Experimental and theoretical studies on stereo- and regioselectivity in intramolecular nitrone-alkene cycloaddition of Hept-6-enoses derived from carbohydrates

Article abstract of DOI:10.1021/jo060348y

The effect of blocking groups and stereochemistry of the substituents on the regio- and stereoselectivity in intramolecular nitrone-alkene cycloaddition (INAC) of hept-6-enoses are reported. L-ribo-Hept-6-enose 12 and D-lyxo-hept-6-enose 15, both containi

Full text of DOI:10.1021/jo060348y

Experimental and Theoretical Studies on Stereo- and
Regioselectivity in Intramolecular Nitrone-Alkene Cycloaddition of
Hept-6-enoses Derived from Carbohydrates
Tony K. M. Shing,*,† Annie W. F. Wong,† Taketo Ikeno,‡ and Tohru Yamada*,‡
Department of Chemistry, The Chinese UniVersity of Hong Kong, Shatin, NT, Hong Kong, and Department
of Chemistry, Faculty of Science and Technology, Keio UniVersity, Hiyoshi, Kohoku-ku, Yokohama,
223-0085, Japan
tonyshing@cuhk.edu.hk
ReceiVed February 20, 2006
The effect of blocking groups and stereochemistry of the substituents on the regio- and stereoselectivity
in intramolecular nitrone-alkene cycloaddition (INAC) of hept-6-enoses are reported. L-ribo-Hept-6-
enose 12 and D-lyxo-hept-6-enose 15, both containing a 2,3-O-isopropylidene blocking group, and L-xylo-
hept-6-enose 23 and D-arabino-hept-6-enose 30, both with a 2,3-O-trans-diacetal blocking group, were
prepared from D-ribose and D-arabinose, respectively. With N-alkyl hydroxylamine, lactols 12 and 15
underwent an INAC reaction to give cis-fused isoxazolidines exclusively whereas lactols 23 and 30 gave
a mixture of cis-, trans-fused isoxazolidines (cyclohexanols) and bridged isoxazolidines (cycloheptanols).
With the 2,3-O-trans-diacetal protecting group, the bridged bicyclo[4.2.1]isoxazolidines (cycloheptanols),
via the endo mode of INAC cyclization, were synthesized for the first time from unbranched sugar
derivatives 23 and 30. The stereochemical outcomes of these reactions were rationalized on the basis of
transition state energies obtained by computation. The present INAC showed trivial temperature, but
significant solvent dependence. For lactols 23 and 30, performing the INAC in 2-propanol gave the best
yields of fused isoxazolidines (cyclohexanols) whereas in dichloromethane afforded the best yields of
bridged isoxazolidines (cycloheptanols).
Introduction
There are two modes of INAC cyclization, the exo or the
endo mode (Scheme 1), which lead to either a fused or a bridged
isoxazolidine, respectively.3 Searching the literature reveals only
two examples4 of the formation of a bridged bicyclo[4.2.1]
system from branched sugars and one example5 of a fused
bicyclo[5.3.0] system, i.e., a cycloheptane skeleton, from
carbohydrates. A fused bicyclo[5.3.0] system from carbohydrates
via an intramolecular nitrile oxide cyclization (INOC) was also
Intramolecular nitrone-alkene cycloaddition (INAC) consti-
tutes a powerful synthetic method for the preparation of
polyhydroxylated carbocycles from sugars.1 The presence of a
nitrogen functionality within the cycloadduct is especially
attractive for the syntheses of alkaloids and related natural
products.2
† The Chinese University of Hong Kong.
(3) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863-909.
(4) (a) Roy, A.; Chakrabarty, K.; Dutta, P. K.; Bar, N. C.; Basu, N.;
Achari, B.; Mandal, S. B. J. Org. Chem. 1999, 64, 2304-2309. (b) Patra,
R.; Bar, N. C.; Roy, A.; Achari, B.; Ghoshal, N.; Mandal, S. B. Tetrahedron
1996, 52, 11265-11272. (c) Bar, N. C.; Roy, A.; Achari, B.; Mandal, S.
B. J. Org. Chem. 1997, 62, 8948-8951.
‡ Keio University.
(1) (a) Bernet, von B.; Vasella, A. HelV. Chim. Acta 1979, 62, 1990-
2016. (b) Koumbis, A. E.; Gallos, J. K. Curr. Org. Chem. 2003, 7, 585-
628. (c) Osborn, H. M. I.; Gemmell, N.; Harwood: L. M. J. Chem. Soc.,
Perkin Trans 1, 2002, 2419-2438.
(2) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Vol. 2, pp 83-168.
(5) Marco-Contelles, J.; Opazo, E. Tetrahedron Lett. 1999, 40, 4445-
4448.
10.1021/jo060348y CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/22/2006
J. Org. Chem. 2006, 71, 3253-3263
3253

Shing et al.
SCHEME 3. Catalytic Hydrogenolysis of the N-O Bond
SCHEME 1. Two Modes of INAC Cyclization
class of glycosidase inhibitor,17 also contains a cycloheptane
skeleton that is profited from the cleavage of the heterocycle,
such as 6, upon catalytic hydrogenolysis of the N-O bond
(Scheme 3).
SCHEME 2. INAC from a D-Mannose Derivativea
Further synthetic manipulation performed on the amino-
cycloheptanol 7 could lead to another class of alkaloids, the
tropanes 8.18 The regio- and stereoselective formation of the
bridged bicyclo[4.2.1] system via the endo mode of INAC of
hept-6-enose is thus worthy of investigation. However, the
rationalization for the regio- and diastereoselectivity of these
INAC reactions has not been presented. There are no examples
for the construction of the bridged bicyclo[4.2.1] system from
unbranched hept-6-enose derivatives. To develop a general
synthetic protocol for the construction of enantiopure amino-
cycloheptanols from carbohydrates, we need to address the
stereochemical factors that control the regioselectivity (ring size)
as well as the diastereoselectivity of the INAC reactions on hept-
6-enose. This is the subject of the present article.
a Reagents and conditions: (a) CH2CHMgBr, THF, 93%; (b) BnBr, NaH,
THF, 79%; (c) aq AcOH, 64%; (d) NaIO4, aq MeOH; (e) MeNHOH‚HCl,
NaHCO3, aq EtOH, reflux, 65% from 3.
reported.6 However, there are many examples4c,7-11 of un-
branched sugar derivatives giving the fused bicyclo[4.3.0]
system, i.e., a cyclohexane skeleton.
Inspired by the pioneer work from Vasella,1a one of us
reported a rapid entry to 5- and 6-ring carbocycles from
carbohydrates via an INAC reaction (Scheme 2).11 The strategy
involves a Grignard addition of an alkene component to C-1 of
acetonide 1, readily available from D-mannose, and an aldehyde
at C-7 was obtained from a glycol cleavage oxidation of the
corresponding diol 3. With N-methyl hydroxylamine, an exo-
mode INAC reaction occurred to yield, exclusively, a fused
isoxazolidine, cyclohexane 4, but its regio- and stereochemical
outcomes were not rationalized.11
Recent papers19-21 regarding theoretical studies of inter-
molecular 1,3-dipolar cycloaddition discovered that solvent
effects could modify the regio- and the stereochemical outcome
of the reaction. Toward this end, performing the INAC reactions
in different solvents is of interest. However, there are no reports
on the theoretical studies of the INAC reactions of hept-6-enoses
to give carbocycles. In the present Article, we report the first
examples of bridged bicyclo[4.2.1] systems by endo dipolar
cycloaddition of carbohydrate-derived alkenes. This opens a new
route to enantiomerically defined cycloheptane derivatives.
Theoretical analysis was carried out and the transition state (TS)
energies of all the possible cycloadducts, cyclohexanols and
cycloheptanols, were computed.
Both the fused and bridged isoxazolidines were shown to be
key intermediates in the syntheses of natural products or
analogues with biological importance.3,12-14 Examples are (-)-
shikimic acid,8 â-glucosidase inhibitor cyclophellitol,15 and
nucleoside analogues.4,5b The bridged bicyclo[4.2.1] system
already encloses the backbone of the new nor-tropane alkaloids,
calystegines, e.g., calystegine B2, which exhibit specific gly-
cosidase inhibition.16 Aminocycloheptanol 5, proven to be a new
Results and Discussion
INAC of a D-Ribose Derivative. The acetonide 9,22 readily
available from D-ribose, reacted with an excess of allylmag-
nesium bromide in diethyl ether to give triol 10 and its 4-epimer
11 in 17:1 diastereoselectivity, respectively (Scheme 4).
(6) Duclos, O.; Dure´ault, A.; Depezay, J. C. Tetrahedron Lett. 1992,
33, 1059-1062.
(7) Jiang, S.; Singh, G.; Batsanov, A. S. Tetrahedron: Asymmetry 2000,
11, 3873-3877.
(8) Jiang, S.; McCullough, K. J.; Mekki, B.; Singh, G.; Wightman, R.
H. J. Chem. Soc., Perkin Trans. 1 1997, 1805-1814.
(9) Peet, N. P.; Huber, E. W.; Farr, R. A. Tetrahedron 1991, 47, 7537-
7550.
(16) (a) Asano, N. Curr. Top. Med. Chem. 2003, 3, 471-484. (b)
Simmonds, M. S. J.; Kite, G. C.; Porter, E. A. Imino sugars as Glycosidase
InhibitorssNojirimycin and Beyond; Stu¨tz, A. E., Ed.; Wiley-VCH:
Weinheim, Germany, 1999.
(10) Bar, N. C.; Roy, A.; Patra, R.; Achari, B.; Mandal, S. B. Indian J.
Org. Chem. 1997, 366B, 275-277.
(17) Gravier-Pelletier, C.; Maton, W.; Dintinger, T.; Tellier, C.; Merrer,
Y. L. Tetrahaedron 2003, 59, 8705-8720.
(11) Shing, T. K. M.; Elsley, D. A.; Gillhouley, J. G. J. Chem. Soc.,
Chem. Commun. 1989, 1280-1282.
(18) Naylor, A.; Howarth, N.; Malpass, J. R. Tetrahedron 1993, 49, 451-
(12) Koumbis, A. E.; Gallos, J. K. Curr. Org. Chem. 2003, 7, 585-
628.
468.
(19) Domingo, L. R. Eur. J. Org. Chem. 2000, 2265-2272.
(20) Coss´ıo, F. P.; Morao, I.; Jiao, H.; Schleyer, P. v. R. J. Am. Chem.
Soc. 1999, 121, 6737-6746.
(13) Osborn, H. M. I.; Gemmell, N.; Harwood: L. M. J. Chem. Soc.,
Perkin Trans 1, 2002, 2419-2438.
(14) Frederickson, M. Tetrahedron, 1997, 53, 403-425.
(15) Tatsuta, K.; Niwata, Y.; Umezawa, K.; Toshima, K.; Nakata, M.
Tetrahedron Lett. 1990, 31, 1171-1172.
(21) Domingo, L. R.; Arno´, , M.; Andre´s, J. J. Org. Chem. 1999, 64,
5867-5875.
