Generation of nitrile oxides under nanometer micelles built in neutral aqueous media: Synthesis of novel glycal-based chiral synthons and optically pure 2,8-dioxabicyclo[4.4.0]decene core

Article abstract of DOI:10.1021/jo801337k

(Chemical Equation Presented) A highly efficient strategy for chemoselective oxidation of aldoximes to nitrile oxides by iodosobenzene in neutral aqueous media is reported. Their in situ intermolecular 1,3-dipolar cycloaddition (1,3-DC) with olefins in nanometer aqueous micelles occurs with improved stereoselectivity and acceleration of reaction rate toward synthesis of new chiral synthons, 3-(2′-C-3′,4′,6′-tri-O- benzylglycal)-Δ²-isoxazolines and others. Construction of optically pure 2,8-dioxabicyclo[4.4.0]decene skeleta is performed by this green approach, and the stereochemistry of the new chiral center is predicted by B3LYP density functional theory.

Full text of DOI:10.1021/jo801337k

confined chemical reactor also protects water-labile reaction
intermediates from hydrolytic decomposition. It simultaneously
removes generated water to the aqueous environment and makes
chemical transformation faster. It also enhances the possibility
of performing dehydration reactions in water. At the beginning
of the new century, a shift in emphasis in chemistry using water
as solvent for organic reaction is very significant. Water is not
only the most abundant, cheap, and environment friendly
solvent, but it also exhibits unique chemical reactivity, selectiv-
ity, and properties that are different from those of organic
solvents.3
One of the frequently used strategies employed in synthetic
organic chemistry is the 1,3-DC reaction involving nitrile oxides
and alkenes to afford ∆2-isoxazolines.4 These heterocycles offer
significant synthetic potential because they can readily be
converted into a variety of highly functionalized achiral and
chiral compounds.4c-g Nitrile oxides can be prepared either by
the Mukaiyama reaction from a nitro compound and phenyl
isocyanate5 or from an aldoxime and a chlorinating agent in
the presence of base6 and others.7 Most of these methods have
limitations in terms of using a complex combination of reagents
and longer reaction time.
Generation of Nitrile Oxides under Nanometer
Micelles Built in Neutral Aqueous Media:
Synthesis of Novel Glycal-Based Chiral Synthons
and Optically Pure 2,8-Dioxabicyclo[4.4.0]decene
Core
Nirbhik Chatterjee, Palash Pandit, Samiran Halder,
Amarendra Patra, and Dilip K. Maiti*
Department of Chemistry, UniVersity Colleges of Science
and Technology, UniVersity of Calcutta, 92, A. P. C. Road,
Kolkata-700009, India
maitidk@yahoo.com
ReceiVed June 20, 2008
An 1,3-DC reaction proceeds in a highly stereospecific way,
so regiocontrol and stereoselection in their addition step is now
the major challenging task to organic chemists in both academic
and industrial settings. Two major obstacles in controlling the
stereoselectivity are (i) nitrile oxides are generated in situ as
they are very short-lived species8 and (ii) the tertiary amines
used in their preparation can racemize the newly generated chiral
A highly efficient strategy for chemoselective oxidation of
aldoximes to nitrile oxides by iodosobenzene in neutral
aqueous media is reported. Their in situ intermolecular 1,3-
dipolar cycloaddition (1,3-DC) with olefins in nanometer
aqueous micelles occurs with improved stereoselectivity and
acceleration of reaction rate toward synthesis of new chiral
synthons, 3-(2′-C-3′,4′,6′-tri-O-benzylglycal)-∆2-isoxazolines
and others. Construction of optically pure 2,8-
dioxabicyclo[4.4.0]decene skeleta is performed by this green
approach, and the stereochemistry of the new chiral center
is predicted by B3LYP density functional theory.
