Hybrid Solution/Solid‐Phase Synthesis of Oligosaccharides by Using Trichloroacetyl Isocyanate as Sequestration‐Enabling Reagent of Sugar Alcohols

Abstract

In recent years there has been a steady increase in interest in glycoscience with particular emphasis toward programs at the chemistry/biology interface. Current studies are mainly directed toward the understanding at molecular level of the key role exerted by glycoconjugate-derived oligosaccharides in beneficial or detrimental events that occur in living organisms.[1] In most, if not all, of these studies, organic synthesis is required to provide meaningful quantities of native oligosaccharides and their analogues in a pure state with well-defined structures to be used as biological, biochemical, and biophysical probes. Pure oligosaccharides are very difficult to access from natural sources owing to the complexity and microheterogeneity of glycosylated proteins [2] and their instability to many isolation procedures. Enormous progress has been made in the area of oligosaccharide synthesis especially in the last decade, and a plethora of synthetic methods in either the solution or solid phase have been reported. [3,4] However both techniques present their own limitations. For instance, solution-phase reactions require a laborious workup and time-consuming product isolation by chromatography after each glycosidation trail. On the other hand, the solid-phase approach does not entail the above problems and lends itself to automation, however, the polymer-bound substrate suffers an attenuated reactivity for entropic and steric reasons, and monitoring the progress of the reaction and estimating the yield of coupled product by TLC or standard NMR and MS analyses is more difficult. A number of sophisticated analytical methods have therefore been developed as a result.[5] Another serious concern in the solid-phase approach is the need for robust linkers that tolerate various reaction conditions but can be easily cleaved to retrieve the product without affecting its functionalities, especially the labile and stereomutable O-glycosidic bond. Even in the face of spectacular advances in the field of automated solid-phase synthesis of oligosaccharides up to nine-member constructs, [4l] the main way to access complex oligosaccharides that feature a great structural diversity still appears to be the convergent solution-phase approach by coupling tri-or tetrasaccharide building blocks. [6] Hence the search for innovative and practical methods based on recent synthetic techniques is actively pursued. Notable is the tag-assisted solution-phase strategy developed by Hindsgaul and co-workers, [7] Pozgay, [8] and Ito and coworkers [9] in which a suitable group (tag) installed in one of the reactants serves to selectively remove the coupled product from the complex reaction mixture. An oligosaccharide synthesis centered on the use of a highly fluorinated tag was reported by Inazu and co-workers [10] following an earlier approach by Curran et al. based on the fluorous-tag method [11] which, however, was quite limited in scope. We envisaged a novel approach to oligosaccharide synthesis based on a solid-supported sequestering or sca...

N-Chloro-N-sodio-carbamates as a Practical Amidating Reagent for Scalable and Sustainable Amidation of Aldehydes under Visible Light

“…3 Traditional methods to access N-alkoxycarbonyl amides include N-acylation of carbamates, 4 alkylation or arylation of alkoxycarbonyl isocyanates, 5 and alkoxylation of carbonyl isocyanates. 6 Although these processes represent simple addition or substitution reactions, the use of activated carbonyl motifs often causes narrow reaction scopes and consequently limits their synthetic applications.…”

First synthesis of 1,2,3-triazolo-linked (1,6)-α-d-oligomannoses (triazolomannoses) by iterative Cu(i)-catalyzed alkyne–azide cycloaddition

“…The preparation of carbohydrate-based libraries displaying a substantial number of compounds with structural and stereochemical elements of diversity is a basic step in the search for biological, biochemical and biophysical probes in service to glycobiology 1 and in the identification and development of new therapeutics or vaccines against largely diffuse human diseases such as cancer, inflammation, and viral infections. 2 With the current development status of O-glycosidation methodology by solution and solidstate chemistry, 3 including sophisticated techniques to increase the reaction efficiency and simplify the product isolation and purification, 4 there is a widespread perception that synthetic glycochemistry is at the stage that permits one to embark on projects toward the construction of O-oligosaccharides and Oglycoconjugates with high structural complexity. In recent years substantial advancements have also been made in the synthesis of carbohydrate analogues where the glycosidic oxygen atom has been replaced by another atom, functional group, or heteroaromatic ring.…”

Oligosaccharide Synthesis on Solid, Soluble Polymer, and Tag Supports

“…68 The unreacted acceptor was also sequestered and recovered by Dondoni et al based on catch-and-release protocols. 69 By this method, the hydroxyls of the unreacted acceptors were reacted with the trichloroacetyl isocyanate under neutral conditions, and the resulting trichloroacetyl carbamates (urethanes) were extracted by the highly basic and nonnucleophilic polymer-supported BEMP (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine on polystyrene) by making use of strong ionic interactions. The pure acceptor was released from the resin by KOH treatment and again used for glycosylation.…”