(22) Levene, P. A.; Tipson, R. S. J. Biol. Chem., 1936, 115, 731-747
3254 J. Org. Chem., Vol. 71, No. 8, 2006

Nitrone-Alkene Cycloaddition of Hept-6-enoses
SCHEME 4. Syntheses of Isoxazolidine 14 and 17a
SCHEME 5. Preparation of Triols 21 and 22a
a Reagents and conditions: (a) 2,2,3,3-tetramethoxybutane, CH(OMe)3,
(()-CSA, MeOH, reflux, 76%; (b) 10% Pd/C, H2, EtOH, rt, 100%; (c)
allylmagnesium bromide, THF, -78 °C, (21:22 ) 1:1), 100%.
ment. Hence, the cycloadduct 14 should adopt a boatlike
conformation.
Lactol 15, resulting from glycol cleavage of triol 11, was
reacted with MeNHOH to yield cyclohexanol 17 exclusively
through an exo-mode of INAC.
a Reagents and conditions: (a) allylmagnesium bromide, Et2O, -78 °C
f rt, (10:11 ) 17:1), 99%; (b) NaIO4, silica gel, CH2Cl2, rt, 100% for 10
and 11; (c) BnNHOH‚HCl, NaHCO3, CH3CN, reflux, 92%; (d) MeNHOH‚
HCl, NaHCO3, CH3CN, reflux, 92%.
INAC of D-Arabinose Derivatives. Benzyl-â-D-arabino-
pyranoside 18,24 prepared from glycosidation of D-arabinose,
was protected with a trans-diacetal ring to give acetal 19
(Scheme 5). The benzyl group in 19 was then removed by
palladium-catalyzed hydrogenolysis to furnish lactol 20. Reac-
tion of 20 with an excess of allylmagnesium bromide in THF
at -78 °C afforded triols 21 and 22 in equal amounts. The
reason for the poor selectivity might be the inherent multi-
chirality of the blocking group, which could offer chelation and
complicate the transition state model, making no advance for
either side of the nucleophilic attack.
FIGURE 1. Chelation transition model.
The diastereomers 21 and 22 were separated by flash column
chromatography and the individual triol underwent glycol
cleavage to give an INAC precursor, lactol 23 (Scheme 6) or
30 (Scheme 7).
INAC reaction of lactol 23 gave three isomers, cis-fused
cyclohexanol 25, trans-fused cyclohexanol 26, and cycloheptanol
27, in a ratio of 66:18:16, respectively. The ratio was determined
by measuring the integration of the individual N-methyl group
in the 1H NMR spectrum of the mixture of cycloadducts. Only
isoxazolidine 26 could be isolated pure by flash column
chromatography. The remaining alcohols 25 and 27 were
converted into silyl ethers 28 and 29, respectively, for ease
chromatographic separation. Desilylation of silyl ether 28 or
29 then afforded pure isoxazolidine 25 or 27, respectively, for
characterization. The assignment of the ring size was based on
13C DEPT experiments. In the 13C DEPT spectra, cyclohexanols
25 and 26, each having one resonance in the upfield region (δ
25-40 ppm), were assigned to a methylene group showing a
distinct difference from cycloheptanol 27, having two resonances
in that region. The structures of 25 and 27 were confirmed by
X-ray crystallography and that of 26 could be readily assigned
FIGURE 2. Conformation of 14.
The high selectivity was presumably attributed to the chelation
controlled transition model11 shown in Figure 1. The stereo-
chemistry was confirmed by comparing the H and 13C NMR
1
spectra with the published data.8 Following the glycol cleavage
oxidation procedure developed by our group,23 lactol 12 was
obtained in a quantitative yield. On treatment with BnNHOH,
an exo-mode of INAC occurred to furnish cyclohexanol 14 in
one pot as a single diastereomer. The stereochemistry of the
isoxazolidine ring was assigned with the evidence from 1D 1H
NMR, COSY, and NOESY spectra.
The presence of three proton signals in the upfield region (δ
1.0-2.8 ppm) of the 1H NMR spectrum indicated a cyclohexane
ring. The large coupling constant (Jc,f ) 9.6 Hz) between Hf
and Hc suggested a diaxial arrangement. A strong NOE effect
between Hh, Hg and a moderate effect between Hg, Hf shown
in Figure 2 indicated that the heterocyclic ring was bending
upward. The large coupling constant (Jg,h ) 9.0 Hz) between
Hh and Hg demonstrated an eclipsed conformational arrange-
1
by H NMR analysis. Large coupling constants that fell into
the range of axial-axial coupling of Ha with Hc, Hd and those
of Hb with Hc, He demonstrated the stereochemistry of a trans-
fused bicyclic system 26 as shown in Figure 3. The bridged
bicyclo[4.2.1] system 27 via a protecting group directed endo-
(23) Zhong, Y. L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622-
2624.
(24) Kawasaki, M.; Matsuda, F.; Terashima, S. Tetrahedron 1988, 44,
5695-5711.
J. Org. Chem, Vol. 71, No. 8, 2006 3255

Shing et al.
SCHEME 6. INAC of Nitrone 24a
FIGURE 3. Conformation of 26. The substituents on the trans-acetal
ring are omitted for clarity.
FIGURE 4. Conformation of 33 and 35. The substituents on the trans-
acetal ring are omitted for clarity.
the mixture of cycloadducts. The cycloheptanols 34 and 35 were
synthesized in a combined yield of 39%. The four isomers were
not separable by flash column chromatography, but using the
same method as described above, they were converted into silyl
ethers 36, 37, and 38 with unreacted 35 recovered. After
chromatographic fractionation of the silyl ethers followed by
desilylation, individual isoxazolidine 32, 33, or 34 could be
characterized. The ring size was determined by 13C DEPT
experiments as described above. Single crystals of 32 and 34
confirmed their constitution by X-ray crystallography. The
axial-axial coupling of Ha with Hb and those of Hc with Hb,
Hd indicated the stereochemistry of a trans-fused cycloadduct
33 as illustrated in Figure 4a. The strong NOE effects of He
with Hf and Hh with Hg in cycloheptanol 35 shown in Figure
4b concluded that the bridgehead was pointing upward.
The purified isoxazolidines 25-27 and 32-35 were heated
individually in a sealed tube to 210 °C in toluene for 24 h and
were recovered unchanged. There was no indication of equili-
bration of the cyclized products.
a Reagents and conditions: (a) NaIO4, silica gel, CH2Cl2, rt; (b)
MeNHOH‚HCl, NaHCO3, CH3CN, reflux, 98% from 21 (ratio 25:26:27 )
66:18:16); (c) TBSCl, imidazole, DMF, rt, 99%
SCHEME 7. INAC of Nitrone 31a
With a change in the blocking group from isopropylidene in
D-ribose to the trans-diacetal ring in D-arabinose, the regio- and
stereochemical outcomes of the INAC reactions differ signifi-
cantly. It is noteworthy that some endo-mode of cyclization was
induced by the trans-diacetal ring. This was first realized with
lactol 23 in which cycloheptanol 27 was obtained in a ratio of
16%. The ratio of endo-cyclized products, cycloheptanols, 34
and 35 emerges to 39% for lactol 30. The next question is on
how the blocking group affects the regio- and stereochemistry.
Several papers on the theoretical analysis of intermolecular 1,3-
dipolar cycloaddition of nitrone and alkene have appeared.19-21,25
However, there are no reports on the computational studies of
the INAC reactions of hept-6-enoses to give hydroxylated
a Reagents and conditions: (a) NaIO4, silica gel, CH2Cl2, rt; (b)
MeNHOH‚HCl, NaHCO3, CH3CN, reflux, 100% from 22, (ratio 32:33:34:
35 ) 27:34:18:21); (c) TBSCl, imidazole, DMF, rt, 98%, 78% conversion.
mode of cyclization was synthesized from an unbranched sugar
for the first time.
(25) (a) Brown, F. K.; Singh, U. C.; Kollman, P. A.; Raimondi, L.; Houk,
K. N.; Bock, C. W. J. Org. Chem. 1997, 57, 44862-4869. (b) Carda, M.;
Portole´s, R.; Murga, J.; Ureil, S.; Marco, J. A.; Domingo, L. R.; Zaragoza´,
R. J.; Ro¨per, H. J. Org. Chem. 2000, 65, 7000-7009. (c) Liu, J.; Niwayama,
S.; You, Y.; Houk, K. N. J. Org. Chem. 1998, 63, 1064-1073. (d)
Magnuson, E. C.; Pranata, J. J. Comput. Chem. 1998, 19, 1795-1804. (e)
Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi, L. Eur.
J. Org. Chem. 1998, 1823-1832.
INAC reaction of lactol 30 gave four cycloadducts, cis-fused
cyclohexanol 32, trans-fused cyclohexanol 33, along with
cycloheptanols 34 and 35 in a ratio of 27:34:18:21, respectively.
The ratio was again determined by measuring the integration
1
of the individual N-methyl group in the H NMR spectrum of
3256 J. Org. Chem., Vol. 71, No. 8, 2006

Nitrone-Alkene Cycloaddition of Hept-6-enoses
TABLE 1. Theoretical Analysis of INAC of Nitrone 39 from D-Ribosea
ground state ∆E (∆G at 80 °C), kcal mol-1
1.34 (0)
C-C: 2.20
C-O: 2.12
92
0
0
4.24 (2.02)
C-C: 2.15
C-O: 2.19
0
4.85
4.81
2.75 (3.10)
C-C: 2.23
C-O: 2.17
0
7.77
7.99
2.18 (0.92)
C-C: 2.11
C-O: 2.37
0
5.72
5.82
0 (0.61)
C-C: 2.13
C-O: 2.30
0
4.52
5.83
bond distance in TS, Åb
exptl yield,c %
TS ∆E, kcal mol-1
TS ∆G (80 °C), kcal mol-1
a B3LYP/6-31G* calculations were performed. Relative energies are shown. b The new bonds formed in the INAC reaction. c Yield for the N-benzyl
group 14.
TABLE 2. Theoretical Analysis of INAC of Nitrone 16a
ground state ∆E (∆G at 80 °C), kcal mol-1
1.56 (0.13)
C-C: 2.23
C-O: 2.08
92
0
0
5.87 (3.07)
C-C: 2.15
C-O: 2.18
0
4.13
4.40
4.57 (3.14)
C-C: 2.17
C-O: 2.08
0
6.40
7.63
0 (0)
2.30 (0.82)
C-C: 2.17
C-O: 2.24
0
5.21
6.11
bond distance in TS, Åb
C-C: 2.09
C-O: 2.42
0
0.90
2.69
exptl yield, %
TS ∆E, kcal mol-1
TS ∆G (80 °C), kcal mol-1
a B3LYP/6-31G* calculations were performed. Relative energies are shown. b The new bonds formed in the INAC reaction
carbocycles. Our present theoretical studies are therefore war-
ranted to determine the transition state energies.
The results of nitrone 39 from D-ribose are shown in Table
1. The achiral alkyl group on the nitrogen is usually not crucial
for controlling the stereoselectivity in INAC reactions. For
simplicity, the benzyl group in 13 was therefore replaced with
a methyl moiety in the calculation. Since the reaction was
performed in acetonitrile at a boiling range of 80-82 °C, the
set of data calculated with single point energy and the Gibbs
energy at 80 °C should be considered. The experimental results
are consistent with the theoretical analysis since the energy of
the TS leading to cyclohexanol 40 is significantly lower than
those of the rest of the TSs. Consequently it is not surprising
that the cis-fused isoxazolidine 40 was the exclusive product.