(2) (a) Fendler, J. H.; Fendler, E. J. Catalysis in Micellar and Macromolecular
Systems; Academic Press: New York, 1975. (b) Ruasse, M.-F.; Blagoeva, I. B.;
Ciri, R.; Garcia-Rio, L.; Leis, J. R.; Marques, A.; Mejuto, J.; Monnier, E. Pure
Appl. Chem. 1997, 69, 1923–1932. (c) Manabe, K.; Limura, S.; Sun, X.-M.;
Kobayashi, S. J. Am. Chem. Soc. 2002, 124, 11971–11978. (d) Buwalda, R. T.;
Stuart, M. C. A.; Engberts, J. B. F. N. Langmuir 2002, 18, 6507–6512. (e)
Chatterjee, A.; Maiti, D. K.; Bhattacharya, P. K. Org. Lett. 2003, 5, 3967–3969.
(f) Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329–1332, and references
therein.
(3) (a) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; John
Wiley & Sons: New York, 1997. (b) Anastas, P. T.; Kirchhoff, M. M. Acc.
Chem. Res. 2002, 35, 686–694. (c) Chatterjee, A.; Bhattacharya, P. K. J. Org.
Chem. 2006, 71, 345–348, and references therein.
Chemical coupling, reaction control, fine-tuning of the
product, use of the outcome of one reaction as substrate of a
next reaction and many others are performed in nature using a
well-defined reaction environment through construction of
extremely complex assemblies in the cell. This fosters the
expectation to enhance the efficiency of chemical conversions
in such a designed self-assembled reactor of nanometer to
micrometer size.1 Aqueous organized media (AOM) is one such
confined environment, and the reactor is built up from molecular
assemblies of amphiphilic surfactants in water media.2 It is
sufficiently hydrophobic in nature and makes organic substrates
and reagents soluble and also brings them in close proximity,
which enhances the efficiency of chemical transformations. This
(4) (a) Caramella, P.; Gru¨nanger, P. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; John Wiley and Sons: New York, 1984; Vol. 1. (b) Torssell,
K. B. G. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis; VCH:
New York, 1988. (c) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826–5833.
(d) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410–416. (e) Bode, J. W.;
Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611–3612. (f) Paek, S.-M.; Seo,
S.-Y.; Kim, S.-H.; Jung, J.-W.; Lee, Y.-S.; Jung, J.-K.; Suh, Y.-G. Org. Lett.
2005, 7, 3159–3162. (g) Lee, J. Y.; Schiffer, G.; Jager, V. Org. Lett. 2005, 7,
2317–2320, and references therein.
(5) (a) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339–
5342. (b) Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45, 3916–
3918. (c) Lee, G. A. Synthesis 1982, 508–509. (d) Kadowaki, A.; Nagata, Y.;
Uno, H.; Kamimura, A. Tetrahedron Lett. 2007, 48, 1823–1825, and references
therein.
(6) (a) Hassner, A.; Rai, K. Synthesis 1989, 57–59. (b) Muri, D.; Bode, J. W.;
Carreira, E. M. Org. Lett. 2000, 2, 539–541. (c) Shing, T. K. M.; Wong, W. F.;
Cheng, H. M.; Kwok, W. S.; So, K. H. Org. Lett. 2007, 9, 753–756, and
references therein.
(7) (a) Maiti, D. K.; Bhattacharya, P. K. Synlett 1998, 386–387. (b) Kiegiel,
J.; Poplawska, M.; Jozwik, J.; Kosior, M.; Jurczak, J. Tetrahedron Lett. 1999,
40, 5605–5608. (c) Das, B.; Holla, H.; Mahender, G.; Banerjee, J.; Reddy, M. R.
Tetrahedron Lett. 2004, 45, 7347–7350. (d) Das, B.; Mahender, G.; Holla, H.;
Banerjee, J. ArkiVoc 2005, iii, 27–35, and references therein.
(8) (a) Grundmann, C.; Dutta, S. J. Org. Chem. 1969, 34, 2016–2018. (b)
Grundmann, C. Synthesis 1970, 344–358, and references therein.
(1) (a) Albert, B.; Bray, D.; Lewis, J.; Raff, M.; Roberts, K.; Watson, J. D.
