Stereoselective synthesis of chiral oxepanes and pyrans through intramolecular nitrone cycloaddition in organized aqueous media

Article abstract of DOI:10.1021/jo051414j

A highly stereoselective surfactant-catalyzed intramolecular nitrone (formed by dehydration in water) cycloaddition in aqueous media leading to exclusive formation of a single isomer is reported. Either oxepane or pyran is formed from 3-O-allyl furanoside

Full text of DOI:10.1021/jo051414j

drying of solvents and substrates.3 Also, water has unique
physical and chemical properties, and these sometimes lead to
reactivity or selectivity that cannot be attained in organic
solvents.3c,d
Stereoselective Synthesis of Chiral Oxepanes and
Pyrans through Intramolecular Nitrone
Cycloaddition in Organized Aqueous Media
The problem of insolubility of most organic compounds in
water may be solved by the use of a surfactant, which in water
forms an organized media at the border between the homoge-
neous (solution phase) and heterogeneous phase. This border
region is a gray area consisting of micellar, reverse micellar,
microheterogeneous, colloidal phase, etc. Studies of new reac-
tions in organized media, with the exception of kinetic studies,
are not very common. Although various efficient catalytic
systems in water have been developed,2,4-6 there are still many
reactions that are difficult to carry out in water. One such
reaction is dehydration. Although water as a solvent impedes
dehydration, there are some examples of dehydration reactions
in water.2d,5a In the course of developing efficient organic
reactions in water, we recently reported nitrone formation in
water, followed by its intermolecular cycloaddition to isoxazo-
lidines in a one-pot process.2d During the course of surfactant-
catalyzed reactions,2b-e,4f,g,5 the organized media acts as a
nanoreactor,6 which solubilizes and conforms hydrophobic
organic compounds into its hydrophobic cores where dehydra-
tion, i.e., nitrone formation, occurs. A dynamic light scattering
study6c shows that the surfactant in aqueous solution is self-
assembled with hydrodynamic radii of 1.296 nm (29.36%) and
295.3 nm (70.64%) to form the nanoreactor. Although the steric
disposition of the substrate inside the organized media is
expected to be achiral since the media is formed from achiral
surfactant, we noted that when chiral substances are used along
with the achiral surfactant some stereoselectivity is observed.2d
Therefore, a chiral substrate along with an achiral surfactant in
aqueous media might produce better selectivity than in organic
solvents. To investigate the concept, we report here the use of
arious 3-O-allyl analogues of carbohydrate in stereoselective
Amrita Chatterjee and Pranab K. Bhattacharya*
Chemistry DiVision, Indian Institute of Chemical Biology, 4,
Raja S. C. Mullick Road, JadaVpur, Kolkata 700032, India
pranabbhatta@iicb.res.in
ReceiVed July 8, 2005
A highly stereoselective surfactant-catalyzed intramolecular
nitrone (formed by dehydration in water) cycloaddition in
aqueous media leading to exclusive formation of a single
isomer is reported. Either oxepane or pyran is formed from
3-O-allyl furanoside derivatives, which constitute the frame-
work of a large number of biologically active compounds.
Therefore, the environmentally friendly, efficient, and highly
stereoselective syntheses of these chiral intermediates are still
a meaningful pursuit.
The design of reaction systems for environmentally benign
conditions (green chemistry)1 and highly stereoselective produc-
tion is the cherished goal now. From the standpoint of green
chemistry and its 12 principles,1g,h water is the solvent of
choice,2-6 being both cheap and nontoxic. In recent years
organic reactions in aqueous media attracted a great deal of
attention, because these reactions eliminate both the use of
volatile organic solvents (toxic) and the necessity of vigorous
(4) (a) Aqueous-Phase Organometallic Catalysis. Concepts and Applica-
tions; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim; 1998.
(b) Engberts, J. B. F. N.; Feringa, B. L.; Keller, E.; Otto, S. Recl. TraV.
