MS) were
measured at 120 eV unless otherwise specified. Microanalyses
were performed by the Australian National University Mi-
croanalytical Service. High-performance liquid chromatogra-
phy (HPLC) involved analysis with a differential refractometer
operating at 254 nm. Preparative HPLC was conducted using
a YMC ODS-AQ 250 × 10 mm column. Analytical HPLC was
performed on an Alltima C18 250 × 4.6 mm column, eluting
6.49; N, 1.04. Found: C, 42.73; H, 6.76; N, 0.74.
Gen er a l P r oced u r e for Rea ction s of th e CD Der iva -
tives 6 a n d 8a ,b w ith th e Nitr ile Oxid es 11a -c in
Aqu eou s Solu tion . To a rapidly stirred solution of the CD
derivative 6 or 8a ,b (0.04 mmol) in water (3 cm ) was added
the appropriate hydroximinoyl chloride 10a ,b, or c (0.16
mmol), and the mixture was allowed to stir at ambient
3
temperature for 1 h. NEt (0.17 mmol) was then added, and
the mixture was stirred for a further 15 h. It was then diluted
with aqueous EtOH (20% v/v, 10 cm ) and washed with EtOAc
3
3
-1
3
at 0.9 cm min with acetonitrile/water (10% v/v). The t
R
of
3
a CD derivative indicates its retention time relative to that of
â-CD (3). Compounds were recrystallized from water. Thin-
layer chromatography was performed on alumina plates coated
with Merck silica gel 60 F254. Flash column chromatography22
was carried out on Merck silica gel 60 (230-440 mesh).
Melting points were performed on a hot-stage apparatus and
are uncorrected. Water was purified using a Waters Millipore
filtration system. Petroleum ether refers to that fraction
(3 × 15 cm ). The solvent was removed in vacuo to give a fine
colorless powder.
Gen er a l P r oced u r e for Rea ction s of th e CD Der iva -
tives 6 a n d 8a ,b w ith th e Nitr ile Oxid es 11a -c in DMF .
To a solution of the CD derivative 6 or 8a ,b (0.04 mmol) in
DMF (1.5 cm ) was added the appropriate hydroximinoyl
3
chloride 10a ,b, or c (0.045 mmol) and NEt (0.045 mmol), and
3
the solution was allowed to stir at ambient temperature for
15 h. It was then poured into acetone (50 cm ), and the
3
boiling between 40 and 60 °C. DMF was dried over CaH
2
and
then distilled and stored over 4 Å molecular sieves prior to
use. Commercially available compounds were used as re-
precipitate which formed was collected by centrifugation (4000
rpm, 5 min) and isolated as a fine colorless powder.
A
A
ceived. (E)-3-Ethoxycarbonylpropenoyl chloride (7b) was pre-
N-(6 -Deoxy-â-cyclod extr in -6 -yl)-4-(a m in oca r bon yl)-
3-(4-ter t-bu tylp h en yl)isoxa zole (12a ). The title compound
was prepared as a 15:1 mixture with the regioisomer 13a , in
71% yield, as described above from reaction of the CD 6 with
the nitrile oxide 11a in aqueous solution. It was isolated by
A
pared from fumaric acid monoethyl ester using SOCl
2
.
6 -
A
15
Amino-6 -deoxy-â-cyclodextrin (4) and propynoyl chloride
1
6
(
5) were prepared as reported.
Gen er a l P r oced u r e for P r ep a r a tion of th e CD Der iva -
3
-3
HPLC (acetonitrile/water, 10% v/v) and had the following:
tives 6 a n d 8a ,b. Aqueous NaOH (0.24 cm , 1 mol dm , 0.24
1
A
A
HPLC t
R
) 2.7; H NMR δ 9.27 [s, 1H, isoxazole C(5)-H], 7.98
mmol) was added to an ice-cooled solution of 6 -amino-6 -
deoxy-â-cyclodextrin (4) (250 mg, 0.22 mmol) in water (10 cm ).
3
(m, 1H, NH), 7.58 (d, 2H, J ) 8.0 Hz, PhH), 7.47 (d, 2H, J )
8
4
.0 Hz, PhH), 5.86-5.66 (m, 14H), 4.90-4.80 (m, 7H), 4.57-
The relevant acid chloride 5 or 7a ,b (0.24 mmol) was then
added, and the mixture was stirred vigorously for 2 h at 0 °C.