Molecular Biology of the Cell; Garland: New York, 1983. (b) Lowik,
D. W. P. M.; van Hest, J. C. M. Chem. Soc. ReV. 2004, 33, 234–245. (c)
Vriezema, D. M.; Argones, M. C.; Elemans, J. A. A. W.; Cornelissen, J. J. L. M.;
Rowan, A. E.; Nolte, R. J. M. Chem. ReV 2005, 105, 1445–1489, and references
therein.
10.1021/jo801337k CCC: $40.75
Published on Web 09/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7775–7778 7775

TABLE 1. Generation of Nitrile Oxide and Trapping with Olefin
in AOM
substituents
product
time yield
(3)
R
X; Y
(h)
(%)
3a
3b
3c
3d
3e
3f
4-bromophenyl-
4-nitrophenyl-
4-hydroxyphenyl- X ) H; Y ) CO2Et
(E)-cinnamyl-
4-bromophenyl-
4-bromophenyl-
2-furyl-
X ) H; Y ) OCOCH3
X ) H; Y ) CO2Et
3.5
3.0
3.0
3.0
2.5
3.0
2.5
4.0
81
71
81
82
81
82
82
79
FIGURE 1. DLS data of nanoreactors formed in aqueous CTAB.
X ) H; Y ) CO2Et
X ) H; Y ) CO2Et
X ) H; Y ) CN
X ) H; Y ) CO2Et
X ) Ph; Y ) CO2Et (E)
SCHEME 1. Formation of Nitrile Oxide inside the
Nanoreactor
3g
3h
(E)-cinnamyl-
center in isoxazolines.9a For our ongoing project in the stereo-
selective synthesis of isoxazoline synthons and important
skeletons for bioactive natural products, we have sought to
develop a new method of preparation of nitrile oxides especially
in neutral condition utilizing a commonly used oxidant.
Development of this reaction in neutral aqueous media is
required not only for simplification in preparation but also for
improving regio- and stereoselectivities, large-scale industrial
applications, and many other advantages.3 However, the 1,3-
DC reaction is studied in aqueous media in the synthesis of a
variety of five-membered heterocycles including isoxazolines.10
Iodosobenzene (PhIO) serves as a source of oxygen in various
metal-catalyzed oxidation reactions.11 Interestingly other than
its well-known property as oxygen donor, evolution of its
oxidizing property has not been much investigated compared
to the other hypervalent organoiodanes.12c PhIO has been used
for synthesis of polyester through the formation of epoxides,12a
oxidation of R-keto carboxylic acids and activated primary
alcohols,12d synthesis of sugar derivatives and iminosugars12b
and also the recently reported oxidative cleavage of olefinic
double bonds to carbonyl compounds.12e In this paper, we wish
to report another excellent oxidizing property of iodosobenzene
as it has transformed aldoximes to corresponding nitrile oxides
in neutral aqueous organized media at room temperature.
Formation of nitrile oxide was confirmed by in situ trapping
with olefins to obtain known ∆2-isoxazolines (Table 1). The
cycloaddition reaction proceeds with a large acceleration of
reaction rate (2.5-4.0 h) with excellent isolated yields (71-82%).
The results in Table 1 demonstrate that the reaction rate and
yield were almost independent of the nature of the substrates
used. We could not find any byproduct from our experiments,
which is the major concern of the existing methods. As an
example, in an attempt to prepare furyl isoxazoline 3g (Table
1) by a widely employed method using NCS and DMAP, we
found only the undesired 5-chlorofuryl derivative of 3g (3i,
Supporting Information).
A survey was conducted with several commercially available
cationic (CTAB), anionic (SDS), and neutral (Tween 40)
surfactants to prepare nitrile oxides in neutral aqueous media.
Best yield (3a, Table 1) was obtained using CTAB (∼33 mol
%). In the absence of CTAB the reaction did not proceed in
aqueous media. We have already reported the nature of the
micelles formed upon dissolution of CTAB in water by optical
micrograph.2e Dynamic light scattering (DLS)2d,f measurement
of the reaction mixture showed formation of a small nanoreactor
of about 1 nm diameter and a larger one of 300 nm (Figure 1).