Chim. Pays-Bas 1996, 115, 457-464. (c) Fringuelli, F.; Piermatti, O.; Pizzo,
F.; Vaccaro, L. Eur. J. Org. Chem. 2001, 439-455. (d) Genet, J. P.;
Savignac, M. J. Organomet. Chem. 1999, 576, 305-317. (e) Kobayashi,
S.; Manabe, K. In Stimulating Concepts in Chemistry; Shibasaki, M.,
Stoddart, J. F., Vo¨gtle, F., Eds.; Wiley-VCH: Weinheim, 2000. (f)
Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209-217. (g)
Aoyama, N.; Manabe, K.; Kobayashi, S. Chem. Lett. 2004, 33, 312-313.
(h) Kobayashi, S.; Hirano, K.; Sugiura, M. Chem. Commun. 2005, (1), 104-
106. (i) Pirrung, M. C.; Das Sarma, K. J. Am. Chem. Soc. 2004, 126, 444-
445. (j) Okuhara, T.; Kimura, M.; Kawai, T.; Xu, Z.; Nakato, T. Catal.
Today 1998, 45, 73-77.
(5) (a) Manabe, K.; Iimura, S.; Sun, X.-M.; Kobayashi, S. J. Am. Chem.
Soc. 2002, 124, 11971-11978. (b) Okino, T.; Takemoto, Y. Org. Lett. 2001,
3 (10), 1515-1517. (c) Kita, Y.; Nambu, H.; Ramesh, N. G.; Anilkumar,
G.; Matsugi, M. Org. Lett. 2001, 3 (8), 1157-1160. (d) Hamada, T.;
Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 7768-7769. (e)
Gogoi, P.; Hazarika, P.; Konwar, D. J. Org. Chem. 2005, 70, 1934-1936.
(f) Chen, L.; Li, C.-J. Org. Lett. 2004, 6 (18), 3151-3153. (g) Tian, H.-Y.;
Li, H.-J.; Chen, Y.-J.; Wang, D.; Li, C.-J. Ind. Eng. Chem. Res. 2002, 41
(18), 4523-4527. (h) Jew, S.-s; Lee, J.-H.; Jeong, B.-S.; Yoo, M.-S.; Kim,
M.-J.; Lee, Y.-J.; Lee, J.; Choi, S.-h.; Lee, K.; Lah, M. S.; Park, H.-g. Angew.
Chem., Int. Ed. 2005, 44 (9), 1383-1385. (i) Bhattacharya, S.; Srivastava,
A.; Sengupta, S. Tetrahedron Lett. 2005, 46 (20), 3557-3560. (j) Wang,
W.; Wang, S.-X.; Qin, X.-Y.; Li, J.-T. Synth. Commun. 2005, 35, 1263-
1269. (k) Das, D.; Roy, S.; Das, P. K. Org. Lett. 2004, 6 (22), 4133-4136.
(6) (a) Lee, M.; Jang, C.-J.; Ryu, J.-H. J. Am. Chem. Soc. 2004, 126,
8082-8083. (b) Research Highlights. In Nat. Mater. 2004, 3 (8), 501. (c)
See Supporting Information.
* To whom correspondence should be addressed. Ph: +91-33-24733491, ext
243. Fax +91-33-24730284.
(1) (a) Warner, J. C.; Cannon, A. S.; Dye, K. M. EnViron. Impact Assess.
ReV. 2004, 24, 775-799. (b) Lancaster, M. In Handbook of Green Chemistry
and Technology; Clark, J. H., Macquarrie, D. J., Eds.; Blackwell Publish-
ing: Abingdon, 2002. (c) Matlack, A. S. Introduction to Green Chemistry;
Marcel Dekker: New York, 2001. (d) Murphy, J. A. Pure Appl. Chem.
2000, 72 (7), 1327-1334. (e) Green Chemistry: Theory and Practice;
Anastas, P. T., Warner, J. C., Eds.; Oxford University Press: Oxford, 1998.
