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

LETTER 45 A No el App oach o he Syn hesis o N-Subs i u ed 1-C-Aminome hyl Glyco u anosides Syn hesis o N-Subs i u ed 1- C -Aminome hyl Glyco u anosides Yolanda Ve a-Ayoso,a Pas o a Bo ache o,a F ancisca Cab e a-Esc ibano,*a Manuel Gómez-Guillén,a Pie e Vogelb aDepa amen o de Química O gánica ‘P o eso Ga cía González’, Facul ad de Química, Uni e sidad de Se illa, Apa ado de Co eos No. 553, 41071 Se illa, Spain Fax +34(95)4624960; E-mail: cab e [email protected] bLabo a oi e de Glycochimie e Syn hèse Asymé ique, Swiss Fede al Ins i u e o Technology (EPFL), BCH-EPFL, 1015 Lausanne, Swi ze land Recei ed 18 Oc obe 2005 SYNLETT 2006, No. 1, pp 0045–0048 05.01.2006 Ad anced online publica ion: 16.12.2005 DOI: 10.1055/s-2005-922762; A ID: D32105ST © Geo g Thieme Ve lag S u ga · New Yo k Abs ac : Reduc i e amina ion o o myl C-glyco u anosides, eas- ily a ailable om hexose-de i ed equa o ial-2-OH-glycopy ano- sides by DAST-p omo ed ing con ac ion, a o ded N-subs i u ed 1-C-aminome hyl glyco u anosides in mos cases in high yields. Key wo ds: 1-C-aminome hyl glyco u anosides, o myl C-glyco- u anosides, educ i e amina ion, DAST-p omo ed ing con ac- ion, suga diamines The s e eoselec i e syn hesis o unc ionalized C-glyco- sides has become an impo an a ea o ca bohyd a e e- sea ch, as many na u ally occu ing C-glycosides show use ul an ibac e ial, an i i al, and an i umo al p ope ies.1 One signi ican ype o C-glycoside de i a i es a e 1-C- aminome hyl glycosides. These compounds a e key in e - media es o glycoconjuga e syn heses, and a numbe o hem ha e p o ed o be glycosidase inhibi o s.2 Suga amino acids 23 and 3,4 which con aining he subs uc u e 1 (Figu e 1), a e dipep ide isos e s and ha e been used as seconda y s uc u e inducing elemen s o he gene a ion o pep ide-based d ugs. This kind o subs uc u e is also ound in he na u ally occu ing alkaloid musca ine (4), a igid musca inic agonis o ace ylcholine,5 o which a enewed in e es is due, in pa , o he sugges ion ha a ious sub ypes o musca inic ecep o s seem o be implica ed6 in Alzheime ’s disease. Syn heses o 1-C-aminome hyl glycosides so a de- sc ibed ely on he in oduc ion o a CH2NH2 equi alen a he anome ic posi ion: (a) as CH3NO2 ia nucleophilic aldol eac ion,7 (b) by educing he co esponding glyco- syl cyanide8 o , (c) by deg ada ion o a C- inyl glycoside and subsequen o ma ion o he azidome hyl in e medi- a e.3b Al e na i ely, ea angemen in ol ing 5-exo SN2- opening o a e minal azi idine ing, and ans o ma ion o a p ima y hyd oxyl unc ion in o he co esponding azide ga e access o he 2,5-anhyd o de i a i es 34 and 4,9 e- spec i ely. These ou es a e a he complica ed, and o hose in ol ing an anome ic ca bon–ca bon bond- o m- ing eac ion, chemical e iciency and s e eocon ol emain a di icul ask. Mo eo e , o eaching an N-subs i u ed 1-C-aminome hyl glycoside, addi ional N-alkyla ion p o- cess would be s ill equi ed. He e we in oduce a s aigh o wa d app oach o N-sub- s i u ed 1-C-aminome hyl glyco u anosides om hexose- de i ed equa o ial-2-OH-glycopy