Synthesis of novel dihydrooxazine and oxazoline based sugar hybrids from sugar azides

Article abstract of DOI:10.1016/j.tetlet.2011.06.035

A convenient one-step method for the synthesis of novel dihydrooxazine and oxazoline based sugar hybrids is reported starting from the readily accessible sugar azides and aldehydes. We have used Aube's protocol to achieve this transformation. The resultin

Full text of DOI:10.1016/j.tetlet.2011.06.035

Tetrahedron Letters 52 (2011) 4313–4315
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Tetrahedron Letters
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Synthesis of novel dihydrooxazine and oxazoline based sugar hybrids from
sugar azides q
Suresh E. Kurhade a,b, Sudhir Ravula a, V. Siddaiah b, Debnath Bhuniya a, D. Srinivasa Reddy a,c,
⇑
a Discovery Chemistry, Advinus Therapeutics Ltd, Quantum Towers, Plot No. 9, Rajiv Gandhi Infotech Park, Phase-I, Hinjewadi, Pune 411 057, India
b Department of Organic Chemistry, Andhra University, Visakhapatnam 530 003, India
c National Chemical Laboratory (CSIR), Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient one-step method for the synthesis of novel dihydrooxazine and oxazoline based sugar
hybrids is reported starting from the readily accessible sugar azides and aldehydes. We have used Aubé’s
protocol to achieve this transformation. The resulting glycoconjugates could be used to increase the
diversity on the sugar backbone and may find applications as potential glycomimetics and in drug
discovery.
Received 21 April 2011
Revised 7 June 2011
Accepted 9 June 2011
Available online 16 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Sugar hybrids
Oxazoline
Dihydrooxazine
Hydroxy azide
Sugar azide
Glycoconjugate
Construction of sugar-based hybrids with biologically interest-
ing scaffolds is an attractive area of research due to their wide-
spread applications, especially in the area of drug discovery.1
Recently, we have reported the synthesis of sugar-lactam conju-
gates using the Aubé reaction conditions starting from readily
accessible sugar azides and cyclic ketones (Scheme 1).2 Replacing
cyclic ketones with aromatic aldehydes under the Aubé reaction
conditions resulted in dihydrooxazine or oxazoline-based sugar
hybrids in good to moderate yields. This observation is in line with
Aube’s group reports for the synthesis of dihydrooxazines/oxazo-
lines using azido alcohols.3 The oxazoline and dihydrooxazine het-
erocycles appear in numerous biologically active compounds
which include natural products and synthetic drugs.4,5 These com-
pounds are also valuable synthetic intermediates6 and they are of-
ten used as protecting groups.7 Combining these important classes
of compounds with sugars is always interesting and rewarding.
The scope of the method with various substrates was tested and
the results are disclosed in this Letter.
methane solvent to furnish the dihydrooxazine-based glucose
hybrid 2 in 59% isolated yield.9 Compound 2 was characterized
Previous work from this group Ref .2
O
O
O
O
O
O
N3
HO
N
OH
HO
OH
BF3.Et2O, DCM;
aq.KOH
OH
OH
sugar azide
sugar-lactam conjugate
Present work
O
O
O
O
N
N3
HO
PhCHO
O
OH
OH
BF3.Et2O, DCM
Initially, we have chosen readily accessible sugar azide 18 to
check the feasibility of the planned synthesis. The reaction was car-
ried out with benzaldehyde in the presence of BF3ꢀEt2O in dichloro-
OH
OH
1
2
(59%)
H
N
O
O
N2
q
Advinus Publication No. ADV-A-0014.
HO
⇑
Corresponding author at present address: National Chemical Laboratory (CSIR),
Dr. Homi Bhabha Road, Pune 411 008, India. Tel.: +91 20 25902445; fax: +91 20
25902629.
OH
plausible intermediate OMe
E-mail address: ds.reddy@ncl.res.in (D.S. Reddy).
Scheme 1. Strategy to access proposed sugar hybrids.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.035

