O-Benzoxazolyl imidates as versatile glycosyl donors for chemical glycosylation

Abstract

Herein, we report a new class of glycosyl donors, benzoxazolyl imidates, for chemical glycosylation. The O-benzoxazolyl (OBox) leaving group was designed with an aim to compare the relative reactivity and stability of similarly structured S-benzoxazolyl (SBox) glycosides (thioimidates) developed in our lab and glycosyl trichloroacetimidates (TCAI, O-imidates) developed by Schmidt. Novel OBox donors can be activated under catalytic conditions and provided excellent yields in glycosylation. The OBox imidates were found to be more reactive than either SBox or TCAI donors. The high reactivity profile was confirmed in direct competitive experiments and was found beneficial for HPLC-assisted solid-phase synthesis.

Regenerative Glycosylation

“…22,23 O -Imidates can be activated for glycosylation in the presence of catalytic amounts of TMSOTf, 24,25 BF 3 ·Et 2 O, 26 p -TsOH, 27 Bi(OTf) 3 , 28 Yb(OTf) 3 , 29 Sm(OTf) 3 , 29 AgOTf, 30 or MeOTf. 18 For the further expansion of the regenerative glycosylation reaction we chose TMSOTf, which is arguably the most commonly used promoter.…”

“…First, a reaction of bromide 2 with acceptor 4 was performed in the presence of TMSOTf (0.08 equiv) as the activator and Ag 2 O (3.0 equiv) as the HBr scavenger. This sluggish reaction was stopped after 4 h, and disaccharide 5 18 was isolated in 18% yield ( α / β = 1/5.4, entry 1). When essentially the same reaction was performed in the presence of HOFox catalyst (0.25 equiv) disaccharide 5 was isolated in 81% yield ( α / β = 1/2.5, entry 1).…”

“…36 We were pleased to observe a very prominent effect of HOFox in all reactions of deactivated bromides. Thus, glycosidation of perbenzoylated glucosyl bromide 10 with glycosyl acceptor 4 without HOFox produced disaccharide 11 18 in a poor yield of 35%. When the same reaction was performed in the presence of HOFox (0.25 equiv), disaccharide 11 was obtained in a significantly improved yield of 85% (Table 1, entry 4).…”

“…Recently, our laboratory reported O -benzoxazolyl (OBox) 18 and 3,3-difluoro-3 H -indol-2-yl (OFox) imidates. 19 While investigating approaches to the synthesis of OFox imidates, we discovered that these compounds can be generated and glycosidated in a regenerative fashion in situ.…”

Automated Chemical Synthesis of Oligosaccharides and Glycoconjugates

“…This experimental set up offers the following advantages in comparison to that of conventional (manual) oligosaccharide synthesis on polymer supports: faster reaction times, real-time reaction monitoring using an HPLC detection system, and all steps and sequences can be automated using the standard HPLC-managing computer software. Novel O-benzoxazolyl (OBox) imidates were found to be promising glycosyl donors for HPLC-based applications [119].…”