For the 4-epimer nitrone 16, the cis-fused isoxazolidine 17
was synthesized as the only product, which is also in agreement
with the theoretical analysis (Table 2). The energy of the TS
leading to cyclohexanol 17 is significantly lower than those of
the rest of the TSs.
The calculated results for nitrone 24 from D-arabinose in
Table 3 suggested that the cis-fused cyclohexanol 25 (ratio 66%)
is the major isomer because it had the lowest Gibbs TS energy.
The energy differences between the TSs of 25 and 26 and
between 25 and 27 were relatively smaller, thus allowing
concomitant formation of trans-fused cyclohexanol 26 (ratio
18%) and cycloheptanol 27 (ratio 16%) in low yields. The
relatively high TS energy (3.31 kcal mol-1) would not afford
an appreciable amount of cycloheptanol 49. The theoretical
analysis is in accord with the experimental results.
Theoretical Analysis. The TS energies were calculated in
the following way. At first, the ground-state structures were
calculated with molecular mechanics by using the CONFLEX
program for conformational search.26 Many conformers were
obtained and the relatively stable conformers (within 10 kcal
mol-1 compared to the most stable one) were selected for further
analysis. Then the ground states and all the transition states
based on the ground-state structures were calculated by B3LYP/
6-31G* with a suite of Gaussian 98 programs.27,28 The obtained
TS energies were compared with each other. The obtained
structures were similar to previous reports25,29 and the imaginary
frequencies were checked to ensure that the vectors were
directed toward the reaction pathway. IRC calculations were
performed for the most stable TSs. Only the concerted pathway
was calculated since this was reported to be more favorable
than the biradical pathway.25
(26) CONFLEX Ver 4.0.2, Revision T, Conflex Corp.: Tokyo, Japan,
2000,26a,b Although it is well established that the force field approach is
useful for the TS search of flexible molecules26c and was successfully applied
to the 1,3-diplar cyloadddtion,25e considering that the CONFLEX does not
support the TS MM model and the tricyclic structures investigated in this
paper are relatively rigid, TSs were calculated based on the ground state
conformers: (a) Goto, H.; Osawa, E. J. Am. Chem. Soc. 1989, 111, 8950-
8951. (b) Goto, H.; Osawa, E. J. Chem. Soc., Perkin Trans. 2 1993, 187-
198. (c) Houk, K. N.; Paddon-row, M. N.; Rondan, N. G.; Wu, Y.-D.;
Brown, F. K.; Spellmeyer, D. C.; Mets, J. T.; Li, Y.; Loncharich, R. J.
Science 1986, 231, 1108-1117.
(27) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C. T.;
Yang, W. T.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
(28) Frisch et al. Gaussian 98, Revision A.11; Gaussian, Inc.: Pittsburgh,
PA, 1998.
(29) Valentin, C. D.; Freccero, M.; Gandolfi, R.; Rastelli, A. J. Org.
Chem. 2000, 65, 6112-6120.
The same calculations for nitrone 31 are illustrated in Table
4. Since the energies of the TSs leading to cycloadducts 32-
35 are similar with a difference not larger than 1.8 kcal mol-1
,
we would expect the formation of all of them. The amount of
cycloheptanols should increase and our experimental results have
J. Org. Chem, Vol. 71, No. 8, 2006 3257

Shing et al.
TABLE 3. Theoretical Analysis of INAC of Nitrone 24a
ground state ∆E (∆G at 80 °C), kcal mol-1
0 (0)
C-C: 2.21
C-O: 2.15
66
0.08
0
0.76 (0.19)
C-C: 2.15
C-O: 2.18
18
1.74
2.72
0.12 (0.40)
C-C: 2.19
C-O: 2.23
16
0
1.10
0.46 (0.91)
bond distance in TS, Åb
C-C: 2.13
C-O: 2.31
0
2.29
3.31
exptl ratio, %
TS ∆E, kcal mol-1
TS ∆G (80 °C), kcal mol-1
a B3LYP/6-31G* calculations were performed. Relative energies are shown. b The new bonds formed in the INAC reaction.
TABLE 4. Theoretical Analysis of INAC of Nitrone 31a
ground state ∆E (∆G at 80 °C), kcal mol-1
0.16 (0.05)
C-C: 2.19
C-O: 2.19
27
0.35
0
0.96 (0.06)
C-C: 2.14
C-O: 2.20
34
1.55
1.47
2.29 (2.58)
C-C: 2.09
C-O: 2.37
18
1.12
1.75
0 (0)
C-C: 2.18
C-O: 2.26
21
0
0.05
bond distance in TS, Åb
exptl ratio, %
TS ∆E, kcal mol-1
TS ∆G (80 °C), kcal mol-1
a B3LYP/6-31G* calculations were performed. Relative energies are shown. b The new bonds formed in the INAC reaction.
shown that this is the case. Cycloheptanols 34 and 35 were
obtained in a combined yield of 39%.
These calculations also indicate several points. (1) The
bridged bicyclo[4.2.1] compounds are equally stable compared
with bicyclo[4.3.0] compounds in the ground states, which
means that selective endo-mode cyclization would be potentially
possible by the rational design of the protective group. (2)
Stabilization by the intramolecular hydrogen bonding between
the free hydroxy group and the oxygen atom of the protective
group or nitrone reaches several kilocaloriess per mole, which
significantly affects the stability of the conformer in both the
ground state and TS. For example, the TS energy of 49 was
too high to give the product, whereas a hydrogen bonding
between the hydroxy group and nitrone lowered the TS energy
of 34 and led to the product. (3) The TS structures of endo-
and exo-cyclizations are very different. In the TS of exo-
cyclization, the C-C bonds are almost the same length as the
C-O bonds. On the contrary, the C-O bonds are much longer
than the C-C bonds in the TS of endo-cyclization. (4) By
comparing the single point energy and the Gibbs free energy
with the distribution of the products, the entropy factor would
influence the stability of the conformer. It might be considered
that one of the main reasons for the deviation from the
FIGURE 5. TS of 40, 17, 25-27, and 32-35.
experimental and theoretical results would be the solvation effect
(vide infra).
the TSs leading to the products 40 (TS-40) and 17 (TS-17)
respectively adopt a boatlike conformation. The bonding orbitals
are therefore aligned to the same plane in space, resulting in
better orbital overlap that lowers the TS energy (Figure 6a). In
contrast, cyclohexanols 25, 26, 32, and 33 adopt a chairlike
conformation, which is imposed by the rigidity of the trans-
diacetal blocking group. For a chair conformation, the orienta-
The conformation of the TSs shown in Figure 5 may provide
the rationalization for the effect of the blocking groups on the
regioselectivity as well as the diastereoselectivity.
Only the skeleton atom was shown to simplify the figures.
For the isopropylidene blocking group of nitrones 39 and 16,
3258 J. Org. Chem., Vol. 71, No. 8, 2006

Nitrone-Alkene Cycloaddition of Hept-6-enoses
TABLE 5. Solvent and Temperature Effects on INAC of Nitrone
24
temp,
ratio
ratio
yield, reaction
entry
solvent
°C
25:26:27 exo:endo
%
time
1a
2a
3a
4a
5a
6a
7a
8a
9a
CH3CNa
CH3CN
toluene
CH2Cl2
CH3CN
CHCl3
80-82 66:18:16
80-82 74:12:14
85:15
86:14
89:11
82:18
83:17
86:14
91:9
90:10
79:21
86:14
86:14
92:8
98
100
100
86
100
99
89
100
98
1 h
1 h
40
40
40
40
78:11:11
65:17:18
71:12:17
73:13:14
78:13:9
24 h
68 h
40 h
40 h
36 h
5 d
13 d
11 d
10 d
6 d
2-propanol 40
toluene
CH2Cl2
CH3CN
CHCl3
rt
rt
rt
rt
80:10:10
62:17:21
73:13:14
74:12:14
79:13:8
10a
11a
12a
97
99
86
FIGURE 6. Conformation of TS.
2-propanol rt
SCHEME 8. Preparation of Nitrone 22 and 31a
a INAC reaction performed without isolation of the nitrone.
TABLE 6. Solvent and Temperature Effects on INAC of Nitrone
31
temp,
ratio
ratio
yield, reaction
entry
solvent
°C
32:33:34:35 exo:endo
%
time
1b CH3CNa
2b CH3CN
3b toluene
4b CH2Cl2
5b CH3CN
6b CHCl3
80-82 27:35:17:21
80-82 25:39:15:21
62:38
64:36
70:30
58:42
61:39
68:32
70:30
71:29
57:43
62:38
66:34
70:30
99
98
100
99
100
100
99
98
100
92
94
100
1 h
1 h
40
40
40
40
35:35:8:22
21:37:21:21
26:35:18:21
26:43:14:17
20:50:7:23
35:36:8:21
20:37:21:22
24:38:16:22
23:43:16:18
19:51:6:24
72 h
72 h
72 h
72 h
48 h
23 d
17 d
14 d
22 d
14 d
7b 2-propanol 40
8b toluene
9b CH2Cl2
10b CH3CN
11b CHCl3
rt
rt
rt
rt
12b 2-propanol rt
a Reagents and conditions: (a) NaIO4, silica gel, CH2Cl2, rt; (b)
MeNHOH‚HCl, NaHCO3, CH3CN, rt, 100% from 21, 92% from 22.
a INAC reaction performed without isolation of the nitrone.
tions of the bonding orbitals are no longer aligned on the same
plane as illustrated in Figure 6b,c. The poor overlap of orbitals
results in higher TS energies. TS-32 is further destabilized by
the pseudo-1,3-diaxial interaction between the hydroxyl group
and the developing isoxazolidine ring. The amount of cyclo-
hexanols from nitrone 31 was therefore the lowest compared
to those from nitrones 24, 39, and 16. For the endo-cyclized
products 27, 34, and 35, the chair conformation of TS allows
the orientation of bonding orbitals to be aligned on the same
plane (Figure 6d,e). Their TS energies become comparable to
those of the exo-cyclized ones and they were therefore obtained
in considerable amounts.
an interesting feature is an increment of the endo-cyclized
product (cycloheptanol) of around 10% when the solvent is
switched from 2-propanol (entries 12a and 12b) or toluene
(entries 8a and 8b) to CH2Cl2 (entries 9a and 9b). The
stereochemistry of the cycloadducts is also modified by different
solvents. For nitrone 24, the ratio of cis-fused cyclohexanol 25
to trans-fused cyclohexanol 26 is 3.6:1 in CH2Cl2 (entry 9a),
which increased to 8:1 in toluene (entry 8a); whereas with
nitrone 31, the ratio of cis-fused cyclohexanol 32 to trans-fused
cyclohexanol 33 (32:33 ) 1:1) in toluene (entry 8b) decreased
to 1:2.7 in 2-propanol (entry 12b).
The cyclohexanol cycloadducts were usually cis-fused as in
the case of 25 and 40 resulting from better overlap of bonding
orbitals. The unexpected formation of the trans-fused cyclohex-
anol 33 as the major product was due to the destabilization of
the diastereomer 32 by the pseudo-1,3-diaxial interaction be-
tween the hydroxyl group and the developing isoxazolidine ring.