(f) Nameroff, T. J.; Garant, R. J.; Albert, M. B. Res. Policy 2004, 33, 959-
974. (g) Hjeresen, D. L.; Kirchhoff, M. M.; Lankey, R. L. Corporate
EnViron. Strategy 2002, 9 (3), 259-266. (h) U. S. Environmental Protection
Agency: http://www.epa.gov/greenchemistry/principles.html. (i) Anastas,
P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35, 686-694.
(2) (a) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; John
Wiley & Sons: New York, 1997. (b) Li, C.-J. Chem. ReV. 2005, 105, 3095-
3165 and references therein. (c) Lindstro¨m, U. M. Chem. ReV. 2002, 102,
2751-2772. (d) Chatterjee, A.; Maiti, D. K.; Bhattacharya, P. K. Org. Lett.
2003, 5 (21), 3967-3969 and references therein. (e) Li, C.-J. Chem. ReV.
1993, 93, 2023-2035.
(3) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic
and Professional: London, 1998. (b) Rideout, D. C.; Breslow, R. J. Am.
Chem. Soc. 1980, 102, 7816-7817. (c) Breslow, R. Acc. Chem. Res. 1991,
24, 159-164. (d) Engberts, J. B. F. N.; Blandamer, M. J. Chem. Commun.
2001, 1701-1708.
10.1021/jo051414j CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/07/2005
J. Org. Chem. 2006, 71, 345-348
345

SCHEME 1. Synthesis of Furanoside Aldehydes 3a
intramolecular nitrone cycloadditions.7 Dipolar cycloadditions
of nitrones7,8 to alkenes have received much synthetic interest7g-l
because the newly generated ring systems are highly amenable
to further transformations leading to versatile intermediates.
Also, sugar-based chiral cyclic ethers constitute the framework
of a large number of naturally occurring biologically active
compounds such as ciguatoxin,9 other marine toxins,10 zoapa-
tanol,11 sepholenol,12 laurencin,13 etc. The high importance of
these systems resulted in the development of number of synthetic
methods,14 including nitrone cycloaddition.7
To our knowledge, stereoselective intramolecular nitrone
cycloaddition in aqueous media has not been reported, and so,
in continuation of our effort, we herein describe the stereose-
lective synthesis of chiral oxepanes and pyrans by 3-O-allyl
carbohydrate nitrone cycloaddition starting from D-glucose. The
requisite furanoside-5-aldehydes (3) were prepared from the
corresponding 1,2:5,6-diisopropylidene-3-O-allyl furanosides (1)
via a standard sequence of reactions7g (Scheme 1) and were
a Reagents and conditions: (i) 75% aq CH3COOH, rt, 15 h; (ii) NaIO4,
MeOH, H2O, 3 h, 0 °C to rt.
TABLE 1. Effect of Surfactant on Intramolecular Nitrone
Cycloaddition in Water
(7) (a) Shing, T. K. M.; Elsley, D. A.; Gillhouley, J. G. J. Chem. Soc.,
Chem. Commun. 1989, 1280-1282. (b) Collins, P. M.; Ashwood, M. S.;
Eder, H. Tetrahedron Lett. 1990, 31, 2055-2058. (c) Bhattacharjya, A.;
Chattopadhyay, P.; McPhail, A. P.; McPhail, D. R. J. Chem. Soc., Chem.
Commun. 1990, 6, 1508. (d) Shing, T. K. M.; Fung, W.-C.; Wong, C.-H.
J. Chem. Soc., Chem. Commun. 1994, 4, 449-450. (e) Sharma, G. V. M.;
Reddy, K. R.; Sankar, A. R.; Kunwar, A. C. Tetrahedron Lett. 2001, 42,
8893-8896. (f) Shing, T. K. M.; Zhong, Y.-L. Tetrahedron 2001, 57, 1573-
1579. (g) Bhattacharjee, A.; Datta, S.; Chattopadhyay, P.; Ghoshal, N.;
Kundu, A. P.; Pal, A.; Mukhopadhyay, R.; Chowdhury, S.; Bhattacharjya,
A.; Patra, A. Tetrahedron 2003, 59, 4623-4639. (h) Shing, T. K. M.; Zhong,
Y.-L.; Mak, T. C. W.; Wang, R.; Xue, F. J. Org. Chem. 1998, 63, 414-
415. (i) Pal, A.; Bhattacharjya, A.; Mukhopadhyay, R. Tetrahedron Lett.
