Synthesis of a Sialic Acid Containing Complex‐Type N‐Glycan on a Solid Support

Abstract

A new solid-phase synthesis of N-linked glycans featuring 1) highly stereoselective beta-mannosylation and microfluidic alpha-sialylation and 2) efficient glycosylation of the N-phenyltrifluoroacetimidate units on JandaJel resin is reported. Reagent concentration effects by a fluorous solvent are effectively applied, and the use of these methods results in the first synthesis of a sialic acid containing complex-type N-glycan on a solid support.

Recent Strategies for Stereoselective Sialylation and Their Application to the Synthesis of Oligosialosides

“…The N-phthalimide protected building block having a N-phenyltrifluoroacetimidate leaving group 12, developed by Tanaka-Fukase, is applicable to microreactor syntheses of various sialylglycans (32,33). A remarkable result on the application of microfluidic chemistry is the improved stereoselectivity of the sialylation reaction under microflow conditions.…”

Oligosaccharide Synthesis on Solid, Soluble Polymer, and Tag Supports

“…38 Two challenging glycosyl bond formations (b-mannosylation and a-sialylation) were constructed in advance in solution-phase or under microfluidic conditions; the synthesis of the fragment c, Manb(1-4)GlcNTroc, was achieved by their highly b-selective mannosylation method, which utilized the trimethylsilyl tetrakis (pentafluorophenyl)borate, TMSB(C 6 F 5 ) 4 , as a Lewis acid/cation trap activator, 39 and by using microfluidic conditions. 40 On the other hand, the quantitative and a-selective sialylation (a : b > 20 : 1) was achieved for the large-scale preparation of the NeuNAca (2-6)Gal disaccharide (fragment d) by using C5-substitued phthalimide or azide imidates through the mechanism of fixed-dipole moment effects under microfluidic conditions (see Section 16.3.4).…”

Acid-mediated reactions under microfluidic conditions: A new strategy for practical synthesis of biofunctional natural products

“…Although a number of new chemical and/or combined methods employing biological technology have actively been investigated [39–40], an efficient approach to these complex oligosaccharides has yet to be established in terms of (i) selectivity in the glycosyl bond formations, i.e., β-mannosylation and α-sialylation, and (ii) a non-tedious purification process during each step of glycosylation and deprotection. Our interests in elucidating unknown biological functions of mammalian N -glycans of the diverse structures, have motivated us to establish a practical and library-directed synthesis of the complex-type N -glycans on solid-support [32]; the initial target of our strategy is a sialic acid-containing N -glycan with asymmetric branching chains (Fig. 1), which is difficult to obtain from natural sources.…”

“…We have been applying these advantageous features of the microfluidic systems to the “key” but “problematic” acid-mediated reactions under the conventional batch apparatus, in practically preparing bioactive natural products [27–33]. Our successful examples are cation-mediated reactions, such as α-sialylation [28,32], β-mannosylation [31], and reductive opening of the benzylidene acetal groups in sugars [30], for which improved procedure under the microfluidic conditions enabled the preparation of key synthetic intermediates for oligosaccharides on a multi-gram scale, eventually leading to a total synthesis of the asparagine-linked oligosaccharide ( N -glycan) [32]. A significant improvement has also been achieved for dehydration, which resulted in the industrial scale-synthesis of the immunostimulating natural terpenoid, pristane, of about 500–1000 kg in a year [29].…”