4314
S. E. Kurhade et al. / Tetrahedron Letters 52 (2011) 4313–4315
O
O
N3
N
N
R
O
Ar
O
OH
HO
RCHO
O
O
H
OH
O
H
O
BF3.Et2O, DCM
-20 to 0 oC,
6-8h
BnO
BnO
O
O
17
Cl
HO
Cl
Ph
Cl
3 (64%)
4 (48%)
5 (49%)
Cl
HO
MeO
18
19
20
(39%)
(43%)
(73%)
21 (40%)
F3C
S
N
Cl
Br
6
7
8
(34%)
(46%)
(24%)
Ph
Cl
Figure 1. Products obtained from the reactions of 1 with various aldehydes.
22 (61%)
23 (62%)
24 (21%)
using the spectral data (1H, 13C NMR, HRMS, and IR). Having this
protocol in hand, azide 1 was reacted with different aromatic alde-
hydes and the results are outlined in Figure 1. Reaction of dichlo-
robenzaldehyde, p-hydroxy benzaldehyde, and p-phenyl
benzaldeyhde with the sugar azide 1 under the same conditions
furnished the desired products 3, 4, and 5 in good yields, respec-
tively. Pharmaceutically important m-trifluoromethyl phenyl con-
taining sugar hybrid 6 was also produced in 46% yield using the
corresponding aldehyde.10 In the case of heteroaryl aldehydes,
products 7 and 8 were isolated in low yields compared to the aro-
matic ones.
Scheme 3. Synthesis of oxazoline-based sugar hybrids.
our lab. All four sugar azides 9–1211 with embedded azido alcohol
functions smoothly reacted under the same conditions to produce
the desired products 13–16 in good yields (Scheme 2).12 It is inter-
esting to note that the protection of free hydroxyl groups is not re-
quired for the present method.
To amplify the scope of this method, we have attempted the
reactions with 1,2-azido alcohol embedded sugar azides to pro-
duce oxazoline-based sugar hybrids. Sugar azide 17 prepared from
D
-glucose was treated with a variety of aldehydes and the results
By choosing the best among the examples, 3,5-dichlorobenzal-
dehyde was reacted with a variety of sugar azides prepared in
are shown in Scheme 3. The benzaldehyde and all other substi-
tuted benzaldehydes gave the corresponding products 18–23 in
yields ranging from 40% to 70%.12 However, when we attempted
the reaction with cyclohexylaldehyde, product 24 was formed in
poor yield (21%). In all oxazoline cases, the best yields are obtained
at low temperatures.
In short, we have developed an access to novel sugar hybrids
based on dihydrooxazine and oxazoline frameworks starting from
the readily available sugar azides using Lewis acid (BF3ꢀEt2O) med-
iated conditions. These compounds can be useful as such or may be
used for further manipulations to increase the diversity of the su-
gar framework.
Cl
CHO
O
O
N
O
O
N3
HO
Cl
Cl
O
OH
OH
BF3.Et2O, DCM
0 oC to RT,
overnight
OH
OH
Cl
9
13 (49%)
O
O
N
O
O
Acknowledgments
N3
HO
Cl
Cl
Cl
O
OH
OH
We are grateful to Drs. Rashmi Barbhaiya, Kasim Mookhtiar,
and Venkata Palle for their support and encouragement. Help from
analytical department in recording spectral data is appreciated.
The authors thank Venkat Panchangula and Ajeet Singh of NCL,
Pune for the MALDI spectra.
OH
OH
Cl
Cl
Cl
10
14 (64%)
O
N
N
O
N3
HO
O
Supplementary data
OH
OH
Supplementary data (general methods, experimental details
and characterization data for compounds) associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2011.06.035.
11
15
O
(54%)
O
O
N3
HO
References and notes
1. Selected reviews and publications on sugar hybrids (a) Meutermans, W.; Le, G.
T.; Becker, B. Chem. Med. Chem. 2006, 1, 1164; (b) Varki, A. Glycobiology 1993, 3,
97; (c) Reddy, B. G.; Vankar, Y. D. Angew. Chem. Int. Ed. 2005, 44, 2001; (d)
Chakraborty, T. K.; Srinivasu, P.; Tapadar, S.; Mohan, B. K. Glycoconjugate J.
12
16 (61%)
Scheme 2. Synthesis of dihydrooxazine based hybrids.

