Letter pubs.acs.org/OrgLett
Iminosugar C‑Nitromethyl Glycosides and Divergent Synthesis of Bicyclic Iminosugars Sure Siva Prasad, Soundararasu Senthilkumar, Akriti Srivastava, and Sundarababu Baskaran* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India S Supporting Information *
ABSTRACT: An efficient one-pot method for the stereoselective synthesis of novel iminosugar C-nitromethyl glycosides is described. This new class of iminosugar glycosides has versatile nitromethyl functionality whose utility was further demonstrated in the single-step synthesis of bicyclic iminosugars. Under reagent-free conditions, the N-allyl-C-nitromethyl glycosides resulted in intramolecular cyclization to iminosugar-oximes, whereas under SET oxidation, they furnished cyclopropane-fused iminosugars. The N-propargyl-C-nitromethyl glycosides underwent an unprecedented ketenimine−acrylamidine−Michael addition cascade reaction to give bicyclic amidines.
minosugars inhibit glycosidases and glycosyltransferases and have served as lead molecules for treatment of various diseases, including cancer, diabetes, viral infections, and lysosomal storage disorders.1 Slight modifications in both mono- and bicyclic iminosugars, including stereochemical changes and functional group variation like introduction of lipophilic substituents at the N-/C1-position, alter their potency and specificity.1,2 N-Alkylated derivatives of 1-deoxynojrimycin, Glyset and Zaveska, are prescribed drugs for the oral treatment of type II diabetes and Gaucher’s disease, respectively (Figure 1). Naturally occurring bicyclic iminosugars, swainsonine and castanospermine and its derivatives, exhibit antitumor and immunosuppressive activities, respectively.3,4 Celgosivir, a 6-Obutanoyl castanospermine, is in phase II clinical trials for treatment of acute dengue fever, Hepatitis C, and HIV (Figure
I
1).5 Development of mild and efficient routes for synthesis of iminosugars has evoked much interest among synthetic chemists.6 The nitromethyl motif is one of the most versatile functional groups in organic synthesis. It serves as a source of a wide variety of functional groups and as an excellent participant in nitroMannich, Henry, dipolar cycloaddition, and radical reactions. It has been extensively investigated in the construction of Nheterocyclic ring systems by selective manipulation of nitromethyl functionality.7 Our interest in the synthesis of biologically significant iminosugars,8 coupled with the usefulness of the nitromethyl unit, inspired us to develop a general and operationally simple strategy for stereoselective synthesis of novel C-nitromethyl glycosides. Treatment of D-ribose tosylate 1 with allyl amine at rt and subsequent alkylation of the in situ generated iminium ion with nitromethane resulted in isolation of β-C-nitromethyl glycoside 2 as a single diastereomer in 83% yield (Scheme 1). Nitromethane reacted smoothly with the iminium ion derived from various aliphatic amines and D-ribose tosylate to furnish the corresponding N-alkylated β-C-nitromethyl glycosides 3−5 (dr 1:0) and 6−8 (dr 9:1) in good yields (Figure 2). Iminium ions derived from D-lyxose tosylate8a underwent smooth alkylation with
Figure 1. Biologically active mono/bicyclic iminosugars.
Received: July 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02175 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
oxime derivative 18 as an inseparable Z-/E-mixture of oximes (3:1) in 70% yield (Scheme 3). Minor isomer (E)-18 crystallized
Scheme 1. One-Pot Synthesis of Piperidine-Based 2
Scheme 3. Reagent-Free Synthesis of Bicyclic IminosugarOxime Derivativesa
a
Reaction conditions: toluene (5 mL per 100 mg), reflux for 10 h.
out of the mixture, and its structure and stereochemistry were unambiguously confirmed by single-crystal X-ray analysis. Under reflux conditions in toluene, the reaction was complete in 10 h to furnish 18 as a 3:1 mixture of isomers in 75% yield (Scheme 3). Under similar conditions, 9 and 14 afforded the corresponding oxime derivatives 19 (9:1 mixture of Z-/E-isomers) and 20 (only Z-isomer), respectively, in good yields (Scheme 3). This stereoselective nitro-olefin dipolar cycloaddition reaction does not require any promoter.7f A plausible mechanism is shown in Figure 4.
