Synthesis of sugar oxazolines by intramolecular Ritter-like reaction of D-fructose precursors

LETTER2230 Syn hesis o Suga Oxazolines by In amolecula Ri e -Like Reac ion o D-F uc ose P ecu so s Syn hesis o Suga Oxazolines José L. Jiménez Blanco,a En ique M. Rubio,b Ca men O iz Melle ,*a José M. Ga cía Fe nández*b aDepa amen o de Química O gánica, Facul ad de Química, Uni e sidad de Se illa, Ap do. 553, 41071 Se illa, Spain Fax +34(954)624960; E-mail: melle @us.es bIns i u o de In es igaciones Químicas, CSIC, Amé ico Vespucio 49, Isla de la Ca uja, 41092 Se illa, Spain Fax +34(954)460565; E-mail: joga [email protected] Recei ed 20 May 2004 SYNLETT 2004, No. 12, pp 2230–2232 01.10.2004 Ad anced online publica ion: 04.08.2004 DOI: 10.1055/s-2004-830891; A ID: D12704ST © Geo g Thieme Ve lag S u ga · New Yo k Abs ac : T ea men o D- uc opy anose and D- uc o u anose 1,2-O-ace onide de i a i es wi h i lic acid in he p esence o a a- ie y o ni iles esul s in he o ma ion o used o spi o 2-oxazo- lines. The eac ion implies (i) ac i a ion o he anome ic cen e wi h simul aneous isop opylidene clea age, (ii) nucleophilic addi ion o he ni ile o he co esponding oxoca benium ca ion in e media e and (iii) subsequen apping o he esul ing ni ilium ion species by he emaining hyd oxyl g oup in an in amolecula Ri e -like eac ion. Key wo ds: ca bohyd a es, ni iles, 2-oxazolines, spi o com- pounds, Ri e eac ion 2-Oxazolines cons i u e a wide amily o i e-membe ed he e ocycles wi h impo an applica ions in he ields o o ganic syn hesis,1 ca alysis,2,3 and pha macology.4 2- Amino-2-deoxysuga 2-oxazoline de i a i es ha e been b oadly used as glycosyl dono s in he syn hesis o na u al oligosaccha ides5 and ha e also been p oposed as glycosi- dase subs a es6 and inhibi o s.7 Recen ly, in e es in he syn hesis o he isome ic glycosylamine 2-oxazoline de- i a i es (glycosyl isooxazolines) has g own because hese compounds can se e as in e media es in he s e eo- selec i e cons uc ion o he glycosyl amide bond, a key s uc u al ea u e o N-glycop o eins.8 Howe e , u he applica ions ha e been limi ed so a due o he lack o sui able p epa a i e me hods and he ela i e ins abili y o he anome ic 2-oxazoline ing. The Ri e eac ion,9 i.e., he gene a ion o a ela i ely s a- ble ca boca ion and i s in si u apping by ni iles, o gi e ansien ni ilium species ha can unde go u he in e o in amolecula nucleophilic a ack by a sui ably loca ed g oup, is an a ac i e s a egy o he p epa a ion o a a- ie y o amide p oduc s and azahe e ocycles ha has al- eady ound u ili y in ca bohyd a e chemis y.10 T ansien glycosyl isooxazoline in e media es ha e been al eady in- oked in some Ri e -like ans o ma ions.11 Ye , only in a ew cases hey ha e been isola ed and ully cha ac e - ized.12 In p e ious wo k, we ha e shown ha D- uc ose isop opylidene de i a i es can be eadily ac i a ed wi h i lic acid o gi e a ansien b-hyd oxy oxoca benium ca ion.13 In he absence o any o he nucleophile, spi odi- saccha ides (di-D- uc ose dianhyd ides) a e o med. We now epo he ex ension o his s