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

Abstract

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.

---

A carbohydrate inspired molecular hybridization approach incorporating natural chiral carbohydrate templates with heterocyclic rings offers an opportunity for the generation of an interesting array of structures and templates for drug discovery.¹ For instance, small molecule carbohydrate-triazole hybrids have been utilized either as drug candidates or as mechanistic probes to unravel intricate biological pathways (Fig. 1).²

Fig. 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 properties such as antibacterial and anti-HIV,³ we were interested to design and synthesize a set of tailor made tricyclic monosaccharide-derived analogues incorporating a pharmacophoric 1,2,3-triazole ring (Fig. 2).

Fig. 2 Typical tricyclic scaffold of 1,2,3-triazolyl furanose/pyranose hybrids.

In this regard, construction of triazoles by Huisgen's 1,3-dipolar cycloaddition reaction⁴ between alkynes and alkyl azides, termed as ‘click-chemistry’ by Sharpless,⁵ appeared to us as a preferred means to rapidly assemble the tricyclic framework shown in 7 and 8. Though similar approaches have been described earlier for the synthesis of triazole-carbohydrate analogues,^6,7 triazole 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 drug-like with favourable C log P values.

In the results described here-in, we have focussed on the introduction of a 4-aryl-triazole at the non-reducing end of the sugar by effecting an intramolecular [3 + 2] Huisgen's cycloaddition between a propargyl and an azide moiety anchored at the 4- and 6-OH groups of D-glucopyranoside derivative, to construct a triazole ring along with the concomitant formation of 1,4-oxazepine ring.

Starting from methyl α-D-glucopyranoside 9, benzylidene protection using benzaldehyde dimethyl acetal in the presence of catalytic I₂ afforded 4,6-O-benzylidene derivative 10 (ref. 8) in good yield (Scheme 1). The 2- and 3-hydroxyl 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, which on regioselective tosylation of the primary hydroxyl using TsCl/Py gave 13 (ref. 11) in good yield. S_N2 displacement of the tosylate moiety in 13 with sodium azide afforded the 6-azido compound 14 (ref. 10) in 92% yield. The methyl 6-azido-2,3-O-benzyl-α-D-glucopyranoside 14 obtained was chosen as the key carbohydrate precursor for further functionalization with the propargyl tosylate 18a and various substituted aryl-propargyl alcohol tosylates 18b–g (Schemes 2 and 3).

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 °C, 24 h, 92%.

Scheme 2 Reagents and conditions: (a) Pd(PPh₃)₄, CuI (cat), K₂CO₃, DMF, 80 °C, 12 h, 80–90%; (b) TsCl, KOH, CH₂Cl₂, 0 °C, 1 h, 80–90%.

Scheme 3 Reagents and conditions: (a) NaH, DMF, 0 °C – RT, 2 h; (b) DMF, 140 °C, 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.

Substituted aryl-propargyl 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) afforded 17b–g. Tosylation using TsCl/KOH¹² on 17b–g gave the corresponding tosylates 18b–g in good yields. Various propargyl tosylates 18a–g synthesized are shown in Table 1 and were utilized for the proparglyation of the 4-OH in 14.

Table 1 3-Arylprop-2-ynyl tosylates 18b–g used for the coupling O-propargylation of 14

Entry	R (H or Ar)	Product
1	H
2
3
4
5
6
7

---

Alkylation of 14 with the tosylates 18a–g was achieved in the presence of NaH base to obtain azido–alkyne glucopyranosides 19a–g (Scheme 3). This set the stage for [3 + 2] cyclization^13,14 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 intermolecular products would dominate affording dimeric or oligomeric mixtures. Satisfactorily, intramolecular [3 + 2] cycloaddition afforded the desired product 20a(ref. 6) in good yield and we did not observe products from intermolecular couplings when the reaction was monitored by LCMS. Subsequently debenzylation in 20a afforded compound 8a. The presence of a one proton singlet at δ 7.60 in ¹H 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. Encouraged by this result, cycloadditions were performed on 19b–g to obtain 20b–g in good yields (Table 2). Debenzylation of 20a–g furnished the diols 8a–g in excellent yields.

Table 2 Aryl substituted hexahydro-4H-pyrano[2,3-f][1,2,3]triazolo[5,1-c][1,4]oxazepines 8a–g

Entry	R (H or Ar)	Product
1	H
2
3
4
5
6
7

---

The pivotal ‘click-reaction’ was therefore a one-step process for the construction of fused tricyclic system from a differentially derivatized glycopyranoside. In conclusion, we have developed a efficient route for the synthesis of tricyclic monosaccharide-triazole hybrids by employing 1,3-dipolar cycloaddition reaction. These new chemical motifs can serve as promising leads as drug candidates or probes for metabolic pathways.

