Synthesis, regioselective hydrogenolysis, partial hydrogenation, and conformational study of dioxane and dioxolane-type (9'-anthracenyl)methylene acetals of sugars

Accep ed Manusc ip Syn hesis, egioselec i e hyd ogenolysis, pa ial hyd ogena ion and con o ma‐ ional s udy o dioxane and dioxolane ype (9’-an h acenyl)me hylene ace als o suga s Zsol Jakab, A ila Mándi, Anikó Bo bás, A ila Bényei, Is án Komá omi, László Lázá , Sándo An us, And ás Lip ák PII: S0008-6215(09)00444-3 DOI: 10.1016/j.ca es.2009.09.007 Re e ence: CAR 5156 To appea in: Ca bohyd a e Resea ch Recei ed Da e: 15 July 2009 Re ised Da e: 26 Augus 2009 Accep ed Da e: 9 Sep embe 2009 Please ci e his a icle as: Jakab, Z., Mándi, A., Bo bás, A., Bényei, A., Komá omi, I., Lázá , L., An us, S., Lip ák, A., Syn hesis, egioselec i e hyd ogenolysis, pa ial hyd ogena ion and con o ma ional s udy o dioxane and dioxolane ype (9’-an h acenyl)me hylene ace als o suga s, Ca bohyd a e Resea ch (2009), doi: 10.1016/j.ca es. 2009.09.007 This is a PDF ile o an unedi ed manusc ip ha has been accep ed o publica ion. As a se ice o ou cus ome s we a e p o iding his ea ly e sion o he manusc ip . The manusc ip will unde go copyedi ing, ypese ing, and e iew o he esul ing p oo be o e i is published in i s inal o m. Please no e ha du ing he p oduc ion p ocess e o s may be disco e ed which could a ec he con en , and all legal disclaime s ha apply o he jou nal pe ain. ACCEPTED MANUSCRIPT 1 Syn hesis, egioselec i e hyd ogenolysis, pa ial hyd ogena ion and con o ma ional s udy o dioxane and dioxolane ype (9’-an h acenyl)me hylene ace als o suga s Zsol Jakab, A ila Mándi, Anikó Bo bás*, A ila Bényei, Is án Komá omi, László Lázá , Sándo An us and And ás Lip ák ACCEPTED MANUSCRIPT 2 Syn hesis, egioselec i e hyd ogenolysis, pa ial hyd ogena ion and con o ma ional s udy o dioxane and dioxolane ype (9’- an h acenyl)me hylene ace als o suga s Zsol Jakaba, A ila Mándia, Anikó Bo bása,*, A ila Bényeib, Is án Komá omic, László Lázá a, Sándo An usa,d, And ás Lip áka aResea ch G oup o Ca bohyd a es o he Hunga ian Academy o Sciences, Uni e si y o Deb ecen, H-4010, Deb ecen, PO Box 94, Hunga y bIns i u e o Physical Chemis y, Facul y o Science, Uni e si y o Deb ecen, Deb ecen, PO Box 7, H-4010 Hunga y cHaemos asis, Th ombosis and Vascula Biology Resea ch G oup o he Hunga ian Academy o Sciences, Uni e si y o Deb ecen, H-4032 Deb ecen, Hunga y dDepa men o O ganic Chemis y, Uni e si y o Deb ecen, H-4010, Deb ecen, PO Box 20 Dedica ed o P o esso Ká oly Lempe on he occasion o his 85 h bi hday Abs ac Dioxane- ype (9’-an h acenyl)me hylene ace al o me hyl 2,3-di-O-me hyl--D- glucopy anoside was clea ed wi h LiAlH4-AlCl3 (3:1) o wi h Na(CN)BH3-HCl egioselec i ely o p o ide he 4- o 6-O-(9’-an h acenyl)me hyl e he , espec i ely. Hyd ogenoly ic eac ion o he exo and endo isome s o dioxolane- ype ace als p o ed o be di ec ed by he con igu a ion o he ace alic ca bon as well as he in amolecula pa icipa ion o he adjacen ee hyd oxyl; ing opening eac ion o he endo isome o he me hyl 2,3-O- (9’-an h acenyl)me hylene-α-L- hamnopy anoside ook place wi h comple e selec i i y ACCEPTED MANUSCRIPT 3 esul ing in he axial (9’-an h acenyl)me hyl e he , whe eas a 1:1 mix u e o he axial and equa o ial e he s was o med upon same eac ion o he exo isome . Ca aly ic hyd ogena ion o he suga ace als esul ed in (9’,10’-dihyd o-9’-an h acenyl)me hylene de i a i es wi hou a ec ing he ace alic cen e . High- empe a u e molecula dynamics simula ions and DFT (Densi y Func ional Theo y) geome y op imiza ions we e ca ied ou o s udy he con o ma ion o he dioxane- ype (9’,10’-dihyd o-9’-an h acenyl)me hylene ace al. Keywo ds 9-An h acenylme hylene ace al, Regioselec i e, Hyd ogenolysis, High- empe a u e MD, DFT Co esponding au ho . Tel.: +36 52512900/22462; ax: +36 52512900/22342. E-mail add ess: [email p o ec ed] (A. Bo bás). 