A novel approach to the synthesis of N-substituted 1-C-aminomethyl glycofuranosides

LETTER 45 A Novel Approach to the Synthesis of N-Substituted 1-C-Aminomethyl Glycofuranosides Synthesis of N-Substituted 1- C -Aminomethyl Glycofuranosides Yolanda Vera-Ayoso,a Pastora Borrachero,a Francisca Cabrera-Escribano,*a Manuel Gómez-Guillén,a Pierre Vogelb aDepartamento de Química Orgánica ‘Profesor García González’, Facultad de Química, Universidad de Sevilla, Apartado de Correos No. 553, 41071 Sevilla, Spain Fax +34(95)4624960; E-mail: [email protected] bLaboratoire de Glycochimie et Synthèse Asymétrique, Swiss Federal Institute of Technology (EPFL), BCH-EPFL, 1015 Lausanne, Switzerland Received 18 October 2005 SYNLETT 2006, No. 1, pp 0045–0048 05.01.2006 Advanced online publication: 16.12.2005 DOI: 10.1055/s-2005-922762; Art ID: D32105ST © Georg Thieme Verlag Stuttgart · New York Abstract: Reductive amination of formyl C-glycofuranosides, easily available from hexose-derived equatorial-2-OH-glycopyrano- sides by DAST-promoted ring contraction, afforded N-substituted 1-C-aminomethyl glycofuranosides in most cases in high yields. Key words: 1-C-aminomethyl glycofuranosides, formyl C-glyco- furanosides, reductive amination, DAST-promoted ring contraction, sugar diamines The stereoselective synthesis of functionalized C-glyco- sides has become an important area of carbohydrate research, as many naturally occurring C-glycosides show useful antibacterial, antiviral, and antitumoral properties.1 One significant type of C-glycoside derivatives are 1-C- aminomethyl glycosides. These compounds are key intermediates for glycoconjugate syntheses, and a number of them have proved to be glycosidase inhibitors.2 Sugar amino acids 23 and 3,4 which containing the substructure 1 (Figure 1), are dipeptide isosters and have been used as secondary structure inducing elements for the generation of peptide-based drugs. This kind of substructure is also found in the naturally occurring alkaloid muscarine (4), a rigid muscarinic agonist of acetylcholine,5 for which a renewed interest is due, in part, to the suggestion that various subtypes of muscarinic receptors seem to be implicated6 in Alzheimer’s disease. Syntheses of 1-C-aminomethyl glycosides so far described rely on the introduction of a CH2NH2 equivalent at the anomeric position: (a) as CH3NO2 via nucleophilic aldol reaction,7 (b) by reducing the corresponding glycosyl cyanide8 or, (c) by degradation of a C-vinyl glycoside and subsequent formation of the azidomethyl intermediate.3b Alternatively, rearrangement involving 5-exo SN2- opening of a terminal aziridine ring, and transformation of a primary hydroxyl function into the corresponding azide gave access to the 2,5-anhydro derivatives 34 and 4,9 respectively. These routes are rather complicated, and for those involving an anomeric carbon–carbon bond-form- ing reaction, chemical efficiency and stereocontrol remain a difficult task. Moreover, for reaching an N-substituted 1-C-aminomethyl glycoside, additional N-alkylation process would be still required. Here we introduce a straightforward approach to N-sub- stituted 1-C-aminomethyl glycofuranosides from hexosederived equatorial-2-OH-glycopyranosides (Scheme 1). The strategy takes advantage of a diethylaminosulfur trifluoride (DAST)-promoted ring contraction that, under remarkably mild conditions, leads to formyl C-glyco- furanosides.10 The use of these compounds in standard coupling reactions with nucleophiles should provide a ready access to hydrolytically