It was then allowed to warm to ambient temperature and
stirred at that temperature overnight. The mixture was then
13
.13 (m, 6H), 3.68-3.26 (m, 42H), 1.32 (s, 9H, t-Bu); C NMR
δ 160.7 (quaternary), 160.6 (isoxazole C-5), 159.4 and 152.7
(quaternary), 128.1 and 125.3 (methine, Ph), 124.8 (quater-
3
nary, Ph), 116.1 (isoxazole C-4), 102.2-101.8 (CD C-1), 83.7
and 81.7-81.3 (CD C-4), 73.1-72.0 and 70.2 (CD C-2, C-3, and
C-5), 60.0-59.8 (CD C-6), 34.6 (quaternary, t-Bu), 31.1 (methyl,
poured into acetone (75 cm ), and the precipitate which formed
was collected by centrifugation (4000 rpm, 5 min). This
3
material was dissolved in water (5 cm ) and the solution was
+
+
t-Bu); ESI-MS (50 eV) m/z 1360 (M ). Anal. Calcd for
passed through a column of Bio-Rex 70 ion-exchange resin (H
3
C
56
H
84
N
2
O
36‚8H
2
O: C, 44.68; H, 6.70; N, 1.86. Found: C,
form) by eluting with water (300 cm ). The eluant was recycled
4
4.40; H, 6.98; N, 1.81.
N-(6 -Deoxy-â-cyclod extr in -6 -yl)-4-(a m in oca r bon yl)-
through the column a further eight times in order to remove
A
A
A
A
6
-amino-6 -deoxy-â-cyclodextrin (4). The column was then
3
3-(4-bip h en yl)isoxa zole (12b). The title compound was
prepared as a 5:1 mixture with the regioisomer 13b, in 100%
yield, as described above from reaction of the CD 6 with the
nitrile oxide 11b in aqueous solution. It was isolated by HPLC
rinsed with water (300 cm ), and the combined eluants were
concentrated in vacuo, to give the amide 6 or 8a ,b, as a fine
colorless powder.
6A-Deoxy-6A-p r op yn a m id o-â-cyclod extr in (6): yield 184
(
acetonitrile/water, 12% v/v) and had the following: HPLC t
R
2.8; H NMR δ 9.30 [s, 1H, isoxazole C(5)], 8.42 (m, 1H, NH),
1
mg (71%); HPLC t ) 1.1; H NMR δ 8.56 (m, 1H, NH), 5.83-
R
1
)
5
3
8
6
1
6
.64 (m, 14H), 4.88-4.78 (m, 7H), 4.50-4.38 (m, 6H), 3.68-
13
7.83 (d, J ) 8.5 Hz, 2H, PhH), 7.76 (d, J ) 8.5 Hz, 2H, PhH),
.15 (m, 43H); C NMR δ 151.9 (CdO), 102.2-101.6 (C-1),
3.8 and 81.7-81.2 (C-4), 78.2 and 75.6 (CtC), 73.0-72.0 and
7
7
.72 (d, J ) 7.0 Hz, 2H, PhH), 7.49 (t, J ) 7.5 Hz, 2H, PhH),
.40 (m, 1H, PhH), 5.89-5.69 (m, 14H), 4.92-4.80 (m, 7H),
9.5 (C-2, C-3, and C-5), 59.9-59.5 (C-6); ESI-MS (50 eV) m/z
1
3
+
4.63-4.45 (m, 6H), 3.75-3.29 (m, 42H); C NMR δ 161.0
185 (M ). Anal. Calcd for C45
H
2
71NO35‚8H O: C, 40.63; H,
(
1
isoxazole C-5), 160.9, 159.4, 141.8 and 139.4 (quaternary),
29.2, 129.1, 128.0 and 126.9 (methine, Ph), 126.9 (quaternary,
Ph), 115.9 (isoxazole C-4), 102.5-101.8 (CD C-1), 83.6 and
1.9-81.4 (CD C-4), 73.1-72.1 and 69.8 (CD C-2, C-3, and
.59; N, 1.05. Found: C, 40.82; H, 6.29; N, 1.38.