1. In oduc ion Regioselec i e ans o ma ion o polyhyd oxy compounds, such as ca bohyd a es, necessi a es he applica ion o p o ec i e g oups which can be a ached o clea ed in a selec i e manne o ob ain pa ially subs i u ed molecules. Modi ica ion o simple suga s and syn hesis o highe oligosaccha ides can no be ca ied ou wi hou he use o hese me hodologies.1 The ace al- ype p o ec ing g oups possess signi ican ad an ages such as simul aneous p o ec ion o wo hyd oxyls, he easy emo al and he possibili y o a pa ial dep o ec ion. By he adequa e selec ion o he hyd ide dono and a ious p o ic o Lewis acid eagen s as well as sol en s, any o he wo p o ec ed hyd oxyls can be libe a ed egioselec i ely.2 ACCEPTED MANUSCRIPT 4 Mos ecen ly he 9-an h aldehyde ace al as a new p o ec ing g oup was p oposed by Elle ik3 epo ing he syn hesis o (9’-an h acenyl)me hylene ace als o he 2- ( ime hylsilyl)e hyl -D-glucopy anoside and he phenyl 1- hio--D-galac opy anoside in an ace al exchange eac ion. The an h aldehyde ace als can be clea ed unde educ i e condi ions wi h Na(CN)BH3 and HCl/E 2O in THF o gi e 6-O-(9’-an h acenyl)me hyl e he s, and can be selec i ely emo ed in he p esence o benzylidene ace als. Due o he good c ys alline p ope ies and s ong abso bance and luo escence he (9’-an h acenyl)me hylene ace al and (9’-an h acenyl)me hyl e he may become use ul as new p o ec ing g oups. These esul s p omp ed us o in es iga e he egioselec i e ing opening eac ion and dep o ec ion p ocedu es o dioxane- and dioxolane- ype (9’-an h acenyl)me hylene-ace als o suga s. 2. Resul s and discussion 2.1. Syn hesis and eac i i y o dioxane- ype (9’-an h acenyl)me hylene ace als To p epa e he dioxane- ype ace al 2, me hyl α-D-glucopy anoside 1 was ea ed wi h an h aldehyde dime hyl ace al in he p esence o (±)10-campho sul onic acid (CSA). The OH g oups o posi ion 2 and 3 we e me hyla ed o ob ain he ully p o ec ed me hyl 4,6-O-(9’- an h acenyl)me hylene-2,3-di-O-me hyl--D-glucopy anoside 3 (Scheme 1). Upon ea men o compound 3 wi h LiAlH4-AlCl34 (3:1) he me hyl 4-O-(9’- an h acenyl)me hyl-2,3-di-O-me hyl--D-glucopy anoside 4 could be isola ed in c ys alline o m in a yield o 70%. T ans o ma ion o 3 wi h Na(CN)BH3 and HCl/E 2O in d y THF5 mainly esul ed in me hyl 6-O-(9’-an h acenyl)me hyl-2,3-di-O-me hyl--D-glucopy anoside 5, and i s egioisome 4 was also o med as a mino p oduc . ACCEPTED MANUSCRIPT 5 I has been known since 1936 ha 4,6-O-benzylidene ace als o glucose can be ca aly ically educed in o he co esponding 4,6-diols.6 Howe e , ca aly ic hyd ogena ion o 3 su p isingly did no a ec he ace alic cen e , bu a ec ed he an acenyl ing esul ing in me hyl 4,6-O-(9’,10’-dihyd o-9’-an h acenyl)me hylene-2,3-di-O-me hyl--D- glucopy anoside 6 which was s able unde hyd ogen a mosphe e in he p esence o Pd ca alys o as long as 5 days. The s uc u e o compound 6 was de e mined on he basis o 1H- and 13C-NMR spec oscopy and X- ay c ys allog aphy as well. Molecula modeling was also applied o in es iga e he con o ma ion o he (9’,10’-dihyd o-9’-an h acenyl)me hylene moie y. In o de o s udy he selec i e emo al o he (9’-an h acenyl)me hyl e he moie y in he p esence o ace yl, benzoyl o p-me hoxybenzyl (PMB) g oups he ee hyd oxyl o compound 4 was subs i u ed by a simple ace yla ion, benzoyla ion and p-me hoxybenzyla ion o u nish compounds 7-9, espec i ely. All h ee ully p o ec ed de i a i es 7-9 we e ea ed wi h BF3OE 2 in d y CH2Cl2 a 0 °C. Selec i e clea age o he (9’-an h acenyl)me hyl g oup o 7 and 8 libe a ing he OH-4 ook place in 20 minu es o a o d compounds 107 and 11,8,9 espec i ely. In he case o compound 9 no only he (9’-an h acenyl)me hyl g oup bu also he PMB g oup was clea ed unde hese condi ions o gi e he diol 12.10 Reduc i e ing opening eac ion o he pa ially hyd ogena ed ace al de i a i e 6 was also s udied. We assumed ha he ace alic cen e o 4,6-O-ace al ing ancho ed o he alipha ic 9’-ca bon is less eac i e unde hyd ogenoly ic condi ions han ha o compound 3 ancho ed o an a oma ic ca bon. Compound 6 was ea ed wi h LiAlH4-AlCl3 (3:1) unde he condi ions applied o he con e sion o 3 in o 4, howe e no eac ion could be obse ed. In e es ingly, he eac ion o 6 wi h E 3SiH in he p esence o BF3OE 211 in d y CH2Cl2 esul ed in wo p oduc s, 13 and 14. Un eac ed s a ing ma e ial 6 also emained a e 24 h. Compound 13 p o ed o be me hyl 6-O-(9’,10’-dihyd o-9’-an h acenyl)me hyl-2,3-di-O- ACCEPTED MANUSCRIPT 6 me hyl--D-glucopy anoside. The byp oduc 14 could be pu i ied a e ace yla ion (1415) and was iden i ied as 1,5-anhyd o-4-O-ace yl-6-O-(9’,10’-dihyd o-9’-an h acenyl)me hyl-2,3- di-O-me hyl-D-gluci ol on he basis o NMR. This esul has expe imen ally p o ed he high s abili y o his ype o ace al 6 and he o ma ion o 14 is assumed o ake place