Intramolecular Glycosidation by Click Reaction Mediated Spacer Generation Followed by Spacer Cleavage

Abstract

2‐O‐Propargyl‐substituted glycosyl donors and O‐(2‐azidobenzyl)‐substituted acceptors having a vicinal hydroxy group readily underwent the click reaction. Intramolecular glycosidation with N‐iodosuccinimide/trifluoromethansulfonic acid as the activating system afforded β‐(1–3)‐ and α‐(1–2)‐linked disaccharides as part of 14‐membered macrocycles. Descriptors for these reactions are proposed that consider the donor and acceptor attachment sites and the stereochemistry of the functional groups. Investigation of the influence of 2‐O‐linked 1‐aryl‐1,2,3‐triazol‐4‐ylmethyl groups, as contained in the spacer, on the anomeric selectivity exhibited no anchimeric assistance. In addition, it was shown that the spacer group can be readily cleaved under Birch reduction conditions.

Intramolecular glycosylation

“…In a recent attempt to simplify the synthesis of the non-symmetrical tethers, a highly trendy triazole-forming click chemistry was combined with rigid spacers by the Schmidt group. α,α’-Dibromo ortho - and meta -xylene-derived rigid spacers were used in this application, and this approach allowed to investigate the size of the macrocycle formed during the glycosylation ( Scheme 12 ) [ 80 – 81 ]. Thioglycoside donor 45 containing a 2- O -propargyl group and acceptor 46 with an azide-containing protecting group were connected using a click reaction to afford the tethered intermediate 47 .…”

“…As in the previous example with the xylylene-derived linker, the triazole linker was removed under standard hydrogenation conditions followed by global acetylation. The results obtained with the 6-hydroxyglucopyranosyl acceptor were somewhat mixed [ 81 ]. Attaching the template at various positions of the acceptor to achieve either 16- or 17-membered macrocycles resulted in high yields of 90% and 82%, respectively.…”

“…With the varying anomeric stereoselectivities and yields, it was hypothesized that the benzylic methylene group may be responsible for the increased rotational freedom between the triazoyl and benzyl moieties. Investigations with o -azidobenzyl protecting groups were used to reduce the degrees of freedom and also to form smaller ring sizes [ 81 ].…”

The Click Reaction as an Efficient Tool for the Construction of Macrocyclic Structures

“…The use of CuAAC click chemistry for the synthesis of sugar-containing macrocycles has been recently reported by several groups, and very interesting properties have been demonstrated for these derivatives [52,53,54,55], such as metal complexation ability, and the possibility to address simply stereochemical diversity. The Chen group [56] reported the synthesis and characterization of structurally well-defined macrocyclic oligosaccharides of various dimensions.…”

C2‐(1 N/2 N‐Methyl‐tetrazole)methyl Ether (MeTetMe) as a Stereodirecting Group for 1,2‐trans‐β‐O‐Glycosylation

“…Of note, the earlier reported C2‐ O ‐(1‐phenyl‐1,2,3‐triazol‐4‐yl)methyl group 1 d by Schmidt et al. failed to display stereoselectivity through anchimeric assistance (Figure 1d) [15] . In continuation to our endeavors with developing effective glycosylation methods, [16] we intended to improve β‐selectivity by introducing more efficient directing group at the C2‐position of glycosyl donors.…”