2000, 41, 10135-10139. (j) Majumdar, S.; Bhattacharjya, A.; Patra, A.
Tetrahedron 1999, 55, 12157-12174. (k) Osborn, H. M. I.; Gemmell, N.;
Harwood, L. M. J. Chem. Soc., Perkin Trans. 1 2002, 2419-2438. (l) Patra,
R.; Bar, N. C.; Roy, A.; Achari, B.; Ghoshal, N.; Mandal, S. B. Tetrahedron
1996, 52, 11265-11272. (m) Bar, N. C.; Roy, A.; Achari, B.; Mandal, S.
B. J. Org. Chem. 1997, 62, 8948-8951. (n) Singha, K.; Roy, A.; Dutta, P.
K.; Tripathi, S.; Sahabuddin, S.; Achari, B.; Mandal, S. B. J. Org. Chem.
2004, 69, 6507-6510. (o) Sharma, G. V. M.; Begum, A.; Reddy, K. R.;
Sankar, A. R.; Kunwar, A. C. Tetrahedron: Asymmetry 2003, 14, 3899-
3905.
(8) (a) Little, R. D. Selectivity, Strategy & Efficiency in Modern Organic
Chemistry. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1999; Vol. 5, pp 247-260. (b) Adams,
J. P. J. Chem. Soc., Perkin Trans. 1 2002, 2586-2597. (c) Brandi, A.;
Cicchi, S.; Cordero, F. M.; Goti, A. Chem. ReV. 2003, 103, 1213-1269.
(d) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863-910. (e)
Adams, J. P.; Box, D. S. J. Chem. Soc., Perkin Trans. 1 1999, 749-764.
(f) Gholami, M. R.; Yangjeh, A. H. J. Chem. Res., Synop. 1999, 226-227.
(g) Karlsson, S.; Hogberg, H.-E. Org. Prep. Proced. Int. 2001, 33, 103-
172. (h) Gothelf, K. V.; Jørgensen, K. A. Chem. Commun. 2000, 1449-
1458. (i) Kanemasa, S. Synlett 2002, 1371-1387. (j) Rastelli, A.; Gandolfi,
R.; Sarzi-Amade, M.; Carboni, B. J. Org. Chem. 2001, 66, 2449-2458.
(k) Tamura, O.; Mita, N.; Okabe, T.; Yamaguchi, T.; Fukushima, C.;
Yamashita, M.; Morita, Y.; Morita, N.; Ishibashi, H.; Sakamoto, M. J. Org.
Chem. 2001, 66, 2602-2610. (l) Denmark, S. E.; Gomez, L. Org. Lett.
2001, 3, 2907-2910.
(9) Scheuer, P. J.; Takahashi, W.; Tsutsumi, J.; Yoshida, T. Science 1967,
155, 1267-1268.
(10) Murata, M.; Legrand, A. M.; Yasumoto, T. Tetrahedron Lett. 1989,
30, 3793-3796.
(11) (a) Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897-1909.
(b) Levine, S. D.; Adams, R. E.; Chem, R.; Cotter, M. L.; Hirsch, A.-F.;
Kane, V. V.; Kanojia, R. M.; Shaw, C.; Wachter, M. P.; Chin, E.;
Huettermann, R.; Ostrowski, P.; Mateos, J. L.; Noriega, L.; Guzmann, A.;
Mijazez, A.; Tavor, L. J. Am. Chem. Soc. 1979, 101, 3404-3405.
(12) Shmueli, U.; Carmely, S.; Groweiss, A.; Kashman, Y. Tetrahedron
Lett. 1981, 22, 709-712.