a egy o he s e eo- selec i e p epa a ion o used and spi o glycosyl isoxazo- lines by a Ri e -like eac ion in ol ing (i) ni ile addi ion o he uc osyl ca ion and (ii) subsequen in amolecula apping o he ini ially o med ni ilium ion by he icinal ee hyd oxyl g oup (Scheme 1). Scheme 1 Syn hesis o used and spi o glycosyl isooxazolines om D- uc ose isop opylidene de i a i es by Ri e -like eac ion A wide a ie y o ni iles was ound o pa icipa e in he addi ion-cycliza ion eac ion. In he case o 1-O-benzyl- 2,3:4,5-di-O-isop opylidene-b-D- uc opy anose (1),14 he co esponding used isooxazoline wi h b-anome ic con igu a ion (6a–d) was he only eac ion p oduc (Figu e 1 and Table 1, en ies 1–4). The s e eochemical ou come is go e ned in his case by he o ien a ion o OH- 3, o ma ion o a ans- used bicyclic sys em being p e- en ed due o s e ic s ain. Con a y o ha epo ed o p e ious p epa a ions o aldose-de i ed glycosyl isoox- azolines, compounds 6a–d we e ound o be a he s able. In ac , i is known ha he s abili y o he oxazolinium ca ion inc eases wi h he numbe o elec on-dona ing ca bon subs i uen s in he ing.15 Mo eo e , oxazolinium O O O RO O RO OH O OH N RO C R' O O N RO R' O RO O O O RO OR OH O RO OH N OR OR C R' O RO O N OR R' R'CN R'CN acid p omo o Downloaded by: Uni e sidad de Se illa. Copy igh ed ma e ial. LETTER Syn hesis o Suga Oxazolines 2231 Synle 2004, No. 12, 2230–2232 © Thieme S u ga · New Yo k i la es a e s ill mo e s able, since he i la e coun e ion is a e y weak nucleophile, which is unable o a ack he oxazolinium ing.16 Ac i a ion o 1,2:4,5-di-O-isop opylidene-b-D- uc opy - anose p ecu so s (2 and 3)14 wi h i lic acid in he p es- ence o a ni ile a o ded spi o isooxazolines (7a–d and 8, espec i ely).17 Only he b-con igu ed compounds, ha - ing he py anose ing in he 1C4 con o ma ion, we e de- ec ed, i espec i e o he pa icipa ing (benzoyl) o non- pa icipa ing cha ac e (benzyl) o he hyd oxyl p o ec ing g oup a O-3 (Table 1, en ies 5–9). I is no ewo hy ha his si ua ion implies he axial o ien a ion o he N-subs i - uen a he anome ic posi ion, a gene ally un a o able a - angemen o N-glycosidic de i a i es due o he e e se anome ic e ec .18 In ac , he p e e ence o he axial o i- en a ion has p e iously been obse ed in he case o glycosylace oni ilium ions, which ha e been apped as he co esponding imides by eac ion wi h ca boxylic acids.19 Ou esul s indica e ha his scena io is p obably gene al o glycosylni ilium sal s. Mo eo e , he de- c eased posi i e cha ge densi y a he isooxazoline ni o- gen a om, as compa ed wi h amines, in combina ion wi h he p e e ed equa o ial o ien a ion o he ca bon subs i - uen , p obably p e en s anome iza ion o he inal com- pounds, a ypical p oblem in he case o pe -O-p o ec ed glycosylamine de i a i es.20 3,4,6-T i-O-p o ec ed 1,2-O-isop opylidene-b-D- uc o- u anose de i a i es (4 and 5)21 likewise a o ded spi o isooxazolines ha ing he b-anome ic con igu a ion a he uc ose moie y upon eac ion wi h ace oni ile unde he abo e eac ion condi ions (9 and 10, espec i ely, Table 1, en ies 10 