Click chemistry route to tricyclic monosaccharide triazole hybrids: Design and synthesis of substituted hexahydro-4H-pyrano[2,3-f][1,2,3]triazolo[5,1-c][1,4]oxazepines

Article abstract of DOI:10.1039/c4ra11035h

A click chemistry approach to novel tricyclic monosaccharide triazole hybrids, namely, aryl substituted hexahydro-4H-pyrano[2,3-f][1,2,3]triazolo[5,1-c][1,4]oxazepine derivatives from an intramolecular 1,3-dipolar cycloaddition of 6-azido-4-O-propargyl glycopyranosides has been reported.

Full text of DOI:10.1039/c4ra11035h

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ARTICLE TYPE
Click Chemistry route to tricyclic monosaccharide triazole hybrids:
Design and Synthesis of Substituted Hexahydro-4H-pyrano[2,3-
f][1,2,3]triazolo[5,1-c][1,4]oxazepines
Saidulu Konda, Pallavi Rao, and Srinivas Oruganti*
5
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
25 properties such as antibacterial and antiꢀHIV,3 we were interested
A click chemistry approach to novel tricyclic monosaccharide
to design and synthesize
monosaccharideꢀderived
a set of tailor made tricyclic
triazole hybrids, namely, aryl substituted hexahydro-4H-
pyrano[2,3-f][1,2,3]triazolo[5,1-c][1,4]oxazepine derivatives
analogues
incorporating
a
pharmacophoric 1,2,3ꢀtriazole ring (Figure 2).
10 from an intramolecular 1,3-dipolar cycloaddition of 6-azido-
4-O-propargyl glycopyranosides has been reported.
N
H
H
N
O
O
O
N
N
OH
N
30
N
A
carbohydrate inspired molecular hybridization approach
incorporating natural chiral carbohydrate templates with
15 heterocyclic rings offers an opportunity for the generation of an
interesting array of structures and templates for drug discovery.1
For instance, small molecule carbohydrateꢀtriazole hybrids have
been utilized either as drug candidates or as mechanistic probes to
unravel intricate biological pathways (Figure 1).2
OH
O
O
OH
H
H
OH
7
8
Figure 2: Typical tricyclic scaffold of 1,2,3ꢀtriazolyl furanose/pyranose
hybrids
35 In this regard, construction of triazoles by Huisgen’s 1,3ꢀdipolar
cycloaddition reaction4 between alkynes and alkyl azides, termed
as ‘clickꢀchemistry’ by Sharpless,5 appeared to us as a preferred
means to rapidly assemble the tricyclic framework shown in 7
OTBS
N
O
O
N
N
N
O
H2N
O
HO
N
N
NH2
R
HO
OH
and 8. Though similar approaches have been described earlier for
O
S
OTBS
6,7
40 the synthesis of triazoleꢀcarbohydrate analogues,
triazole
O
TSAO 2
Ribavirin 1
moiety in these cases was invariably fused at the reducing end of
the pentoses and hexoses. We were interested to synthesize fused
carbohydrate aryl triazole hybrids, wherein the presence of aryl
rings render the analogues drugꢀlike with favourable ClogP
45 values.
R
OH
N
H
O
CO2R1
N
HO
N
OH
AcHN
OH
O
In the results described hereꢀin, we have focussed on the
introduction of a 4ꢀarylꢀtriazole at the nonꢀreducing end of the
sugar by effecting an intramolecular [3+2] Huisgen’s
cycloaddition between a propargyl and an azide moiety anchored
50 at the 4ꢀ and 6ꢀOH groups of Dꢀglucopyranoside derivative, to
construct a triazole ring along with the concomitant formation of
1,4ꢀoxazepine ring.