Mechanistic path of this oxidation-cum-dehydration of al-
doximes to corresponding nitrile oxides under the confined
nanoreactor is depicted in Scheme 1. We propose that the
oxygen atom transfer to imine bond is accomplished through
nucleophilic attack of PhIO followed by loss of PhI. N-O bond
rupture of unstable intermediate II leads to formation of
hydroxyaldoxime (IV) through breaking of the C-H bond.
Removal of hydroxyl anion and deprotonation in successive
steps produce nitrile oxides (VI).
We have extended this green approach for stereoselective
synthesis of 3-(2′-C-3′,4′,6′-tri-O-benzyl glycal)-∆2-isoxazolines
(6 and 7, Table 2), which will be used as versatile synthons for
the synthesis of various chiral heterocycles. For example,
reduction of the isoxazoline ring and subsequent Ferrier
rearrangement13 of the glycal double bond lead to analogues of
the chiral pyranopyran motif present in natural products.14 These
sugar-based isoxazolines can also be converted into various
unnatural compounds15 for their potential application in animal
(9) (a) Jones, R. H.; Robinson, G. C.; Thomas, E. J. Tetrahedron 1984, 40,
177–184. (b) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863–909,
and references therein.
(10) Molteni, G. Heterocycles 2006, 68, 2177–2202, and references therein.
(11) (a) Adam, W.; Gelalcha, F. G.; Saha-Moller, C. R.; Stegmann, V. R. J.
Org. Chem. 2000, 65, 1915–1918. (b) McGarrigle, E. M.; Gilheany, D. G. Chem.
ReV 2005, 105, 1563–1602, and references therein.
(12) (a) Moriarty, R. M.; Gupta, S. C.; Hu, H.; Berenschot, D. R.; White,
K. B. J. Am. Chem. Soc. 1981, 103, 686–688. (b) Francisco, C. G.; Freire, R.;
Gonzalez, C. C.; Leon, E. I.; Reisco-Fagundo, C.; Suarez, E. J. Org. Chem.
2001, 66, 1861–1866. (c) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102,
2523–2584. (d) Tohma, H.; Maegawa, T.; Takizawa, S.; Kita, Y. AdVn. Synth.
Catal. 2002, 344, 328–337. (e) Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem.
Soc. 2007, 129, 2772–2773, and references therein.
(13) For the Ferrier rearrangement, see: (a) Ramesh, N. G.; Balasubramanian,
K. K. Eur. J. Org. Chem. 2003, 447, 7–4487. (b) Kim, H.; Men, H.; Lee, C.
J. Am. Chem. Soc. 2004, 126, 1336–1337, and references therein.
(14) (a) Nakata, T. Chem. ReV. 2005, 105, 4314–4347. (b) Kadota, I.; Nishii,
H.; Ishioka, H.; Takamura, H.; Yamamoto, Y. J. Org. Chem. 2006, 71, 4183–
4187, and references therein.
(15) (a) Chapleur, Y. Carbohydrate Mimics: Concepts and Methods; Wiley-
VCH: Weinheim, 1998. (b) Pan, S.; Amankulor, N. M.; Zhao, K. Tetrahedron
1998, 54, 6587–6604. (c) Gallos, J. K.; Koumbis, A. E. Curr. Org. Chem. 2003,
7, 397–426; 585-628. (d) Sengupta, J.; Mukhopadhyay, R.; Bhattacharjya, A.;
Bhadbhade, M. M.; Bhosekar, G. V. J. Org. Chem. 2005, 70, 8579–8582, and
references therein.
7776 J. Org. Chem. Vol. 73, No. 19, 2008

TABLE 2. Generation and 1,3-DC of Glycal Nitrile Oxides in
AOM
TABLE 3. Formation of Nitrile Oxide and Their INOC in AOM
SCHEME 2. DFT Energy Calculation for Favorable TS
models16 and studies of molecular assembly properties.17 In an
attempt to make these isoxazolines using NCS and DMAP, the
reactions were very slow (∼3 days) and stereoselectivity was
not observed in their cycloaddition (Supporting Information).