ia compound 13. Hyd ogenolysis o he glycosidic ace al esul ing in a gluci ol de i a i e is ex emely a e upon educ i e clea age o benzylidene ype ace als,12 since glycosides a e mo e s able han he a oma ic ace als. Scheme 1. Reagen s and condi ions: (a) an h aldehyde dime hylace al, ca . CSA, d y MeCN, , 3 h, 79%; (b) MeI, NaH, DMF, 0 °C, 3 h, 90%; (c) om 3: LiAlH4, AlCl3 (3:1), E 2O, CH2Cl2, , 4 h, 70%; (d) om 3: Na(CN)BH3 in THF, HCl/E 2O, , 5 min, 48% o 5, 12% o 4; (e) Pd(C), H2, E OH, , 6 h, 90%; ( ) Ac2O, py idine, , 2 h, 80% o 7; (g) BzCl, py idine, CH2Cl2, 0 °C, 2 h, 89% o 8; (h) PMBCl, NaH, DMF, 0 °C, 2 h, 82% o 9; (i) ACCEPTED MANUSCRIPT 7 BF3OE 2, CH2Cl2, 0 °C, 20 min, 75% o 10, 76% o 11, 79% o 12; (j) BF3OE 2, E 3SiH, CH2Cl2, 0 °C, o e nigh , 20% o 13; (k) Ac2O, py idine, , 2 h, 14% o wo s eps. 2.2. Syn hesis and eac i i y o dioxolane- ype (9’-an h acenyl)me hylene ace als The icinal cis-axial/equa o ial hyd oxyl g oups o py anosides eac wi h ace ala ing eagen s o o m dioxolane- ype ace al de i a i es. The co esponding an h aldehyde dime hylace al ha e no been used as p o ec ing g oup o icinal diols so a . Me hyl α-L- hamnopy anoside was conside ed o be an excellen model compound o s udy he syn hesis and hyd ogenolysis o dioxolane- ype (9’-an h acenyl)me hylene ace als. T ea men o me hyl -L- hamnopy anoside 16 wi h an h aldehyde dime hylace al esul ed in a 1:4.5 mix u e o he 17endo and 17exo isome s, in a mode a e yield (55%). Since hese isome s could no be comple ely sepa a ed by column ch oma og aphy, he mix u e was ace yla ed, and he sepa a ion o he ob ained mix u e o 18endo and 18exo was success ul. A e deace yla ion o 18endo and 18exo, espec i ely, he 17endo- and exo-ace als could be ob ained in c ys alline o m (Scheme 2). ACCEPTED MANUSCRIPT 8 Scheme 2. Reagen s and condi ions: (a) an h aldehyde dime hylace al, ca . CSA, d y MeCN, , 1 d, 46% o 17exo, 9% o 17endo. (b) Ac2O, py idine, , 1 h; (c) NaOMe, MeOH, , 1 h. The de e mina ion o he absolu e con igu a ion o he dioxolane- ype ace als is a a he complex ask al hough he 1H-NMR spec a can help i bo h isome s a e a ailable. Since he la e se en ies he chemical shi alues o ace alic p o ons and ca bons ha e been applied o he s uc u e elucida ion o he dioxolane- ype s uc u es.13 The ace alic con igu a ion o compounds 17 and 18 we e p o en by 1H-NMR spec oscopy; H-ace alic o 17- and 18endo isome s esona e a highe ield ( 7.08 and 7.12 ppm) while H-ace alic signals o 17- and 18exo isome s a e a lowe ield ( 7.47 and 7.58 ppm). Resonance alues o he ace alic ca bons a e he ollowings: 17endo: 102.2 ppm, 18endo: 101.8 ppm and 17exo:100.3 ppm, 18exo:100.8 ppm. We s udied ing-opening eac ion o he dioxolane- ype ace als 17endo and 17exo possessing an ex emely bulky an h acenyl subs i uen a he ace alic cen e . I was ea lie shown ha he clea age o he i e-membe ed benzylidene- ype ace al ings is di ec ed by he s e eochemis y o he ace alic cen e . Namely, upon exo a angemen o he bulky subs i uen , he eagen a acks he axial oxygen a om o ming he axial hyd oxyl and equa o ial benzyl-e he de i a i es, selec i ely. On he con a y, in he case o endo a angemen o he bulky g oup, he equa o ial oxygen a om is a acked leading o he o ma ion o he equa o ial hyd oxyl and axial e he ype p oduc s, also wi h ull selec i i y. Recen ly a ule o humb (x, x, x) was o mula ed o he ing opening eac ions o he dioxolane ace als by he ollowing way: exo isome gi es axial hyd oxyl.14 In good ag eemen wi h ou expec a ions he clea age o 17endo wi h LiAlH4-AlCl3 (3:1) ga e me hyl 2-O-(9’- an h acenyl)me hyl--L- hamnopy anoside 20, exclusi ely. Su p isingly, ea men o 17exo wi h LiAlH4-AlCl3 (3:1) esul ed in a 1:1 mix u e o he equa o ial (9’-an h acenyl)me hyl- ACCEPTED MANUSCRIPT 15 exis ence o o he axial con o ma ion also migh ha e con ibu ion o he obse ed p ope ies. Ano he consequence o he axial ace al con o ma ion and he oo - ype shape o he hyd ogena ed an h acenyl g oup is he loss o igh i o he su ace o ca alysa o and his way he loss o ull hyd ogena ion. 4. Expe imen al 4.1. Gene al Me hods Op ical o a ions we e measu ed a oom empe a u e wi h a Pe kin-Elme 241 au oma ic pola ime e . Mel ing poin s we e de e mined on a Ko le ho -s age appa a us and a e unco ec ed. TLC was pe o med on Kieselgel 60 F254 (Me ck) wi h de ec