stable C-glycofuranoside- based molecules (C-oligosaccharides and C-glycocon- jugates). With this aim, our first goal has been to explore their coupling with biologically relevant amines as nitrogen-containing nucleophiles. Scheme 1 We describe herein the synthesis of enantiopure orthogonally protected C-glycofuranosyl diamines by reductive amination of formyl C-glycofuranosides, easily obtained as their synthetic equivalents 6 and 12 from the methyl equatorial-2-OH-glycohexopyranosides 5 and 11, respectively, by DAST methodology.10,11 Treatment of the crude aldehyde obtained in situ by hydrolysis (9:1 TFA–H2O, r.t., 1 h) of the dimethyl acetal 6, with diverse primary or secondary amines (1.4 mol equiv) + HNR1R2 O HOOMe R O HO R OMe OH R O ONR1R 2 R F igure 1 O Me CH2NM e2 HO 4 O O OH HO HO HOOC NH2 2 3 CH2NH2 H OOC O n NH2 R 1 n = 0, 1 HO OH Downloaded by: Universidad de Sevilla. Copyrighted material. 46 Y. Vera-Ayoso et al. LETTER Synlett 2006, No. 1, 45–48 © Thieme Stuttgart · New York in dry 1,2-dichloroethane, and subsequent reduction of the respective, not isolated, imine using sodium triacetoxyborohydride (1.4 mol equiv), afforded the respective compounds 7a–h in moderate to high yields (Scheme 2, Table 1).12 Their deprotection with 1 M NaMeO–MeOH gave the corresponding products 8a–h.13 As shown in Table 1, primary and secondary aliphatic amines (benzylamine, piperidine, benzyloxycarbonyl piperazine, and morpholine, entries 1–4), as well as the aromatic amine 4-hydroxymethyl aniline (entry 6), gave the corresponding reductive amination compounds 7a–e as the sole product. In the case of the other aniline derivatives (2-biphenylamino, ethyl 4-aminobenzoate and 4- aminobenzonitrile, entries 8–10), however, reductive amination products 7f–h were obtained together with the primary alcohol 10. Starting from N-aminomorpholine as the amine (entry 5), the only isolated product was the hydrazone 9, which could not be reduced by the reagent employed. When using imidazole as the starting amine (entry 7), the expected S cheme 2 O OO P h N3HOOMe O AcO N3 AcO OMe 6OMe 1. 9:1 TFA/H2O, r.t., 1 h 2. RNH2 or R1R2NH, NaBH(OAc)3 DCE, 25 °C 2. i. MeOH, PTSA, r.t., 1 h ii. Ac2O, pyridine, 0 °C O AcO N3 AcO NR1R2 7 (35–88%) MeONa, MeOH 1M r.t., 2 h O HO N3 HO NR1R 2 8 (75–95%) 1. DAST, MeCN, reflux, 12 min (69%) 5 T able 1 Reductive Amination Products 7 of the Formyl Azido-C-glycofuranoside Synthetic Equivalent 6 with Various Amines, and Their D eacetylated Products 8a E ntry Amines R1R2NH Reaction time (h) Products 712 (yield after purification, %) Products 813 (yield, %) 137a (55) 8a (75) 257b (65) 8b (92) 32.57c (80) 8c (95) 467d (67) 8d (87) 51.5 9 (88) –b 627e (77) 8e (90) 720 1011 (56) – 8187f (63) + 10 (19) 8f (85) 9187g11 (47) + 10 (34) 8g (86) 1 0187h (35) + 10 (48) 8h (89) a All products were fully characterized by their IR, 1H NMR, 13C NMR, and HRMS spectral data.14 b Complex mixture of products. H 2N H N H N NCb z H N O O N H2 N O A cO N3 AcO NN O H2 N O H N N H O A cO N 3 AcO O H Ph H2 N H2 N COOEt H2 N CN Downloaded by: Universidad de Sevilla. Copyrighted material. LETTER Synthesis of N-Substituted 1-C-Aminomethyl Glycofuranosides 47 Synlett 2006, No. 1, 45–48 © Thieme Stuttgart · New York 2,5-anhydro-1-(imidazol-1-yl)-D-altritol derivative was not obtained, only 10 was obtained. The reason of this behavior of imidazole may be its weak nucleophilic character, much lower than those of the remainder amines used. In the same way, formation of the primary alcohol 10 as accompanying product