By applying this environmentally benign approach to sugar
aldoximes (5), corresponding nitrile oxides are generated in
neutral media. Their in situ 1,3-DC with olefins produces the
new chiral cycloadducts (6 and 7) in good isolated yield
(57-64%). Results in Table 2 demonstrate that a large ac-
celeration of reaction rate and improvement in stereoselectivity
are observed by this robust protocol. Even though the newly
generated chiral center is far away (three bond distance) from
the chiral center, we found good diastereoisomeric excess, in
contrary to the previous report of near absence of stereoselec-
tivity in the 1,3-DC of common chiral nitrile oxides to achiral
olefins.9
Intramolecular nitrile oxide cycloaddition (INOC) especially
with sugar-nitrile oxides is a versatile synthetic tool for the
fabrication of fully functionalized heterocycles of different ring
sizes.5d,15c,18 We are curious to determine whether this cycload-
dition approach could be extended to construct a novel pyran-
opyran framework in one step (Table 3). Elegant routes have
been devised19c for the synthesis of this 2,8-dioxabicyclo-
[4.4.0]decane core. This is an important skeleton of biologically
active natural products such as blepharocalyxin D, which is an
antiproliferative agent against human fibrosarcoma HT-1080 and
murine colon 26-L5 carcinoma cells.19a,b The results in Table
3 reveal that glycal-based aldoximes (8a, 8b) are oxidized by
PhIO in aqueous media to corresponding nitrile oxides and their
in situ INOC constructed optically pure 2,8-dioxabicyclo-
[4.4.0]decene skeleta (9a, 9b) in one step. Exclusive formation
of ꢀ-stereoisomer (+)-(3aS,5aR,6R,7R)-6-allyloxy-7-allyloxym-
ethyl-3a,4,6,7-tetrahydro-3H,5aH-2,5,8-trioxa-1-aza-cyclopen-
ta[a]naphthalene (9a) is in agreement with the results obtained
by a geometry- and energy-optimized intermediate state (TS I,
Scheme 2) computed in B3LYP density functional theory
(DFT).20 Intermediate state TS I for 9ꢀ stereoisomer is stabilized
by -11.77 kcal/mol compared with the alternative intermediate
(16) (a) Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojiromycin
and Beyond; Wiley-VCH: Weinhein, 1998. (b) Compain, P.; Martin, O. R.
Bioorg. Med. Chem 2001, 9, 3077–3092, and references therein.
(17) Ghosh, R.; Chakraborty, A.; Maiti, D. K.; Puranik, V. G. Org. Lett.
2006, 8, 1061–1064, and references therein.
(18) Ghorai, S.; Mukhopadhyay, R.; Kundu, A. P.; Bhattacharjya, A.
Tetrahedron 2005, 61, 2999–3012, and references therein.
(19) (a) Ali, M. S.; Tezuka, Y.; Banskota, A. H.; Kadota, S. J. Nat. Prod.
2001, 64, 491–496. (b) Li, W.; Mead, K. T.; Smith, L. T. Tetrahedron Lett.
2003, 44, 6351–6353. (c) Ko, H. M.; Lee, D. G.; Kim, M. A.; Kim, H. J.; Park,
J.; Lah, M. S.; Lee., E. Org. Lett. 2007, 9, 141–144, and references therein.
J. Org. Chem. Vol. 73, No. 19, 2008 7777

127.6, 127.9, 127.9, 128.1, 128.1, 128.3, 128.5, 128.7, 137.6, 138.1,
138.9, 140.9, 147.1, 154.1. EI-MS (m/z): 561 (M+), 337, 278, 253,
224, 223. IR (neat, cm-1): 898, 1098, 1187, 1402, 1452, 1633, 1733,
2926, 2867. Anal. Calcd for C36H35NO5: C 76.98, H 6.28, N 2.49.