anosides (Scheme 1). The s a egy akes ad an age o a die hylaminosul u i luo ide (DAST)-p omo ed ing con ac ion ha , unde ema kably mild condi ions, leads o o myl C-glyco- u anosides.10 The use o hese compounds in s anda d coupling eac ions wi h nucleophiles should p o ide a eady access o hyd oly ically s able C-glyco u anoside- based molecules (C-oligosaccha ides and C-glycocon- juga es). Wi h his aim, ou i s goal has been o explo e hei coupling wi h biologically ele an amines as ni o- gen-con aining nucleophiles. Scheme 1 We desc ibe he ein he syn hesis o enan iopu e o hogo- nally p o ec ed C-glyco u anosyl diamines by educ i e amina ion o o myl C-glyco u anosides, easily ob ained as hei syn he ic equi alen s 6 and 12 om he me hyl equa o ial-2-OH-glycohexopy anosides 5 and 11, espec- i ely, by DAST me hodology.10,11 T ea men o he c ude aldehyde ob ained in si u by hy- d olysis (9:1 TFA–H2O, . ., 1 h) o he dime hyl ace al 6, wi h di e se p ima y o seconda y amines (1.4 mol equi ) + HNR1R2 O HOOMe R O HO R OMe OH R O ONR1R 2 R F igu e 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: Uni e sidad de Se illa. Copy igh ed ma e ial. 46 Y. Ve a-Ayoso e al. LETTER Synle 2006, No. 1, 45–48 © Thieme S u ga · New Yo k in d y 1,2-dichlo oe hane, and subsequen educ ion o he espec i e, no isola ed, imine using sodium iace oxy- bo ohyd ide (1.4 mol equi ), a o ded he espec i e com- pounds 7a–h in mode a e o high yields (Scheme 2, Table 1).12 Thei dep o ec ion wi h 1 M NaMeO–MeOH ga e he co esponding p oduc s 8a–h.13 As shown in Table 1, p ima y and seconda y alipha ic amines (benzylamine, pipe idine, benzyloxyca bonyl pip- e azine, and mo pholine, en ies 1–4), as well as he a o- ma ic amine 4-hyd oxyme hyl aniline (en y 6), ga e he co esponding educ i e amina ion compounds 7a–e as he sole p oduc . In he case o he o he aniline de i a- i es (2-biphenylamino, e hyl 4-aminobenzoa e and 4- aminobenzoni ile, en ies 8–10), howe e , educ i e amina ion p oduc s 7 –h we e ob ained oge he wi h he p ima y alcohol 10. S a ing om N-aminomo pholine as he amine (en y 5), he only isola ed p oduc was he hyd azone 9, which could no be educed by he eagen employed. When us- ing imidazole as he s a ing amine (en y 7), he expec ed S cheme 2 O OO P h N3HOOMe O AcO N3 AcO OMe 6OMe 1. 9:1 TFA/H2O, . ., 1 h 2. RNH2 o R1R2NH, NaBH(OAc)3 DCE, 25 °C 2. i. MeOH, PTSA, . ., 1 h ii. Ac2O, py idine, 0 °C O AcO N3 AcO NR1R2 7 (35–88%) MeONa, MeOH 1M . ., 2 h O HO N3 HO NR1R 2 8 (75–95%) 1. DAST, MeCN, e lux, 12 min (69%) 5 T able 1 Reduc i e Amina ion P oduc s 7 o he Fo myl Azido-C-glyco u anoside Syn he ic Equi alen 6 wi h Va ious Amines, and Thei D eace yla ed P oduc s 8a E n y Amines R1R2NH Reac ion ime (h) P oduc s 712 (yield a e pu i ica ion, %) P oduc s 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) – 8187 (63) + 10 (19) 8 (85) 9187g11 (47) + 10 (34) 8g (86) 1 0187h (35) + 10 (48) 8h (89) a All p oduc s we e ully cha ac e ized by hei IR, 1H NMR, 13C NMR, and HRMS spec al da a.14 b Complex mix u e o p oduc s. 