of 7f–h, arise from the lack of nucleophilicity provoked by the electron-withdrawing substituent at the para position of the anilines. A shorter experimental protocol, in which a 2,5-anhydro- 1-fluoro-1-O-methylhexitol (a formyl C-glycofuranoside synthetic equivalent directly formed in the ring-contrac- tion reaction promoted by DAST) is subjected to hydrolysis and subsequent in situ reductive amination process, can be applied. Adopting this one-pot procedure, fluoro aldehyde 13 obtained in situ by hydrolysis (9:1 TFA– H2O, r.t., 1 h) of (1R,1S)-2,5-anhydro-3,6-di-O-benzyl-4- deoxy-1,4-difluoro-1-O-methyl-D-talitol (12),10a was made react with diamine 14,15 furnishing fluoro-C-glyco- furanosyl aminomethylpyrrolidine derivative 15 in good yield (Scheme 3).16 In conclusion, this work provides a simple approach to the synthesis of functionalized N-substituted aminomethyl C- glycofuranosides by reductive amination of formyl C-gly- cofuranosides, readily available by DAST methodology from hexose-derived equatorial-2-OH-glycopyranosides. The method works well with good nucleophilic amines and allows complete stereocontrol at the anomeric center. Stereo- and functional diversity on the furanoid ring could be achieved on starting from different equatorial-2-OH- glycohexopyranosides. Extension of this work to other substrates as well as studies with other nucleophiles is currently under investigation. Acknowledgment We thank the European Commission, Directorate General for Science and Development (FP6-508430), the Spanish ‘Ministerio de Ciencia y Tecnología’ (predoctoral fellowship to Y.V.-A.), and the ‘Junta de Andalucía’ (FQM142) for financial support. References and Notes (1) (a) Fischer, C.; Lipata, F.; Rohr, J. J. Am. Chem. Soc. 2003, 125, 7818. (b) Faizi, S.; Ali, H. Planta Med. 1999, 65, 383. (2) (a) Gremyachinskiy, D. E.; Samoshin, V. V.; Gross, P. H. Tetrahedron Lett. 2003, 44, 6587. (b) Bhat, A. S.; Gervay- Hague, J. Org. Lett. 2001, 3, 2081. (c) BeMiller, J. N.; Gilson, R. J.; Myers, R. W.; Santoro, M. M.; Yadav, M. P. Carbohydr. Res. 1993, 250, 93. (d) Lai, W.; Martin, O. R. Carbohydr. Res. 1993, 250, 185. (e) Maity, S. K.; Dutta, S. K.; Banerjee, A. K.; Achari, B.; Singh, M. Tetrahedron 1994, 50, 6965. For 2-(aminomethyl)pyrrolidine-3,4-diol derivatives, see: (f) Saotome, C.; Wong, C.-H.; Kanie, O. Chem. Biol. 2001, 8, 1061. (g) Popowycz, F.; Gerber- Lemaire, S.; Schütz, C.; Vogel, P. Helv. Chim. Acta 2004, 87, 800. (h) Fiaux, H.; Popowycz, F.; Favre, S.; Schütz, C.; Vogel, P.; Gerber-Lemaire, S.; Juillerat-Jeanneret, L. J. Med. Chem. 2005, 48, 4237. (i) Popowycz, F.; Gerber- Lemaire, S.; Rodriguez-García, E.; Schütz, C.; Vogel, P. Helv. Chim. Acta 2003, 86, 1914. (3) (a) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491. (b) Durrat, F.; Xie, J.; Valéry, J.-M. Tetrahedron Lett. 2004, 45, 1477. (4) For recent reviews see: (a) Chakraborty, T. K.; Srinivasu, P.; Tapadar, S.; Mohan, B. K. Glycoconjugate J. 2005, 22, 83. (b) Chakraborty, T. K.; Srinivasu, P.; Tapadar, S.; Mohan, B. J. Chem. Sci. 2004, 116, 187. See also: (c) Prasad, S.; Mathur, A.; Jaggi, M.; Sharma, R.; Gupta, N.; Reddy, V. R.; Sudhakar, G.; Kumar, S. U.; Kumar, S. K.; Kunwar, A. C.; Chakraborty, T. K. J. Pept. Res. 2005, 66, 75. (d) Chakraborty, T. K.; Jayaprakash, S.; Diwan, P. V.; Nagaraj, R.; Jampani, S. R. B.; Kunwar, A. C. J. Am. Chem. Soc. 1998, 120, 12962. (e) Chakraborty, T. K.; Ghosh, S.; Jayaprakash, S.; Sarma, J. A. R. P.; Ravikanth, V.; Diwan, P. V.; Nagaraj, R.; Kunwar, A. C. J. Org. Chem. 2000, 65, 6441. (5) Patrick, G. L. An Introduction to Medicinal Chemistry, 2nd ed.; Oxford University Press: Oxford, 2002, 446. (6) (a) Broadley, K. J.; Kelly, D. R. Molecules 2001, 6, 142. (b) Liu, J.