HO
HO
N
N
OMe
N
R2
Mannosyl transferase
inhibitor 4
3
Zanamivir analogues
N
N
HO
O
N
R
Starting from methyl αꢀDꢀglucopyranoside 9, benzylidene
protection using benzaldehyde dimethyl acetal in the presence of
55 catalytic I2 afforded 4,6ꢀOꢀbenzylidene derivative 108 in good
yield (Scheme 1). The 2ꢀ and 3ꢀhydroxyl groups in 10 were
protected as benzyl ethers using benzyl bromide/NaH milieu9 to
obtain 11 in quantitative yield. Deprotection of the benzylidene
acetal 11 by treatment with pTSA in MeOH afforded diol 12,
60 which on regioselective tosylation of the primary hydroxyl using
TsCl/Py gave 1311 in good yield. SN2 displacement of the tosylate
moiety in 13 with sodium azide afforded the 6ꢀazido compound
1410 in 92% yield. The methyl 6ꢀazidoꢀ2,3ꢀOꢀbenzylꢀαꢀmethylꢀ
Dꢀglucopyranoside 14 obtained was chosen as the key
H
N
O
N
HO
HO
N
N
n
NH
R
N
O
O
OH
OH
O
R = COOMe, Ar
5
N-alkylaminocyclitols
6
1,2,3-triazolyluridine derivatives
20
Figure 1: Representative examples of bioactive triazole carbohydrate
hybrids
Against this background and given that the triazole moiety itself
is present in many compounds exhibiting different biological
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carbohydrate precursor for further functionalization with the
Encouraged by this result, cycloadditions were performed on
propargyl tosylate 18a and various substituted arylꢀpropargyl 40 19b–g to obtain 20b-g in good yields (Table 2). Debenzylation of
alcohol tosylates 18b-g (Schemes 2 and 3).
20a-g furnished the diols 8a-g in excellent yields.
18a-g
H
TsO
O
O
O
O
HO
HO
R
a
b
d
O
O
O
O
O
N3
N3
b
a
c
OH
Ph
O
OH
HO
OBn
O
OBn
H
OH
OH
OBn
R
OBn
10
9
19a-g
14
N
N
H
H
H
N
N
O
O
O
O
O
O
N
N
O
O
c
HO
HO
O
R
R
OBn
OH
O
O
OBn
H
Ph
O
OBn
H
OBn
20a-g
OH
H
OBn
12
R = H or Ar
OBn
8a-g
11
o
Scheme 3: Reagents and conditions: (a) NaH, DMF, 0 C – RT, 2 h; (b)
45 DMF, 140 oC, 12 h; (c) 10% Pd/C, MeOH, H2 (1 atm), RT, 16 h.
# Debenzylation of 8d was very slow and completed over 2 days giving
low yields of the product
O
O
O
O
e
TsO
HO
N3
OBn
HO
OBn
OBn
13
OBn
Table 1. 3ꢀArylpropꢀ2ꢀynyl 4ꢀtosylates 18bꢀg used for the
50 coupling Oꢀpropargylation of 14
14
5
Scheme 1: Reagents and conditions: (a) PhCH(OMe)2, cat. I2, DMF, RT,
12 h, 75% (b) BnBr, NaH, DMF, RT, 12 h, 99%; (c) pTSA, MeOH, RT,
24 h, 90%; (d) TsCl, Py, CH2Cl2, RT, 2 h, 90%; (e) NaN3, DMF, 80 oC,
24 h, 92%.
Product
Entry
R (H or Ar)
H
1
TsO
10
18a
Substituted arylꢀpropargyl tosylates 18b-g were synthesized from
corresponding substituted aryl bromides and propargyl alcohol.
Sonogashira coupling11 of aryl bromides with propargyl alcohol
15 in the presence of Pd(PPh3)4/CuI/K2CO3 milieu (Scheme 2)
TsO
2
3
15 afforded 17b–g. Tosylation using TsCl/KOH12 on 17b–g gave the
corresponding tosylates 18bꢀg in good yields. Various propargyl
tosylates 18a-g synthesized are shown in Table 1 and were
utilized for the proparglyation of the 4ꢀOH in 14.
18b
TsO
ArBr
18c
18d
16b-g
HO
TsO
18b-g
HO
a
b
Ar
Ar
15
17b-g
b
TsO
S
S
4
5
TsO
18a
20
Scheme 2: Reagents and conditions: (a) Pd(PPh3)4, CuI (cat), K2CO3,
DMF, 80 oC, 12 h, 80ꢀ90%; (b) TsCl, KOH, CH2Cl2, 0 oC, 1 h, 80ꢀ90%.
TsO
18e
18f
O
O
Alkylation of 14 with the tosylates 18aꢀg was achieved in the
25 presence of NaH base to obtain azidoꢀalkyne glucopyranosides
19a-g (Scheme 3). This set the stage for [3+2] cyclization13,14 and
we initially attempted cycloaddition in 19a. One of the concerns
was whether the orientation of the azide and alkyne moieties was
suited for the intramolecular reaction and any competing
30 intermolecular products would dominate affording dimeric or
oligomeric mixtures. Satisfactorily, intramolecular [3+2]
cycloaddition afforded the desired product 20a6 in good yield and
we did not observe products from intermolecular couplings when
the reaction was monitored by LCMS. Subsequently
35 debenzylation in 20a afforded compound 8a. The presence of a
TsO
6
7
EtO
O
O
OEt
TsO
18g
1
one proton singlet at δ 7.60 in H NMR and carbon signals at δ
136.1 and 132.9 in 13C NMR corresponding to the two carbon
atoms of the triazole ring confirmed the formation of 8a.