Solvent and Temperature Effects. The lactol 23 was
allowed to react with MeNHOH at room temperature to afford
nitrone 24, which was isolated and purified for the study of
solvent effects. The same operation was performed on lactol
30 to afford nitrone 31 (Scheme 8). The INAC reactions of
nitrones 24 and 31 were carried out in toluene, dichloromethane,
chloroform, acetonitrile, and 2-propanol at 40 °C and at room
temperature. The ratios of the cycloadducts are summarized in
Tables 5 (nitrone 24) and 6 (nitrone 31).
Conclusion
From the experimental results and theoretical studies, the
regio- and stereochemical outcomes of the INAC reactions of
hep-6-enoses derived from D-ribose and D-arabinose derivatives
were significantly affected by the blocking group and the
stereochemistry of the substituents. The stereochemical out-
comes of these reactions were rationalized on the basis of
transition state energies obtained by computation. The nitrones
13 and 16 containing a 2,3-O-isopropylidene ring afforded exo-
cyclized cis-fused isoxazolidines (cyclohexanol) 13 and 17
exclusively. The endo-cyclization mode was enhanced when the
TS is restricted to adopt a chair conformation imposed by the
blocking group. Hence, unbranched sugar nitrones 24 and 31,
both containing a 2,3-trans-acetal ring, afforded appreciable
amounts of endo-cyclized bicyclo[4.2.1] isoxazolidines (cyclo-
heptanols) for the first time. For the transformation of nitrone
31 into cis-fused isoxazolidine 32, the formation of 32 was
Lowering the reaction temperature from 40 °C to room
temperature exerts no significant effect on the regio- and
stereoselectivity, beyond increasing the reaction time. However,
J. Org. Chem, Vol. 71, No. 8, 2006 3259

Shing et al.
addition of silica gel (230-400 mesh, 1 g) with vigorous swirling
and shaking. The mixture was suspended in CH2Cl2 (5 mL) and
then a solution of alkene 10 (98.9 mg, 0.426 mmol) in CH2Cl2 (3
mL) was added. After vigorous stirring at room temperature for 1
h, the mixture was filtered. The filtrate was concentrated under
reduced pressure and the residue was purified by flash chroma-
tography (hexane:EtOAc, 2:1) to give lactol 12 (85.0 mg, 100%)
as a colorless oil: [R]20D +6.77 (c 3.52, CHCl3) {lit.10 [R]24D -3.9
(c 0.36, CHCl3)}; Rf 0.41 (hexane:Et2O, 1:1); IR (thin film) 3431,
2942, 1375, 1211, 1074, 870 cm-1; 1H NMR (mixture of R and â
isomer with ratio R:â ) 1:11) δ 1.32 (3.0H, s), 1.38 (0.27H, s),
1.48 (3.0H, s), 1.57 (0.27H, s), 2.26-2.53 (2.19H, m), 2.84 (1.0H,
d, J ) 2.7 Hz), 3.89 (0.09H, d, J ) 9.3 Hz), 4.14 (0.09H, td, J )
6.9, 3 Hz), 4.25 (1.0H, t, J ) 7.5 Hz), 4.49 (0.09H, dd, J ) 6.6,
2.4 Hz), 4.61-4.66 (2.09H, m), 5.10-5.16 (2.19H, m), 5.29 (0.09H,
dd, J ) 9.1, 4.2 Hz), 5.45 (1.0H, d, J ) 2.4 Hz), 5.74-5.88 (1.09H,
m); 13C NMR δ 25.3, 26.6, 26.8, 37.5, 40.3, 79.8, 80.2, 83.4, 84.0,
86.4, 86.7, 96.2, 103.4, 112.7, 118.1, 118.6, 133.5, 134.5; MS (CI)
m/z (rel intensity) 201 ([MH]+, 11), 183 (100), 125 (40); HRMS
(CI) calcd for C10H16O4 [MH]+ 201.1121, found 201.112458.
Isoxazolidine 14. N-Benzylhydroxylamine hydrochloride (620
mg, 3.88 mmol) and NaHCO3 (544 mg, 6.47 mmol) were added to
a solution of lactol 12 (259 mg, 1.30 mmol) in CH3CN (15 mL).
The reaction mixture was stirred at room temperature for 48 h until
the disappearance of the starting material as shown on TLC. The
mixture was then heated under reflux for 16 h. After cooling, the
mixture was partitioned between CH2Cl2 (30 mL) and water (30
mL). The aqueous layer was extracted with CH2Cl2 (2 × 30 mL).
The combined organic extracts were washed with brine, dried over
anhydrous MgSO4, and filtered. Concentration of the filtrate
followed by flash chromatography (hexane:EtOAc, 1:1) gave
decreased, attributable to 1,3-diaxial steric interaction between
OH-4 and the developing C-C bond. The intramolecular
hydrogen bonding between the free hydroxy group and the
oxygen atom of the protective group or nitrone significantly
increases the stability of the conformer both in the ground state
and TS, which was shown in the formation of cycloheptanol
34 but not cycloheptanol 49. Moreover, the TS structures of
endo- and exo-cyclizations are very different. In the TS of exo-
cyclization, the lengths of the C-C bonds and C-O bonds are
almost the same. On the contrary, the C-O bonds are much
longer than the C-C bonds in the TS of endo-cyclization. The
present INAC showed trivial temperature, but significant solvent
dependence. For lactols 23 and 30, performing the INAC in
2-propanol gave the best yields of fused isoxazolidines (cyclo-
hexanols) whereas that in dichloromethane afforded the best
yields of bridged isoxazolidines (cycloheptanols).
In summary, we describe a novel blocking group strategy in
controlling the mode of cyclization of INAC reactions. With
2,3-trans-acetal as the protecting group, cycloheptanols 27, 34,
and 35 were synthesized from unbranched hept-6-enoses for
the first time. The regio- and stereoselectivity can be further
modified by an appropriate solvent. Following this discovery,
other protecting groups are under active investigation with an
aim to develop INAC reactions of unbranched sugar derivatives
into a general synthetic avenue for the construction of enantio-
pure polyhydroxylated aminocycloheptanols.
Experimental Section
isoxazolidine 14 (362 mg, 92%) as a colorless oil: [R]20 -98.8
D
1,2,3-Trideoxy-5,6-O-isopropylidene-D-allo-oct-1-enitol (10).
To a stirred solution of 2,3-O-isopropylidene-D-ribofuranose (9)
(119 mg, 0.626 mmol) in dry Et2O (25 mL) was added a 1 M Et2O
solution of allylmagnesium bromide (5.0 mL, 5.01 mmol) dropwise
at -78 °C under N2. After the addition, the mixture was allowed
to rise to room temperature and stirred for another 12 h. The mixture
was quenched with saturated NH4Cl solution and the aqueous phase
was extracted with EtOAc (3 × 20 mL). The combined organic
extracts were dried over anhydrous MgSO4 and filtered. The filtrate
was concentrated under reduced pressure and the residue was
purified by flash chromatography (hexane:EtOAc, 3:2) to afford
first alkene 10 (135 mg, 93%) and second its 4-epimer 11 (8.0 mg,
(c 0.74, CHCl3); Rf 0.28 (hexane:EtOAc, 1:2); IR (thin film) 3457,
1
2932, 1377, 1210, 1057, 866 cm-1; H NMR δ 1.33-1.40 (4H,
m), 1.47 (3H, s), 2.07 (1H, ddd, J ) 13.8, 9.6, 7.5 Hz), 2.28 (1H,
d, J ) 6.3 Hz), 2.99-3.09 (1H, m), 3.22 (1H, dd, J ) 8.7, 3.6
Hz), 3.58 (1H, dd, J ) 8.4, 5.7 Hz), 3.95 (1H, d, J ) 13.8 Hz),
4.01 (1H, d, J ) 13.8 Hz), 4.13-4.29 (4H, m), 7.25-7.40 (5H,
m); 1H NMR (C6D6) δ 1.02 (1H, ddd, J ) 13.5, 4.8, 2.7 Hz), 1.13
(3H, s), 1.32 (3H, s), 1.80 (1H, ddd, J ) 13.5, 9.6, 7.5 Hz), 2.20
(1H, d, J ) 6.3 Hz), 2.68 (1H, hextet, J ) 7.8 Hz), 3.12 (1H, dd,
J ) 9, 4.2 Hz), 3.23 (1H, dd, J ) 8.4, 6 Hz), 3.73 (1H, t, J ) 8.1
Hz), 3.75 (1H, d, J ) 14.1 Hz), 3.81 (1H, d, J ) 14.1 Hz), 3.99
(1H, dd, J ) 7.5, 4.2 Hz), 4.08-4.12 (2H, m), 7.05-7.19 (11H,
m), 7.36-7.38 (2H, m); 13C NMR δ 24.5, 26.6, 29.1, 38.2, 61.5,
64.9, 66.2, 72.5, 74.9, 75.1, 108.8, 127.7, 128.7, 129.1, 137.6; MS
(FAB) m/z (rel intensity) 306 ([MH]+, 47), 185 (100), 93 (86);
HRMS (FAB) calcd for C17H23O4N [MH]+ 306.1700, found
306.170960. Anal. Calcd for C17H23O4N: C, 66.86; H, 7.59; N,
4.58. Found: C, 67.36; H, 7.71, N, 4.57.
6%) as colorless oils. Data for 10: [R]20 +17.6 (c 1.14, CHCl3);
D
Rf 0.11 (CHCl3:MeOH, 20:1); IR (thin film) 3304, 2981, 2935,
1
1642. 1371, 1221, 1067, 872 cm-1; H NMR δ 1.33 (3H, s), 1.38
(3H, s), 2.22 (1H, dt, J ) 16.5, 8.4 Hz), 2.54 (1H, s), 2.64 (1H,
dddd, J ) 14.4, 6.3, 3, 1.5 Hz), 3.36 (1H, d, J ) 2.4 Hz), 3.70-
3.72 (1H, m), 3.85-3.88 (3H, m), 3.02 (1H, dd, J ) 9.3, 5.4 Hz),
4.13 (1H, dd, J ) 9.3, 5.4 Hz), 4.20 (1H, s), 5.18 (1H, s), 5.23
(1H, d, J ) 3.9 Hz), 5.82-5.93 (1H, m); 13C NMR δ 25.8, 28.4,
38.9, 64.8, 68.9, 69.8, 78.1, 80.0, 109.2, 119.5, 134.3; MS (FAB)
m/z (rel intensity) 232 ([M]-, 11), ([M - H]-, 100); HRMS (FAB)
calcd for C11H20O5 [M - H]- 231.1238, found 231.123154.
1,2,3-Trideoxy-5,6-O-isopropylidene-D-altro-oct-1-enitol (11).