-K. Chem. Rev. 2005, 105, 2723. (7) (a) Locardi, E.; Stöke, M.; Gruner, S.; Kessler, H. J. Am. Chem. Soc. 2001, 123, 8189. (b) Graf von Roedern, E.; Kessler, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 687. (c) Graf von Roedern, E.; Kessler, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 684. (8) Benksim, A.; Beaupère, D.; Wadouahi, A. Org. Lett. 2004, 6, 3913. (9) Mantell, S. J.; Fleet, G. W. J.; Brown, D. J. Chem. Soc., Perkin Trans. 1 1992, 3023. S cheme 3 O H O BnO HO DAST, CH 2 Cl 2 , reflux, 1.5 h BnO OMe O BnO OMe 12 9:1 TFA/H2O, r.t., 1 h NaBH(OAc)3 DCE, r.t., 1.5 h (65–79%) FOBn F H O B nO 13 FOBn O HO BnO 15 FOBn N 11 NH2 OO Boc 14 NH N Boc OO (92%) (70% from 12) 1 26' 1' 2' 3' 4' 5 ' Downloaded by: Universidad de Sevilla. Copyrighted material. 48 Y. Vera-Ayoso et al. LETTER Synlett 2006, No. 1, 45–48 © Thieme Stuttgart · New York (10) (a) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.; Carmona, A. T.; Gómez-Guillén, M. Tetrahedron: Asymmetry 2004, 15, 429. (b) Borrachero, P.; Cabrera- Escribano, F.; Carmona, A. T.; Gómez-Guillén, M. Tetrahedron: Asymmetry 2000, 11, 2927. (c) Borrachero- Moya, P.; Cabrera-Escribano, F.; Gómez-Guillén, M.; Madrid-Díaz, F. Tetrahedron Lett. 1997, 38, 1231. (11) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.; Gómez-Guillén, M. Tetrahedron: Asymmetry 2005, 16, 889. (12) General Procedure for the One-Pot Preparation of Compounds 7. Compound 6 (100 mg, 0.315 mmol) was dissolved in a 9:1 TFA–H2O mixture (2.7 mL) and the solution was kept at r.t. for 1 h. The reaction mixture was poured into ice-water (100 mL) and extracted with CH2Cl2 (4 ×20 mL). The combined organic layers were successively washed with sat. aq NaHCO3 and brine, then dried (Na2SO4), and concentrated. The residue (crude aldehyde) was dissolved in 1,2- dicloroethane (3.1 mL) and treated with the amine (0.437 mmol) and sodium triacetoxyborohydride (93.0 mg, 0.441 mmol). The reaction was stirred at r.t. for the appropriate time (Table 1). The mixture was then diluted with sat. aq NaHCO3 (25 mL) and the aqueous layer was extracted with EtOAc (3 ×20 mL). The combined organic layers were dried (Na2SO4), and concentrated under reduced pressure to give the crude product, which was purified by column chromatography using EtOAc–hexane, Et2O–hexane or Et2O–acetone as eluent. Compound 7a: Rf = 0.37 (5:1 Et2O–acetone); [a]D26 +19.3 (c 0.56, CH2Cl2). IR: nmax = 3324 (NH), 2106 (N3), 1746 (CO), 1231 and 1119 (CO) cm–1. 1H NMR (300 MHz, acetone-d6): d = 7.25–7.08 (m, 5 H, Ph), 5.31 (dd, 1 H, J4,5 = 7.8 Hz, J3,4 = 5.1 Hz, H-4), 4.48 (dd, 1 H, J2,3 = 3.9 Hz, H-3), 4.32 (ddd, 1 H, J1,2 =J1¢,2 = 6.6 Hz, H-2), 4.23 (dd, 1 H, J6,6¢= 10.8 Hz, J5,6 = 2.4 Hz, H-6), 4.07–3.95 (m, 2 H, H-5 and H-6′), 3.83 (d, 1 H, JH,H¢= 13.5 Hz, CHaPh), 3.78 (d, 1 H, JH,H¢= 13.8 Hz, CHbPh), 2.82 (d, 2 H, H-1 and H-1′), 2.11 and 2.02 (each 2 s, 3 H, 2 COMe) ppm. 13C NMR (75.4 MHz, acetone-d6): d = 170.8, 170.7 (2 CO), 141.8–127.5 (Ph), 80.0 (C-2), 78.1 (C-5), 75.8 (C-4), 64.6 (C-6), 64.4 (C-3), 54.4 (CH2Ph), 49.4 (C-1), 20.7 and 20.4 (2 COMe) ppm. HRMS (CI): m/z calcd for C17H22N4O5 + H: 363.1668; found 363.1671. (13) General Procedure for Deacetylation of 7 and Preparation of Compounds 8. The corresponding reductive amination product 7 (0.070 mmol) was dissolved in: (i) (2 mL of 1:1 MeOH–CHCl3), (ii) (2 mL