ion by 5% sul u ic acid in e hanol. Column ch oma og aphy was pe o med on Silica Gel 60 (E. Me ck 0.062–0.200 nm). The o ganic solu ions we e d ied o e MgSO4 and concen a ed in acuum. The 1H (200.13, 360.13 and 500.13 MHz) and 13C NMR (50.3, 90.54, 125.76 MHz) spec a we e eco ded wi h B uke WP-200SY, B uke AM-360 and B uke DRX-500 spec ome e s o solu ions in CDCl3. In e nal e e ences: TMS (0.00 ppm o 1H), CDCl3 (77.00 ppm o 13C). MALDI-TOF MS spec a we e eco ded on a B uke Bi lex III spec ome e in posi i e, linea mode using sa u a ed 2,4,6- ihyd oxy-ace o enon in wa e as ma ix. X- ay di ac ion da a was collec ed a 293 K, En a Nonius MACH3 di ac ome e , Mo K adia ion = 0.71073 Å. The s uc u e was sol ed by SIR-92 p og am18 and e ined by ull-ma ix leas - squa es me hod on F2, wi h all non-hyd ogen a oms e ined wi h aniso opic he mal pa ame e s using he SHELXL-97 package19, publica ion ma e ial was p epa ed wi h he WINGX- sui e.20 All hyd ogen a oms we e loca ed geome ically and e ined in he igid mode. The molecula dynamics simula ions and he p elimina y geome y op imiza ions using he sui ably de eloped GAFF empi ical o ce ield on he ajec o y snapsho geome ies we e ACCEPTED MANUSCRIPT 16 ca ied ou by means o he Ambe molecula dynamics simula ion package.21 B3LYP/6- 31G(d) densi y unc ional calcula ions we e ca ied ou using he Gaussian 03 package.22 A he B3LYP/6-31G(d) minima he ze o poin ib a ional ene gy co ec ion a he same le el o heo y also we e compu ed. Ball-and-s ick ep esen a ions o he con o me s we e gene a ed by he Molekel23 and VMD24 so wa es. 4.1.1. Me hyl 4,6-O-(9’-an h acenyl)me hylene--D-glucopy anoside (2) To a mix u e o me hyl -D-glucopy anoside 1 (3.0 g 15.4 mmol) and an h aldehyde dime hylace al3 (4.56 g 18.1 mmol) in MeCN (20 mL) was added ca aly ic amoun o (±)10- campho sul onic acid (CSA) and was s i ed a oom empe a u e o 3 h. The mix u e was neu alized by addi ion o E 3N and concen a ed, hen co-e apo a ed wi h oluene h ee imes. The esidue was c ys allized om E 2O-hexane o gi e 2 (4.64 g, 79%) as whi e needles: mp 192-194 °C; []D +106 (c 0.14, CHCl3); 1H NMR (200 MHz, CDCl3): δ (ppm) 8.59 (d, 2H, J 8.5 Hz), 8.46 (s, 1H), 7.97 (d, 2H, J 8.0 Hz), 7.58-7.37 (m, 4H), 6.80 (s, 1H, ace alic), 4.50 (d, 1H, J1,2 3.9 Hz, H-1), 4.33 (dd, 1H, J 10.4 Hz, J 4.7 Hz), 4.0 (d , 1H, J 9.9 Hz, J 4.7 Hz), 3.87 (dd, 1H, J 9.3 Hz, J 2.4 Hz), 3.82 (d, 1H, J 11.6 Hz), 3.7 (d, 1H, J 10.3 Hz), 3.50-3.35 (m, 2H), 3.31 (s, 3H, OCH3), 2.73 (d, 1H, J 8.7 Hz, OH); 13C NMR: (50 MHz, CDCl3): δ (ppm) 131.5, 129.9, 129.6, 129.0, 126.6, 126.2, 124.8 (a oma ic), 100.5 (C ace alic), 99.9 (C-1), 82.1 (C-4), 72.5, 71.3 (C-2, C-3), 69.9 (C-6), 62.3 (C-5), 55.6 (OCH3); Anal. Calcd. o C22H22O6 (382.41): C 69.10, H 5.80. Found: C 69.43, H 5.71. 4.1.2. Me hyl 4,6-O-(9’-an h acenyl)me hylene-2,3-di-O-me hyl--D-glucopy anoside (3) ACCEPTED MANUSCRIPT 17 Compound 2 (1.58 g, 4.36 mmol) was s i ed in d y DMF (10 mL), ea ed wi h NaH (0.40 g, 60%, 3 equi ) a 0 °C. Me hyl iodide (0.70 mL, 11.2 mmol, 2.71 equi ) was added d opwise and he eac ion empe a u e was kep a 0 °C o 1 h. Then i was allowed o wa m up o , and no s a ing ma e ial was indica ed by TLC a e 2 h. To he mix u e MeOH was added o decompose he un eac ed NaH and hen i was concen a ed, dilu ed wi h CH2Cl2, washed wice wi h wa e , d ied (MgSO4) and concen a ed. A e column ch oma og aphy (6:4 hexane-E OAc) compound 3 (1.52 g, 90%) was isola ed as a sy up: []D +85 (c 0.16, CHCl3); 1H NMR (200 MHz, CDCl3): δ (ppm) 8.66 (d, 2H, J 8.7 Hz), 8.42 (s, 1H), 7.93 (dd, 2H, J 8.4 Hz, J 0.8 Hz), 7.55-7.36 (m, 4H), 6.89 (s, 1H, ace alic), 4.89 (d, 1H, J 3.8 Hz, H-1), 4.43 (dd, 1H, J 10.1 Hz, J 4.7 Hz), 4.26-4.11 (m, 1H), 4.09 (dd, 1H, J 14.3 Hz, J 7.2 Hz), 3.90 ( , 1H, J 10.2 Hz), 3.80-3.72 (m, 1H), 3.52 (2s, 6H, 2 x OCH3), 3.41 (s, 3H, OCH3), 3.34 (dd, 1H, J2,3 8.9 Hz, H-2); 13C NMR (50 MHz, CDCl3): δ (ppm) 131.4, 129.6, 129.6, 128.8, 126.9, 125.9, 124.9, 124.7 (a oma ic), 100.6 (C ace alic), 98.5 (C-1), 83.1, 81.4, 79.8 (C-2, C-3, C- 4), 69.9 (C-6), 62.3 (C-5), 60.8, 59.2 (2 x OCH3), 55.5 (anome ic OCH3). MALDI-TOF MS m/z calcd. o C24H26O6 : 410.17. Found: 410.42 [M]+ and 433.38 [M+Na]+. Anal. Calcd. o C24H26O6: C 70.23, H 6.38. Found: C 70.33, H 6.32. 