Unexpected Orthogonality of S-Benzoxazolyl and S-Thiazolinyl Glycosides: Application to Expeditious Oligosaccharide Assembly

Abstract

Thorough mechanistic studies of the alkylation pathway for the activation of glycosyl thioimidates have led to the development of the “thioimidate-only orthogonal strategy”. Discrimination amongst S-thiazolinyl (STaz) and S-benzoxazolyl (SBox) anomeric leaving group was achieved by fine-tuning of the activation conditions. Preferential glycosidation of a certain thioimidate is not simply determined by the strength of activating reagents; instead, the type of activation – direct vs. indirect – comes to the fore and plays the key role.

S-Benzimidazolyl (SBiz) Imidates as a Platform for Oligosaccharide Synthesis via Active–Latent, Armed–Disarmed, Selective, and Orthogonal Activations

“…24–27 Yet this strategy remains somewhat under-developed with too few known examples to become universally applicable. Only the following examples are known to date: the original S -phenyl vs fluoride introduced by Kanie et al, 24,25,28 thioimidate-based approaches developed in our lab, 19,29–31 Hotha’s O -pentenyl vs O -propargyl, 32 and O -allylphenyl-based approach also introduced by our group. 33 Likewise, we reported a related, albeit less flexible, semiorthogonal approach using S -ethyl vs O -pentenyl, 34 which was extended to fluoride vs O -pentenyl by Fraser-Reid and Lopez.…”

Glycosyl thioimidates as versatile building blocks for organic synthesis

“…It was also reported that the SBaz leaving group can be very rapidly activated for glycosylation in the presence of AgBF 4 and is applicable to selective activation over other types of leaving groups involving S -alkyl and O -pentenyl glycosides [55]. It was also observed that the SBaz leaving group can be activated in the presence of MeOTf, but not in the presence of weaker alkylating reagents, which created a basis for selective activation of STaz donors with benzyl bromide or methyl iodide in the presence of glycosyl acceptors equipped with SBaz anomeric group [35]. …”

“…SBox glycosides also showed promising orthogonal combinations with glycosyl alkoxyimidates [64] and STaz glycosides [35]. The orthogonality with other thioimidates is a unique feature of this methodology because conventional orthogonal activation [65, 66] requires two different classes of leaving groups, whereas here both leaving groups are of the same class.…”

“…Resultantly, the synthesis becomes increasingly inefficient which is particularly evident at the advanced stages of the assembly [29, 30] and often leads to a dramatic drop in yield, and as a conesquence, the availability of oligosaccharides. Further study of glycosyl thioimidates allowed for the design of novel strategies for the synthesis of oligosaccharides including temporary deactivation concept [31, 32], inverse armed-disarmed strategy [33], surface-tethered iterative carbohydrate synthesis (STICS) [34], and the thioimidate-only orthogonal strategy [35]. It also helped to uncover the O-2/O-5 cooperative effect in glycosylation that allows for superarming and superdisarming of building blocks by simple alteration of protecting group pattern [36–39], and to perform basic mechanistic aspects of glycosylation [33, 40], the most common but least understood reaction in glycochemistry [4].…”

OFox imidates as versatile glycosyl donors for chemical glycosylation

“…As previously shown in our laboratory, S -thiazolinyl donors are activated via the remote nitrogen. 17 In strong contrast, bicyclic leaving groups SBox or OBox are activated via the anomeric sulfur or oxygen atom, respectively (Fig. 1).…”