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.

Advanced Chemical Methods for Stereoselective Sialylation and Their Applications in Sialoglycan Syntheses

“…reported a C1‐picolinyl donor that favored the formation of the α‐anomer in the glycosylation of the C6 hydroxyl of Gal acceptor 17 (Scheme 10). [37] High α‐selectivity was also observed for the glycosylation of the C3 hydroxyl of Gal 35 (42 %, α only). They demonstrated that the protonated picolinyl group stabilizes the β‐sialyl triflate, which then undergoes S N 2‐like substitution to provide α‐sialosides.…”

“…[31,36] Sun et al introduced a picolinyl group as a C1 auxiliary. [37] Compared with the general C1-methyl ester derivative, the (2-methylthio)ethyl derivative 25 showed significantly higher α-selectivity in primary alcohol glycosylation. [35] The use of dimethoxyethane (DME) as a solvent enhanced α-selectivity (α : β = 95 : 5) compared to the cases of MeCN (α : β = 80 : 20) and CH 2 Cl 2 (α : β = 68 : 32).…”

Influence of Remote Picolinyl and Picoloyl Stereodirecting Groups for the Stereoselective Glycosylation

“…The versatility and exclusive stereoselectivity of the above-mentioned approach paved the way to the efficient synthesis of N-glycan antennae (type I and II) in combination with the MPEP glycosylation protocol using a "latent-active" strategy (Scheme 31). [49] This synthesis involved the coupling of picolinyl group containing donor 112 and primary acceptor 115 upon activation of NIS/TfOH to give stereoselective disaccharide sialoside 116 in 90% yield and then undergo several reaction steps to ultimately delivered type I antennae. However, the synthesis of type II antenna 124 was even more challenging and involved an eight-steps longest linear sequences starting with common picolinyl protected donor 112 as well as diol acceptor 121.…”

“…Thereafter Jian‐Song Sun and group (2019) [49] utilized the efficacy of the picolinyl group to design and prepared the versatile 1‐Pic‐5‐N 3 sialyl donor. To elaborate the act of the Pic group they used two types of donors ( 111 and 112 ) and performed their glycosylation with several acceptors.…”

“…The versatility and exclusive stereoselectivity of the above‐mentioned approach paved the way to the efficient synthesis of N‐glycan antennae (type I and II) in combination with the MPEP glycosylation protocol using a “latent‐active” strategy (Scheme 31). [49] …”