6A-Deoxy-6 -pr open am ido-â-cyclodextr in (8a): yield 207
A
1
mg (79%); HPLC t
R
) 1.2; H NMR δ 7.95 (m, 1H, NH), 6.26
8
(
5
4
dd, J ) 17.5, 11.0 Hz, 1H), 6.03 (d, J ) 17.5 Hz, 1H), 5.83-
+
C-5), 60.2-59.8 (CD C-6); ESI-MS m/z 1403 (M + Na ). Anal.
Calcd for C58 O: C, 47.93; H, 6.10; N, 1.93.
Found: C, 47.83; H, 5.99; N, 1.93.
.64 (m, 14H), 5.55 (d, J ) 11.0 Hz, 1H), 4.87-4.81 (m, 7H),
H
80
N
2
O
36‚4H
2
.50-4.44 (m, 6H), 3.78-3.15 (m, 42H); 13C NMR δ 164.8 (Cd
O), 131.6 (dCH
2
), 125.1 (dCH), 102.2-101.5 (C-1), 83.8 and
A
A
N-(6 -Deoxy-â-cyclod extr in -6 -yl)-4-(a m in oca r bon yl)-
-p h en ylisoxa zole (12c). The title compound was prepared
8
5
1.7-81.1 (C-4), 73.2-71.9 and 69.6 (C-2, C-3, and C-5), 59.9-
9.5 (C-6); ESI-MS m/z 1187 (M ). Anal. Calcd for C45
3
+
73
H -
as a 1:2 mixture with the regioisomer 13c, in 100% yield, as
described above from reaction of the CD 6 with the nitrile oxide
1
1c in aqueous solution. It was isolated by HPLC (acetonitrile/
(
22) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
1
2
925.
R
water, 10% v/v) and had the following: HPLC t ) 5.1; H

9
074 J . Org. Chem., Vol. 63, No. 24, 1998
Meyer et al.
+
NMR δ 9.29 [s, 1H, isoxazole C(5)-H], 8.41 (m, 1H, NH), 7.70
m, 2H, PhH), 7.46 (m, 3H, PhH), 5.85-5.69 (m, 14H), 4.89-
.80 (m, 7H), 4.56-4.44 (m, 6H), 3.81-3.29 (m, 42H); 13C NMR
δ 160.9 (isoxazole C-5), 160.7 and 159.8 (quaternary), 130.0,
28.6 and 128.5 (methine, Ph), 127.8 (quaternary, Ph), 115.7
isoxazole C-4), 102.4-101.8 (CD C-1), 83.8 and 81.8-81.3 (CD
C-4), 73.0-72.0 and 69.8 (CD C-2, C-3, and C-5) 60.1-59.7
t-Bu); ESI-MS m/z 1385 (M + Na ). Anal. Calcd for
O: C, 45.16; H, 6.77; N, 1.88. Found: C,
45.38; H, 6.68; N, 1.49.
(
4
C
56
H
86
N
2
O
36‚7H
2
A
A
tr a n s-N-(6 -Deoxy-â-cyclod ext r in -6 -yl)-4-(a m in oca r -
bon yl)-3-(4-ter t-bu tylp h en yl)-4,5-d ih yd r oisoxa zole-5-ca r -
boxylic a cid (14c). The title compound was prepared as a
3:1 mixture with the regioisomer 15c, in 100% yield, as
described above from reaction of the CD 8b with the nitrile
oxide 11a in aqueous solution. It was isolated by HPLC
1
(
+
(
CD C-6); ESI-MS m/z 1327 (M + Na ). Anal. Calcd for
O: C, 45.95; H, 6.08; N, 2.06. Found: C,
6.19; H, 5.85; N, 2.12.