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 COOE H2 N CN Downloaded by: Uni e sidad de Se illa. Copy igh ed ma e ial. LETTER Syn hesis o N-Subs i u ed 1-C-Aminome hyl Glyco u anosides 47 Synle 2006, No. 1, 45–48 © Thieme S u ga · New Yo k 2,5-anhyd o-1-(imidazol-1-yl)-D-al i ol de i a i e was no ob ained, only 10 was ob ained. The eason o his be- ha io o imidazole may be i s weak nucleophilic cha ac- e , much lowe han hose o he emainde amines used. In he same way, o ma ion o he p ima y alcohol 10 as accompanying p oduc o 7 –h, a ise om he lack o nucleophilici y p o oked by he elec on-wi hd awing subs i uen a he pa a posi ion o he anilines. A sho e expe imen al p o ocol, in which a 2,5-anhyd o- 1- luo o-1-O-me hylhexi ol (a o myl C-glyco u anoside syn he ic equi alen di ec ly o med in he ing-con ac- ion eac ion p omo ed by DAST) is subjec ed o hyd o- lysis and subsequen in si u educ i e amina ion p ocess, can be applied. Adop ing his one-po p ocedu e, luo o aldehyde 13 ob ained in si u by hyd olysis (9:1 TFA– H2O, . ., 1 h) o (1R,1S)-2,5-anhyd o-3,6-di-O-benzyl-4- deoxy-1,4-di luo o-1-O-me hyl-D- ali ol (12),10a was made eac wi h diamine 14,15 u nishing luo o-C-glyco- u anosyl aminome hylpy olidine de i a i e 15 in good yield (Scheme 3).16 In conclusion, his wo k p o ides a simple app oach o he syn hesis o unc ionalized N-subs i u ed aminome hyl C- glyco u anosides by educ i e amina ion o o myl C-gly- co u anosides, eadily a ailable by DAST me hodology om hexose-de i ed equa o ial-2-OH-glycopy anosides. The me hod wo ks well wi h good nucleophilic amines and allows comple e s e eocon ol a he anome ic cen e . S e eo- and unc ional di e si y on he u anoid ing could be achie ed on s a ing om di e en equa o ial-2-OH- glycohexopy anosides. Ex ension o his wo k o o he subs a es as well as s udies wi h o he nucleophiles is cu en ly unde in es iga ion. Acknowledgmen We hank he Eu opean Commission, Di ec o a e Gene al o Science and De elopmen (FP6-508430), he Spanish ‘Minis e io de Ciencia y Tecnología’ (p edoc o al ellowship o Y.V.-A.), and he ‘Jun a de Andalucía’ (FQM142) o inancial suppo . Re e ences and No es (1) (a) Fische , C.; Lipa a, F.; Roh , J. J. Am. Chem. Soc. 2003, 125, 7818. (b) Faizi, S.; Ali, H. Plan a Med. 1999, 65, 383. (2) (a) G emyachinskiy, D. E.; Samoshin, V. V.; G oss, P. H. Te ahed on Le . 2003, 44, 6587. (b) Bha , A. S.; Ge ay- Hague, J. O g. Le . 2001, 3, 2081. (c) BeMille , J. N.; Gilson, R. J.; Mye s, R. W.; San o o, M. M.; Yada , M. P. Ca bohyd . Res. 1993, 250, 93. (d) Lai, W.; Ma in, O. R. Ca bohyd . Res. 1993, 250, 185. (e) Mai y, S. K.; Du a, S. K.; Bane jee, A. K.; Acha i, B.; Singh, M. Te ahed on 1994, 50, 6965. Fo 2-(aminome hyl)py olidine-3,4-diol de i a i es, see: ( ) Sao ome, C.; Wong, C.-H.; Kanie, O. Chem. Biol. 2001, 8, 1061. (g) Popowycz, F.; Ge be - Lemai e, S.; Schü z, C.; Vogel, P. Hel . Chim. Ac a 2004, 87, 800. (h) Fiaux, H.; Popowycz, F.; Fa e, S.; Schü z, C.; Vogel, P.; Ge be -Lemai e, S.; Juille a -Jeanne e , L. J. Med. Chem. 2005, 48, 4237. (i) Popowycz, F.; Ge be - Lemai e, S.; Rod iguez-Ga cía, E.; Schü z, C.; Vogel, P. Hel . Chim. Ac a 2003, 86, 1914. (3) (a) G une , S. A. W.; Loca di, E.; Loho , E.; Kessle , H. Chem. Re . 