[R]20 +11.6 (c 0.82, CHCl3) {lit.8 [R]20 +9.6 (c 1.66, CHCl3};
5,6,7-Trideoxy-2,3-O-isopropylidene-r-D-lyxo-hept-6-eno-
furanose (15). Following the glycol cleavage procedure for alkene
10, triol 11 (33.1 mg, 0.165 mmol) was converted into lactol 15
(34.9 mg, 100%) as a colorless oil. [R]20 +15.8 (c 3.00, CHCl3)
D
{lit.8 [R]20D +15.9 (c 1.48, CHCl3)}; Rf 0.58 (hexane:EtOAc, 1:1);
IR (thin film) 3423, 2982, 2941, 1374, 1210, 1064, 1013, 917, 871
1
cm-1; H NMR δ 1.33 (3H, s), 1.47 (3H, s), 2.45-2.50 (2H, m),
D
D
Rf 0.11 (CHCl3:MeOH, 20:1); IR (thin film) 3392, 2936, 1642,
2.56 (1H, br s), 4.19 (1H, td, J ) 6.9, 3.3 Hz), 4.61 (1H, d, J ) 6
Hz), 4.69 (1H, dd, J ) 5.7, 3.6 Hz), 5.08-5.12 (1H, m), 5.18 (1H,
dq, J ) 17.1, 1.5 Hz), 5.36 (1H, d, J ) 2.4 Hz), 5.88 (1H, ddt, J
) 17.1, 10.2, 6.9 Hz); 13C NMR δ 25.3, 26.5, 33.4, 80.0, 80.6,
86.0, 101.3, 112.8, 117.6, 134.8; MS (CI) m/z (rel intensity) 201
([MH]+, 99), 183 (100), 177 (27), 159 (40), 125 (23), 91 (57);
HRMS (CI) calcd for C10H16O4 [MH]+ 201.1121, found 201.112621.
Isoxazolidine 17. N-Methylhydroxylamine hydrochloride (138
mg, 1.65 mmol) and NaHCO3 (139 mg, 1.65 mmol) were added to
a solution of lactol 15 (33.1 mg, 0.165 mmol) in CH3CN (6 mL).
The reaction mixture was stirred at room temperature for 24 h until
the disappearance of the starting material as shown on TLC.
1
1382, 1217, 1057, 873 cm-1; H NMR δ 1.35 (3H, s), 1.47 (3H,
s), 2.07-2.11 (1H, m), 2.41-2.47 (3H, m), 3.47 (1H, br s), 3.64-
3.68 (1H, m), 3.84-3.89 (1H, m), 3.97 (1H, d, J ) 9 Hz), 3.98
(1H, d, J ) 9.6 Hz), 4.05-4.14 (2H, m), 5.13-5.20 (2H, m), 5.86
(1H, ddt, J ) 17.4, 10.2, 7.2 Hz); 13C NMR δ 25.6, 27.9, 40.3,
64.9, 68.5, 69.9, 77.5, 78.6, 108.6, 118.5, 134.9; MS (FAB) m/z
(rel intensity) 233 ([MH]+, 100), 175 (56), 93 (47); HRMS (FAB)
+
calcd for C11H20O5 [MH] 233.1384, found 233.139379.
5,6,7-Trideoxy-2,3-O-isopropylidene-r,â-L-ribo-hept-6-eno-
furanose (12). NaIO4 (228 mg, 1.07 mmol) was dissolved in a
minimum amount of hot water (∼80 °C, 0.5 mL) followed by the
3260 J. Org. Chem., Vol. 71, No. 8, 2006

Nitrone-Alkene Cycloaddition of Hept-6-enoses
NaHCO3 (27.8 mg, 0.331 mmol) was added to acquire a basic
medium and the mixture was then heated under reflux for 8 h. After
cooling, the mixture was partitioned between EtOAc (10 mL) and
water (10 mL). The aqueous layer was extracted with EtOAc (2 ×
10 mL). The combined organic extracts were washed with brine,
dried over anhydrous MgSO4, and filtered. Concentration of the
filtrate followed by flash chromatography (CHCl3:MeOH, 50:1)
with saturated NH4Cl solution and the aqueous phase was extracted
with EtOAc (3 × 100 mL). The combined organic extracts were
dried over anhydrous MgSO4 and filtered. The filtrate was
concentrated under reduced pressure and the residue was purified
by flash chromatography (CHCl3:EtOAc, 1:4) to afford first triol
22 (1.68 g, 50%) and second triol 21 (1.68 g, 50%) as colorless
oils. Data for 21: [R]20 +148.0 (c 1.7, CHCl3); Rf 0.24 (CHCl3:
D
gave isoxazolidine 17 (34.9 mg, 92%) as a colorless oil: [R]20
EtOAc, 1:3); IR (thin film) 3385, 2946, 1379, 1130, 1038 cm-1
;
D
-113.2 (c 1.63, CHCl3) {lit.8 [R]20 -115.6 (c 1.45, CHCl3)}; Rf
1H NMR δ 1.26-1.28 (6H, 2s), 2.32-2.51 (2H, 1dt, J ) 14.1, 6.6
Hz, 1dt, J ) 14.1, 7.2 Hz), 2.83-2.95 (2H, m), 3.23-3.25 (6H,
2s), 3.59 (1H, d, J ) 5.7 Hz), 3.67-3.78 (4H, m), 3.91 (1H, br s),
4.00 (1H, dd, J ) 9.9, 6 Hz), 5.08-5.16 (2H, m), 5.84 (1H, ddt, J
) 17.4, 10.2, 7.2 Hz); 13C NMRδ17.8, 17.9, 37.9, 48.5, 48.5, 63.8,
69.7, 70.5, 71.5, 72.2, 99.0, 99.2, 118.0, 135.5; MS (FAB) m/z (rel
intensity) 329 ([M + Na]+, 100), 243 (45), 115 (55), 101 (33);
HRMS (FAB) calcd for C14H26O7 [M + Na]+ 329.1571, found
329.157304.
D
0.20 (EtOAc); IR (thin film) 3418, 3987, 2937, 2880, 1679, 1457,
1382, 1215, 1060, 862 cm-1; H NMR δ 1.34 (3H, s), 1.46 (3H,
1
s), 1.59 (1H, ddd, J ) 14.1, 6.3, 3.6 Hz), 2.01 (1H, ddd, J ) 14.1,
7.5, 2.7 Hz), 2.74 (3H, s), 2.91-2.95 (2H, m), 3.73-3.77 (2H, m),
4.18-4.24 (2H, m), 4.31 (1H, dd, J ) 7.2, 2.4 Hz); 13C NMR δ
24.6, 27.2, 29.2, 37.7, 44.2, 68.2, 69.0, 72.7, 73.6, 77.5, 108.6;
MS (ESI) m/z (rel intensity) 230 ([MH]+, 100), 185 (2); HRMS
(ESI) calcd for C11H19O4N [MH]+ 230.1387, found 230.138771.
Benzyl-2,3-O-[(2S,3S)-2,3-dimethoxybutan-2,3-dioxy]-â-D-
arabinopyranoside (19). To a suspension of benzyl-â-D-arabino-
pyranoside 18 (501 mg, 2.09 mmol) in methanol (25 mL) were
added 2,2,3,3-tetramethoxybutane (483 mg, 2.71 mmol), trimethyl-
orthoformate (0.91 mL, 8.34 mmol), and (()-10-camphorsulfonic
acid (48.4 mg, 10 mol %) and the mixture was heated under reflux
for 12 h. Powered NaHCO3 (0.1 g) was then added to the cooled
reaction mixture, which was stirred for 5 h. The mixture was filtered
and the filtrate was concentrated under reduced pressure. The
residue was dissolved in EtOAc and the solution was washed with
saturated NaHCO3 solution. The organic layer was dried over
anhydrous MgSO4 and filtered. The filtrate was concentrated under
reduced pressure and the crude residue was purified by flash
chromatography (hexane:EtOAc, 1:1) to afford glycoside 19 (558
mg, 76%) as a white solid. Recrystallization from EtOAc-hexane
Data for 22: [R]20 +148.7 (c 1.43, CHCl3); Rf 0.33 (CHCl3:
D
EtOAc, 1:3); IR (thin film) 3381, 2947, 1378, 1129, 1038 cm-1
;
1H NMR δ 1.27-1.28 (6H, 2s), 2.15 (1H, dt, J ) 14.4, 9 Hz),
2.49 (1H, br s), 2.81 (1H, dddd, J ) 14.1, 5.7, 2.7, 1.2 Hz), 3.14-
3.15 (1H, m), 3.26-3.27 (6H, 2s), 3.55 (1H, dd, J ) 9.8, 8.1 Hz),
3.71-3.91 (5H, m), 4.46 (1H, br s), 5.18-5.22 (2H, m), 5.84 (1H,
dddd, J ) 17.7, 9.3, 8.4, 6 Hz); 13C NMR δ 17.8, 17.8, 37.8, 48.6,
63.7, 70.4, 70.7, 73.8, 98.8, 99.1, 119.7, 134.9; MS (FAB) m/z (rel
intensity) 329 ([M + Na]+, 100), 115 (92), 101 (70), 57 (69), 43
(70); HRMS (FAB) calcd for C14H26O7 [M + Na]+ 329.1571, found
329.157350.
5,6,7-Trideoxy-2,3-O-[(2S,3S)-2,3-dimethoxybutan-2,3-dioxy]-
r,â-L-xylo-hept-6-eneofuranose 23. Following the glycol cleavage
procedure for alkene 10, triol 21 (811 mg, 2.65 mmol) was
converted into lactol 23 (723 mg) as a colorless oil. It was used in
the next step without characterization.
gave white crystals: mp 144-145 °C; [R]20 -3.94 (c 1.27,
D
CHCl3); Rf 0.33 (hexane:EtOAc, 1:1); IR (thin film) 3465, 2938,
1
Isoxazolidines 25, 26, and 27. N-Methylhydroxylamine hydro-
chloride (660 mg, 7.91 mmol) and NaHCO3 (1.11 g, 13.2 mmol)
were added to a solution of lactol 23 (723 mg) in CH3CN (80 mL).
The reaction mixture was stirred at room temperature for 30 min
until the disappearance of the starting material as shown on TLC.
The mixture was then heated under reflux for 1 h. After being
cooled, the mixture was partitioned between EtOAc (100 mL) and
water (60 mL). The aqueous layer was extracted with EtOAc (3 ×
100 mL). The combined organic extracts were washed with brine,
dried over anhydrous MgSO4, and filtered. Concentration of the
filtrate followed by flash chromatography (CHCl3:MeOH, 30:1)
gave a mixture of isoxazolidines 25, 26, and 27 (783 mg, 98%
from 21) as a colorless oil. Flash chromatography (EtOAc:hexane,
2:1) afforded first a mixture of 25 and 27 (0.643 g, 80%) as a
colorless oil and second isoxazolidine 26 (0.134 g, 17%) as a white
solid.
1132, 1057, 884 cm-1; H NMR δ 1.31-1.33 (6H, 2s), 2.59 (1H,
s), 3.22 (3H, s), 3.26 (3H, s), 3.71 (1H, dd, J ) 12.6, 1.5 Hz), 3.81
(1H, d, J ) 12.6 Hz), 3.93 (1H, s), 4.13 (1H, dd, J ) 10.5, 2.7
Hz), 4.19 (1H, dd, J ) 10.5, 3.3 Hz), 4.67 (1H, d, J ) 12.3 Hz),
4.75 (1H, d, J ) 12.6 Hz), 4.95 (1H, d, J ) 3 Hz), 7.28-7.42 (5H,
m); 13C NMR δ 18.2, 48.3, 48.4, 63.4, 65.6, 66.3, 68.4, 69.8, 97.3,
100.6, 100.7, 128.1, 128.5, 128.8, 138.0; MS (FAB) m/z (rel
intensity) 377 ([M + Na]+, 27), 323 ([M - OCH3]+, 26), 101 (60),
91 (100); HRMS (FAB) calcd for C18H26O7 [M + Na]+ 377.1571,
found 377.157871.
