On the Reactivity and Selectivity of Galacturonic Acid Lactones

Abstract

The reactivity and stereoselectivity of a galacturonic acid 3,6‐lactone thioglycosyl donor, previously described as a highly reactive glycosylating agent, has been investigated by using a series of competition experiments and condensation reactions with different thiophilic activator systems. It is revealed that the relative reactivity of the thioglycosides depends on the activator system used and that p‐nitrophenylsulfenyl triflate shows overall attenuated reactivity differences with respect to the commonly used N‐iodosuccinimide/triflic acid promoter system. With respect to the stereoselectivity of the studied galacturonic acid 3,6‐lactone thioglycosyl donor, it is revealed that a preactivation‐based glycosylation system gives rise to α‐selective glycosylation, whereas an in situ activation protocol leads to the formation of the β‐product with good selectivity. It is hypothesized that these opposingstereoselectivities are the result of different product‐forming intermediates. Where preactivation of the donor leads to the formation of an intermediate β‐triflate, which is substituted in a concerted fashion to provide the α‐product, a 3H4 oxocarbenium ion like species is substituted in the in situ activation experiment to provide the β‐linked product.

The Glycosylation Mechanisms of 6,3‐Uronic Acid Lactones

“…The lactone bridge presumably leads to a β‐selective oxocarbenium ion conformer 5 , but also allows for remote participation of the C‐4 benzyl ether ( 4 ) as evidenced by the formation of a 1,4‐anhydrosugar byproduct (Scheme ). These results contrast those reported for galacturonic acid 6,3‐lactone 3 , which is highly α‐selective . In this case, reaction of a β‐triflate intermediate 6 via an S N 2‐like pathway is presumably responsible for the α‐selectivity.…”

“…Glycosylation of 9 – 10 by pre‐activation with Ph 2 SO/Tf 2 O, followed by addition of glycosyl acceptor 7 (Table , entries 1,3, and 5), mainly led to 1,4‐anhydrosugar as expected . Galactoside 11 does not suffer from 1,4‐anhydrosugar formation as the C‐4 benzyl is positioned equatorially and afforded the α‐galactoside with excellent stereoselectivity ( α / β =20/1, Table , entry 5), in line with earlier reports . Glycosylation of 9 using the N‐iodosuccinimide (NIS)/AgOTf promoter system under pre‐mix conditions led to an improved yield of the β‐disaccharide (22 %), although a significant amount of 1,4‐anhydrosugar was still formed (Table , entry 2) .…”

Preactivation: An Alternative Strategy in Stereoselective Glycosylation and Oligosaccharide Synthesis

“…As evidence for this pathway, triflate 79 has been identified by NMR studies. [63] Huang and co-workers reported that the introduction of electron-donating protecting groups onto the glycosyl donors can enhance their glycosylating reactivity, which leads to improved yields even with unreactive acceptors (Scheme 32). The intermediate structures formed upon pre-activation of several representative thioglycosyl donors with 2-O-acyl groups were investigated by low-temperature NMR spectroscopy.…”

Red Algal Molecules - Synthesis of Methyl Neo-β-carrabioside and Its S-Linked Variant via Two Synthetic Routes: A Late Stage Ring Closure and Using a 3,6-Anhydro-d-galactosyl Donor

“…We were buoyed by previous studies which utilised orthoester 13 and cyanoethylidene 14 3,6-anhydro-galactose derivatives as glycosyl donors to prepare β-glycosides. Moreover, Christina et al 15 whilst exploring galacturonic acid lactone thioglycoside donors for use in making α-glycosides demonstrated the possible use of a 3,6-anhydro-galactosyl-type donor in this regard. Overall though, the αglycoside is inherently more difficult to form as it is a 1,2-cis-equitorial product, which is disfavoured by a combination of both neighbouring group participation and the anomeric effect.…”