and 11). In he case o he benzoyla ed p ecu so , howe e , he cis- used bicyclic isooxazoline 11, a ising om O-3 o O-1 acyl mig a ion p io o oxazo- line ing closu e, was he majo eac ion p oduc (Table 1, en y 11), in ag eemen wi h he highe s abili y o he used isooxazoline skele on as compa ed wi h he spi o glycosyl isooxazoline amewo k. In summa y, he Ri e -based s a egy epo ed he ein is e ec i e o accessing used as well as spi o glycosyl isooxazolines om eadily ob ainable D- uc ose ace- onides. The comme cial a ailabili y o a la ge numbe o ni iles and he simplici y o he me hod should be a ac- i e no only o exploi he ich chemis y o 2-oxazolines in ca bohyd a e ans o ma ion schemes bu also o he p epa a ion o chi al 2-oxazoline lib a ies, o in e es as ligands in asymme ic ca alysis. Wo k in bo h di ec ions is cu en ly being in es iga ed in ou labo a o ies. Gene al p ocedu e: To a 0.114 M solu ion o he co esponding D- uc ose p ecu so 1–5 and he ni ile coun e pa (10 equi ) in dis- illed CH2Cl2 a –20 °C, T OH (1.5 equi ) was added unde A a - mosphe e. The eac ion mix u e was allowed o wa m up o . . and s i ed o he ime indica ed in Table 1. Then E 3N was added, he sol en s we e e apo a ed unde educed p essu e and he p oduc s we e pu i ied by column ch oma og aphy using mix u es o E OAc–pe oleum e he as eluen . All p oduc s ga e sa is ac o y MS and mic oanalysis da a in ag eemen wi h he p oposed s uc- u es. The isola ed yields a e indica ed in Table 1. Selec ed da a22 o 6a: R = 0.22 (1:2 E OAc–pe oleum e he ); [a]D –90 (c 0.8, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 7.22 (m, 5 H, Ph), 4.62 (d, 1 H, CH2Ph), 4.60 (dd, 1 H, H-4), 4.56 (d, 1 H, H-3), 4.55 (d, 1 H, CH2Ph), 4.13 (dd, 1 H, H-5), 3.73 (d, 1 H, H-1a), 3.71 (d, 1 H, H-6a) 3.59 (d, 1 H, H-1b), 3.31 (dd, 1 H, H-6b), 2.04 (s, 3 H, NMe), 1.39, 1.30 (2 s, each 3 H, CMe2) ppm. 13C NMR (125.7 MHz, CDCl3): d = 168.0 (CN), 138.1, 128.3, 127.6, 127.5 (Ph), 109.1 (CMe2), 98.7 (C-2), 73.5 (CH2Ph), 73.1 (C-1), 72.8 (C-3), 70.4 (C-5), 69.8 (C-4), 60.9 (C-6), 26.0, 24.3 (2 CMe2), 13.9 (NMe) ppm. Table 1 Glycosyl Isooxazolines Fo med by Reac ion o D-F uc ose 1,2-O-Ace onides wi h Ni iles Using T i lic Acid as P omo o a En y D-F uc ose p ecu so Ni ile Reac ion ime (h) P oduc s (yield, %) 11MeCN 1 6a (80) 21E CN 1 6b (71) 31n-P CN 5 6c (75) 41PhCN 3 6d (65) 52MeCN 1 7a (50) 62E CN 0.5 7b (63) 72n-P CN 0.5 7c (83) 82PhCN 0.5 7d (65) 93MeCN 1 8 (41) 10 4MeCN 0.5 9 (48) 11 5MeCN 3 10 (15) 11 (44) a All eac ions we e ca ied ou in CH2Cl2 a –20 °C o . . using 10 equi o he ni ile and 1.5 equi o he acid p omo o . Figu e 1 S uc u es o he used and spi o glycosyl isooxazolines p epa ed in his s udy and o he co esponding D- uc ose p ecu so s OO O O O OR OO N O O OR R' O O O O O OBn O N O O O OBn R' O OR RO O O RO O OR RO O N RO O OBz BzO O N OBz 2 R = Bn 3 R = Bz 4 R = Bn 5 R = Bz 6a–d 7a–d R = Bn 8 R = Bz, R' = Me a R' = Me b R' = E c R' = n–P d R = Ph 9 R = Bn 10 R = Bz 11 1 Downloaded by: Uni e sidad de Se illa. Copy igh ed ma e ial. 2232 J. L. Jiménez Blanco