O-[(2S,3S)-2,3-Dimethoxybutan-2,3-dioxy]-r,â-D-arabinose (20).
To a solution of glycoside 19 (4.17 g, 11.8 mmol) in EtOH (80
mL) was added 10% Pd-on-charcoal (626 mg, 5% mol) and the
mixture was stirred under an atmosphere of H2 (balloon). After
being stirred at room temperature under H2 for 12 h, the mixture
was filtered and the filtrate was concentrated. Flash chromatography
(hexane:EtOAc, 1:3) of the residue gave lactol 20 (3.11 g, 100%)
as a white solid: mp 189-190 °C; [R]20D +92.7 (c 2.69, MeOH);
Rf 0.30 (EtOAc); IR (thin film) 3435, 2947, 1379, 1133, 1060, 1001
cm-1; 1H NMR (mixture of R and â isomer with ratio R:â ) 1:1.3)
δ 1.31-1.33 (10.8H, m), 2.59 (1.0H, br s), 2.72 (0.8H, br s), 3.20
(1.0H, br s), 3.25-3.29 (10.8H, m), 3.60-3.64 (1.6H, m), 3.72-
4.20 (8.2H, m), 4.66 (0.8H, t, J ) 6.3 Hz), 5.30 (1.0H, s); 13C
NMR δ 17.9, 18.0, 48.3, 48.3, 63.3, 65.6, 65.8, 67.5, 67.8, 68.3,
68.7, 70.2, 92.1, 95.9, 100.1, 100.5, 100.5; MS (FAB) m/z (rel
intensity) 233 ([M - OCH3]+, 37), 185 (100), 93 (93); HRMS
(FAB) calcd for C11H20O7 [M - OCH3]+ 233.1020, found
233.102450.
Data for 26: mp 174-175 °C; [R]20 +159.6 (c 0.40, CHCl3);
D
Rf 0.14 (EtOAc); IR (thin film) 3419, 2950, 1134, 1034, 974, 868
1
cm-1; H NMR (C6D6) δ 1.08 (1H, td, J ) 12.6, 10.8 Hz), 1.27
(3H, s), 1.33 (3H, s), 1.60 (1H, dt, J ) 12.3, 3.6 Hz), 1.98-2.09
(1H, m), 2.13-2.16 (1H, br d, J ) 9.6), 2.21 (1H, t, J ) 10.5 Hz),
2.94 (3H, s), 3.09-3.10 (6H, 2s), 3.25 (1H, dd, J ) 10.2, 6.0 Hz),
1
3.47-3.64 (3H, m), 3.82 (1H, t, J ) 9.3 Hz); H NMR (C6D6-
D2O) δ 1.07 (1H, td, J ) 12.6, 10.5 Hz), 1.27 (3H, s), 1.32 (3H,
s), 1.59 (1H, dt, J ) 12.9, 4.8 Hz), 2.02-2.12 (1H, m), 2.21 (1H,
t, J ) 10.2 Hz), 2.94 (3H, s), 3.09-3.10 (6H, 2s), 3.24 (1H, dd, J
) 10.5, 6.3 Hz), 3.50 (1H, td, J ) 9.3, 4.8 Hz), 3.58 (1H, d, J )
6.6 Hz), 3.61 (1H, t, J ) 9.3 Hz), 3.82 (1H, t, J ) 9.3 Hz); 13C
NMR δ 18.1, 18.1, 31.1, 44.8, 47.5, 48.4, 48.5, 69.2, 70.4, 70.7,
72.0, 75.7, 99.7, 100.2; 13C DEPT135 NMR δ 18.1 (+ve), 18.1
(+ve), 31.1 (-ve), 44.8 (+ve), 47.5 (+ve), 48.4 (+ve), 48.5 (+ve),
69.2 (-ve), 70.4 (+ve), 70.7 (+ve), 72.0 (+ve), 75.7 (+ve); MS
(FAB) m/z (rel intensity) 304 ([MH]+, 65), 303 ([M]+, 52), 272
([M - OCH3]+, 16), 154 (57), 83 (56), 69 (90), 57 (100); HRMS
(FAB) calcd for C14H25O6N [MH]+ 304.1755, found 304.175464.
1,2,3-Trideoxy-5,6-O-[(2S,3S)-2,3-dimethoxybutan-2,3-dioxy]-
D-gluco-oct-1-enitol (21) and 1,2,3-Trideoxy-5,6-O-[(2S,3S)-2,3-
dimethoxybutan-2,3-dioxy]-D-manno-oct-1-enitol (22). A 1 M
THF solution of allylmagnesium bromide (44.0 mL, 44.0 mmol)
was added dropwise to a stirred solution of lactol 20 (2.90 g, 11.0
mmol) in THF (200 mL) at -78 °C under N2 over 30 min. After
being stirred at -78°C for another 1 h, the mixture was quenched
J. Org. Chem, Vol. 71, No. 8, 2006 3261

Shing et al.
Anal. Calcd for C14H25O6N: C, 55.43; H, 8.31; N, 4.62. Found:
C, 55.04; H, 8.42, N, 4.43.
Hz), 4.11 (1H, dt, J ) 8.7, 2.7 Hz), 4.31 (1H, t, J ) 9.6 Hz); 13C
NMR δ 17.85, 17.96, 30.97, 38.94, 47.01, 48.36, 67.13, 71.00,
72.82, 74.04, 99.07, 99.96; 13C NMR (C6D6) δ 18.0, 18.2, 31.0,
40.0, 46.8, 47.9, 67.4, 67.7, 71.2, 73.6, 74.1, 99.1, 100.0; 13C
DEPT135 NMR (C6D6) δ 18.0 (+ve), 18.2 (+ve), 31.0 (-ve), 40.0
(-ve), 46.8 (+ve), 47.9 (+ve), 67.4 (+ve), 67.7 (+ve), 71.2 (+ve),
73.6 (+ve), 74.1 (+ve); MS (FAB) m/z (rel intensity) 304 ([MH]+,
28), 303 ([M]+, 14), 272 ([M - OCH3]+, 24), 154 (100), 137 (72),
69 (69), 55 (66); HRMS (FAB) calcd for C14H25O6N [MH]+
304.1755, found 304.175796.
5,6,7-Trideoxy-2,3-O-[(2S,3S)-2,3-dimethoxybutan-2,3-dioxy]-
r,â-D-arabino-hept-6-eneofuranose (30). Following the glycol
cleavage procedure for alkene 10, triol 22 (852 mg, 2.78 mmol)
was converted into lactol 30 (0.763 g) as a colorless oil. It was
used in the next step without characterization.
Silyl Ethers 28 and 29. A solution of a mixture of isoxazolidines
25 and 27 (643 mg, 2.12 mmol), imidazole (721 mg, 10.6 mmol),
and TBSCl (798 mg, 5.30 mmol) in dry DMF (4 mL) was stirred
at room temperature for 24 h. The mixture was quenched with
saturated NaHCO3 solution and the aqueous phase was extracted
with Et2O (2 × 20 mL). The combined organic extracts were
washed with brine, dried over anhydrous MgSO4, and filtered. The
filtrate was concentrated under reduced pressure and the residue
was purified by flash chromatography (hexane:Et2O, 1:2) to afford
first silyl ether 28 (708 mg, 80%) and second silyl ether 29 (172
mg, 19%) as white solids. Data for 28: mp 99-100 °C; [R]20
D
+103.8 (c 2.67, CHCl3); Rf 0.67 (hexane:EtOAc, 1:2); IR (thin film)
2952, 2857, 1463, 1373, 1252, 1129, 1037, 836 cm-1; 1H NMR δ
0.05 (3H, s), 0.09 (3H, s), 0.87 (9H, s), 1.28-1.29 (6H, 2s), 1.51
(1H, dt, J ) 14.1, 4.8 Hz), 1.88 (1H, ddd, J ) 14.7, 9.6, 5.4 Hz),
2.75 (3H, s), 2.78 (1H, t, J ) 8.4 Hz), 2.97-3.06 (1H, m), 3.28
(6H, s), 3.38 (1H, t, J ) 7.8 Hz), 3.55 (1H, dd, J ) 11.4, 6.3 Hz),
3.64 (1H, dd, J ) 11.4, 8.4 Hz), 3.92 (1H, q, J ) 5.1 Hz), 4.14
(1H, t, J ) 8.4 Hz); 13C NMR δ -4.4, -4.2, 18.1, 18.2, 18.4,
26.2, 33.1, 38.4, 45.7, 48.3, 48.5, 69.2, 69.5, 70.1, 71.3, 75.0, 99.4;
MS (EI) m/z (rel intensity) 418 ([MH]+, 12), 417 ([M]+, 40), 386
([M - OCH3]+, 17), 286 ([M - OTBS]+, 16), 85 (57), 75 (98), 57
(99), 43 (100); HRMS (EI) calcd for C20H39O6NSi [M]+ 417.2541,
found 417.253508.
Isoxazolidines 32, 33, 34, and 35. Following the INAC
procedure for lactol 23, lactol 30 (763 mg) was converted into a
mixture of isoxazolidines 32, 33, 34, and 35 (843 mg, 100% from
22) as a colorless oil.
Silyl Ethers 36, 37, and 38. Following the silylation procedure
for isoxazolidines 25 and 27, isoxazolidines 32, 33, 34, and 35 (843
mg, 2.78 mmol) were converted into silyl ethers 36, 37, and 38.
Purification by flash chromatography (hexane:EtOAc, 4:1 to 1:5)
afforded first silyl ether 37 (395 mg, 34%) as a colorless oil, second
silyl ether 38 (197 mg, 17%) as a colorless oil, third silyl ether 36
(309 mg, 27%) as a white solid, and finally the starting isoxazolidine
35 (232 mg, 20%) as a colorless oil.