2002, 102, 491. (b) Du a , F.; Xie, J.; Valé y, J.-M. Te ahed on Le . 2004, 45, 1477. (4) Fo ecen e iews see: (a) Chak abo y, T. K.; S ini asu, P.; Tapada , S.; Mohan, B. K. Glycoconjuga e J. 2005, 22, 83. (b) Chak abo y, T. K.; S ini asu, P.; Tapada , S.; Mohan, B. J. Chem. Sci. 2004, 116, 187. See also: (c) P asad, S.; Ma hu , A.; Jaggi, M.; Sha ma, R.; Gup a, N.; Reddy, V. R.; Sudhaka , G.; Kuma , S. U.; Kuma , S. K.; Kunwa , A. C.; Chak abo y, T. K. J. Pep . Res. 2005, 66, 75. (d) Chak abo y, T. K.; Jayap akash, S.; Diwan, P. V.; Naga aj, R.; Jampani, S. R. B.; Kunwa , A. C. J. Am. Chem. Soc. 1998, 120, 12962. (e) Chak abo y, T. K.; Ghosh, S.; Jayap akash, S.; Sa ma, J. A. R. P.; Ra ikan h, V.; Diwan, P. V.; Naga aj, R.; Kunwa , A. C. J. O g. Chem. 2000, 65, 6441. (5) Pa ick, G. L. An In oduc ion o Medicinal Chemis y, 2nd ed.; Ox o d Uni e si y P ess: Ox o d, 2002, 446. (6) (a) B oadley, K. J.; Kelly, D. R. Molecules 2001, 6, 142. (b) Liu, J.-K. Chem. Re . 2005, 105, 2723. (7) (a) Loca di, E.; S öke, M.; G une , S.; Kessle , H. J. Am. Chem. Soc. 2001, 123, 8189. (b) G a on Roede n, E.; Kessle , H. Angew. Chem., In . Ed. Engl. 1994, 33, 687. (c) G a on Roede n, E.; Kessle , H. Angew. Chem., In . Ed. Engl. 1994, 33, 684. (8) Benksim, A.; Beaupè e, D.; Wadouahi, A. O g. Le . 2004, 6, 3913. (9) Man ell, S. J.; Flee , G. W. J.; B own, D. J. Chem. Soc., Pe kin T ans. 1 1992, 3023. S cheme 3 O H O BnO HO DAST, CH 2 Cl 2 , e lux, 1.5 h BnO OMe O BnO OMe 12 9:1 TFA/H2O, . ., 1 h NaBH(OAc)3 DCE, . ., 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% om 12) 1 26' 1' 2' 3' 4' 5 ' Downloaded by: Uni e sidad de Se illa. Copy igh ed ma e ial. 48 Y. Ve a-Ayoso e al. LETTER Synle 2006, No. 1, 45–48 © Thieme S u ga · New Yo k (10) (a) Ve a-Ayoso, Y.; Bo ache o, P.; Cab e a-Esc ibano, F.; Ca mona, A. T.; Gómez-Guillén, M. Te ahed on: Asymme y 2004, 15, 429. (b) Bo ache o, P.; Cab e a- Esc ibano, F.; Ca mona, A. T.; Gómez-Guillén, M. Te ahed on: Asymme y 2000, 11, 2927. (c) Bo ache o- Moya, P.; Cab e a-Esc ibano, F.; Gómez-Guillén, M.; Mad id-Díaz, F. Te ahed on Le . 1997, 38, 1231. (11) Ve a-Ayoso, Y.; Bo ache o, P.; Cab e a-Esc ibano, F.; Gómez-Guillén, M. Te ahed on: Asymme y 2005, 16, 889. (12) Gene al P ocedu e o he One-Po P epa a ion o Compounds 7. Compound 6 (100 mg, 0.315 mmol) was dissol ed in a 9:1 TFA–H2O mix u e (2.7 mL) and he solu ion was kep a . . o 1 h. The eac ion mix u e was pou ed in o ice-wa e (100 mL) and ex ac ed wi h CH2Cl2 (4 ×20 mL). The combined o ganic laye s we e successi ely washed wi h sa . aq NaHCO3 and b ine, hen d ied (Na2SO4), and concen a ed. The esidue (c ude aldehyde) was dissol ed in 1,2- diclo oe hane (3.1 mL) and ea ed wi h he amine (0.437 mmol) and sodium iace oxybo ohyd ide (93.0 mg, 0.441 mmol). The eac ion was s i ed a . . o he app op ia e ime (Table 1). The mix u e was hen dilu ed wi h sa . aq NaHCO3 (25 mL) and he aqueous laye was ex ac ed wi h E OAc (3 ×20 mL). The combined o ganic laye s we e