Ingrid 't Hart

59 Synthesis of globo-series glycolipids 3 6 as the pure β-anomer in 71% yield. Having solved the β-glycosyla�on without neighbouring group par�cipa�on, we tried to extend lactosylsphingosine 6 with a α1,4- galactose to form globotriaosylsphingosine (Gb3-Sph). First the benzylidene acetal of 6 was selec�vely opened using Et 3 SiH, TfOH at -70 °C to give 7 having C-4 hydroxyl. 28 Various glycosyla�on condi�ons of galactosyl donors ( 8a-c ) with acceptor 7 were tested to provide the desired trisaccharide 9 (Scheme 1A). In each case low product yields and mul�ple by-products were obtained, which could be caused to side reac�ons of ac�va�ng agents with the sphingosine alkene and low reac�vity of the axial C-4 hydroxyl in the acceptor. Pure protected Gb3-Sph 9 could, however, be isolated in a 29% by prepara�ve TLC. It was envisaged that glycosyla�ons with Gb3-Sph 9 would result in poor yields and by-products. Therefore, we aimed for glycosyla�on of sphingosine acceptor 5 and pentasaccharide donor 11 (Scheme 1B). Protected pentasaccharide Gb5 10 was synthesized as described before. 28 Donor 11 was prepared from compound 10 in two steps. First, the pMP protec�ng group was removed by mul�ple cycles of treatment with 1.3 eq cerium ammonium nitrate (CAN) to avoid by-product forma�on. The intermediate lactol was converted into trichloroace�midate 11 by reac�on with trichloroacetonitrile in the presence of 1,8-diazabicyclo(5.4.0)undec-7ene (DBU). Glycosyla�on of donor 11 with sphingosine acceptor 5 in the presence of BF 3 OEt 2 in DCM at -50 °C resulted in the forma�on of 12 as a separable mixture of α/β anomers . The pure β-anomer of 12 (33%) was isolated a�er silica gel and SX1 size exclusion column chromatography. Next, we explored another strategy based on C-2 neighbouring group par�cipa�on to provide β-anomeric selec�vity. A C-2 benzoyl ester was chosen as a par�cipa�ng group, since it is less prone to migra�on compared to an acetyl ester. Donor 14 , containing the C-2 benzoyl ester, was synthesized from pentasaccharide 13 in six steps. Thus, pentasaccharide 13 was treated with Zn and AcOH to remove N HTroc. The resul�ng free amine was by protected by TFA, using trifluoroace�c anhydride and Et 3 N. The N HTroc was replaced by N HTFA to avoid dechlorina�on under subsequent reduc�ve condi�ons. The benzyl ethers were cleaved by hydrogena�on using Pd(OH) 2 /C in a mixture of MeOH/ H 2 O/HOAc. The resul�ng free hydroxyls were protected by benzoyl esters by treatment with benzoyl chloride and pyridine. Finally, pMP was removed as described above and N -phenyl trifluoroace�midate was installed to obtain Gb5 donor 14 . Unfortunately, none of the tested glycosyla�on condi�ons of donor 14 with sphingosine accepter 5 provided the desired product. It was noted that 4 Å molecular sieves completely abolished glycosyla�on with sphingosine and only trace product 15 (<1%) was detected in the absence of molecular sieves (Scheme 1C). The lower reac�vity of benzoylated donors over benzylated donors has been described before. This phenomenon is o�en described as “armed” for benzylated and “disarmed” for benzoylated glycosyl donors and is explained by the stronger electron-withdrawing proper�es of the ester groups over the ether groups. 42 The combina�on of both poor donor and poor acceptor reac�vity are unfavorable for the chemical glycosyla�on.