Acknowledgements

The authors thank Prof. Prabhat Arya for his valuable inputs. S.K. thanks UGC, New Delhi, for the award of research fellowship.

Notes and references

1. (a) B. Gabrielsen, M. J. Phelan, L. Barthel-Rosa, 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. San-Felix, S. Aquaro, E. D. Clercq, C.-F. Perno, A. Karlsson, J. Balzarini and M. J. Camarasa, J. Med. Chem., 1994, 37, 4185; (c) J. Li, M. Zheng, W. Tang, P.-L. He, W. Zhu, T. Li, J.-P. Zuo, H. Liu and H. Jiang, Bioorg. Med. Chem. Lett., 2006, 16(19), 5009; (d) C. Hager, R. Miethchen and 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, 53(14), 5248.
2. (a) G. O'Mahony, E. Ehrman and M. Grøtli, Tetrahedron Lett., 2005, 46, 6745; (b) K. P. Kaliappan, P. Kalanidhi and S. Mahapatra, Synlett, 2009, 13, 2162; (c) V. S. Sudhir, N. Y. P. Kumar, R. B. N. Baig and S. Chandrasekaran, J. Org. Chem., 2009, 74, 7588; (d) C. M. Klemm, A. Berthelmann, S. Neubacher and C. Arenz, Eur. J. Org. Chem., 2009, 17, 2788; (e) B. L. Wilkinson, H. Long, E. Sim and A. J. Fairbanks, Bioorg. Med. Chem. Lett., 2008, 18(23), 6265; (f) M. Singer, M. Lopez, L. F. Bornaghi, A. Innocenti, D. Vullo, C. T. Supuranand and S. A. Poulsen, Bioorg. Med. Chem. Lett., 2009, 19(8), 2273; (g) B. K. Singh, A. K. Yadav, B. Kumar, A. Gaikwad, S. K. Sinha, V. Chaturvedi and R. P. Tripathi, Carbohydr. Res., 2008, 343(7), 1153; (h) L. Diaz, J. Casas, J. Bujons, A. Llebaria and A. Delgado, J. Med. Chem., 2011, 54, 2069; (i) R. I. Anegundi, V. G. Puranik and S. Hotha, Org. Biomol. Chem., 2008, 6, 779.
3. (a) C. H. Zhou and Y. Wang, Curr. Med. Chem., 2012, 19(2), 239; (b) R. Kharb, P. C. Sharma and M. S. Yar, J. Enzyme Inhib. Med. Chem., 2011, 26(1), 1; (c) R. Kharb, M. S. Yar and P. C. Sharma, Mini-Rev. Med. Chem., 2011, 11(1), 8496.
4. R. Huisgen, R. Grashey and J. Sauer, Chemistry of Alkenes, Interscience, New York, 1964, sp. 806.
5. V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596.
6. A similar strategy has been reported by Hotha and co-workers for the synthesis of 1,2,3-triazole and 1,2,3,4-tetrazole fused polycyclic compounds from carbohydrate derived azido–alkyne and azido–cyanide precursors. See: S. Hotha, R. I. Anegundi and A. A. Natu, Tetrahedron Lett., 2005, 46, 4585.
7. 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.
8. R. Panchadhayee and A. K. Misra, J. Carbohydr. Chem., 2008, 27, 148.
9. M. A. Fernández-Herrera, H. López-Muñoz, J. M. V. Hernández-Vázquez, M. López-Dávila, S. Mohan, M. L. Escobar-Sánchez, L. Sánchez-Sánchez, B. M. Pinto and J. Sandoval-Ramírez, Eur. J. Med. Chem., 2011, 46, 3877.
10. (a) B. Elchert, J. Li, J. Wang, Y. Hui, R. Rai, R. Ptak, P. Ward, J. Y. Takemoto, M. Bensaci and C.-W. T. Chang, J. Org. Chem., 2004, 69, 1513; (b) Y. Hui and C.-W. T. Chang, Org. Lett., 2002, 4, 2245.
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 and M. S. Gin, J. Am. Chem. Soc., 2004, 126, 1638.
14. (a) P. Chattopadhyay and N. D. Adhikary, J. Org. Chem., 2012, 77, 5399; (b) L. Marmuse, S. A. Nepogodiev and R. A. Field, Org. Biomol. Chem., 2005, 3, 2225; (c) S. G. Agalave, S. R. Maujan and V. S. Pore, Chem.–Asian J., 2011, 6, 2696; (d) W. Shi, R. S. Coleman and T. L. Lowary, Org. Biomol. Chem., 2009, 7, 3709; (e) I. Kumar, N. A. Mir, C. V. Rode and B. P. Wakhloo, Tetrahedron: Asymmetry, 2012, 23, 225.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra11035h

---