(13) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron 1968, 24, 4193-
4205.
(14) (a) Alvarez, E.; Candenas, M.-L.; Perez, R.; Ravelo, J. L.; Martin,
J. D. Chem. ReV. 1995, 95, 1953-1980. (b) Nicolaou, K. C. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 589-607. (c) Mori, Y. Chem. Eur. J. 1997, 3,
849-852. (d) Hoberg, J. O. Tetrahedron 1998, 54, 12631-12670.
time yield
time yield
entry surfactant (h)
(%)
entry
surfactant
(h)
(%)
1
2
3
4
48
8
8
5
6
7
8
Triton X-100 30
80
80
61
79
CTAB
SDS
SDBS
79
75
75
Tween-20
DBSA
Triton CF 10
30
16
36
8
sufficiently pure to be used directly in the next step. The
corresponding nitrones, formed in aqueous media catalyzed by
surfactant using phenyl hydroxylamine with the respective
aldehyde at room temperature, underwent stereoselective in-
tramolecular cycloaddition (Scheme 2). By carrying out the
model reaction shown in Table 1, it was found that the type of
surfactant used influenced both the yield and the reaction time.
Nonionic surfactants (entries 5, 6, and 8) were effective but
required longer reaction time, an acidic surfactant (entry 7)
reduced the yield, and anionic surfactants (entries 3 and 4) were
slightly less effective than a cationic surfactant (entry 2). From
these observations we concluded that CTAB is the most efficient
surfactant for this reaction. When performing these reactions
in water without surfactant, we recovered starting materials as
reported earlier.2d No reaction was obtained under neat condi-
tion. We conclude that surfactants have a prominent role in
nitrone formation and the subsequent cycloaddition in aqueous
medium by the formation of an organized media. Similar
reactions when performed in organic solvents, which require
maintaining dry, refluxing condition in most cases, gave a
mixture of pyrans and oxepane isomers.7a-j Often these cy-
cloadditions lead to the formation of nonseparable mixture of
isomers.7a-j
The role of solvent on the ring size selectivity was studied
by Mandal et al.,7k-m who noted changes from five to six
members when the solvent was changed from aprotic to protic
for the substrate with a hydroxyl group at C-3 position. Indeed,
this hydroxyl group has a profound influence over the course
of cyclization, but they still obtained a mixture of products upon
cyclization. However, in our case, there is no free hydroxyl
group present anywhere. The most attractive observation in these
surfactant-mediated intramolecular nitrone cycloaddition reac-
tions of sugar in aqueous media is the formation of a single
isomer out of the four possible isomers (Table 2). The nitrones
of 3-O-allyl glucofuranose and the corresponding allose deriva-
346 J. Org. Chem., Vol. 71, No. 1, 2006

SCHEME 2. Synthesis of Oxepanes (7-10) and Pyrans (11-12)
TABLE 2. Surfactant-Catalyzed Dehydrative Intramolecular
Nitrone Cycloaddition of 3-O-Allyl Furanoside-5-aldehydes in Water
multiplate near δ 2.3 due to H6a and H6b, respectively, and a
relatively high field methylene carbon signal near δ 30.0 due
to C6 in the 13C NMR spectra.7g For crotyl derivatives one
1
quartet appears near δ 3.13 in H NMR spectrum, confirming
oxepane formation. Two-dimensional NMR studies on com-
pound 7 showed a cross-peak between H8b and H3 in the
NOESY spectrum, indicating their diaxial disposition in the
seven-membered ring.7e Cross-peaks between H8a/H7 and H7/
H5 established the â orientation of the bridge (Figure 2). In the
case of the cyclized product of 4b, the cross-peaks between the
doublet of doublet at δ 3.9 due to H4 and the doublet at δ 2.11
due to one of the bridge methylene protons in the NOESY
spectrum established the R-orientation of the bridge in 8.7g For
entry RCHO time (h) product yield (%)
[R]2D5 (CHCl3)
1.
2.
3.
4.
5.
6.