Figure 2. Synthesis of piperidine-based iminosugar C-nitromethyl glycosides.
nitromethane to furnish α-C-nitromethyl glycosides 9 (dr 3:1) and 10 (dr 9:1) in good yields (Figure 2). The iminium ion derived from L-rhamnose lactol-mesylate 11 and propargylamine at 80 °C in DMF reacted with nitromethane at rt to furnish pyrrolidine-based iminosugar β-C-nitromethyl glycoside 12 as a single isomer in good yield (Scheme 2). Scheme 2. One-Pot Synthesis of Pyrrolidine-Based 12
Figure 4. Plausible mechanism based on intramolecular cycloaddition of a nitromethyl group with olefin.
The structure and stereochemistry of 12 were unambiguously confirmed by single-crystal X-ray analysis. The scope of this reaction was tested with various primary amines, and the results are summarized in Figure 3.
SET oxidative radical cyclization of 2 using Ag2O and DBU under Kamimura reaction conditions9 resulted in a 5-exo-trig radical cyclization to furnish indolizidine derivative 21 in good yield with excellent stereoselectivity (Scheme 4). However, exposure of 2 to Ag2O, DBU, and iodine resulted in a smooth cyclization to give cyclopropane-fused indolizidine derivative 22 in 74% yield as a single diastereomer. The structure and stereochemistry of 21 and 22 were unambiguously confirmed by single-crystal X-ray analyses (Scheme 4). Ag2O/DBU-mediated reaction of 9 with or without iodine afforded the corresponding cyclized indolizidine derivatives 23 and 24, respectively, in good yields (Table 1, entry 1) (Figure 5). Application of this SET oxidative cyclization was further extended to pyrrolidine-based 13 and proceeded smoothly via 6exo-trig mode of cyclization to afford indolizidine derivative 25 with excellent stereoselectivity (Table 1, entry 2). Under these conditions, 14 underwent facile cyclization to furnish the cyclopropane-fused pyrrolizidine derivative 26 in good yield (Table 1, entry 3) (Figure 5). Our present two-step
Figure 3. Synthesis of pyrrolidine-based iminosugar C-nitromethyl glycosides.
The presence of a nitromethyl group in the iminosugar Cglycosides imparts unique synthetic importance to these scaffolds, as selective transformation of this nitromethyl group provides easy access to a wide range of functionalized bicyclic iminosugars. Iminosugar 2 on standing at rt underwent a novel intramolecular cyclization to furnish polyhydroxylated indolizidineB
DOI: 10.1021/acs.orglett.7b02175 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
protocol provides easy access to structurally novel indolizidine and pyrrolizidine derivatives in very good yields. We envisaged that N-propargyl-C-nitromethyl glycoside 5 upon exposure to TsN3/CuI10 would generate ketenimine 5a which could undergo intramolecular aza-Henry reaction to give bicyclic N-tosyl imine derivative 28. However, treatment 5 with TsN3 and CuI at rt resulted in a smooth reaction to furnish structurally novel bicyclic amidine derivative 27 as a single diastereomer in excellent yield, whose structure and stereochemistry were unambiguously confirmed by a single-crystal Xray analysis (Scheme 5). Under similar reaction conditions, 10
Scheme 4. Stereoselective Synthesis of Novel Bicyclic Iminosugars via SET Oxidative Radical Cyclization
Scheme 5. Stereoselective Synthesis of Novel Bicyclic Iminosugars
Table 1. Ag2O-Mediated Oxidative Cyclization of Iminosugar C-Nitromethyl Glycosides
and 12 also underwent intramolecular cyclization to give the corresponding bicyclic amidine derivatives 29 and 30, respectively, in good yields (Scheme 5). Remarkably, iminosugars possessing amidine functionality exhibit selective inhibition of various glycosidases.11 A plausible mechanism for formation of cyclic amidine 27 from 5 is shown in Figure 6. 5a would undergo intramolecular
Figure 6. Plausible mechanism for the formation of 27.
cyclization to give the azetium ion intermediate 5b, which, on subsequent ring opening, leads to intermediate 5c.12 Intramolecular Michael with 5c could lead to 27 (Figure 6). The synthetic scope of this novel intramolecular cyclization was further demonstrated in the stereoselective synthesis of cyclic amidines such as the epiquinamide analogue 34,13 indolizidine 35, and benzoquinolizidine 36 from corresponding imines (Scheme 6). This cascade reaction is found to be very general and works equally well with an acyclic system (Scheme 7). In conclusion, a simple and facile one-pot method was developed for stereoselective synthesis of novel iminosugar Cnitromethyl glycosides. Synthetic versatilities of N-alkenyl/ alkynyl-C-nitromethyl glycosides are demonstrated in the divergent single-step synthesis of (i) novel iminosugar-oximes under reagent-free conditions, (ii) cyclopropane-fused iminosu-
a
Isolated yields. bReaction performed with A (1 equiv), Ag2O (2 equiv), DBU (1.2 equiv), I2 (2 equiv) in THF (5 mL) for 4 h. c Reaction performed with A (1 equiv), Ag2O (2 equiv), DBU (1.2 equiv) in THF (5 mL) for 4 h.