C
4
52
H
76
N
2
O
36‚3H
2
(acetonitrile/water, 10% v/v) and had the following: HPLC t
R
A
A
1
N-(6 -Deoxy-â-cyclod extr in -6 -yl)-5-(a m in oca r bon yl)-
) 1.0; H NMR δ 8.27 (br s, 1H, NH), 7.47 (d, 2H, J ) 8.0 Hz,
PhH), 7.37 (d, 2H, J ) 8.0 Hz, PhH), 5.88-5.64 (m, 15H),
4.92-4.53 (m, 15H), 3.69-3.12 (m, 42 H) 1.27 (s, 9H, t-Bu);
3
-(4-ter t-bu tylp h en yl)isoxa zole (13a ). The title compound
was prepared as a 1.5:1 mixture with the regioisomer 12a , in
6% yield, as described above from reaction of the CD 6 with
the nitrile oxide 11a in DMF. It was isolated by recrystalli-
1
3
8
C NMR δ 170.9 and 168.2 (CdO), 155.1 and 153.1 (quater-
nary), 126.8 and 125.4 (methine, Ph), 125.1 (quaternary, Ph),
102.5-101.6 (CD C-1), 83.1 and 81.8-81.3 (CD C-4), 82.7
(isoxazole C-5), 73.3-71.9 and 70.2 (CD C-2, C-3, and C-5),
60.4-59.7 (CD C-6), 58.3 (isoxazole C-4), 34.7 (quaternary,
1
zation and had the following: HPLC t
(
R
) 1.1; H NMR δ 8.76
m, 1H, NH), 7.82 (d, 2H, J ) 8.5 Hz, PhH), 7.58 [s, 1H,
isoxazole C(4)-H], 7.54 (d, 2H, J ) 8.5 Hz, PhH), 5.88-5.70
+
(
(
m, 14H), 4.95-4.77 (m, 7H), 4.53-4.35 (m, 6H), 3.84-3.26
t-Bu), 31.2 (methyl, t-Bu); ESI-MS (90 eV) m/z 1406 (M ). Anal.
1
3
m, 42H), 1.31 (s, 9H, t-Bu); C NMR δ 164.0, 162.2, 155.9
Calcd for C57
H
86
N
2
O
2
38‚8H O: C, 44.13; H, 6.63; N, 1.81.
and 153.3 (quaternary), 126.5 and 126.0 (methine, Ph), 125.1
quaternary, Ph), 104.4 (isoxazole C-4), 102.4-101.6 (CD C-1),
4.3 and 81.5-81.3 (CD C-4), 73.1-72.0 and 69.7 (CD C-2, C-3,
and C-5), 60.0-59.3 (CD C-6), 34.7 (quaternary, t-Bu), 31.1
Found: C, 44.14; H, 6.77; N, 1.75.
A
A
(
8
N-(6 -Deoxy-â-cyclod extr in -6 -yl)-5-(a m in oca r bon yl)-
3-(4-ter t-bu tylp h en yl)-4,5-d ih yd r oisoxa zole (15a ). The
title compound was prepared as a 4:1 mixture with the
regioisomer 14a , in 87% yield, as described above from reaction
of the CD 8a with the nitrile oxide 11a in DMF. It was
+
(
methyl, t-Bu); ESI-MS (50 eV) m/z 1383 (M + Na ). Anal.
Calcd for C56 O: C, 44.15; H, 6.74; N, 1.83.
Found: C, 44.00; H, 6.63; N, 1.59.
