Intramolecular nitrile oxide-alkene cycloaddition of sugar derivatives with unmasked hydroxyl group(s)

Article abstract of DOI:10.1021/ol062873p

(Chemical Equation Presented) Intramolecular nitrile oxide-alkene cycloaddition (INOC) of sugar derivatives with one to four free hydroxyl group(s) is reported. The INOC reaction, using chloramine-T, in the presence of silica gel, to generate nitrile oxid

Full text of DOI:10.1021/ol062873p

ORGANIC
LETTERS
2007
Vol. 9, No. 5
753-756
Intramolecular Nitrile Oxide−Alkene
Cycloaddition of Sugar Derivatives with
Unmasked Hydroxyl Group(s)
Tony K. M. Shing,* Wai F. Wong, Hau M. Cheng, Wun S. Kwok, and King H. So
Department of Chemistry and Center of NoVel Functional Molecules,
The Chinese UniVersity of Hong Kong, Shatin, NT, Hong Kong, China
tonyshing@cuhk.edu.hk
Received November 27, 2006
ABSTRACT
Intramolecular nitrile oxide−alkene cycloaddition (INOC) of sugar derivatives with one to four free hydroxyl group(s) is reported. The INOC
reaction, using chloramine-T, in the presence of silica gel, to generate nitrile oxides from oximes, proceeded smoothly to afford five- or
six-membered carbocycles in good to excellent yields. This new methodology alleviates protection/deprotection steps and makes the synthetic
route shorter and more efficient.
Intramolecular nitrile oxide-alkene cycloaddition (INOC)
and intramolecular nitrone-alkene cycloaddition (INAC) are
versatile synthetic tools for the fabrication of fully func-
tionalized carbocycles of different ring sizes from sugars.1a-c
The heavily oxygenated carbocycles prepared via the
INOC reaction are valuable precursors for the syntheses
of cyclopentanoid and cyclohexanoid natural products
and analogues. Examples are cyclophellitol,1d trehazolin,1e
(+)-gabosines C and E,1f glycosidase inhibitors aminocyclo-
pentitols,1g and carbocyclic nucleosides noraristeromycin and
neplanocin A.1h
Scheme 1. Formation of Oximolactone 2 (an Undesired
Reaction)
Magnesium ion mediated intermolecular cycloaddition of
nitrile oxides with allyl alcohols is known,1i-k but the alco-
hol in nitrile oxide is protected.1i Most INOC reactions of
sugar derivatives proceed with masked hydroxyl groups.1d,g,h,2
Only two examples have been realized in the presence of a
free hydroxyl group at the δ position.3 INOC of sugar deriv-
atives with free hydroxyl group(s) present in other positions
(1) (a) Gallos, J. K.; Koumbis, A. E. Curr. Org. Chem. 2003, 7, 397-
426. (b) Ferrier, R. J.; Furneaux, R. H.; Prasit, P.; Tyler, P. C.; Brown, K.
L.; Gainsford, G. J.; Diehl, J. W. J. Chem. Soc., Perkin Trans. 1 1983,
1621-1628. (c) Ferrier, R. J.; Prasit, P.; Gainsford, G. J.; Page, Y. L. J.
Chem. Soc., Perkin Trans. 1 1983, 1629-1634. (d) Tatsuta, K. Pure Appl.
Chem. 1996, 68, 1341-1346. (e) Kobayashi, Y.; Miyazaki, H.; Shiozaki,
M. J. Org. Chem. 1994, 59, 813-822. (f) Lygo, B.; Swiatyj, M.; Trabsa,
H.; Voyle, M. Tetrahedron Lett. 1994, 35, 4197-4200. (g) Kleban, M.;
Hilgers, P.; Greul, J. N.; Kugler, R. D.; Li, J.; Picasso, S.; Vogel, P.; Ja¨ger,
V. ChemBioChem 2001, 365-368. (h) Gallos, J. K.; Koumbis, A. E.;
Xiraphaki, V. P.; Dellios, C. C.; Coutouli-Argyropoulou, E. Tetrahedron
1999, 55, 15167-15180. (i) Bode, J. W.; Fraefel, N.; Muri, D.; Carreira,
E. M. Angew. Chem., Int. Ed. 2001, 40, 2082-2085. (j) Kamimura, A.;
Kaneko, Y.; Ohta, A.; Matsuura, K.; Fujimoto, Y.; Kakehi, A.; Kanemasa,
S. Tetrahedron 2002, 58, 9613-9620. (k) Kamimura, A.; Kaneko, Y.; Ohta,
A.; Kakehi, A.; Matsuda, H.; Kanemasa, S. Tetrahedron Lett. 1999, 40,
4349-4352.
(2) (a) Peet, N. P.; Huber, E. W.; Farr, R. A. Tetrahedron 1991, 47,
7537-7550. (b) Shing, T. K. M.; Wong, C.-H.; Yip, T. Tetrahedron:
Asymmetry 1996, 7, 1323-1340. (c) Shing, T. K. M.; Fung, W. C.; Wong,
C. H. J. Chem. Soc., Chem. Commun. 1994, 449-450. (d) Takahashi, T.;
Nakazawa, M.; Sakamoto, Y.; Houk, K. N. Tetrahedron Lett. 1993, 34,
4075-4078. (e) Nakata, M.; Akazawa, S.; Kitamura, S.; Tatsuta, K.
Tetrahedron Lett. 1991, 32, 5363-5366.
10.1021/ol062873p CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/31/2007