4.1.3. Me hyl 4-O-(9’-an h acenyl)me hyl-2,3-di-O-me hyl--D-glucopy anoside (4) To a s i ed suspension o he s a ing ace al 3 (2.1 g, 5.1 mmol) in d y CH2Cl2 and E 2O (30 mL, 2:1) LiAlH4 (0.86 g, 4.5 equi ) and solu ion o AlCl3 (1.0 g, 1.5 equi ) in E 2O (10 mL) we e added ca e ully unde a gon a 0 °C, hen s i ed o 4 h a . A e comple e con e sion 2-3 mL o E OAc and 1-5 d ops o wa e we e added, he mix u e was dilu ed wi h E OAc, washed 3 imes wi h wa e , d ied and concen a ed. The c ude sy up was c ys allized om E OH o gi e pale yellow c ys alline p oduc and mo he liquo was pu i ied by column ACCEPTED MANUSCRIPT 18 ch oma og aphy (7:3 hexane-ace one) o gi e 4 wi h 70% o e all yield (1.46 g): mp 145-146 °C; []D +112 (c 0.10, CHCl3); 1H NMR (500 MHz, CDCl3): δ (ppm) 8.47 (d, 2H, J 9.0 Hz, H-1’, H-8’), 8.44 (s, 1H, H-10’), 7.98 (d, 2H, J 8.5 Hz, H-4’, H-5’), 7.55-7.40 (m, 4H, H-2’, H-3’, H-6’, H-7’), 5.81 (d, 1H, J 11.0 Hz, A CH2), 5.71 (d, 1H, J 11.0 Hz, A CH2), 4.80 (d, 1H, J1,2 3.6 Hz, H-1), 3.80 (s, 3H, OCH3), 3.75-3.60 (m, 4H), 3.55-3.50 (m, 1H), 3.53 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 3.29 (dd, 1H, J2,3 9.1 Hz, H-2), 1.80 (bs, 1H, OH); 13C NMR (125 MHz, CDCl3): δ (ppm) 131.4, 130.9, 129.0, 128.7, 128.5, 126.3, 124.9, 124.3 (a oma ic), 97.2 (C-1), 83.5, 82.8, 76.6 (C-2, C-3, C-4), 70.6 (C-5), 66.6 (A CH2-), 61.7 (C-6), 61.3, 58.6 (2 x OCH3), 55.0 (OCH3 anome ic); Anal. Calcd. o C24H28O6 (412.48): C 69.88, H 6.84. Found: C 69.96, H 6.75. 4.1.4. Me hyl 6-O-(9’-an h acenyl)me hyl-2,3-di-O-me hyl--D-glucopy anoside (5) and compound (4) To a s i ed suspension o he s a ing ace al 3 (0.39 g, 0.96 mmol) and Na(CN)BH3 (0.54 g, 9 equi ) in d y THF (5 mL) con aining 3 Å MS was added HCl in E 2O d opwise un il he e olu ion o gas ceased. A e 5 min TLC showed comple e con e sion o he s a ing ma e ial. The mix u e was dilu ed wi h CH2Cl2 (100 mL), washed wi h sa d NaHCO3 and wa e , hen d ied (MgSO4) and concen a ed. A e column ch oma og aphy (1:1 hexane- E OAc) compound 5 (227 mg, 48%) was isola ed as a sy up: []D +63 (c 0.17, CHCl3); 1H NMR (360 MHz, CDCl3): δ (ppm) 8.39 (d, 3H), 7.95 (d, 2H, J 8.4 Hz), 7.47 (d , 4H), 5.55 (d, 1H, J 11.5 Hz, A CH2), 5.47 (d, 1H, J 11.6 Hz, A CH2), 4.84 (s, 1H, J1,2 3.4 Hz, H-1), 3.90- 3.75 (m, 2H), 3.68 (m, 1H, H-5), 3.60-3.33 (m, 12H, incl. 3x OCH3), 3.17 (dd, 1H, J2,3 9.1 Hz, H-2); 13C NMR (90 MHz, CDCl3): δ (ppm) 130.9, 130.5, 128.5, 128.3, 127.9, 125.7, 124.5, 124.0 (a oma ic), 97.0 (C-1, JC1,H1 170 Hz), 82.5, 81.2, 70.2, 70.0 (C-2, C-3, C-4, C-5), ACCEPTED MANUSCRIPT 19 69.2 (A CH2-), 65.3 (C-6), 60.5, 58.1 (2 x OCH3), 54.7 (OCH3 anome ic); Anal. Calcd. o C24H28O6 (412.48): C 69.88, H 6.84. Found: C 70.06, H 6.63. Compound 4 was also o med (56 mg, 12%). 4.1.5. Me hyl 4,6-O-(9’,10’-dihyd o-9’-an h acenyl)me hylene-2,3-di-O-me hyl--D- glucopy anoside (6) Compound 3 (0.45 g, 1.1 mmol) was dissol ed in 96% E OH (25 mL) and s i ed unde H2 a mosphe e in he p esence o 10% Pd/C (75 mg) o 6 h. The ca alys was emo ed by il a ion h ough a laye o Celi e, washed wi h E OH, and he sol en was e apo a ed. The esidue was c ys allized om MeOH o gi e 6 (360 mg, 79%) as whi e needles: mp 172-174 °C; []D +51 (c 0.19, CHCl3); 1H NMR (200 MHz, CDCl3): δ (ppm) 7.40-7.10 (m, 8H, a oma ic), 4.72 (d, 1H, J1,2 3.7 Hz, H-1), 4.63 (d, 1H, J 5.2 Hz, H-ace alic), 4.22 (d, 1H, J 4.4 Hz, H-9’), 4.17 (d, 1H, J 16.9 Hz, H-10’a), 3.99 (dd, 1H, J 10 Hz, J 4.6 Hz), 3.78 (d, 1H, J 18.1 Hz, H-10’b), 3.60-3.40 (m, 8H, incl. 2 x OCH3), 3.33 (s, 3H, anome ic OCH3), 3.30 ( , 1H, J 10.1 Hz), 3.14 ( , 1H, J 9.4 Hz), 3.12 (dd, 1H, J2,3 9.3 Hz, H-2); 13C NMR (50 MHz, CDCl3): δ (ppm) 137.3, 137.2, 135.1, 134.9, 130.0, 129.8, 127.4, 127.3, 126.7, 125.6 (a oma ic), 103.5 (C-ace alic), 98.3 (C-1), 81.8, 80.9, 79.8 (C-2, C-3, C-4), 68.6 (C-6), 61.9 (C-5), 60.6, 59.3 (2 x OCH3), 55.0 (anome ic OCH3), 51.0 (C-9’), 35.8 (C-10’). MALDI-TOF MS m/z calcd. o C24H28O6 : 412.19. Found: 435.40 [M+Na]+. Anal. Calcd. o C24H28O6: C 69.88, H 6.84. Found: C 70.03, H 6.69. 