Ingrid 't Hart

79 Chemical synthesis of sulfoglycolipid analog SM1a-core3 4 inseparableα/βmixtureof compound 20 (Scheme2C). A�er deacetyla�onunder Zemplén condi�ons ( cat. NaOMe in MeOH) compound 21 was obtained. Protec�on of the C-4 and C-6 hydroxyls of compound 21 by a benzylidene acetal provided 9 as a separable mixture of α/β anomers. The desired α-anomer 9 was isolated by silica column chromatography. Scheme 2. Chemical glycosyla�ons of GalN 3 donors 15 , 18 and 19 with acceptor 16 were performed to obtain building block 9 as the α-anomer. ( A ) Donor 15 solely provided the undesired β-anomer. ( B ) Replacement of the benzylidene acetal by an α-direc�ng di- tert -butyl-silane protec�ng group, provided donor 18 . Chemical glycosyla�on of donor 18 with acceptor 16 did not provide any product. ( C ) Glycosyla�on of acetylated donor 19 with acceptor 16 provided an α/β mixture (1/1) of compound 20 . Deacetyla�on of 20 provided compound 21 and subsequent protec�on of the C-4 and C-6 hydroxyl by a benzylidene acetal provided a separable mixture of anomers. Purifica�on by silica column chromatography provided compound 9 . Reagents and condi�ons: (a) NIS, TfOH, -20 °C, 4 Å MS; (b) i. HF·Pyr, pyridine, ii. ( t -Bu) 2 Si(OTf) 2 , pyridine, DMF, - 40 °C; (c) TMSOTf, thiophene, Et 2 O, 0 °C, 4 Å MS; (d) NaOMe, MeOH; (e) PhCH(OMe) 2 , pTsOH·H 2 O, CH 3 CN. Protected glucosamine 22 was synthesized from glucosamine·HCl in eight steps as described before. 29 Star�ng from GlcNH 2 ·HCl, phthalimide was chosen as a protec�ng group for the amine, since it enables neighboring group par�cipa�on during glycosyla�on and sufficiently stabile towards bases such as sodium hydride required for benzyla�on of hydroxyls.Thesubsequentacetyla�onofallhydroxyls,anomericdeacetyla�onbyhydrazine acetate and protec�on with tert -hexyl- di -methyl-silyl (TDS) group were performed as described (40%, 4 steps). Then, all acetyl esters were cleaved and the 4- and 6- hydroxyls were protected as benzylidene acetal, a�er which the C-3 hydroxyl was protected with a benzyl ether (70%, 3 steps). The benzylidene acetal was opened in a regioselec�ve manner by Et 3 SiH and TfOH in DCM at -70 °C to expose the C-4 hydroxyl ( 22 , 52%). O AcO OAc AcO N 3 O NBnCbz O AcO OAc AcO N 3 O CCl 3 NH 16 , c 20 , 62% O RO OR HO N 3 O NBnCbz d 21 : R = H, 9 : R:R = CHPh, 50% n = 5 n = 5 19 O O O AcO N 3 O O O HO N 3 Ph 17 , 60% HO NBnCbz n = 5 15 Ph O NBnCbz n = 5 A B a SPh C + b O O O AcO N 3 Si SPh 16 , a 16 18 , 51% e O O O AcO N 3 Si O NBnCbz n = 5 quant