Data for 29: mp 53-54 °C [R]20 +132.3 (c 2.65, CHCl3); Rf
D
0.60 (hexane:EtOAc, 1:2); IR (thin film) 2950, 1465, 1374, 1251,
Data for 36: mp 62-63 °C; [R]20D +100.7 (c 1.31, CHCl3); Rf
0.19 (hexane:EtOAc, 2:1); IR (thin film) 2951, 1462, 1375, 1253,
1
1127, 1036, 842, 777 cm-1; H NMR (C6D6) δ 0.13 (3H, s), 0.22
1
(3H, s), 1.01 (9H, s), 1.13 (1H, d, J ) 12.9 Hz), 1.36 (3H, s), 1.40
(3H, s), 1.79 (1H, ddd, J ) 14.7, 6.9, 4.2 Hz), 1.85-1.98 (1H, m),
2.39 (3H, s), 2.92 (1H, dd, J ) 7.5, 2.4 Hz), 3.10 (3H, s), 3.13
(3H, s), 3.36 (1H, dd, J ) 9, 2.7 Hz), 3.65 (1H, td, J ) 9.3, 7.2
1126, 1044, 838 cm-1; H NMR (C6D6) δ 0.12 (3H, s), 0.27 (3H,
s), 1.01 (9H, s), 1.18 (1H, ddd, J ) 15, 6.9, 3 Hz), 1.31 (3H, s),
1.39 (3H, s), 1.59 (1H, dd, J ) 15, 1.2 Hz), 2.40 (1H, pentet, J )
8.4 Hz), 2.74 (1H, t, J ) 7.8 Hz), 3.10 (3H, s), 3.33-3.37 (4H,
m), 3.84 (1H, q, J ) 3 Hz), 3.89 (1H, dd, J ) 9.6, 6.6 Hz), 4.13
(1H, dd, J ) 9.3, 6.6 Hz), 4.28 (1H, dd, J ) 10.5, 9.6 Hz); 13C
NMR δ -4.9, -4.4, 17.9, 18.2, 18.6, 26.2, 29.7, 38.3, 46.1, 48.1,
48.2, 65.9, 69.4, 69.6, 71.1, 71.2, 99.4, 99.6; MS (FAB) m/z (rel
intensity) 418 ([MH]+, 84), 417 ([M]+, 67), 386 ([M - OCH3]+,
17), 109 (57), 95 (79), 83 (81), 69 (100), 55 (98); HRMS (FAB)
calcd for C20H39O6NSi [MH]+ 418.2619, found 418.261484.
Hz), 4.12 (1H, dd, J ) 8.7, 2.4 Hz), 4.29 (1H, t, J ) 9.6 Hz); 13
C
NMR δ -4.8, -3.9, 17.8, 18.6, 26.2, 31.0, 42.3, 46.9, 48.2, 67.4,
68.6, 71.0, 72.9, 74.2, 98.8, 99.6; MS (FAB) m/z (rel intensity)
418 ([MH]+, 23), 417 ([M]+, 10), 386 ([M - OCH3]+, 46), 286
([M - OTBS]+, 12), 95 (60), 73 (75), 69 (83), 55 (100), 43 (66);
HRMS (FAB) calcd for C20H39O6NSi [MH]+ 418.2619, found
418.262570.
Isoxazolidine 25. To a solution of silyl ether 28 (29.0 mg, 0.0694
mmol) in THF (3 mL) was added a 1 M THF solution of TBAF
(0.14 mL, 0.139 mmol). The reaction mixture was stirred at room
temperature for 12 h and the solvent was removed under reduced
pressure. Flash chromatography of the residue (CHCl3:MeOH, 30:
1) afforded isoxazolidine 25 (21.0 mg, 100%) as a white solid:
mp 141-142 °C; [R]20D +144.8 (c 0.93, CHCl3); Rf 0.15 (EtOAc);
IR (thin film) 3445, 2950, 1123, 1035 cm-1; 1H NMR δ 1.32 (6H,
s), 1.66 (1H, ddd, J ) 15.9, 9.6, 6 Hz), 2.11 (1H, dt, J ) 14.4, 4.8
Hz), 2.48 (1H, br s), 2.67 (3H, s), 2.99 (1H, t, J ) 8.4 Hz), 3.08-
3.17 (1H, m), 3.29-3.30 (6H, 2s), 3.44 (1H, t, J ) 8.4 Hz), 3.46
(1H, d, J ) 9.0 Hz), 3.59 (1H, t, J ) 10.5 Hz), 3.86 (1H, td, J )
8.7, 5.4 Hz), 4.16 (1H, dd, J ) 9.3, 7.5 Hz); 13C NMR δ 18.0,
29.8, 37.7, 45.6, 48.4, 48.6, 67.3, 68.6, 68.8, 70.2, 74.0, 99.5, 99.6;
13C DEPT135 NMR δ 18.0 (+ve), 29.8 (-ve), 37.7 (+ve), 45.6
(+ve), 48.4 (+ve), 48.6 (+ve), 67.3 (+ve), 68.6 (+ve), 68.8 (+ve),
70.2 (-ve), 74.0 (+ve); MS (FAB) m/z (rel intensity) 304 ([MH]+,
65), 303 ([M]+, 65), 272 ([M - OCH3]+, 42), 154 (77), 55 (100);
HRMS (FAB) calcd for C14H25O6N [MH]+ 304.1755, found
304.176525.
Isoxazolidine 27. According to the desilylation procedure for
silyl ether 28, silyl ether 29 (91.3 mg, 0.219 mmol) gave
isoxazolidine 27 (66.2 mg, 100%) as a white solid: mp 207-208
°C; [R]20D +220.9 (c 1.10, CHCl3); Rf 0.18 (EtOAc); IR (thin film)
3415, 2961, 1462, 1378, 1125, 1026 cm-1; 1H NMR (C6D6) δ 1.08
(1H, d, J ) 13.2 Hz), 1.21 (3H, s), 1.35 (3H, s), 1.85 (1H, ddd, J
) 12.9, 9.3, 8.1 Hz), 1.96 (1H, dd, J ) 8.1, 3 Hz), 2.34 (3H, s),
2.88 (1H, dd, J ) 7.8, 2.7 Hz), 2.95 (3H, s), 3.08 (3H, s), 3.21
(1H, br s), 3.33 (1H, dd, J ) 9, 2.7 Hz), 3.60 (1H, td, J ) 9.9, 8.4
Data for 37: [R]20 +91.5 (c 0.70, CHCl3); Rf 0.54 (hexane:
D
EtOAc, 2:1); IR (thin film) 2946, 2763, 375, 1251, 1133, 837, 775
1
cm-1; H NMR δ 0.04 (3H, s), 0.10 (3H, s), 0.87 (9H, s), 1.23
(3H, s), 1.26 (3H, s), 1.43 (1H, td, J ) 12.9, 2.1 Hz), 1.80 (1H, dt,
J ) 13.2, 3.3 Hz), 2.33 (1H, t, J ) 10.2 Hz), 2.93-3.01 (1H, m),
3.19 (3H, s), 3.22 (3H, s), 3.49 (1H, dd, J ) 9.6, 2.4 Hz), 3.61
(1H, dd, J ) 11.1, 6 Hz), 3.96 (1H, t, J ) 6.6 Hz), 4.04 (1H, q, J
) 2.7 Hz), 4.10 (1H, t, J ) 9.6 Hz); 13C NMR δ -4.8, -4.3, 18.0,
18.2, 18.6, 26.1, 32.5, 42.8, 47.6, 48.0, 48.1, 68.9, 69.5, 69.6, 72.8,
73.1, 99.2, 100.2; MS (FAB) m/z (rel intensity) 418 ([MH]+, 100),
417 ([M]+, 70), 386 ([M - OCH3]+, 12), 101 (25), 73 (43); HRMS
(FAB) calcd for C20H39O6NSi [MH]+ 418.2619, found 418.261854.
Data for 38: [R]20 +62.4 (c 1.41, CHCl3); Rf 0.38 (hexane:
D
EtOAc, 2:1); IR (thin film) 2951, 2855, 1125, 1040, 836 cm-1; 1H
NMR δ 0.03 (3H, s), 0.09 (3H, s), 0.91 (9H, s), 1.23 (3H, s), 1.25
(3H, s), 1.45 (1H, ddd, J ) 15, 4.5, 1.5 Hz), 2.01 (1H, dt, J )
15.3, 3.3 Hz), 2.22 (1H, d, J ) 13.2 Hz), 2.48 (1H, dt, J ) 13.5,
8.4 Hz), 2.62 (3H, s), 3.09 (1H, d, J ) 6.9 Hz), 3.20 (3H, s), 3.22
(3H, s), 3.64 (1H, dd, J ) 9.6, 1.2 Hz), 3.97 (1H, t, J ) 2.1 Hz),
4.28 (1H, d, J ) 9.3 Hz), 4.58 (1H, dd, J ) 8.7, 4.5 Hz); 13C NMR
δ -4.9, -4.4, 17.7, 18.1, 18.6, 26.2, 32.2, 39.9, 47.9, 48.1, 68.5,
72.0, 76.3, 99.1, 99.3; MS (FAB) m/z (rel intensity) 418 ([MH]+,
100), 417 ([M]+, 76), 386 ([M - OCH3]+, 20), 154 (53), 95 (56),
69 (67), 55 (69); HRMS (FAB) calcd for C20H39O6NSi [MH]+
418.2619, found 418.262098.
Data for 35: [R]20 +169.4 (c 1.72 CHCl3); Rf 0.38 (EtOAc:
D
MeOH, 10:1); IR (thin film) 3432, 2948, 1127, 1039, 756 cm-1
;
1H NMR (C6D6) δ 1.31 (3H, s), 1.40 (3H, s), 1.72 (1H, ddd, J )
15.6, 3.6, 1.2 Hz), 1.89 (1H, dd, J ) 15.6, 5.1 Hz), 2.04 (1H, dt,
3262 J. Org. Chem., Vol. 71, No. 8, 2006

Nitrone-Alkene Cycloaddition of Hept-6-enoses
J ) 12.3, 8.4 Hz), 2.27 (1H, br s), 2.35 (1H, d, J ) 12.6 Hz), 2.39
(3H, s), 2.97 (3H, s), 3.05 (1H, dd, J ) 7.8, 2.7 Hz), 3.11 (3H, s),
3.96 (1H, d, J ) 6 Hz), 4.05 (1H, dd, J ) 9.3, 2.7 Hz), 4.23 (1H,
d, J ) 9.3 Hz), 4.44 (1H, dd, J ) 9.6, 1.5 Hz); 13C NMR δ 18.0,
30.4, 38.1, 47.2, 48.2, 67.8, 69.3, 70.7, 70.9, 75.1, 99.4, 99.6; 13C
DEPT135 NMR δ 18.0 (+ve), 30.4 (-ve), 38.1 (-ve), 47.2 (+ve),
48.2 (+ve), 67.8 (+ve), 69.3 (+ve), 70.7 (+ve), 70.9 (+ve), 75.1
(+ve); MS (FAB) m/z (rel intensity) 326 ([M + Na]+, 30), 304
([MH]+, 26), 303 ([M]+, 55), 272 ([M - OCH3]+, 40), 95 (56), 69
(77), 55 (100); HRMS (FAB) calcd for C14H25O6N [M]+ 303.1676,
found 303.167070. Anal. Calcd for C14H25O6N: C, 55.43; H, 8.31;
N, 4.62. Found: C, 55.26; H, 8.16, N, 4.04.