Found: C 76.89, H 6.26, N 2.50.
state TS II for 9r. Calculations were made using the 6-31+G(d,p)
basis set as implemented in the Gaussian 03 program.20a For
clarity substituents at C6 and C7 were omitted from the optimized
TSs. Easily accessible by this green approach, the chromano
motif (9c, 9d) is found in important bioactive natural products.21
Glycal aldehydes17 and PhIO22 were prepared cheaply and
conveniently by literature methods.
In conclusion, we have for the first time prepared nitrile
oxides in neutral aqueous media. Reaction rate, regioselectivity,
and stereoselectivity in their 1,3-DC with olefins are improved.
This green approach also presents the first use of PhIO as
oxidant for preparation of nitrile oxides. Generation of protected
2-C-glycal nitrile oxides in neutral media and their inter- and
intramolecular 1,3-DC under the nanometer aqueous micelles
lead to new chiral synthons and an optically pure 1,4-
pyranopyran motif found in bioactive natural products. Exclusive
formation of one stereoisomer in INOC is justified by DFT
method. Extensions of the present strategy to other 1,3-DC
reactions, conversion of chiral synthons to heterocycles, and
theoretical calculation for the stereocontrolled 1,3-DC reaction
are under progress.
Compound 7a. Yellow color viscous liquid; [R]20 -8.2° (c
D
1
1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 2.95 (1H, dd, J )
8.1, 15.9 Hz), 3.42 (1H, dd, J ) 10.5, 15.9 Hz), 3.94-4.06 (3H,
m), 4.43-4.91 (8H, m), 5.55 (1H, dd, J ) 8.1, 10.5 Hz), 6.58 (1H,
s), 7.24-7.36 (20H, m). 13C NMR (75 MHz, CDCl3): δ 42.5, 68.2,
68.2, 71.6, 73.3, 73.9, 74.9, 76.6, 81.9, 107.5, 125.8, 126.9, 127.3,
127.5, 127.8, 127.9, 128.1, 128.3, 128.5, 128.7, 137.6, 138.1, 139.1,
140.8, 146.9, 154.2. EI-MS (m/z): 561 (M+), 300, 278, 253, 224,
212, 206. IR (neat, cm-1): 699, 744, 899, 1098, 1187, 1402, 1452,
1633, 1733, 2866, 2926. Anal. Calcd for C36H35NO5: C 76.98, H
6.28, N 2.49. Found: C 76.92, H 6.29, N 2.48.
General Procedure for Intramolecular 1,3-DC Reaction. The
aldoxime 8 (0.5 mmol), water (12 mL), and CTAB (100 mg, 0.27
mmol) were added to a round-bottom flask (25 mL,) and the mixture
was stirred at 0 °C for 15 min to prepare the aqueous micelles.
PhIO (275 mg, 1.25 mmol) was added, and the reaction mixture
was allowed to attain room temperature. The reaction was complete
after 3 h. The post reaction mixture was extracted with ethyl acetate
(3 × 5 mL), and the combined organic portion was washed with
brine solution (2 × 10 mL), dried on activated sodium sulfate, and
concentrated in a rotary evaporator under reduced pressure at room
temperature. The crude product was chromatographed on basic
alumina (70-230 mesh) and eluted with ethyl acetate-petroleum
ether. Thus, the reaction with 2-C-(3,4,6-tri-O-allyl)-galactal al-
doxime (8a, 155 mg) afforded (+)-(3aS,5aR,6R,7R)-6-allyloxy-7-
allyloxymethyl-3a,4,6,7-tetrahydro-3H,5aH-2,5,8-trioxa-1-aza-cy-
clopenta[a]naphthalene (9a) after processing in an isolated yield
of 64% (98 mg, 0.32 mmol). Elucidation of structure and the
stereochemistry were confirmed by 2D NMR (Supporting Informa-
tion). Yield: 63%, yellow semisolid; [R]20D +79.9° (c 1.08, CHCl3).