Table 1. INOC of Substrates 3, 5, 7, and 9 under Different Conditions
has not been reported. This paper describes, using chloram-
ine-T/silica gel to generate nitrile oxide from oxime, success-
ful INOC of sugar derivatives with free hydroxyl groups that
alleviate protection/deprotection steps which, in turn, renders
the various synthetic schemes shorter and more efficient.
The nitrile oxides derived from sugars are highly oxygen-
ated, and the free hydroxyl group, when present, could attack
the electrophilic carbon of nitrile oxide 1, forming oximo-
lactone 24 as the side product (Scheme 1 and entry 3 in
Table 1).
Common reagents for the conversion of oxime into nitrile
oxide include NaOCl, NaOCl with NEt3, and N-chlorosuc-
cinimide with NEt3.5 Such reaction conditions are basic
enough to deprotonate the hydroxyl function and increase
Table 2. INOC Using Chloramine-T and Silica Gel
754
Org. Lett., Vol. 9, No. 5, 2007

its nucleophilicity. Hence, the formation of the undesired
oximolactone product is enhanced. A new nonbasic method
for the transformation of oximes derived from sugars into
nitrile oxides is therefore warranted. Reaction of oxime 3
with aqueous NaOCl gave an oximolactone that was
hydrolyzed immediately to afford lactone 46 in 38% yield
(entry 1). Stirring oximes 5 or 9 with aqueous NaOCl resulted
in decomposition of the starting material and provided no
cycloadducts. Condensation of lactol 7 with NH2OH afforded
an oxime that was oxidized with aqueous NaOCl to give
the unwanted oximolactone 24 exclusively (entry 3).
Chloramine-T7 has been reported for the generation of
nitrile oxides from oximes, and by applying such conditions
to oxime 5, the oxime derived from lactol 7, and oxime 9,
the corresponding isoxazolines 6, 8,8 and 109 were obtained,
respectively, but in moderate yields (entries 2, 4, and 5).
The formation of the undesired oximolactone 2 might be the
major reason for the moderate yields (entry 4).
Scheme 2. Preparation of Substrates
Silica gel was therefore added together with chloramine-T
to attain a slightly acidic environment for the INOC reactions
of substrates having one to four free hydroxyl group(s), and
the results are summarized in Table 2. With this new
methodology, isoxazolines 11 and 12 were obtained for the
first time from oxime 3 in a combined yield of 79% (entry
6). Oxime 5 now gave a much improved 94% yield of
isoxazoline 6 (entry 7, cf. entry 2). Similar improvements
in reaction yields were also observed with substrates 7 and
9 (entries 8 and 9). Applying the silica gel mediated reaction
conditions to other substrates afforded the desired five-
membered or six-membered carbocycles in good to excellent
yields (entries 10-17). For substrate 27, two isoxazolines
were obtained after the INOC reaction which were insepa-
rable by column chromatography; these were converted into
the acetates 28 and 29 to allow chromatographic separation.
The combined overall yield for the four-step transformation
was a respectable 73%.
All the substrates employed for the INOC reactions were
synthesized from carbohydrates, and their preparations are
shown in Scheme 2.
Diacetonide 32,10 readily available from D-mannose,
reacted with excess allylmagnesium bromide to give alkene
(3) (a) Duclos, O.; Mondange, M.; Dure´ault, A.; Depezay, J. C.
Tetrahedron Lett. 1992, 33, 8061-8064. (b) Tatsuta, K.; Niwata, Y.;
Umezawa, K.; Toshima, K.; Nakata, M. Carbohydr. Res. 1991, 222, 189-
203.
33 with 5:1 diastereoselectivity. Selective hydrolysis of the
terminal isopropylidene group in 33, followed by glycol
oxidative cleavage, was performed with periodic acid11 in
one pot to furnish lactol 34 in 79% yield. Oximation of lactol
34 then gave substrate 3 in quantitative yield. Benzyl-â-L-
arabinopyranoside 35,12 prepared from glycosidation of
L-arabinose, was protected with a trans-diacetal ring to give
acetal 36. Upon hydrogenolysis and allylation, alkenes 37
and 23 were harvested from 36 in equal amounts. Alkene
37 was then converted into substrate 5 by glycol oxidative
cleavage and oximation. Alkenes 39 and 40, prepared from
(4) The enantiomer of oximolactone 2 was prepared from the oxime with
NCS and NEt3 by Professor V. Ja¨ger. See: Gu¨ltekin, Z.; Frey, W.; Ja¨ger,
V. Z. Kristallogr. - New Cryst. Struct. 2002, 217, 403-404.
(5) Caramella, P.; Gru¨nanger, P. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, pp 291-392.
(6) Krishna, U. M.; Deodhar, K. D.; Trivedi, G. K. Tetrahedron 2004,
60, 4829-4836.
(7) (a) Pal, A.; Bhattacharjee, A.; Bhattacharjya, A.; Patra, A. Tetrahedron
1999, 55, 4123-4132. (b) Majumdar, S.; Mukhopadhyay, R.; Bhattacharjya,
A. Tetrahedron 2000, 56, 8945-8951.
(8) The X-ray structure of the enantiomer of the acetate derivative of 8
was published by Professor V. Ja¨ger. See: Gu¨ltekin, Z.; Frey, W.; Ja¨ger,
V. Z. Kristallogr. - New Cryst. Struct. 2002, 217, 405-406.
(9) Structure confirmed by comparing the spectroscopic data of the acetate
derivative. See: (a) Henkel, S.; Kleban, M.; Ja¨ger, V. Z. Kristallogr. - New
Cryst. Struct. 1997, 212, 53-54. (b) Hilgers, P. Dissertation, Universita¨t
Stuttgart, 1996. (c) Kleban, M. Dissertation, Universita¨t Stuttgart, 1996.
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of Carbohydrates; Whistler, R. L., Wolfrom, M. L., Eds.; Academic Press
Inc.: New York and London, 1963; Vol. 2, pp 318-319.
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(12) Kawasaki, M.; Matsuda, F.; Terashima, S. Tetrahedron 1988, 44,
5695-5711.
Org. Lett., Vol. 9, No. 5, 2007
755