H
84
N
2
O
36‚9H
2
isolated by recrystallization and had the following: HPLC t
R
A
A
1
N-(6 -Deoxy-â-cyclod extr in -6 -yl)-5-(a m in oca r bon yl)-
-(4-bip h en yl)isoxa zole (13b). The title compound was
) 1.3; H NMR δ 7.93 (m, 1H, NH), 7.61 (d, 2H, J ) 8.5 Hz,
PhH), 7.47 (d, 2H, J ) 8.5 Hz, PhH), 5.84-5.68 (m, 14H), 5.09
[m, 1H, isoxazole C(5)-H], 4.89-4.81 (m, 7H), 4.74-4.34 (m,
6H), 3.86-3.14 (m, 44 H) 1.29 (s, 9H, t-Bu); 13C NMR δ 169.7,
156.4 and 153.2 (quaternary), 126.7 and 125.7 (methine, Ph),
125.9 (quaternary, Ph), 102.3-101.8 (CD C-1), 83.8 and 81.6-
81.4 (CD C-4), 78.9 (isoxazole C-5), 73.0-72.0 and 69.8 (CD
C-2, C-3, and C-5), 59.8-60.3 (CD C-6), 34.7 (quaternary, t-Bu),
3
prepared as a 5:1 mixture with the regioisomer 12b, in 93%
yield, as described above from reaction of the CD 6 with the
nitrile oxide 11b in DMF. It was isolated by recrystallization
1
and had the following: HPLC t
1
2
R
) 1.3; H NMR δ 8.81 (br s,
H, NH), 8.00 (d, J ) 4.2 Hz, 2H, PhH), 7.85 (d, J ) 7.5 Hz,
H, PhH), 7.75 (d, J ) 7.5 Hz, 2H, PhH), 7.66 [s, 1H, isoxazole
+
C(4)-H], 7.50 (m, 2H, PhH), 7.41 (m, 1H, PhH), 5.86-5.64
31.0 (methyl t-Bu); ESI-MS m/z 1385 (M + Na ). Anal. Calcd
(
(
(
m, 14H), 4.96-4.77 (m, 7H), 4.54-4.36 (m, 6H), 3.90-3.28
for C56
H
86
N
2
O
2
36‚7H O: C, 45.16; H, 6.77; N, 1.88. Found: C,
1
3
m, 42H); C NMR δ 164.2, 162.1, 155.7, 142.1 and 139.2
44.93; H, 6.47; N, 1.68.
A
A
quaternary), 129.1, 127.5, 127.4 and 126.8 (methine, Ph),
N-(6 -Deoxy-â-cyclod extr in -6 -yl)-5-(a m in oca r bon yl)-
3-p h en yl-4,5-d ih yd r oisoxa zole (15b). Reaction of the CD
8a with the nitrile oxide 11c in either aqueous solution or
DMF, as described above, gave the title compound 15b as the
only detectable cycloadduct. It was isolated by recrystalliza-
tion and had the following: 1H NMR δ 7.95 (m, 1H, NH), 7.68
(m, 2H, PhH), 7.44 (m, 3H, PhH), 5.84-5.67 (m, 14H), 5.10
[m, 1H, isoxazole C(5)-H], 4.89-4.80 (m, 7H), 4.52-4.36 (m,
1
28.1 (quaternary, Ph), 104.4 (isoxazole C-4), 102.4-101.4 (CD
C-1), 84.3 and 81.7-81.1 (CD C-4), 73.3-71.9 and 69.5 (CD
C-2, C-3, and C-5), 60.1-59.7 (CD C-6); ESI-MS (50 eV) m/z
+
1
403 (M + Na ). Anal. Calcd for C58
H
80
N
2
O
2
36‚3H O: C, 48.54;
H, 6.04; N, 1.95. Found: C, 48.60; H, 5.82; N, 2.03.
A
A
N-(6 -Deoxy-â-cyclod extr in -6 -yl)-5-(a m in oca r bon yl)-
3
-p h en ylisoxa zole (13c). The title compound was prepared
1
3
as a 10:1 mixture with the regioisomer 12c, in 87% yield, as
described above from reaction of the CD 6 with the nitrile oxide
6H), 3.82-3.10 (m, 44 H); C NMR δ 169.6 and 156.6
(quaternary), 130.4, 128.9 and 126.8 (methine, Ph), 128.7
(quaternary, Ph), 102.3-101.7 (CD C-1), 83.9 and 81.6-81.4
(CD C-4), 79.0 (isoxazole C-5), 73.0-72.0 and 69.7 (CD C-2,
1
1c in DMF. It was isolated by recrystallization and had the
1
following: HPLC t
m, 2H, PhH), 7.61 [s, 1H, isoxazole C(4)-H], 7.53 (m, 3H,
PhH), 5.87-5.67 (m, 14H), 4.95-4.77 (m, 7H), 4.53-4.35 (m,
R
) 3.1; H NMR δ 8.78 (m, 1H, NH), 7.91
+
(
C-3, and C-5), 60.2-59.6 (CD C-6); ESI-MS m/z 1306 (M ).
Anal. Calcd for C52
H
78
N
2
O
2
36‚7H O: C, 43.57; H, 6.47; N, 1.95.
6
H), 3.90-3.19 (m, 42H); 13C NMR δ 164.3, 162.5 and 155.9
Found: C, 43.84; H, 6.55; N, 2.02.
