Ingrid 't Hart

60 Chapter 3 3 Scheme 1. ( A ) Chemical glycosyla�on of benzylated lactose donor 4 and sphingosine accepter 5 to obtain β-linked lactosylsphingosine without neighbouring group par�cipa�on. Lactosylsphingosine 6 was turned into acceptor 7 and glycosylated with donors 8a-c in various condi�ons. A�er prepara�ve TLC protected Gb3Sph 9 was isolated. (a) BF 3 OEt 2 , DCM, -40 °C to -20 °C, 4 Å mol sieves; (b) Et 3 SiH, TfOH, DCM, -70 °C; (c) i. NBS, acetone/H 2 O; ii. NCCCl 3 , DBU, DCM, 0 °C; (d) i. NBS, acetone/H 2 O, ii. DAST, DCM, -40 °C to -25 °C; (e) 8a , NIS, TfOH, DCM, -35 °C; (f) xa , Ph 2 SO, Tf 2 O, TTBP, DCM, -70 °C; (g) 8b , TMSOTf, DCM -60 °C; (h) 8c , Sn(II)Cl 2 , AgClO 4 , DCM, -15 °C. ( B ) Chemical synthesis of protected Gb5-sphingosine (Gb5-Sph) 12 . Pentasaccharide donor 11 was synthesized from pentasaccharide 10 in two steps and glycosylated with sphingosine acceptor 5 . Reagents and condi�ons: (i) i. CAN, CH 3 CN/H 2 O, 0 °C, ii. NCCCl 3 , DBU, DCM, 0 °C; (j) 5 , BF 3 OEt 2 , DCM, -50 °C, 4 Å mol sieves; ( C ) Replacement of protec�ng groups on compound 13 provided pentasaccharide donor 14 . Glycosyla�on with sphingosine acceptor 5 provided only traces of protected Gb5Sph 15 , in absence of molecular sieves. Reagents and condi�ons: (k) i. Zn, AcOH, ii. TFAA, Et 3 N, DCM, 0 °C, iii. Pd(OH) 2 /C, H 2 , MeOH/H 2 O/HOAc, iv. BzCl, pyridine, v. CAN, ACN/H 2 O, 0 °C, vi. ClC(NPh)CF 3 , Cs 2 CO 3 , 0 °C; (l) TfOH, DCM, 0 °C. O O OBn BnO OBn O R 1 O OR 2 BnO BnO O C 13 H 27 OBz N 3 O O OBn BnO BnO O O O BnO BnO Ph HO C 13 H 27 OBz N 3 O NH CCl 3 a 6 : R 1 :R 2 = CHPh, 71% 7 : R 1 = OH, R 2 = Bn, 72% 4 5 e, f, g or h O O O NapO BnO O O OBn BnO OBn O O OBn BnO BnO Si O C 13 H 27 OBz N 3 9 , 29 % O O O NapO BnO Si R b 8a : R = SPh 8b : R = OC(NH)CCl 3, 25% 8c : R = F, 24% 8a,b,c c d + O AcO OAc O TrocHN O AcO OAc AcO AcO O O O O BnO O O OBn BnO OBn O O OBn BnO BnO Si O C 13 H 27 OBz N 3 O AcO OAc O TrocHN O AcO OAc AcO AcO O O O O BnO O O OBn BnO OBn O O OBn BnO BnO Si OR 5 , j 11 : R = C(NH)CCl 3 , 36% 12 , 33% 10 : R = pMP i A B + O R 2 O OR 3 O R 1 HN O AcO OAc AcO AcO O O O O R 4 O O O OR 4 R 4 O OR 4 O O OR 4 R 4 O R 4 O Si O BzO OBz O TFAHN O AcO OAc AcO AcO O O O O BzO O O OBz BzO OBz O O OBz BzO BzO Si O C 13 H 27 OBz N 3 5 , l OR 5 15 , <1% 14 : R 1 = TFA, R 2 = R 3 = R 4 = Bz R 5 = C(NPh)CF 3 , 18% 13: R 1 = Troc, R 2 :R 3 =CHPh R 4 = Bn, R 5 = pMP k C