Ingrid 't Hart

78 Chapter 4 4 and trisaccharide 4 provides pentasaccharide 2 . Disaccharide 3 is similar to the Galβ1,3- GalNAc disaccharides synthesized before (Chapter 2 of this Thesis). Trisaccharide 4 (Galβ1,4GlcNAcβ1,3-GalNAc-α-(CH) 2 NH 2 ) was synthesized from three monosaccharide building blocks and an aminopentyl linker. Monosaccharide building blocks 5 - 9 were synthesized from the respec�ve free reducing monosaccharides. Scheme 1. Chemical synthesis of SM1-core3. Reagents and condi�ons: (a) TMSOTf, CH 2 Cl 2 , 4 Å MS, -40 °C; (b) i. Et 3 SiH, Cl 2 PhB, CH 2 Cl 2 , 4 Å MS, -68 °C, ii. Ac 2 O, pyridine; (c) i. HF·pyridine, pyridine, ii. CF 3 C(NPh)Cl, Cs 2 CO 3 , CH 2 Cl 2 , 0 °C; (d) TMSOTf, CH 2 Cl 2 , 4 Å MS, -70 °C; (e) NaOMe, CH 2 Cl 2 /MeOH; (f) NH 2 NH 2 HOAc, CH 2 Cl 2 /MeOH, 50 °C. Benzylidene protected GalN 3 donor 15 was chosen to form the α-linkage with the protected aminopentanol linker 16 26 (Scheme 2A). Surprisingly, only the β-anomer of 17 was formed, even though the C-2 ester was expected to provide neighboring group par�cipa�on. This was confirmed by decoupled HSQC NMR spectroscopy ( 1 J CH = 162.0 Hz). The high β-anomeric selec�vity can be a�ributed to a combina�on of high reac�vity of the nucleophile 16 and stabiliza�on of the intermediate anomeric triflate in presence of a C-2 azide. The C-2 azide has an electron withdrawing effect, thereby stabilizing a covalent α-triflate intermediate. A strong nucleophile can replace the α-triflate, providing the β-product. 27 To incorporate an α-direc�ng protec�ng group, the benzylidene acetal of donor 15 was replaced in two steps for a di- tert -butylsilylene group ( 18 , Scheme 2B). However, this donor proved to be highly unreac�ve a�er ac�va�on by NIS/TfOH and no product was formed. Also, no donor hydrolysis was observed and intact donor 18 was recovered from the reac�on mixture. Finally, glycosyla�on of trichloroac�midate 19 28 and protected aminopentanol acceptor 16 in the presence of thiophene provided an O NPhth O BnO BnO O N 3 O O O O NBnCbz Ph O OBn O NapO OBz O BnO OAc O TrocHN O BzO OBz BzO BzO O BnO OAc O TrocHN O BzO OBz BzO BzO O NPhth O BnO BnO O N 3 O O O O NBnCbz Ph O OBn RO OBz NapO O BzO OBz BzO BzO O OBn LevO OBz NapO O NPhth RO BnO BnO O N 3 O O O O NBnCbz Ph O PhthN AcO BnO BnO O N 3 O HO O O NBnCbz Ph O NHTroc HO O O Ph OTDS O CCl 3 NH O R 1 O OR 2 O TrocHN O BzO OBz BzO BzO 1 2 , 40% 3 , 62% 5 6 7 8 9 OTDS 5 + 6 8 + 9 7 , d 3 + 4 a c d d 10 : R 1 = Bn, R 2 = Ac, 55% b 11 : R = H, 97% e 4 : R = H, 90% f 12 : R 1 :R 2 = CHPh, 43% 13 : R = Ac, 72% 14 : R = Lev, 70% O NH CCl 3 O CCl 3 NH O CF 3 NPh