(160 mg) as a colorless oil. N-Methylhydroxylamine hydrochloride
(146 mg, 1.75 mmol) and NaHCO3 (244 mg, 2.91 mmol) were
added to a solution of lactol 23 (160 mg) in CH3CN (10 mL). After
being stirred at room temperature for 30 min the reaction mixture
was partitioned between EtOAc (20 mL) and water (20 mL). The
aqueous layer was extracted with EtOAc (2 × 20 mL). The
combined organic extracts were washed with brine, dried over
anhydrous MgSO4, and filtered. Concentration of the filtrate
followed by flash chromatography (CHCl3:MeOH, 15:1) gave
nitrone 24 (269 mg, 100% from 21) as a colorless oil: [R]20
D
+175.4 (c 1.35, CHCl3); Rf 0.31 (EtOAc:MeOH, 30:1); IR (thin
1
film) 3362, 2950, 1642, 1378, 1214, 1120, 1036, 957 cm-1; H
Isoxazolidine 32. According to the desilylation procedure for
silyl ether 28, silyl ether 36 (27.5 mg, 0.0659 mmol) gave
isoxazolidine 32 (19.9 mg, 100%) as a white solid: mp 161-162
°C; [R]20D +149.4 (c 1.60, CHCl3); Rf 0.19 (EtOAc); IR (thin film)
3479, 3390, 2947, 1117, 1037 cm-1; 1H NMR (C6D6) δ 1.19 (1H,
ddd, J ) 15.3, 6.3, 4.5 Hz), 1.33 (3H, s), 1.38 (3H, s), 1.80 (1H,
dt, J ) 15.3, 2.4 Hz), 2.26-2.37 (1H, m), 2.52 (3H, s), 2.58 (1H,
br s), 2.70 (1H, dd, J ) 9, 7.8 Hz), 3.08 (3H, s), 3.33 (3H, s), 3.45
(1H, dd, J ) 10.8, 3.0 Hz), 3.85 (1H, d, J ) 6.6 Hz), 3.87 (1H, dd,
J ) 9.9, 7.2 Hz), 4.09 (1H, dd, J ) 9.0, 7.2 Hz), 4.34 (1H, dd, J
) 10.8, 9.3 Hz); 13C NMR (C6D6) δ 18.1, 18.4, 27.9 (2H), 37.8,
NMR δ 1.29 (3H, s), 1.35 (3H, s), 2.28 (1H, dt, J ) 13.2, 6.3 Hz),
2.56 (1H, dt, J ) 14.4, 6.6 Hz), 3.25 (3H, s), 3.26 (3H, s), 3.45-
3.52 (1H, m), 3.62 (1H, dd, J ) 9.9, 2.1 Hz), 3.37 (3H, s), 4.70
(1H, d, J ) 4.8 Hz), 5.03-5.13 (2H, m), 5.20 (1H, dd, J ) 9.9,
6.6 Hz), 5.89 (1H, ddt, J ) 17.1, 10.2, 6.9 Hz), 6.80 (1H, d, J )
6.6 Hz); 13C NMR δ 17.8, 18.0, 36.4, 48.7, 53.3, 65.9, 69.9, 71.5,
99.1, 99.5, 117.0, 136.2, 138.4; MS (FAB) m/z (rel intensity) 304
([MH]+, 74), 303 ([M]+, 22), 272 ([M - OCH3]+, 36), 116 (100),
115 (66), 101 (96), 73 (55); HRMS (FAB) calcd for C14H25O6N
[MH]+ 304.1755, found 304.175680.
Nitrone 31. Following the procedure for the generation of nitrone
24, triol 22 (129 mg, 0.421 mmol) was converted into nitrone 31
(117 mg, 92% from 22) as a colorless oil: [R]20D +141.8 (c 1.26,
CHCl3); Rf 0.33 (EtOAc:MeOH, 15:1); IR (thin film) 3379, 2950,
45.4, 48.0, 48.2, 65.8, 68.5, 69.6, 71.2 (2H), 71.5, 99.9, 100.3; 13
C
NMR δ 17.9, 18.2, 28.1, 37.9, 45.8, 48.4, 65.5, 68.0, 69.4, 70.7,
71.4, 99.7, 100.0; 13C DEPT135 NMR δ 17.9 (+ve), 18.2 (+ve),
28.1 (-ve), 37.9 (+ve), 45.8 (+ve), 48.4 (+ve), 65.5 (+ve), 68.0
(+ve), 69.4 (+ve), 70.7 (+ve), 71.4 (-ve); MS (FAB) m/z (rel
intensity) 304 ([MH]+, 43), 303 ([M]+, 37), 272 ([M - OCH3]+,
23), 154 (100), 136 (73), 55 (74); HRMS (FAB) calcd for
C14H25O6N [MH]+ 304.1755, found 304.175692.
1
1638, 1376, 1212, 1121, 1036, 888 cm-1; H NMR δ 1.29-1.31
(6H, 2s), 2.14 (1H, dt, J ) 15.3, 8.1 Hz), 2.62 (1H, br d, J ) 14.1
Hz), 3.25-3.26 (6H, 2s), 3.49 (1H, dd, J ) 9.9, 8.7 Hz), 3.67 (3H,
s), 3.76 (1H, td, J ) 8.4, 3.3 Hz), 4.91 (1H, dd, J ) 9.9, 6.3 Hz),
5.05-5.14 (2H, m), 5.52 (1H, br s), 5.91 (1H, ddt, J ) 17.1, 10.2,
6.9 Hz), 6.85 (1H, d, J ) 6.3 Hz); 13C NMR δ 17.7, 17.9, 37.8,
48.7, 48.9, 53.0, 67.5, 70.6, 71.8, 98.5, 98.7, 117.4, 135.7, 140.8;
MS (FAB) m/z (rel intensity) 304 ([MH]+, 100), 272 ([M -
OCH3]+, 55), 185 (70), 93 (92), 101 (53); HRMS (FAB) calcd for
C14H25O6N [MH]+ 304.1755, found 304.175944.
Isoxazolidine 33. According to the desilylation procedure for
silyl ether 28, silyl ether 37 (56.0 mg, 0.134 mmol) gave
isoxazolidine 33 (40.6 mg, 100%) as a colorless oil: [R]20D +86.8
(c 0.96, CHCl3); Rf 0.14 (EtOAc); IR (thin film) 3449, 2947, 1381,
1132, 1036 cm-1; 1H NMR (CDCl3:C6D6, 1:3) δ 0.94 (1H, td, J )
13.5, 2.4 Hz), 1.18 (3H, s), 1.24 (3H, s), 1.73 (1H, dt, J ) 13.5,
3.3 Hz), 2.14 (1H, t, J ) 10.5 Hz), 2.41 (1H, br s), 2.88-2.98
(4H, m), 3.03 (3H, s), 3.08 (3H, s), 3.31 (1H, dd, J ) 10.8, 6 Hz),
3.51 (1H, dd, J ) 9.6, 3 Hz), 3.73 (1H, t, J ) 6.9 Hz), 3.80 (1H,
q, J ) 2.7 Hz), 4.19 (1H, t, J ) 9.9 Hz); 13C NMR (C6D6) δ 14.2,
26.3, 39.2, 43.8, 43.9, 64.9, 65.2, 65.5, 69.2, 69.6, 95.8, 96.9; 13C
NMR δ 18.1, 18.2, 30.3, 42.9, 47.6, 48.3, 48.4, 68.7, 69.1, 69.4,
72.5, 73.0, 99.7, 100.8; 13C DEPT135 NMR δ 18.1 (+ve), 18.2
(+ve), 30.3 (-ve), 42.9 (+ve), 47.6 (+ve), 48.3 (+ve), 48.4 (+ve),
68.7 (+ve), 69.1 (+ve), 69.4 (-ve), 72.5 (+ve), 73.0 (+ve); MS
(FAB) m/z (rel intensity) 304 ([M]+, 100), 303 ([M]+, 74), 272
([M - OCH3]+, 25), 154 (80), 55 (86); HRMS (FAB) calcd for
C14H25O6N [MH]+ 304.1755, found 304.175664. Anal. Calcd for
C14H25O6N: C, 55.43; H, 8.31; N, 4.62. Found: C, 55.19; H, 8.55,
N, 4.42.
General Procedure for Performing INAC Reactions in
Different Solvents. Nitrone 24 or 31 was dissolved in the selected
solvent and the solution was either stirred at room temperature or
heated at 40°C. After the completion of the reaction, the solvent
was removed under reduced pressure and the residue was purified
by flash chromatography (CHCl3:MeOH, 30:1) to give a mixture
of cycloadducts. The ratios of the cycloadducts were determined
1
by H NMR spectral analysis.
General Procedure for Studying Equilibration of the Cyclized
Products 25-27 and 32-35. A solution of the individual cyclo-
adduct in toluene in a sealed tube was degassed and heated at 210
°C (sand bath temperature) for 24 h. The reaction was cooled to
room temperature and the solvent was removed under reduced
pressure. The cycloadduct was recovered almost quantitatively.
Isoxazolidine 34. According to the desilylation procedure for
silyl ether 28, silyl ether 38 (66.3 mg, 0.159 mmol) gave
isoxazolidine 34 (37.6 mg, 78%) as a white solid: mp 157-158
°C; [R]20D +104.3 (c 1.12, CHCl3); Rf 0.26 (EtOAc); IR (thin film)
Acknowledgment. This work was partially supported by a
CERG from the Research Grants Council of the Hong Kong
SAR, China (project no. 402805). This work was also partially
supported by a Grant-in-Aid for the 21st century COE program
“KEIO LCC” from the Ministry of Education, Culture, Sports,
Science and Technology, Japan. The authors thank the Research
Center for Computational Science, Okazaki National Institute,
for their support of the DFT calculations.
1
3254, 2960, 1125, 1045, 847 cm-1; H NMR (C6D6) δ 1.04 (1H,
ddd, J ) 15.3, 4.2, 2.4 Hz), 1.35 (3H, s), 1.41 (3H, s), 1.73 (1H,
dt, J ) 12.9, 7.8 Hz), 1.89 (1H, d, J ) 12.6 Hz), 2.10 (1H, dt, J )
15.0, 3.0 Hz), 2.32 (3H, s), 2.73 (1H, d, J ) 9.0 Hz), 3.03 (3H, s),
3.05 (3H, s), 3.76 (1H, d, J ) 8.7 Hz), 4.06-4.11 (2H, m), 4.25
(1H, d, J ) 8.4 Hz); 13C NMR δ 18.0, 33.0, 39.2, 46.4, 48.0, 48.1,
67.8, 71.0, 71.3, 72.5, 78.0, 100.3, 100.4; 13C DEPT135 NMR δ
18.0 (+ve), 33.0 (-ve), 39.2 (-ve), 46.4 (+ve), 48.0 (+ve), 48.1
(+ve), 67.8 (+ve), 71.0 (+ve), 71.3 (+ve), 72.5 (+ve), 78.0 (+ve);
MS (FAB) m/z (rel intensity) 304 ([MH]+, 22), 303 ([M]+, 16),
272 ([M - OCH3]+, 7), 95 (61), 69 (92), 55 (100); HRMS (FAB)
calcd for C14H25O6N [MH]+ 304.1755, found 304.176109.
Supporting Information Available: Complete ref 28, general
1
experimental methods, copies of H and 13C NMR spectra of all
compounds, X-ray crystallographic structure of 25, 27, 32, and 34
(including CIF files), conformers used for the TS search obtained
by CONFLEX, and Cartesian coordinates and energies of the most
stable ground state and some transition states. This material is
available free of charge via the Internet at http://pubs.acs.org.
Nitrone 24. Following the glycol cleavage procedure for alkene
10, triol 21 (178 mg, 0.582 mmol) was converted into lactol 23
JO060348Y
J. Org. Chem, Vol. 71, No. 8, 2006 3263