3a
3b
3c
3d
3e
3f
8
8
24
20
36
30
7
8
9
10
11
12
79
84
83
85
74
78
-183.49, c ) 1.43
+193.33, c ) 1.14
-110.19, c ) 1.14
+194.43, c ) 1.15
-140.84, c ) 2.12
-100.30, c ) 2.0
tives (4a and 4b) produce bridged isoxazolidines, i.e., oxepanes
(7 and 8), as do the nitrones of crotyl derivatives 4c and 4d
(oxepanes 9 and 10). In contrast, nitrones of prenyl derivatives
(4e and 4f) produce pyrans (11 and 12), which may be due to
the methyl-methyl steric repulsion restricting formation of
the oxepane skeleton (Figure 1). The structural assignment of
the carbohydrate-derived cycloadducts, particularly the stereo-
chemistry of the newly formed centers C5 and C6 in the
pyranoisoxazolidines (11 and 12), appeared to be problematic.
FIGURE 1. Proposed transition state favoring the pyran formation.
1
Analysis of the relevant H,1H coupling constants as well as
decoupling experiments led to the assigned stereochemistry.
However, information about the skeletal pattern of the product,
whether an oxepane or a pyran, was easily established by the
1H and 13C NMR spectral data. The appearance of a one proton
1
multiplate near δ 2.5 in the H NMR spectra due to H6 and a
methine carbon signal near δ 50.0 in the 13C NMR spectra due
to C6 in 11 and 12 are proper indications of a fused isoxazolidine
skeleton.7g The bridged isoxazolidines (i.e., oxepanes) are
characterized, in the case of allyl-derivatives 7 and 8, by the
appearance of a set of a one proton doublet and a one proton
FIGURE 2. Inter-ring NOESY of 7, 8, 11, and 12
J. Org. Chem, Vol. 71, No. 1, 2006 347

the cyclized product of â-3-O-crotyl nitrone (4c), the observation
of a quartet at δ 3.13 in the 1H NMR spectrum due to the bridge
methine proton as well as a peak at δ 36.72 in the 13C NMR
spectrum due to a bridge methine carbon was a fair indication
of the oxepane skeleton in 9. The bridge -CH(CH3)- was
assigned the â-orientation in analogy with 7. In the case of 10,
a similar analogy assigned the R-orientation of the bridge.7g
In conclusion, we have demonstrated that an achiral nanore-
actor is a useful and green tool for the stereoselective intramo-
lecular 1,3-dipolar nitrone cycloaddition of chiral substrates. This
reactor leads to the formation of the chiral oxepanes and pyrans
with much improved stereoselectivity relative to that observed
in conventional organic solvents. We expect that this reactor
approach in aqueous environment will be applicable to a wide
variety of reactions.
1
From the H NMR spectrum of 11, the coupling constant of
11.7 Hz for JH -H indicates a 1,2-diaxial disposition in a chair
6
7
Acknowledgment. We thank CSIR (India) for financial
assistance, as well as for a research fellowship to A.C., MMP
project (no. CMM 0005) of CSIR (India), and we also thank
Prof. Anjan K. Dasgupta, Department of Biochemistry, Uni-
versity of Calcutta for DLS experiments and, finally, the
Director, IICB, for various forms of help.
conformation, and J4,5 ) 0, suggests that H5 is trans to H4.
Coupling constants involving the protons at the center of ring
fusion are consistent with cis-stereochemistry for the five-
membered rings a, b, and d.7e The inter-ring NOESY interaction
shown in Figure 2 confirmed the envelop conformation for rings
a and d7e for 11. Similarly, the stereochemistry of the compound
12 was determined by inter-ring NOESY spectrum.
As there was no cross-peak between H4 and H6 in the NOESY
spectrum, the stereochemistry of the ring juncture was deter-
mined to be cis.
Supporting Information Available: Spectral data for com-
pounds 7-12, DLS data, and experimental procedures. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO051414J
348 J. Org. Chem., Vol. 71, No. 1, 2006