1‐Picolinyl‐5‐azido Thiosialosides: Versatile Donors for the Stereoselective Construction of Sialyl Linkages

Abstract

With the picolinyl (Pic) group as a C‐1 located directing group and N3 as versatile precursor for C5‐NH2, a novel 1‐Pic‐5‐N3 thiosialyl donor was designed and synthesized, based on which a new sialylation protocol was established. In comparison to conventional sialylation methods, the new protocol exhibited obvious advantages, including excellent α‐stereoselectivity in the absence of a solvent effect, broad substrate scope encompassing the challenging sialyl 8‐ and 9‐hydroxy groups of sialic acid acceptors, flexibility in sialoside derivative synthesis, high temperature tolerance and easy scalability. In particular, the applicability to the synthesis of complex and bioactive N‐glycan antennae when combined with the MPEP glycosylation protocol via the “latent‐active” strategy has been shown. Mechanistically, the excellent α‐stereoselectivity of the novel sialylation protocol could be attributed to the dramatic electron‐withdrawing effect of the protonated Pic groups, which was supported by control reactions and DFT calculations.

Synthesis of β‐Glucosides with 3‐O‐Picoloyl‐Protected Glycosyl Donors in the Presence of Excess Triflic Acid: A Mechanistic Study

“…[12] Schmidt, Sun et al also obtained excellents tereoselectivity with 1-Pic-protecteds ialyl donors. [13] In application to our substrates, when glycosidationo fd onor 8 was performed in the presence of NIS and TfOH (2.0 equiv each) disaccharide 9 was obtained in ag ood yield of 79 %a nd with ad ramatically enhanced stereoselectivity (a/b = 1:16.6, entry 9).…”

“…Molecular sieves (3 or 4 )u sed for reactions were crushed and activated in vacuo at 390 8Cf or an initial 8h and then for 2-3 ha t 390 8Cd irectly prior to application. Optical rotation was measured at "Jasco P-2000" polarimeter.U nless noted otherwise, 1 HNMR spectra were recorded in CDCl 3 at 300 or 600 MHz and 13 C{H} NMR spectra were recorded in CDCl 3 at 75 MHz. HRMS was carried out on ESI-TOF mass spectrometer.…”

“…O-(2,4,6-tri-O-benzyl-3-O-picoloyl-b-d-glucopyranosyl)-(1!6)-2,3,4-tri-O-benzyl-a-d-glucopyranoside (9):C ompound 9 was obtained as aw hite amorphous solid from glycosyl donor 8 and acceptor 2[9b] following general glycosylation procedure in 85 %y ield (0.032 g, 0.032 mmol, a/b = 1:23). Analytical data for 9: R f = 0.45 (ethyl acetate/toluene, 2:3, v/v); 1 HNMR: d = 3.40 (s, 3H, OCH 3 ), 3.55-3.60 (m, 3H,H -2, 4, 5'), 3.66 (dd, 1H, J 2',3' = 9.6 Hz, H-2'), 3.75 (dd, 1H, J 6a,6b = 10.9 Hz, H-6a), 3.80 (m, 2H,H -6a", 6b'), 3.89 (m, 1H, J 5,6a = 5.1 Hz, H-5), 3.95 (dd, 1H, J 4',5' = 9.6 Hz, H-4'), 4.06 (dd, 1H, J 3,4 = 9.1 Hz, H-3), 4.23 (dd, 1H,H -6b), 4.51 (d, 1H, J 1',2' = 7.7 Hz, H-1'), 4.51-5.05 (m, 12 H, 6 CH 2 Ph), 4.66 (d, 1H, J 1,2 = 3.1 Hz, H-1), 5.61 (dd, 1H, J 3',4' = 9.5 Hz, H-3'), 7.00-7.42 (m, 30 H, aromatic), 7.52 (m, 1H,P ico-H), 7.84 (m, 1H,P ico-H), 8.02 (d, 1H, J = 7.8 Hz, Pico-H), 8.80 ppm (d, 1H, J = 3.9 Hz, Pico-H);13 C{H} NMR: d = 55.1, 59.4, 60.1, 60.8, 68.5, 70.0, 71.2, 73.4, 74.7, 75.0, 75.9, 77.2, 77.7, 78.0, 79.8, 81.1, 82.1, 98.0, 103.6, 125.6, 126.5, 127.0, 127.7, 127.8, 127.9 ( 3), 128.1 ( 4), 128.4 ( 4), 137.0, 138.1, 138.2, 138.6, 147.9, 149.4, 150.0, 164.6 ppm;E SI-TOF [M + Na] + calcd for C 61 H 63 NNaO 12 : 1024.4248, found:1024.4241.Methyl O-(3-O-benzoyl-2,4,6-tri-O-benzyl-a/b-d-glucopyranosyl)-(1!6)-2,3,4-tri-O-benzyl-a-d-glucopyranoside (13):C ompound 13 was obtained as aw hite amorphous solid from glycosyl donor 12 and acceptor 2 following general glycosylation procedure in 86 %y ield (0.033 g, 0.033 mmol, a/b = 1:1.0). Selected analytical data for a-13: R f = 0.55 (ethyl acetate/hexane, 2:3, v/v);1 HNMR: d = 3.38 (s, 3H,O CH 3 ), 5.04 (d, 1H, J 1',2' = 3.5 Hz, H-1') 5.79 ppm (dd, 1H, J 3',4' = 9.6 Hz, H-3'); 13 C{H} NMR: d = 96.9, 98.0 ppm.…”

Mechanisms of Stereodirecting Participation and Ester Migration from Near and Far in Glycosylation and Related Reactions

“…This hypothesis is supported by recent work from Schmidt, Sun, and coworkers who, as a result of extensive experimental and computational investigations, determined that the enhanced stereoselectivities observed in sialidations with picolinyl as compared to methyl esters of 4,7,8,9-tetra-O-acetyl-5-azido-5-deoxyneuraminic acid thioglycosides is likely due to the stabilization of an anomeric triflate rather than to participation by the picolinyl group (Figure 25). 192 Indeed, there is increasing experimental evidence from several groups that, at least under some conditions, the phenomenon of hydrogen bond mediated aglycone delivery discovered by the Demchenko laboratory 193 is due to protonation of the picolinyl group, or its complexation with a Lewis acid, which renders it more powerfully electron-withdrawing. [194][195][196] This has the effect of destabilizing oxocarbenium ion-like transition states for glycosylation and consequently of promoting bimolecular SN2-like mechanisms.…”

2-Diphenylphosphinoyl-acetyl as a remote directing group for the highly stereoselective synthesis of β-glycosides

“…Although they observed decreased stereoselectivity when electron-deficient or bulky acceptors were glycosylated, 39 this elegant strategy has been successfully applied to prepare various glycosides including -sialic glycosides. [40][41][42][43][44][45][46][47][48] Another N-heterocyclic 2-quinolinecarbonyl group was employed by Yang and coworkers as H-bond-acceptor to effectively construct -arabinofuranosides and /-Kdo glycosides. 49,50 H-bonding also played an important role in several reagentcontrolled strategies for -glycosylation using -glycosyl donors or intermediates (Fig.…”