S. E. Kurhade et al. / Tetrahedron Letters 52 (2011) 4313–4315
4315
2005, 22, 83; (e) Dedola, S.; Nepogodiev, S. A.; Field, R. A. Org. Biomol. Chem.
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Hruby, V. J. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 7114. and references cited there
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5. Selected patents and publications for dihydrooxazine related compounds (a)
Das, B. C.; Madhukumar, A. V.; Anguiano, J.; Mani, S. Bioorg. Med. Chem. Lett.
2009, 19, 4204; (b) Wijtmans, M.; Celanire, S.; Snip, E.; Gillard, M. R.; Gelens, E.;
Colllart, P. P.; Venhuis, B. J.; Christophe, B.; Hulscher, S.; Goot, H.; Lebon, F.;
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Med. Chem. 2008, 51, 2944; (c) Peter, B; Recard, E. WO Patent, WO025798,
2008.; (d) Branch, D. M.; Catherine, E. WO Patent, WO093903, 2004.; (e) Baeur,
S. M.; Jia, Z. J. WO Patent, WO145856, 2009.
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Braun, N. A.; Ciufolini, M. A. Org. Lett. 2001, 5, 765.
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Wiley and Sons: New York, 1991.
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Thorson, J. S. J. Am. Chem. Soc. 2007, 129, 8150.
9. Representative procedures: (a) Dihydrooxazine-based sugar hybrid. To the
mixture of 6-azido-6-deoxy-methyl-
a-
D
-glucopyranoside
1
(150 mg,
0.68 mmol) and benzaldehyde (0.11 mL, 0.75 mmol) in dichloromethane
(5 mL), BF3ꢀEt2O (0.13 mL, 1.02 mmol) was added under argon atmosphere at
0 °C. The reaction mixture was stirred overnight at room temperature and
neutralized with saturated aqueous NaHCO3 and extracted with ethyl acetate
(3 ꢁ 20 mL), combined organic layer was washed with brine (20 mL) and dried
over sodium sulfate evaporated under reduced pressure to get crude product.
The crude material was purified on silica gel column chromatography (1:1
EtOAc-hexane) to afford the desired product (2). Yield 59%; ½a D24:1
= 11.8° (c 0.5,
ꢂ
2. Kurhade, S. E.; Mengawade, T.; Bhuniya, D.; Palle, V. P.; Reddy, D. S. Org. Biomol.
Chem. 2011, 9, 744.
3. (a) Badiang, J. G.; Aubé, J. J. Org. Chem. 1996, 61, 2484; (b) Chaudhry, P.;
Schoenen, F.; Neuenswander, B.; Lushington, G. H.; Aube, J. J. Comb. Chem. 2007,
9, 473.
4. Selected reviews and publications for oxazoline related compounds (a) Onishi,
H. R.; Pelak, B. A.; Silver, L. L.; Kahan, F. M.; Chen, M.-H.; Patxhett, A. A.;
Galloway, S. M.; Hyland, S. A.; Anderson, M. S.; Raetz, C. R. H. Science 1996, 274,
980; (b) Li, Q.; Wood, K. W.; Claireborne, A.; Gwanltey, S. L.-I. I.; Barr, K. J.; Liu,
G.; Gehke, L.; Credo, R. B.; Hua Hui, Y.; Lee, J.; Warner, R. B.; Kovar, P.; Nukkla,
M. A.; Zielinski, N. A.; Tahir, S. K.; Fitzgerald, M.; Kim, K. H.; Marsh, K.; Frost, D.;
Ng, S.-C.; Rosenberg, S.; Sham, H. L. Bioorg. Med. Chem. 2002, 12, 465; Gomaz, R.
E.; Ernasberger, P.; Fienland, G.; Reis, D. J. Eur. J. Pharmacol. 1991, 195, 181;
Chanc, K.; Head, G. A. J. Hypertens. 1996, 14, 855; (d) Prinsep, M. R.; Moore, R. E.;
Levine, I. A.; Patterson, G. M. L. J. Nat. Prod. 1992, 55, 140; (e) Kelly, J. W.; You, S.
L. Chem. Eur. J. 2004, 10, 71; (f) Donohoe, J. T.; Osa, P. C. Org. Lett. 2007, 9, 5509;
(g) Cook, R. G.; Shanker, S. P.; Peterson, S. L. Org. Lett. 1999, 1, 615.
MeOH); IR (CHCl3): 1044, 1263, 1650, and 3368 cmꢃ1 1H NMR (400 MHz,
;
CD3OD) d; 3.40–3.50 (m, 1H), 3.44 (s, 3H), 3.58 (dd, J = 10, 4 Hz, 1H), 3.67–3.78
(m, 2H), 3.86–3.94 (m, 2H), 4.77 (d, J = 4 Hz, 1H), 7.36–7.49 (m, 3H), 7.93 (d,
J = 7.2 Hz, 2H); 13C NMR (100.6 MHz, CD3OD) d 157.6, 133.7, 132.1, 129.2 (2C),
128.7 (2C), 102.0, 79.1, 73.6, 72.0, 63.1, 55.9, 48.7 (merged in solvent peaks);
LC–MS = 280.1 (M+1); HRMS (ESI): m/z calculated for C
14H18NO5 [M+H]+
280.1181, found 280.1178. In case of oxazoline-based sugar hybrids, BF3ꢀEt2O
was added slowly under argon atmosphere at ꢃ20 °C and stirring continued
below 0 °C for 6–8 h. See, supporting information for the details.
10. (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320; (b) Yale, H. L. J. Med. Pharm. Chem. 1959, 1, 121.
11. Sugar azides are prepared using the procedures described in supporting
information or cited literature in Ref. 2.
12. The analytical data (1H, 13C, IR, and MS) of all the products are in good
agreement with proposed structures. All the details are included in supporting
information.