LETTER Synle 2004, No. 12, 2230–2232 © Thieme S u ga · New Yo k Selec ed da a o 7a: R = 0.54 (2:1 E OAc–pe oleum e he ); [a]D –61 (c 0.7, CH2Cl2). The co esponding 1H NMR and 13C NMR da a we e in ag eemen wi h hose epo ed in he li e a u e.17 Selec ed da a22 o 8: R = 0.34 (1:1 E OAc–pe oleum e he ); [a]D –132 (c 0.9, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 8.02–7.41 (m, 5 H, Ph), 5.44 (d, 1 H, H-3), 4.50 (dd, 1 H, H-4), 4.41 (dd, 1 H, H-6a), 4.33 (dd, 1 H, H-5), 4.11 (d, 1 H, H-6b), 4.10 (d, 1 H, H-1a), 4.05 (d, 1 H, H-1b), 2.05 (s, 3 H, NMe), 1.62, 1.36 (2 s, each 3 H, CMe2) ppm. 13C NMR (125.7 MHz, CDCl3): d = 169.5 (CO), 166.0 (CN), 138.1, 129.8, 129.4, 128.4 (Ph), 109.5 (CMe2), 100.7 (C-2), 75.2 (C-4), 74.2 (C-1), 74.1 (C-5), 72.9 (C-3) 61.1 (C-6), 27.8, 26.4 (2 CMe2), 14.3 (NMe) ppm. Selec ed da a22 o 9: R = 0.25 (1:2 E OAc–pe oleum e he ); [a]D +68 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 7.37–7.24 (m, 15 H, 3 Ph), 4.67 (d, 1 H, CH2Ph), 4.62 (d, 1 H, CH2Ph), 4.54 (b s, 2 H, H-1), 4.52 (d, 1 H, CH2Ph), 4.48 (d, 1 H, CH2Ph), 4.41 (d, 1 H, CH2Ph), 4.32 (d , 1 H, H-5), 4.17 (d, 1 H, CH2Ph), 4.16 (d, 1 H, H- 3), 4.02 (dd, 1 H, H-4), 3.58 (dd, 1 H, H-6a), 3.53 (dd, 1 H, H-6b), 2.06 (s, 3 H, NMe) ppm. 13C NMR (125.7 MHz, CDCl3): d = 168.5 (CN), 138.0, 137.9, 137.4, 127.6, 126.9 (Ph), 107.8 (C-2), 87.9 (C- 3), 81.8 (C-4), 80.2 (C-5), 73.3 (C-1), 72.4, 72.1, 72.0, (CH2Ph), 69.7 (C-6), 14.5 (NMe) ppm. Selec ed da a22 o 10: R = 0.53 (1:4 E OAc–pe oleum e he ); [a]D –42 (c 1.1, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 8.08–7.24 (m, 15 H, Ph), 6.03 ( , 1 H, H-4), 4.81 (d, 1 H, H-3), 4.81 (dd, 1 H, H- 6a), 4.71 (dd, 1 H, H-6b), 4.56 (m, 1 H, H-5), 4.51 (d, 1 H, H-1a), 4.33 (d, 1 H, H-1b), 1.98 (s, 3 H, NMe) ppm. 13C NMR (125.7 MHz, CDCl3): d = 169.5 (CN), 166.3, 166.0, 165.6 (CO) 133.7, 133.6, 130.1, 129.9, 128.5, 128.3 (Ph), 106.5 (C-2), 78.8 (C-5), 78.6 (C-3), 77.1 (C-4), 73.5 (C-1), 65.9 (C-6), 14.4 (NMe) ppm. Selec ed da a22 o 11: R = 0.29 (1:4 E OAc–pe oleum e he ); [a]D –28 (c 5.8, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 8.07–7.24 (m, 15 H, Ph), 5.70 (d, 1 H, H-3), 5.61 (dd, 1 H, H-4), 4.79 (dd, 1 H, H- 6a), 4.70 (ddd, 1 H, H-5), 4.65 (dd, 1 H, H-6b), 4.32 (s, 2 H, H-1), 2.09 (s, 3 H, NMe) ppm. 13C NMR (125.7 MHz, CDCl3): d = 169.2 (CN), 133.8, 133.5, 133.3, 129.9, 129.7, 129.2, 128.8, 128.3 (Ph), 108.7 (C-2), 82.3 (C-4), 79.8 (C-5), 79.1 (C-3), 71.5 (C-1), 63.8 (C- 6), 14.5 (NMe) ppm. Acknowledgmen We hank he Spanish Minis e io de Ciencia y Tecnología o inan- cial suppo (con ac s numbe BQU2003-00937 and BCM2001- 2366-CO3-03). E. M. R. hanks he CSIC o a ellowship. Re e ences (1) Fo a e iew, see: G an , T. G.; Meye , A. I. Te ahed on 1994, 50, 2297. (2) Fo e iews, see: (a) Jönsson, C.; Hallman, K.; Ande sson, H.; S emme, G.; Malkoch, M.; Malms ön, E.; Hul , A.; Mobe g, C. Bioo g. Med. Chem. Le . 2002, 12, 1857. (b) Ghosh, A. K.; Ma hi anan, P.; Cappiello, J. Te ahed on: Asymme y 1998, 9, 1. 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