d ied (Na2SO4), and concen a ed unde educed p essu e o gi e he c ude p oduc , which was pu i ied by column ch oma og aphy using E OAc–hexane, E 2O–hexane o E 2O–ace one as eluen . Compound 7a: R = 0.37 (5:1 E 2O–ace one); [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, ace one-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, ace one-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 o C17H22N4O5 + H: 363.1668; ound 363.1671. (13) Gene al P ocedu e o Deace yla ion o 7 and P epa a ion o Compounds 8. The co esponding educ i e amina ion p oduc 7 (0.070 mmol) was dissol ed in: (i) (2 mL o 1:1 MeOH–CHCl3), (ii) (2 mL o MeOH), o (iii) (2 mL o E OH abs.), and 5 d ops o 1 M MeONa–MeOH we e added o he solu ion [ o he dep o ec ion o 7g was used E ONa–E OH abs. (1 M)]. The eac ion mix u e was kep a . . o 2 h. Wo k-up was done by one o he ollowing p ocedu es. P ocedu e 1 (8b–d, ): he eac ion mix u e was cooled and 600 mL TFA was added. The esidue was pu i ied by a Dowex 50 ×8 W column, using MeOH (50 mL), H2O (50 mL) and NH4OH (10% aq soln; 100 mL) as eluen s. P ocedu e 2 (8a,e,g,h): he eac ion mix u e was neu alized wi h Ambe lys 15, he esin was emo ed by il a ion and he sol en unde educed p essu e. (14) In compa ison wi h he NMR spec a o each di ec p ecu so , each ace yla ed compound 7a–h lacked any signal o aldehyde p o on and ca bon, bu showed ins ead he signals co esponding o he wo new dias e eo opic p o ons a C(1). Fo he compounds ob ained om some p ima y amines (7e, –h), he amine p o on ga e ise o he ypical b oad signal in he 1H NMR spec um a d = 4.41 (7e), 4.44– 4.38 (7 ), 5.81 (7g), and 6.00 ppm (7h), alues ha can be co ela ed wi h he elec on-wi hd awing o elec on- dona ing cha ac e o he subs i uen a he pa a posi ion o he a oma ic g oup. Howe e , he amine p o on signal o 7a was no obse ed, p obably because i is o e lapped. The molecula weigh ound o 9 in i s HRMS ag eed wi h he aldimine s uc u e assigned, while i s NMR spec a showed he sp2 (C)H signal a d = 6.86 ppm and he imine ca bon a d = 134.1 ppm, hus co obo a ing he assigna ion. Fo he deace yla ed compounds 8a–h, hei espec i e calcula ed molecula weigh s we e in ag eemen wi h hose ound by HRMS. Fu he mo e, he 1H NMR and 13C NMR spec a o hese compounds showed no signal co esponding o he O- ace yl g oups p esen in he p ecu so s 7a–h, as expec ed. (15) Popowycz, F.; Ge be -Lema ie, S.; Demange, R.; Rod iguez-Ga cía, E.; Asenjo, A. T. C.; Robina, I.; Vogel, P. Bioo g. Med. Chem. Le . 2001, 11, 2489. (16) Compound 15 was ob ained om 12 (100 mg, 0.265 mmol) and diamine 14 (78 mg, 0.287 mmol) in he p esence o NaBH(OAc)3 (60.2 mg, 0.287 mmol) by a simila one-po p ocedu e o ha desc ibed abo e o he p epa a ion o compounds 7 om 6. Mo e ele an da a o 15: R = 0.45 (E 2O); [a]D24 +14.6 (c 0.63, ace one). 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 (d , 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 (d , 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 o C33H45N2O7F + H: 601.3289; ound: 601.3281. Downloaded by: Uni e sidad de Se illa. Copy igh ed ma e ial.