Glycosylations of Simple Acceptors with 2‐O‐Acyl l‐Idose or l‐Iduronic Acid Donors Reveal Only a Minor Role for Neighbouring‐Group Participation

Abstract

Several l‐idose and l‐iduronic acid glycosyl donors (mostly thioglycosides but also halides and trichloroacetimidates) with acyl protecting groups at the C‐2 position were prepared and evaluated in glycosylation reactions with simple acceptors. In glycosaminoglycan oligosaccharide syntheses in the literature, the presence of C‐2 acyl protecting groups in l‐ido‐configured glycosyl donors generally results in exclusive formation of 1,2‐trans glycosidic linkages, a finding that has typically been attributed to neighbouring‐group participation. However, glycosylations of simple alcohols with l‐ido‐configured donors (particularly thioglycosides), reported here, generally displayed incomplete stereocontrol and gave mixtures of the 1,2‐trans and 1,2‐cis products, suggesting that neighbouring‐group participation has lesser importance in these reactions. Glycosyl donors and reaction conditions were identified that gave improved, but not exclusive, selectivity for the desired α‐l‐anomer (1,2‐trans) as the major product. Interestingly, glycosylations under the same reaction conditions with more complex monosaccharide acceptors gave exclusively the expected 1,2‐trans products. The role of neighbouring‐group participation in these glycosylations was explored with density functional theory (DFT) calculations, which revealed that the non‐stereoselective addition of the acceptor alcohol to the intermediate oxocarbenium ion is competitive with the stereospecific addition of the acceptor to the acyloxonium ion intermediate.

Short Synthesis of Idraparinux by Applying a 2‐O‐Methyl‐4,6‐O‐arylmethylene Thioidoside as a 1,2‐trans‐α‐Selective Glycosyl Donor

“…By applying this donor, due to the controlling effect of the 4,6‐acetal group, the GH building block was prepared with full 1,2‐ trans ‐α‐stereoselectivity in the absence of a participating group at C2 position. Typically, l ‐idose or l ‐iduronic acid donors with a C2 participating group have been applied for the construction of the α‐ l ‐idosyl glycosidic linkage , . The demonstrated α‐stereodirecting effect of the 4,6‐cyclic acetal in the presence of an ether protecting group at C2 position pave the way to designing new, more diverse protecting group strategies for the synthesis of heparin and heparin sulfate oligosaccharides.…”

An Efficient Modular One-Pot Synthesis of Heparin-Based Anticoagulant Idraparinux

“…15b The formation of the anomeric mixture was not surprising as a recent study showed that neighboring-group participation has a minor role for idose donors. 23 Removal of the O-acetyl groups under Zempleń reaction condition followed by 4,6-O-benzylidine protection led to the chromatographically separable mixture of 17 in good yield. The α-anomer 17α was treated with BzCl/Py to furnish the fully protected glycosyl donor 18 (Scheme 3).…”

Total Synthesis of Terpioside B

“…Next, the synthesis of tetrasaccharide trichloroacetimidate donor 3 is summarized in Scheme . Benzoylation of 14 with BzCl, followed by treatment of the resulting 17 with TMSSPh and ZnI 2 , provided the ring‐opened β‐thioglycoside 18 with high stereoselectivity. Selective deprotection of the TBDPS group in 18 afforded diol acceptor 5 .…”