D-mannose according to the literature,13 were readily trans-
formed into substrates 7 and 13 with periodic acid.
Iodide 41, constructed from methyl-R-D-glucopyranoside,14
was reacted with zinc15 to give lactol 42 that was converted
into substrate 9 after oximation. Substrates 15,13 17,16 and
2016 were prepared from D-ribose according to the literature.
Diol 43 was obtained from D-mannose in three steps.17 Glycol
oxidative cleavage of diol 43, followed by vinylation,
afforded substrates 25 and 27 in equal amounts. Starting from
D-galactose, alkene 44 was prepared in three steps.18 Acid
hydrolysis of alkene 44 with TFA furnished substrate 30 in
92% yield.
oxime proceed smoothly with unmasked hydroxyl group(s)
to give the desired isoxazolines in good to excellent yields.
A general method for the construction of highly function-
alized five- and six-membered carbocycles from sugar
derivatives via the INOC strategy is now revealed. This new
methodology alleviates protection/deprotection steps and
makes the entire synthetic avenue shorter and more efficient.
Acknowledgment. This work was supported by a grant
administered by the Center of Novel Functional Molecules,
CUHK. Special thanks go to Prof. V. Ja¨ger of the University
1
of Stuttgart for kindly providing us with the H and 13C
spectra of the enantiomer of 2, the enantiomer of the acetate
derivative of 8, and the acetate derivative of 10 for
comparison.
To conclude, INOC reactions that use chloramine-T and
silica gel in ethanol to generate the nitrile oxide from the
(13) Shing, T. K. M.; Elsley, D. A.; Gillhouley, J. G. J. Chem. Soc.,
Chem. Commun. 1989, 1280-1282.
Supporting Information Available: Experimental pro-
cedures and product characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(14) Anisuzzaman, A. K. M.; Whistler, R. L. Carbohydr. Res. 1978, 61,
511-518.
(15) (a) Skaanderup, P. R.; Hyldtoft, L.; Madsen, R. Monatsh. Chem.
2002, 133, 467-472. (b) Hyldtoft, L.; Madsen, R. J. Am. Chem. Soc. 2000,
122, 8444-8452.
(16) Shing, T. K. M.; Wong, A. W. F.; Ikeno, T.; Yamada, T. J. Org.
Chem. 2006, 71, 3253-3263.
OL062873P
(17) Suhara, Y.; Kittaka, A.; Ono, K.; Kurihara, M.; Fujishima, T.;
Yoshida, A.; Takayama, H. Bioorg. Med. Chem. Lett. 2002, 12, 3533-
3536.
(18) Lee, H. H.; Hodgson, P. G.; Bernacki, R. J.; Korytnyk, W.; Sharma,
M. Carbohydr. Res. 1988, 176, 59-72.
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