2
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† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
25 DOI: 10.1039/b000000x/
Table
2.
Aryl
substituted
hexahydroꢀ4Hꢀpyrano[2,3ꢀ
f][1,2,3]triazolo[5,1ꢀc][1,4]oxazepines 8a–g.
5
1
a) B. Gabrielsen, M. J. Phelan, L. BarthelꢀRosa, C. See, J. W.
Huggins, D. F. Kefauver, T. P. Monath, M. A. Ussery, G. N.
Chmurny, E. M. Schubert, K. Upadhya, C. Kwong, D. A.
Carter, J. A. Secrist III, J. J. Kirsi, W. M. Shannon, R. W.
Sidwell, G. D. Kini and R. K. Robins, J. Med. Chem. 1992,
35, 17, 3231; b) R. Alvarez, S. Velazquez, A. SanꢀFelix, S.
Aquaro, E. D. Clercq, CꢀF. Perno, A. Karlsson, J. Balzarini,
M. J. Camarasa, J. Med. Chem. 1994, 4185; c) J. Li, M.
Zheng, W. Tang, PꢀL. He, W. Zhu, T. Li, JꢀP. Zuo, H. Liu and
H. Jiang, Bioorg & Med. Chem. Lett. 2006, 16, 19, 5009; d) C.
Hager, R. Miethchen, H. Reinke, J. Fluorine. Chem. 2000,
104, 2, 135; e) L. Diaz, J. Bujons, J. Casas, A. Llebaria and A.
Delgado, J. Med. Chem. 2010, 5248.
Product
Entry
R (H or Ar)
N
N
H
N
O
O
N
N
8a
8b
1
30
H
OH
O
H
H
OH
O
N
O
2
3
35
OH
O
H
OH
N
H
H
N
O
O
N
a) G. O
’Mahony, E. Ehrman, M. Grøtli, Tet. Lett., 2005, 46,
8c
40
2
OH
6745; b) K. P. Kaliappan, P. Kalanidhi, S. Mahapatra, Synlett.
2009, 13, 2162; c) V. S. Sudhir, N. Y. P. Kumar, R. B. N.
Baig, S. Chandrasekaran, J. Org. Chem. 2009, 74, 7588; d) C.
M. Klemm, A. Berthelmann, S. Neubacher, C. Arenz, Eur. J.
Org. Chem. 2009, 2788; e) F. Dolhem, F. A. Tahli, C. Lièvre,
G. Demailly, Eur. J. Org. Chem. 2005, 5019; f) B. L.
Wilkinson, H. Long, E. Sim and A. J. Fairbanks Bioorg &
Med. Chem.Lett. 2008, 6265; g) M. Singer, M. Lopez,; L. F.
Bornaghi, A. Innocenti, D. Vullo, C. T. Supuranand S. A.
Poulsen, Bioorganic & Med. Chem. Lett. 2009, 2273; h) B. K.
Singh, A. K. Yadav, B. Kumar, A. Gaikwad, S. K. Sinha, V.
Chaturvedi, R. P. Tripathi, Carb. Res. 2008, 1153; i) L. Diaz,
J. Casas, J. Bujons, A. Llebaria and A. Delgado, J. Med.
Chem. 2011, 2069; j) R. I. Anegundi, V. G. Puranik, S. Hotha,
Org. Biomol. Chem. 2008, 6, 779.
O
OH
N
H
H
N
O
O
N
45
50
55
60
65
70
75
80
8d
8e
S
4
5
OH
O
S
OH
N
H
H
N
O
O
N
OH
O
OH
O
O
N
H
H
3
a) C. H. Zhou and Y. Wang, Curr Med. Chem. 2012, 19, 2,
239; (b) R. Kharb, P. C. Sharma, M. S. Yar, J. Enzyme Inhib
Med Chem 2011, 26, 1, 1; (c) R. Kharb, M. S.Yar, P. C.
Sharma, Mini Rev. Med. Chem 2011, 11, 1, 8496.