4.1.6. Me hyl 6-O-ace yl-4-O-(9’-an h acenyl)me hyl-2,3-di-O-me hyl--D- glucopy anoside (7) ACCEPTED MANUSCRIPT 20 To a solu ion o 4 (250 mg, 0.61 mmol) in py idine (2 mL) was added Ac2O (1 mL), and s i ed o 2 hou s. Then he eac ion mix u e was concen a ed and co-e apo a ed wice wi h oluene. A e column ch oma og aphy (7:3 hexane-E OAc) compound 7 was isola ed (220 mg, 80%) as a sy up: []D +144 (c 0.11, CHCl3); 1H NMR (500 MHz, CDCl3): δ (ppm) 8.42 (d, 2H, J 9.0 Hz, H-1’, H-8’), 8.40 (s, 1H, H-10’), 7.96 (d, 2H, J 8.5 Hz, H-4’, H-5’), 7.60-7.40 (m, 4H, H-2’, H-3’, H-6’, H-7’), 5.75 (d, 1H, J 11.5 Hz, A CH2), 5.70 (d, 1H, J 11.5 Hz, A CH2), 4.80 (s, 1H, J1,2 3.5 Hz, H-1), 4.12-4.08 (m, 1H), 3.95 (dd, 1H, J 12.0 Hz, J 3.5 Hz), 3.81 (s, 3H, OCH3), 3.75-3.60 (m, 3H), 3.59 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.40-3.30 (dd, 1H, J 4.0 Hz), 1.77 (s, 3H, COCH3); 13C NMR (125 MHz, CDCl3): δ (ppm) 170.3 (CO) 131.5, 131.0, 129.0, 128.6, 126.4, 125.0, 124.3 (a oma ic), 97.2 (C-1), 83.9, 82.5, 76.0, 68.4 (C-2, C-3, C-4, C-5), 66.3 (A CH2), 62.9 (C-6) 61.5, 58.7 (2 x OCH3), 55.1 (anome ic OCH3) 20.2 (OCOCH3); Anal. Calcd. o C26H30O7 (454.51): C 68.71, H 6.65. Found: C 68.52, H 6.77. 4.1.7. Me hyl 4-O-(9’-an h acenyl)me hyl-6-O-benzoyl-2,3-di-O-me hyl--D- glucopy anoside (8) To a solu ion o 4 (123 mg, 0.30 mmol) in d y CH2Cl2 (2 mL) and d y py idine (2 mL) was added BzCl (42 µL, 1.2 equi ) a 0 °C and he mix u e was s i ed o 2 h. Then he eac ion mix u e was dilu ed wi h CH2Cl2, washed wice wi h wa e , d ied (MgSO4) and concen a ed. A e column ch oma og aphy (7:3 hexane-E OAc) compound 8 (138 mg, 89%) was isola ed as a sy up: []D +102 (c 0.12, CHCl3); 1H NMR (500 MHz, CDCl3): δ (ppm) 8.43 (d, 2H, J 9.0 Hz, H-1’, H-8’), 8.26 (s, 1H, H-10’), 7.88 (d, 2H, J 8.5 Hz, H-4’, H-5’), 7.82 (d, 2H, J 9.0 Hz,) 7.55-7.45 (m, 3H) 7.40-7.30 (m, 4H, H-2’, H-3’, H-6’, H-7’), 5.83 (d, 1H, J 11.5 Hz, A CH2), 5.76 (d, 1H, J 11.5 Hz, A CH2), 4.82 (s, 1H, J1,2 3.5 Hz, H-1), 4.42 ACCEPTED MANUSCRIPT 21 (dd, 1H, J 11.8 Hz, J 2.0 Hz), 4.23 (dd, 1H, J 12.0 Hz, J 3.5 Hz), 3.85 (s, 3H, OCH3), 3.85- 3.76 (m, 4H), 3.55 (s, 3H, OCH3), 3.36 (s, 4H, incl. OCH3); 13C NMR (125 MHz, CDCl3): δ (ppm) 165.8 (COPh) 132.9, 131.4, 131.0, 129.8, 129.5, 129.1, 128.7, 128.4, 126.4, 125.0, 124.2 (a oma ic), 97.2 (C-1), 84.0, 82.7, 76.3, 68.6 (C-2, C-3, C-4, C-5), 66.5 (A CH2), 63.2 (C-6) 61.5, 58.7 (2 x OCH3), 55.2 (anome ic OCH3); Anal. Calcd. o C31H32O7 (516.58): C 72.08, H 6.24. Found: C 72.66, H 6.01. 4.1.8. Me hyl 4-O-(9’-an h acenyl)me hyl-6-O-p-me hoxybenzyl-2,3-di-O-me hyl--D- glucopy anoside (9) To a solu ion o 4 (127 mg, 0.31 mmol) in d y DMF (3 mL) was added NaH (20 mg, 80%, 1.5 equi ) a 0 °C and he mix u e was s i ed o 20 min, hen PMBCl (50 µL, 1.2 equi ) was added and s i ed o 4 h. Then he eac ion mix u e was dilu ed ca e ully wi h MeOH and concen a ed. The esidue was dissol ed in CH2Cl2, washed wice wi h wa e , d ied (MgSO4) and concen a ed. A e column ch oma og aphy (7:3 hexane-E OAc) compound 9 (135 mg, 82%) was isola ed as a sy up: []D +118 (c 0.09, CHCl3); 1H NMR (500 MHz, CDCl3): δ (ppm) 8.41 (s, 1H, H-10’), 8.41 (d, 2H, J 8.5 Hz, H-1’, H-8’), 7.97 (d, 2H, J 8.0 Hz, H-4’, H-5’), 7.50-7.40 (m, 4H, H-2’, H-3’, H-6’, H-7’), 7.18 (d, 2H, J 8.5 Hz), 6.81 (d, 2H, J 8.5 Hz), 5.77 (d, 1H, J 11.0 Hz, A CH2), 5.66 (d, 1H, J 11.0 Hz, H- A CH2), 4.86 (s, 1H, J1,2 3.5 Hz, H-1), 4.30 (s, 2H, pCH3OPhCH2), 3.82 ( , 1H, J 8.0 Hz), 3.76-3.65 (m, 9H, incl. 2 x OCH3) 3.65-3.60 (m, 4H, incl. OCH3), 3.39-3.35 (m, 4H, incl. OCH3); 13C NMR (125 MHz, CDCl3): δ (ppm) 159.2, 131.6, 131.0, 130.2, 129.2, 128.0, 126.2, 124.9, 124.6, 113.8 (a oma ic), 97.3 (C-1), 83.8, 82.7, 76.7, 70.1 (C-2, C-3, C-4, C-5), 73.0 (pCH3OPhCH2), 66.5 (an h -CH2), 66.6 (C-6), 61.5, 58.7 (2 x OCH3), 55.2, 55.1 ACCEPTED MANUSCRIPT 22 (pCH3OPhCH2, anome ic OCH3); Anal. Calcd. o C32H36O7 (532.62): C 72.16, H 6.81. Found: C 72.32, H 6.71. 4.1.9. Me hyl 6-O-ace yl-2,3-di-O-me hyl--D-glucopy anoside (10) To a solu ion o 7 (42 mg, 0.09 mmol) in d y CH2Cl2 (1 mL) a 0 °C was added BF3OE 2 (2 µL) and he mix u e was s i ed o 20 min. When TLC (4:6 hexane-E OAc) showed comple e con e sion o he s a ing ma e ial (R 0.65) in o he i le compound (R 0.22) 1 d op o E 3N was added and he sol en was e apo a ed. A e column ch oma og aphy (3:7 hexane-E OAc, R 0.27) compound 107 (18 mg, 75%) was isola ed as a sy up: []D = +85 (c 1.28, CHCl3), li .7 +85 (CH2Cl2); 1H NMR (360 MHz, CDCl3): δ (ppm) 4.86 (d, 1H, J1,2 3.5 Hz, H-1), 4.45 (d, 1H, J6a,6b 12.1 Hz, J6a,5 4.8 Hz, H-6a), 4.27 (d, 1H, J6b,5 2.1 Hz, H-6b), 3.80-3.70 (m, 1H, H-5), 3.65 (s, 3H, OCH3), 3.55-3.35 (m, 8H, 2 x OCH3, H-3, H-4), 3.25 (dd, 1H, J2,3 9.4 Hz, H-2), 2.77 (bs, 1H, 4-OH), 2.12 (s, 3H, OCOCH3); 13C NMR (90 MHz, CDCl3): δ (ppm) 97.5 (C-1), 82.5, 81.7 (C-2, C-3), 69.9, 69.3 (C-4, C-5), 63.2 (C- 6), 61.3, 58.6 (2 x OCH3), 55.3 (anome ic OCH3), 20.8 (OCOCH3); Anal. Calcd. o C11H20O7 (264.27): C 49.99, H 7.63. Found: C 50.38, H 7.42. 