A
A
(quaternary), 130.8, 129.5 and 126.9 (methine, Ph), 128.0
N-(6 -Deoxy-â-cyclod extr in -6 -yl)-5-(a m in oca r bon yl)-
3-(4-ter t-bu tylph en yl)-4-(eth oxycar bon yl)-4,5-dih ydr oisox-
a zole (15c). The title compound was prepared as a 15:1
mixture with the regioisomer 14c, in 64% yield, as described
above from reaction of the CD 8b with the nitrile oxide 11a in
(
8
quaternary, Ph), 104.5 (isoxazole C-4), 102.4-101.5 (CD C-1),
4.3 and 81.7-81.2 (CD C-4), 73.3-72.0 and 69.6 (CD C-2, C-3,
+
and C-5), 60.1-59.4 (CD C-6); ESI-MS m/z 1328 (M + Na ).
Anal. Calcd for C52 O: C, 44.19; H, 6.28; N, 1.98.
Found: C, 44.09; H, 6.05; N, 1.91.
H
76
N
2
O
36‚6H
2
DMF. It was isolated by HPLC (acetonitrile/water, 10% v/v)
A
A
1
N-(6 -Deoxy-â-cyclod extr in -6 -yl)-4-(a m in oca r bon yl)-
and had the following: HPLC t
R
) 5.7; H NMR δ 8.25 (br s,
3
-(4-ter t-bu tylp h en yl)-4,5-d ih yd r oisoxa zole (14a ). The
1H, NH), 7.49 (d, 2H, J ) 8.5 Hz, PhH), 7.40 (d, 2H, J ) 8.5
Hz, PhH), 5.92-5.64 (m, 14H), 5.14 [d, 1H, J ) 6.5 Hz,
isoxazole C(5)-H], 4.92-4.77 (m, 8H), 4.55-4.48 (m, 3H),
title compound was prepared as a 2.3:1 mixture with the
regioisomer 15a , in 100% yield, as described above from
reaction of the CD 8a with the nitrile oxide 11a in aqueous
4.41-4.36 (m, 3H), 4.19 (m, 2H, OCH
2 3
CH ), 3.70-3.12 (m, 42
13
solution. It was isolated by HPLC (acetonitrile/water, 10% v/v)
H) 1.29 (s, 9H, t-Bu), 1.25 (t, 3H, J ) 7.5 Hz, OCH
2
CH
3
);
C
1
and had the following: HPLC t
1
R
) 1.6; H NMR δ 7.96 (br s,
NMR δ 169.2 and 168.0 (CdO), 155.1 and 153.4 (quaternary),
126.8 and 125.6 (methine, Ph), 124.8 (quaternary, Ph), 102.4-
101.7 (CD C-1), 82.9 and 81.4-81.2 (CD C-4), 82.1 (isoxazole
H, NH), 7.46 (d, 2H, J ) 8.0 Hz, PhH), 7.37 (d, 2H, J ) 8.0
Hz, PhH), 5.86-5.63 (m, 14H), 4.84-4.75 (m, 7H), 4.66 [m,
1
4
9
1
1
H, isoxazole C(5)-H], 4.60 [m, 1H, isoxazole C(5)-H′], 4.53-
.47 (m, 2H), 4.43-4.35 (m, 5H), 3.72-3.20 (m, 42H), 1.29 (s,
C-5), 73.0-71.9 and 69.8 (CD C-2, C-3, and C-5), 61.7 (OCH
CH ), 60.4-59.7 (CD C-6), 58.2 (isoxazole C-4), 34.7 (quater-
nary, t-Bu), 31.1 (methyl, t-Bu), 14.1 (OCH CH ); ESI-MS m/z
O: C, 45.91; H,
2
-
3
1
3
H, t-Bu); C NMR δ 169.1, 155.6 and 152.6 (quaternary),
26.6 and 125.2 (methine, Ph), 125.7 (quaternary, Ph), 102.2-
01.6 (CD C-1), 83.4 and 81.6 (CD C-4), 73.1-71.8 and 70.3
2
3
+
1435 (M ). Anal. Calcd for C59
H
90
N
2
O
38‚6H
2
6.66; N, 1.82. Found: C, 45.81; H, 6.28; N, 2.11.