1H NMR (300 MHz, CDCl3): δ 3.39-3.44 (2H, m), 3.61-3.69
(3H, m), 3.98-4.24 (6H, m), 4.37-4.54 (3H, m), 5.14-5.31 (4H,
m), 5.84-5.94 (2H, m), 7.04 (1H, s). 13C NMR (75 MHz, CDCl3):
δ 46.9, 68.2, 69.1, 69.8, 72.4, 72.9, 73.9, 76.4, 100.8, 117.4, 117.6,
134.1, 134.9, 143.0, 154.4. IR (neat, cm-1): 925, 1003, 1091, 1146,
1196, 1647, 1725, 2861, 2922. EI-MS (m/z): 307 (M+), 180, 153,
125. HR-MS (m/z) for C16H21NO5: calcd 307.1420, found 307.1419.
Experimental Section
General Procedure for Intermolecular 1,3-DC Reaction. The
aldoxime 5 (0.33 mmol), alkene 2 (0.66 mmol), water (10 mL),
and CTAB (80 mg, 0.22 mmol) were added to a round-bottom flask,
and the mixture was stirred magnetically at 0 °C for 15 min. PhIO
(198 mg, 0.9 mmol) was added, and the content was allowed to
attain room temperature. The reaction was complete after 3 h. The
post-reaction mixture was extracted with ethyl acetate (2 × 10 mL),
and the combined organic portion was washed with brine solution
(2 × 10 mL), dried on anhydrous sodium sulfate, and concentrated
in a rotary evaporator under reduced pressure at room temperature.
The crude product was chromatographed on basic alumina (70-230
mesh) and eluted with ethyl acetate-petroleum ether. Thus, the
reaction with 2-C-(3,4,6-tri-O-benzyl)galactal aldoxime (5a, 150
mg) and styrene (2e, 69 mg) afforded, after the processing, the
faster moving diastereoisomer, 3-(2′-C-3′,4′,6′-tri-O-benzylgalactal)-
5-phenyl-∆2-isoxazoline (6a, 29 mg, 0.05 mmol) and the slower
moving diastereoisomer 7a (77 mg, 0.14 mmol) in combined
isolated yield of 58%.
Acknowledgment. We acknowledge the financial support of
this work by the DST (SR/S1/OC-22/2006), India. N.C. and
S.H. thank CSIR, and P.P. thanks UGC, India for research
fellowships. D.K.M. is grateful to all colleagues, employees,
and research scholars of the Department of Chemistry, C. U.
for their help and cooperation.
Compound 6a. Yellow color viscous liquid; [R]20 -83.7° (c
D
1
1.16, CHCl3). H NMR (300 MHz, CDCl3): δ 2.99 (1H, dd, J )
8.4, 15.9 Hz), 3.40 (1H, dd, J ) 10.5, 15.9 Hz), 3.95-4.07 (3H,
m), 4.44-4.91 (8H, m), 5.58 (1H, dd, J ) 8.4, 10.5 Hz), 6.58 (1H,
s), 7.25-7.38 (20H, m). 13C NMR (75 MHz, CDCl3): δ 42.5, 68.3,
68.3, 71.7, 73.4, 73.9, 75.0, 76.6, 81.8, 107.5, 125.8, 127.3, 127.5,
Supporting Information Available: General methods, ex-
perimental procedures, elucidation of structure by 2D NMR,
spectroscopic data, and spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) (a) Frisch, M. J. et al. Gaussian 03, ReVision B03; Gaussian, Inc.:
Pittsburg, PA, 2003. (b) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.;
Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127,
210–216, and references therein.
(21) Kim, S.; Ko, H.; Son, S.; Shin, K. J.; Kim, D. J. Tetrahedron Lett. 2001,
42, 7641–7643, and references therein.
(22) Lucas, H. J.; Kennedy, E. R.; Formo, M. W. Organic Synthesis; Wiley:
New York, 1955; Collect. Vol. III, pp 482-484.
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