4.1.10. Me hyl 6-O-benzoyl-2,3-di-O-me hyl--D-glucopy anoside (11) To a solu ion o 8 (47 mg, 0.09 mmol) in d y CH2Cl2 (1 mL) a 0 °C was added BF3OE 2 (2 µL) and he mix u e was s i ed o 20 min. TLC (4:6 hexane-E OAc) showed comple e con e sion o he s a ing ma e ial (R 0.72) in o he i le compound (R 0.32). Then 1 d op o TEA was added and he solu ion was e apo a ed. A e column ch oma og aphy (3:7 hexane-E OAc, R 0.52) compound 118,9 (22 mg, 76%) was isola ed as a sy up: []D +81 ACCEPTED MANUSCRIPT 23 (c 0.11, CHCl3), li .9 +75 (CH2Cl2); 1H NMR (360 MHz, CDCl3): δ (ppm) 8.06 (d, 2H, J 7.4 Hz, o-H a oma ic), 7.57 ( , 1H, J 7.4 Hz, p-H a oma ic), 7.44 ( , 2H, J 7.7 Hz, m-H a oma ic), 4.87 (d, 1H, J1,2 3.5 Hz, H-1), 4.67 (d, 1H, J6a,6b 12.1 Hz, J6a,5 4.9 Hz, H-6a), 4.55 (d, 1H, J6b,5 2.1 Hz, H-6b), 3.9-3.8 (m, 1H, H-5), 3.66 (s, 3H, OCH3), 3.55-3.4 (m, 8H, 2 x OCH3, H-3, H- 4), 3.25 (dd, 1H, J2,3 9.1 Hz, H-2), 2.96 (bs, 1H, 4-OH); 13C NMR (90 MHz, CDCl3): δ (ppm) 166.8 (OCOPh), 133.2 (m a oma ic), 129.7, 128.4 (o and p a oma ic), 97.4 (C-1), 82.6, 81.7 (C-2, C-3), 70.1, 69.5 (C-4, C-5), 63.7 (C-6), 61.3, 58.6 (2 x OCH3), 55.2 (anome ic OCH3); Anal. Calcd. o C16H22O7 (326.34): C 58.89, H 6.79. Found: C 58.63, H 6.89. 4.1.11. Me hyl 2,3-di-O-me hyl--D-glucopy anoside (12) To a solu ion o 9 (67 mg, 0.13 mmol) in d y CH2Cl2 (1 mL) a 0 °C was added BF3OE 2 (2 µL) and he mix u e was s i ed o 20 min. TLC (1:1 hexane-E OAc) showed comple e con e sion o he s a ing ma e ial (R 0.82) in o he i le compound (R 0.22). Then 1 d op o TEA was added and he solu ion was e apo a ed. A e column ch oma og aphy (1:1 hexane-E OAc) compound 1210 (24 mg, 86%) was isola ed as a sy up: []D +170 (c 0.98, CHCl3), li .10b +174; 1H- and 13C-NMR da as we e in e y good ag eemen wi h hose epo ed in he li e a u e.10b 4.1.12. Me hyl 6-O-(9’,10’-dihyd o-9’-an h acenyl)me hyl-2,3-di-O-me hyl--D- glucopy anoside (13) and 1,5-anhyd o-6-O-(9’,10’-dihyd o-9’-an h acenyl)me hyl-2,3- di-O-me hyl-D-gluci ol (14) To a solu ion o 6 (250 mg, 0.60 mmol) in d y CH2Cl2 (2 mL) was added E 3SiH (484 µL, 5 equi ) a 0 °C, hen BF3OE 2 (154 µL, 2 equi ) was also added and he mix u e was ACCEPTED MANUSCRIPT 24 s i ed o e nigh a . A e TLC (7:3 hexane-ace one) indica ed he o ma ion o wo p oduc s, he eac ion mix u e was dilu ed wi h CH2Cl2, washed wi h wa e , sa d NaHCO3, hen again wi h wa e , d ied (MgSO4) and concen a ed. A e column ch oma og aphy (8:27:3 hexane-ace one) compound 13 (R 0.42, 49 mg, 20%), compound 14 (R 0.46, 52 mg) and un eac ed 6 (34 mg, 14%) we e isola ed as sy ups. Compound 13: []D +62 (c 0.14, CHCl3); 1H NMR (500 MHz, CDCl3) δ (ppm) 7.36-7.19 (m, 8H, a oma ic), 4.78 (d, 1H, J1,2 3.6 Hz, H-1), 4.22 ( , 1H, J 7.3 Hz, H-9’), 4.13 (d, 1H, J 18.5 Hz, H-10’a), 3.88 (d, 1H, J 18.5 Hz, H-10’b), 3.65-3.56 (m, 6H), 3.61 (s, 3H, OCH3), 3.48 (s, 3H, OCH3), 3.47-3.36 (m, 2H), 3.35 (s, 3H, OCH3), 3.15 (dd, 1H, J 9.1 Hz, H-1); 13C NMR (125 MHz, CDCl3): δ (ppm) 137.1, 137.0, 136.1, 128.8, 128.7, 127.7, 127.7, 126.5, 126.1, 126.0 (a oma ic), 97.3 (C-1), 82.6, 81.6 (C-2, C-3) 75.6 (C-11’), 71.0, 69.8 (C-4, C-5), 70.9 (C-6), 61.0, 58.5 (2 x OCH3), 55.0 (OCH3 anome ic), 47.5 (C-9’), 35.1 (C-10’). MALDI-TOF MS m/z calcd. o C24H30O6 : 414.20. Found: 437.42 [M+Na]+. Anal. Calcd. o C24H30O6 (414.49): C 69.54, H 7.30. Found: C 69.43, H 7.38. Compound 14 con aining impu i ies was pu i ied and cha ac e ized a e ace yla ion. 4.1.13. 4-O-ace yl-1,5-anhyd o-6-O-(9’,10’-dihyd o-9’-an h acenyl)me hyl-2,3-di-O- me hyl-D-gluci ol (15) The isola ed 14 (52 mg) con aining impu i ies was ace yla ed wi h Ac2O (0.5 mL) in py idine (1 mL). The mix u e was dilu ed wi h CH2Cl2, washed wice wi h wa e , d ied and concen a ed. A e column c oma og aphy (7:3 hexane-ace one) compound 15 (37 mg, 14% o wo s eps) was isola ed as a sy up: []D +16 (c 0.14, CHCl3); 1H NMR (500 MHz, CDCl3): δ (ppm) 7.31-7.19 (m, 8H, a oma ic), 4.66 ( , 1H, J 9.3 Hz), 4.18 ( , 1H, J 7.1 Hz, H- 9’), 4.12 (d, 1H, J 18.0 Hz, H-10’a), 4.02 (dd, 1H, J 11.3 Hz, J 5.3 Hz), 3.87 (d, 1H, J 18.5 ACCEPTED MANUSCRIPT 31 This wo k was suppo ed by he Hunga ian Na ional Fund (NK48798 o A.L. and K62802 o A.B.). Re e ences 1. Kocienski, P. J. P o ec ing G oups; Thieme: New Yo k, 1994. 