R. Huisgen, R. Grashey and J. Sauer, Chemistry of Alkenes,
Interscience, New York, 1964, 806.
N
O
O
N
O
8f
6
OH
EtO
O
EtO
OH
O
4
5
6
N
H
H
N
O
O
N
V. V. Rostovtsev, L. G. Green, V. V. Fokin and K.
B. Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596.
8g
7
OH
O
A similar strategy has been reported by Hotha and coꢀworkers
for the synthesis of 1,2,3ꢀtriazole and 1,2,3,4ꢀtetrazole fused
polycyclic compounds from carbohydrate derived azidoꢀ
alkyne and azidoꢀcyanide precursors. See: S. Hotha, R. I.
Anegundi and A. A. Natu, Tet. Lett., 2005, 46, 4585.
References of other approaches: (a) F. Dolhem, F. A. Tahli, C.
Lièvre, and G. Demailly, Eur. J. Org. Chem. 2005, 23, 5019;
(b) V. S. Sudhir, N. Y. P. Kumar, R. B. N. Baig and S
Chandrasekaran J. Org. Chem. 2009, 74, 7588; (c) Y. S.
Reddy, A. P. J. Pal, P. Gupta, A. A. Ansari and Y. D. Vankar
J. Org. Chem. 2011, 76, 5972.
R. Panchadhayee, and A. K. Misra, J. Carbohydr. Chem.
2008, 27, 148.
M. A. FernándezꢀHerrera, H. LópezꢀMuñoz, J. M. V.
HernándezꢀVázquez, M. LópezꢀDávila, S. Mohan, M. L.
EscobarꢀSánchez, L. SánchezꢀSánchez, B. M. Pinto and J.
SandovalꢀRamírez, Eur. J. Med. Chem. 2011, 46, 3877.
OH
The pivotal ‘clickꢀreaction’ was therefore a oneꢀstep process for
the construction of fused tricyclic system from a differentially
7
10 derivatized glycopyranoside. In conclusion, we have developed a
efficient route for the synthesis of tricyclic monosaccharideꢀ
triazole hybrids by employing 1,3ꢀdipolar cycloaddition reaction.
These new chemical motifs can serve as promising leads as drug
candidates or probes for metabolic pathways.
8
9
15 Acknowledgements
The authors thank Prof. Prabhat Arya for his valuable inputs. S.K.
thanks UGC, New Delhi, for the award of research fellowship
.
10 (a) B. Elchert, J. Li, J. Wang, Y. Hui, R. Rai, R. Ptak, P.
Ward,; J. Y. Takemoto, M. Bensaci, and CꢀW, T. Chang, J.
Org. Chem, 2004, 69, 1513; (b) Y. Hui and CꢀW. T. Chang,
Org. Lett., 2002, 4, 2245.
Notes and references
Address for correspondence: E-mail: soruganti@drils.org
20 Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad, 500 046, India.
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11 (a) R. Chinchilla and C. Nájera, Chem. Soc. Rev., 2011, 40,
5084; (b) N. W. Polaske, D. V. McGrath and J. R.
McElhanon, Macromolecules 2010, 43, 1270.
12 R. Srinivasan, M. Uttamchandani, and S. Q. Yao, Org. Lett.,
2006, 8, 713.
13 K. D. Bodine, D. Y. Gin, M. S. Gin, J. Am. Chem. Soc. 2004,
126, 1638.
14 a) P. Chattopadhyay, N. D. Adhikary, J. Org. Chem. 2012, 77,
5399; b) L. Marmuse, S. A. Nepogodiev, R. A. Field, Org.
Biomol. Chem. 2005, 3, 2225; c) S. G. Agalave, S. R. Maujan,
V. S. Pore, Chem. Asian J. 2011, 6, 2696; d) W. Shi, R. S.
Coleman, T. L. Lowary, Org. Biomol. Chem., 2009, 7, 3709;
e) I. Kumar, N. A. Mir, C. V. Rode, B. P. Wakhloo, Tet.
Asymm. 2012, 23, 225.
5
10
15
4
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Graphical Abstract
Leave this area blank for abstract info.
Click Chemistry route to tricyclic
monosaccharide triazole hybrids:
Design and Synthesis of Substituted
Hexahydro-4H-pyrano[2,3-f][1,2,3]triazolo[5,1-c][1,4]oxazepines
Saidulu Konda, Pallavi Rao and Srinivas Oruganti*
Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad, 500 046, India.
N
H
N
N
O
O
Glucose
Ar
OH
O
H
OH
7 examples