of MeOH), or (iii) (2 mL of EtOH abs.), and 5 drops of 1 M MeONa–MeOH were added to the solution [for the deprotection of 7g was used EtONa–EtOH abs. (1 M)]. The reaction mixture was kept at r.t. for 2 h. Work-up was done by one of the following procedures. Procedure 1 (8b–d,f): the reaction mixture was cooled and 600 mL TFA was added. The residue was purified by a Dowex 50 ×8 W column, using MeOH (50 mL), H2O (50 mL) and NH4OH (10% aq soln; 100 mL) as eluents. Procedure 2 (8a,e,g,h): the reaction mixture was neutralized with Amberlyst 15, the resin was removed by filtration and the solvent under reduced pressure. (14) In comparison with the NMR spectra of each direct precursor, each acetylated compound 7a–h lacked any signal of aldehyde proton and carbon, but showed instead the signals corresponding to the two new diastereotopic protons at C(1). For the compounds obtained from some primary amines (7e,f–h), the amine proton gave rise to the typical broad signal in the 1H NMR spectrum at d = 4.41 (7e), 4.44– 4.38 (7f), 5.81 (7g), and 6.00 ppm (7h), values that can be correlated with the electron-withdrawing or electrondonating character of the substituent at the para position of the aromatic group. However, the amine proton signal of 7a was not observed, probably because it is overlapped. The molecular weight found for 9 in its HRMS agreed with the aldimine structure assigned, while its NMR spectra showed the sp2 (C)H signal at d = 6.86 ppm and the imine carbon at d = 134.1 ppm, thus corroborating the assignation. For the deacetylated compounds 8a–h, their respective calculated molecular weights were in agreement with those found by HRMS. Furthermore, the 1H NMR and 13C NMR spectra of these compounds showed no signal corresponding to the O- acetyl groups present in the precursors 7a–h, as expected. (15) Popowycz, F.; Gerber-Lemarie, S.; Demange, R.; Rodriguez-García, E.; Asenjo, A. T. C.; Robina, I.; Vogel, P. Bioorg. Med. Chem. Lett. 2001, 11, 2489. (16) Compound 15 was obtained from 12 (100 mg, 0.265 mmol) and diamine 14 (78 mg, 0.287 mmol) in the presence of NaBH(OAc)3 (60.2 mg, 0.287 mmol) by a similar one-pot procedure to that described above for the preparation of compounds 7 from 6. More relevant data of 15: Rf = 0.45 (Et2O); [a]D24 +14.6 (c 0.63, acetone). IR: nmax = 3295 (NH), 1692 (CO), 1370 (NCO), 1157, 1059 (COC), and 991 (CF) cm–1. 1H NMR (500 MHz, DMSO-d6, 363 K): d = 7.41–7.25 (m, 5 H, Ph), 5.27 (dt, 1 H, 2J4,F = 54.9 Hz, J3,4 =J4,5 = 3.0 Hz, H-4), 4.79, 4.63 (2 d, 1 H each, JH,H¢= 11.5 Hz, CH2Ph), 4.69 (dd, 1 H, J4¢,3¢=J4¢,5¢b=5.7 Hz, H-4′), 4.62 (d, 1 H, H-3′), 4.55 (s, 2 H, CH2Ph), 4.38 (dddd, 1 H, 3J5,F = 30.5 Hz, J5,6a =J5,6b =6.0 Hz, H-5), 4.33–4.21 (m, 2 H, H-2 and H-2′), 4.17 (dt, 1 H, 3J3,F = 23.5 Hz, J2,3 = 8.5 Hz, H-3), 3.75 (dd, 1 H, J6a,6b = 10.2 Hz, H-6a), 3.75 (d, 1 H, J5¢a,5¢b= 14.0 Hz, H-5′a), 3.60 (ddd, 1 H, 4J6b,F = 1.8 Hz, H-6b), 3.32 (dd, 1 H, H-5′b), 3.20–2.91 (m, 4 H, H-1a, H-1b, H-6′a, H-6′b), 1.41 (s, 9 H, CMe3), 1.34 and 1.25 (each 2 s, 3 H, CMe2) ppm. 13C NMR (125.7 MHz, DMSO-d6, 363 K): d = 152 (CO), 137.7–126.8 (Ph), 110.6 (CMe2), 89.1 (d, 1J4,F = 188.2 Hz, C-4), 81.6 (C- 3′), 80.1 (d, 2J3,F = 16.2 Hz, C-3), 79.5 (C-4′), 78.4 (d, 2J5,F = 17.1 Hz, C-5), 78.3 (CMe3), 74.7 (C-2), 72.2 and 71.2 (CH2Ph), 67.0 (d, 3J6,F = 11.6 Hz, C-6), 59.8 (C-2′), 50.4 (C- 5′), 49.0, 46.6 (C-1, C-6′), 27.6 (CMe3), 26.3 and 26.2 (CMe2). HRMS (CI): m/z calcd for C33H45N2O7F + H: 601.3289; found: 601.3281. Downloaded by: Universidad de Sevilla. Copyrighted material.