2. Lip ák, A.; Bo bás, A.; Bajza, I. P o ec ing G oup Manipula ions in Ca bohyd a e Syn hesis. In Comp ehensi e Glycoscience; Kame ling, J. P., Boons, G.-J., Lee, Y. C., Suzuki, A., Taniguchi, N., Vo agen, A. G. J., Eds; Else ie , 2007, 1; pp 203-259. 3. Elle ik U. Te ahed on Le . 2003, 44, 2279-2281. 4. Lip ák, A.; Jodál, I.; Nánási, P. Ca bohyd . Res. 1975, 44, 1-11. 5. Ga egg, P. J.; Hul be g, H. Ca bohyd . Res. 1975, 93, C10-C11. 6. Ze as, L. Be . 1939, 64, 2289-2296. 7. Pe i ou, M.; Imbe y, A.; Duchaussoy, P.; D iguez, P.-A.; Cecca o, M.-L.; Gou enec, F.; Sizun, P.; Hé aul , J.-P.; Pé ez, S.; He be , J.-M. Chem. Eu . J. 2001, 7, 858-873. 8. Sa o, K; Iga ashi, T.; Yanagisawa, Y.; Kawauchi, N.; Hashimo o, H.; Yoshimu a, J. Chem. Le . 1988, 1699-1702. 9. Luzzio, F. A.; Bobb, R. A. Te ahed on Le . 1997, 38, 1733-1736. 10. (a) I ine, J. C.; Sco , J. P. J. Chem. Soc. 1913, 109, 575-586. (b) Robe son, G. J., Lamb, R. A. J. Chem. Soc. 1934, 1321. 11. Debenham, S. D.; Toone, E. J. Te ahed on: Asymme y 2000, 11, 385-387. 12. (a) Lip ák, A.; Neszmélyi, A.; Ko á, P; Hi sch, J. Te ahed on 1981, 37, 2379-2382; (b) Gigg, R.; Conan , R. J. Ca b. Chem. 1982-83, 1, 331-336; (c) Gigg, R.; Conan , R. Ca bohyd . Res. 1982, 104, C14-C17. 13. (a) Bage , N.; Buck, K. W.; Fos e , A. B.; Webbe , J. M. J. Chem. Soc. 1965, 3401- 3407; (b) Neszmélyi, A.; Lip ák, A.; Nánási, P. Ca bohyd . Res. 1977, 58, C7-C9. ACCEPTED MANUSCRIPT 32 14. Osca son, S. P o ec i e G oup S a egies. In The O ganic Chemis y o Suga s; Fügedi, P., Le y, D. E., Eds.; Taylo & F ancis, 2006; pp 53-87. 15. Bo bás, A.; Hajkó, J.; Kaj á -Pe edy, M.; Lip ák, A. J. Ca bohyd . Chem. 1993, 12, 191-200. 16. Hajkó, J.; Bo bás, A.; Szabo ik, G.; Kaj á -Pe edy, M.; Lip ák, A. J. Ca bohyd . Chem. 1997, 16, 1123-1144. 17. Rigaudy J, Ta dieu P. Comp . end. 1956, 242, 2730-2733. 18. Al oma e, A.; Casca ano, G.; Giaco azzo, C.; Guaglia di, A. J. Appl. C ys . 1993, 26, 343-350. 19. Sheld ick, G. M. Ac a C ys . 2008, A64, 112-122. 20. Fa ugia, L. J. J. Appl. C ys . 1999, 32, 837-838. 21. Case, D. A.; Da den, T. A.; Chea ham III, T. E.; Simme ling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; C owley, M.; Walke , R. C.; Zhang, W.; Me z, K. M.; Wang, B.; Hayik, S.; Roi be g, A.; Seab a, G.; Koloss á y, I.; Wong, K. F.; Paesani, F.; Vanicek, J.; Wu, X.; B ozell, S. R.; S einb eche , T.; Gohlke, H.; Yang, L.; Tan, C.; Mongan, J.; Ho nak, V.; Cui, G.; Ma hews, D. H.; See in, M. G.; Sagui, C.; Babin, V.; Kollman, P.A. AMBER 10, Uni e si y o Cali o nia, San F ancisco, 2008. 22. Gaussian 03, Re ision C.02, F isch, M. J.; T ucks, G. W.; Schlegel, H. B.; Scuse ia, G. E.; Robb, M. A.; Cheeseman, J. R.; Mon gome y, J ., J. A.; V e en, T.; Kudin, K. N.; Bu an , J. C.; Millam, J. M.; Iyenga , S. S.; Tomasi, J.; Ba one, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Pe e sson, G. A.; Naka suji, H.; Hada, M.; Eha a, M.; Toyo a, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Ki ao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; H a chian, H. P.; C oss, J. B.; Bakken, V.; Adamo, C.; Ja amillo, J.; Gompe s, R.; S a mann, R. E.; Yazye , O.; Aus in, A. J.; Cammi, R.; Pomelli, C.; Och e ski, J. W.; Ayala, P. Y.; Mo okuma, K.; Vo h, G. ACCEPTED MANUSCRIPT 33 A.; Sal ado , P.; Dannenbe g, J. J.; Zak zewski, V. G.; Dapp ich, S.; Daniels, A. D.; S ain, M. C.; Fa kas, O.; Malick, D. K.; Rabuck, A. D.; Ragha acha i, K.; Fo esman, J. B.; O iz, J. V.; Cui, Q.; Baboul, A. G.; Cli o d, S.; Cioslowski, J.; S e ano , B. B.; Liu, G.; Liashenko, A.; Pisko z, P.; Koma omi, I.; Ma in, R. L.; Fox, D. J.; Kei h, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakka a, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian, Inc., Walling o d CT, 2004. 23. (a) Flükige P.; Lü hi H. P.; Po mann S.; Webe e J. MOLEKEL 5.2 Swiss Cen e o Scien i ic Compu ing, Manno (Swi ze land) 2000-2002; (b) Po mann S.; Lü hi H. P. Chimia 2000, 54, 766-770. 24. Humph ey, W.; Dalke, A.; Schul en, K. J. Molec. G aphics 1996, 14, 33-38. 25. Clode, D. M.; Ho on, D.; Wecke le, W. Ca bohyd . Res. 1976, 49, 305-314.