Figure 5. X-ray crystal structure of 24 and 26.
C
DOI: 10.1021/acs.orglett.7b02175 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(f) Alfonso, P.; Pampin, S.; Estrada, J.; Rodriguez-Rey, J. C.; Giraldo, P.; Sancho, J.; Pocovi, M. Blood Cells, Mol., Dis. 2005, 35, 268. (g) Steinmann, E.; Whitfield, T.; Kallis, T.; Dwek, R. A.; Zitzmann, N.; Pietschmann, T.; Bartenschlager, R. Hepatology 2007, 46, 330. (h) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100, 4683. (i) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515. (2) (a) Nash, R. J.; Kato, A.; Yu, C.-Y.; Fleet, G. W. J. Future Med. Chem. 2011, 3, 1513. (b) Weiss, M.; Hettmer, S.; Smith, P.; Ladisch, S. Cancer Res. 2003, 63, 3654. (c) Wang, G.-N.; Xiong, Y.-L.; Ye, J.; Zhang, L.-H.; Ye, X.-S. ACS Med. Chem. Lett. 2011, 2, 682. (d) Izawa, K.; Acena, J. L.; Wang, J.; Soloshonok, V. A.; Liu, H. Eur. J. Org. Chem. 2016, 2016, 8. (3) (a) Kumar, K. S. A.; Rathee, J. S.; Subramanian, M.; Chattopadhyay, S. J. Org. Chem. 2013, 78, 7406. (b) Li, Q.; Ye, X.-S. Isr. J. Chem. 2015, 55, 336. (c) Pawar, N. J.; Parihar, V. S.; Khan, A.; Joshi, R.; Dhavale, D. D. J. Med. Chem. 2015, 58, 7820. (4) (a) Hino, M.; Nakayama, O.; Tsurumi, Y.; Adachi, K.; Shibata, T.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1985, 38, 926. (b) Galustian, C.; Foulds, S.; Dye, J. F.; Guillou, P. J. Immunopharmacology 1994, 27, 165. (c) Walter, S.; Fassbender, K.; Gulbins, E.; Liu, Y.; Rieschel, M.; Herten, M.; Bertsch, T.; Engelhardt, B. J. Neuroimmunol. 2002, 132, 1. (d) Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer Res. 1995, 1, 935. (5) (a) Whitby, K.; Taylor, D.; Patel, D.; Ahmed, P.; Tyms, A. S. Antiviral Chem. Chemother. 2004, 15, 141. (b) Rathore, A. P. S.; Paradkar, P. N.; Watanabe, S.; Tan, K. H.; Sung, C.; Connolly, J. E.; Low, J.; Ooi, E. E.; Vasudevan, S. G. Antiviral Res. 2011, 92, 453. (c) Low, J. G.; Sung, C.; Wijaya, L.; Wei, Y.; Rathore, A. P. S.; Watanabe, S.; Tan, B. H.; Toh, L.; Chua, L. T.; Hou, Y. a.; Chow, A.; Howe, S.; Chan, W. K.; Tan, K. H.; Chung, J. S.; Cherng, B. P.; Lye, D. C.; Tambayah, P. A.; Ng, L. C.; Connolly, J.; Hibberd, M. L.; Leo, Y. S.; Cheung, Y. B.; Ooi, E. E.; Vasudevan, S. G. Lancet Infect. Dis. 2014, 14, 706. (6) (a) Bergeron-Brlek, M.; Meanwell, M.; Britton, R. Nat. Commun. 2015, 6, 6903. (b) Szczesniak, P.; Stecko, S.; Maziarz, E.; StaszewskaKrajewska, O.; Furman, B. J. Org. Chem. 2014, 79, 10487. (c) Hong, Z.; Liu, L.; Sugiyama, M.; Fu, Y.; Wong, C.-H. J. Am. Chem. Soc. 2009, 131, 8352. (d) Compain, P.; Chagnault, V.; Martin, O. R. Tetrahedron: Asymmetry 2009, 20, 672. (e) Malinowski, M.; Rowicki, T.; Guzik, P.; Wielechowska, M.; Sobiepanek, A.; Sas, W. Eur. J. Org. Chem. 2016, 2016, 3642. (7) (a) Noble, A.; Anderson, J. C. Chem. Rev. 2013, 113, 2887. (b) Barber, D. M.; Sanganee, H. J.; Dixon, D. J. Org. Lett. 2012, 14, 5290. (c) Barber, D. M.; Duris, A.; Thompson, A. L.; Sanganee, H. J.; Dixon, D. J. ACS Catal. 