(
CD C-2, C-3, and C-5), 60.4 (isoxazole C-5), 59.9-59.5 (CD
C-6), 54.8 (isoxazole C-4), 34.6 (quaternary, t-Bu), 31.2 (methyl,
3-(4-ter t-Bu tylp h en yl)-5-(m eth oxyca r bon yl)isoxa zole
(17). To a stirred solution of methyl propynoate (16) (25 mg,

â-Cyclodextrin as a Scaffold
J . Org. Chem., Vol. 63, No. 24, 1998 9075
3
0
.30 mmol) in water (2.5 cm ) was added 4-tert-butylbenzoni-
(21.6 µL, 0.15 mmol). The mixture was allowed to stir at
ambient temperature for 15 h, after which water (5 cm ) was
3
trile oxide (11a ) (69.2 mg, 0.33 mmol) and NEt
mmol). The mixture was allowed to stir at ambient temper-
ature for 15 h, after which water (5 cm ) was added. The
resultant solution was extracted with CH
and the organic extracts were concentrated in vacuo. Flash
chromatography of the residue (ethyl acetate/petroleum ether,
f
:7) yielded the title compound 17 (R ) 0.93) as a colorless
solid (69 mg, 90%). The analogous reaction in DMF afforded
3
(45.6 µL, 0.33
added. The resultant solution was extracted with CH Cl (2
2
2
3
3
×
10 cm ), and the organic extracts were concentrated in vacuo.
Flash chromatography of the residue (ethyl acetate/petroleum
ether, 1:1) yielded the title compound 19 (R ) 0.21) as a
3
2
Cl
2
(2 × 10 cm ),
f
colorless solid (6 mg, 17%). The analogous reaction in DMF
3
afforded the title compound 19 in 93% yield: mp ) 200-201
1
1
°C; H NMR δ 7.62 and 7.42 (2s, 2H, NH
2
), 7.60 (d, 2H, J )
the title compound 17 in 94% yield: mp ) 64-65 °C; H NMR
8
.5 Hz, PhH), 7.45 (d, 2H, J ) 8.5 Hz, PhH), 5.02 [dd, 1H, J
δ 7.89 [s, 1H, isoxazole C(4)-H], 7.88 (d, 2H, J ) 8.0 Hz, PhH),
)
7.0 and 12.0 Hz, isoxazole C(5)-H], 3.63 [dd, 1H, J ) 17.0
7
3
.53 (d, 2H, J ) 8.0 Hz, PhH), 3.92 (s, 3H, OCH ), 1.29 (s, 9H,
1
3
and 7.0 Hz, isoxazole C(4)-H], 3.51 [dd, 1H, J ) 17.0 and 12.0
Hz, isoxazole C(4)-H′], 1.26 (s, 9H, t-Bu); 13C NMR δ 172.3
(CdO), 156.2 and 153.2 (quaternary), 126.7 and 125.7 (me-
thine, Ph), 126.0 (quaternary, Ph), 78.8 (isoxazole C-5), 38.6
(isoxazole C-4), 34.7 (quaternary, t-Bu), 31.0 (methyl, t-Bu);
t-Bu); C NMR δ 162.9, 160.3, 157.0 and 153.8 (quaternary),
26.8 and 126.2 (methine, Ph), 124.9 (quaternary, Ph), 108.2
isoxazole C-4), 53.1 (OCH ), 34.8 (quaternary, t-Bu), 31.1
methyl, t-Bu); ESI-MS m/z 260 (M + H ). Anal. Calcd for
: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.38; H,
.65; N, 5.06.
-(Am in oca r b on yl)-3-(4-t er t -b u t ylp h e n yl)-4,5-d ih y-
d r oisoxa zole (19). To a stirred solution of propenamide (18)
1
(
(
3
+
15 3
C H17NO
6
+
ESI-MS (40 eV) m/z 246 (M + H
: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.08; H,
.35; N, 11.16.
). Anal. Calcd for
5
14 18 2 2
C H N O
7
3
(
10 mg, 0.14 mmol) in water (1.0 cm ) were added 4-tert-
butylbenzonitrile oxide (11a ) (32.8 mg, 0.15 mmol) and NEt
3
J O9817321