2014, 4, 634. (d) Michael, J. P. Indolizidine and quinolizidine alkaloids. Nat. Prod. Rep. 2008, 25, 139. (e) Ono, N., Ed. The Nitro Group in Organic Synthesis; Wiley & Sons, 2001. (f) Gottlieb, L.; Hassner, A. J. Org. Chem. 1995, 60, 3759. (8) (a) Chinthapally, K.; Karthik, R.; Senthilkumar, S.; Baskaran, S. Chem. - Eur. J. 2017, 23, 533. (b) Senthilkumar, S.; Prasad, S. S.; Das, A.; Baskaran, S. Chem. - Eur. J. 2015, 21, 15914. (c) Senthilkumar, S.; Prasad, S. S.; Kumar, P. S.; Baskaran, S. Chem. Commun. 2014, 50, 1549. (d) Aravind, A.; Kumar, P. S.; Sankar, M. G.; Baskaran, S. Eur. J. Org. Chem. 2011, 2011, 6980. (e) Kumar, P. S.; Banerjee, A.; Baskaran, S. Angew. Chem., Int. Ed. 2010, 49, 804. (f) Aravind, A.; Sankar, M. G.; Varghese, B.; Baskaran, S. J. Org. Chem. 2009, 74, 2858. (9) (a) Kamimura, A.; Kadowaki, A.; Yoshida, T.; Takeuchi, R.; Uno, H. Chem. - Eur. J. 2009, 15, 10330. (b) Kamimura, A.; Moriyama, T.; Ito, Y.; Kawamoto, T.; Uno, H. J. Org. Chem. 2016, 81, 4664. (10) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038. (11) (a) Fan, Q.-H.; Claunch, K. A.; Striegler, S. J. Med. Chem. 2014, 57, 8999. (b) Heck, M.-P.; Vincent, S. P.; Murray, B. W.; Bellamy, F.; Wong, C.-H.; Mioskowski, C. J. Am. Chem. Soc. 2004, 126, 1971. (12) Chauhan, D. P.; Varma, S. J.; Vijeta, A.; Banerjee, P.; Talukdar, P. Chem. Commun. 2014, 50, 323. (13) Fitch, R. W.; Sturgeon, G. D.; Patel, S. R.; Spande, T. F.; Garraffo, H. M.; Daly, J. W.; Blaauw, R. H. J. Nat. Prod. 2009, 72, 243.
Scheme 6. Synthesis of Cyclic Amidines
Scheme 7. Synthesis of Cyclic Amidine 39 from 37
gars under SET oxidation conditions, (iii) unique ketenimine− acrylamidine−Michael addition cascade reaction leading to bicyclic amidines, and (iv) functionalized novel bicyclic iminosugars in very good yields with a high degree of stereoselectivity.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02175. Complete experimental details and characterization data (PDF) X-ray data for 12, 18, 21, 22, 24, 26, 27, and 35 (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Sundarababu Baskaran: 0000-0002-7636-2812 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We thank DST-SERB (EMR/2016/004040), India, for financial support and DST-FIST for providing instruments facilities. S. S. P., S. S., and A. S. thank CSIR-New Delhi, UGC-New Delhi, and IIT Madras-Chennai, respectively, for research fellowships. We thank Mr. V. Ram Kumar and Dr. P. K. Sudhadevi Antharjanam for single-crystal X-ray analyses.
■
REFERENCES
(1) (a) Compain, P.; Martin, O. R. Iminosugars: From Synthesis to Therapeutic Applications; Wiley, 2007. (b) Horne, G.; Wilson, F. X.; Tinsley, J.; Williams, D. H.; Storer, R. Drug Discovery Today 2011, 16, 107. (c) Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-VCH, 1999. (d) Tyrrell, B. E.; Sayce, A. C.; Warfield, K. L.; Miller, J. L.; Zitzmann, N. Crit. Rev. Microbiol. 2017, 43, 521. (e) Aoki, K.; Nakamura, A.; Ito, S.; Nezu, U.; Iwasaki, T.; Takahashi, M.; Kimura, M.; Terauchi, Y. Diabetes Res. Clin. Pract. 2007, 78, 30. D
DOI: 10.1021/acs.orglett.7b02175 Org. Lett. XXXX, XXX, XXX−XXX
