At a moment′s notice: Thermal equilibration of 1 and mass spectral analysis of sialyl phosphates suggest that the 4O,5N‐oxazolidinone and the 4,5‐O‐carbonate systems influence the anomeric effect and the mechanisms of sialidation by virtue of their dipole moment in the mean plane of the pyranose ring. The electron‐withdrawing effect destabilizes 2 and promotes associative glycosylation mechanisms. TEMPO=2,2,6,6‐tetramethylpiperidine N‐oxide.
Nitrosation of peracetylated NeuAc glycosides followed by treatment with sodium trifluoroethoxide and then a suitable nucleophile enables late stage modification of sialic acid glycosides with stereospecific replacement of the acetamido functionality. Keywords sialic acids; deamination; diversification; glycosylationThe sialic acids are nine carbon sugars based on the 2-keto-3-deoxy-D-glycero-Dgalactononulosonic acids whose α-glycosides adorn the non-reducing termini of many Nglycoproteins and gangliosides and are the monomeric units of the α-(2→8)-and α-(2→9)-oligosialic acids. [1] The recognition of these sialyl glycoconjugates by various lectins, and the trimming of sialyl residues by sialidase enzymes, play important roles in many human disease states and have stimulated interest in the synthesis of libraries of modified sialyl glycoconjugates and their deployment in the search for improved diagnostics and therapeutics. [1][2] The difficulties inherent in sialic acid chemistry and particularly in the stereocontrolled synthesis of α-sialosides [3] have, however, restricted the preparation of such libraries to enzymatic approaches which are limited by the range of substrates accepted. [4] We describe here a method for the chemical synthesis of sialyl glycoside libraries that combines recent progress in stereocontrolled α-sialoside synthesis [5] with a mild oxidative deamination process to enable late-stage modification of pre-assembled glycosides, thereby extending the range of accessible diversity.Focused libraries of specific classes of oligosaccharides and/or glycoconjugates are arguably best accessed by the late stage modification of pre-assembled substances combining synthetic efficiency with the ability to introduce targeted diversity with the minimum of synthetic effort. This strategy, which differs from the current enzymatic cascade approach to [5] thereby opening the door to the modification of sialyl glycosides as a means of entry into libraries, provided suitably mild chemistry for subsequent modification can be identified. We reasoned that the modified Schreiner and Zbiral oxidative deamination of neuraminic acid glycosides would be a suitable reaction for such modifications if conditions could be found to extend the range of nucleophiles beyond the acetic and and hydrazoic acid-based systems previously employed (Scheme 1, line 2). [6] Oxidative deamination of peractyl N-acetylneuraminic acid (NeuAc) methyl ester was achieved by Schreiner and Zbiral with nitrosyl acetate giving the N-nitroso adduct, [6a] whereas in our laboratory we prefer the more convenient, commercial nitrosyl tetrafluoroborate for this purpose.[6b] Subsequent steps involve selective removal of the acetyl group from the N-nitrosoacetamide with sodium trifluoroethoxide to give a diazo derivative of NeuAc that is then substituted by the incoming nucleophile. Participation by the 4-O-acetate is invoked to explain both the regio-and stereoselectivity of the process. [6a] As nitrosyl tetrafluoroborate is known t...
Polarisierende Wirkung: Die thermische Gleichgewichtseinstellung für 1 und eine massenspektrometrische Analyse von Sialylphosphaten sprechen dafür, dass das 4O,5N‐Oxazolidinon‐ und das 4,5‐O‐Carbonat‐System den anomeren Effekt und den Sialidierungsmechanismus durch ihr Dipolmoment in der Ebene des Pyranoserings beeinflussen. Die elektronenziehende Wirkung destabilisiert 2 und begünstigt assoziative Glycosylierungsmechanismen. TEMPO=2,2,6,6‐Tetramethylpiperidin‐N‐oxid.
Chiral fluorocyclopropyl carbinols were synthesized in high diastereoselectivities via a zinc mediated cyclopropanation reaction, using sec-allylic alcohols as simple building blocks. An enantioselective version of this transformation was achieved through in situ formation of chiral allylic zinc sec-alkoxides from the requisite aldehydes using Walsh's protocol.
A 1-adamantyl thioglycoside derivative of KDN, derived from N-acetylneuraminic acid, carrying a 3,4-O-carbonate protecting group is a highy efficient and α-selective KDN donor on activation with NIS and TfOH in dichloromethane and acetonitrile at −78 °C. Glycosylations conducted with this protecting group do not suffer from competing glycal formation. Seven examples are given, including the use of galactose 3-and 6-hydroxy groups. KeywordsGlycosylation; Sialic Acid; Carbonate; Thioglycoside; Stereoselectivity 2-Keto-deoxy-D-glycero-D-galacto-nonulosonic acid (KDN) is a member of the sialic acid family of carbohydrates that are commonly found at the non-reducing terminus of cell surface glycans and in the form of homopolymers.[1] KDN and its glycosides have been long known in marine organisms and have more recently been detected in humans thanks to improved analytical techniques opening the way to potential applications as markers of disease states.[2] The minute quantities of these materials available by isolation, and their microheterogeneous nature, points to a strong need for efficient, versatile methods for the synthesis of homogeneous substances by enzymatic [3] Cleavage of the acetonide with HCl in THF followed by peracetylation then gave the desired donors 6 (Scheme 1).With two anomeric donors in hand we proceeded to examine their coupling reactions with a variety of acceptor alcohols, with activation by N-iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH) in a mixture of acetonitrile and dichloromethane at −78 °C leading to the results depicted in Table 1.The results laid out in Table 1, entries 1-7 show uniformly high yield and excellent α-selectivity for reactions conducted with activation by the NIS/TfOH combination in a 2:1 dichloromethane acetonitrile mixture.[12] Comparison of entries 1 and 2 of Table 1 reveals that neither the efficiency nor the anomeric selectivity is dependent on the configuration of the donor and consequently all subsequent work was conducted with the more abundant β-isomer. Table 1, entry 3 illustrates the successful application of this chemistry to a tertiary alcohol, while entries 4 and 5 demonstrate applicability to the important galactopyranose 6-OH in the presence of two different protecting group arrays. Table 1 appeared to be devoid of the usual type of byproduct in sialidation chemistry; namely the elimination product. The synthesis of an authentic sample of this glycal (Scheme 2, 19), by elimination of the glycosyl sulfoxide, enabled to confirm this observation. Indeed, inspection of the crude reaction mixtures of the examples from the experiments presented in Table 1 reveals the major byproduct to be the hemiacetal resulting from hydrolysis of the donor.To probe the influence of the cyclic carbonate protecting group on the glycosylation reactions a smaller series of coupling reactions was also conducted with the peracetylated donors 3 as set out in Table 2. With primary acceptors these couplings gave good albeit reduced α-selectivities, but suf...
Unrivaled: A 1‐adamantyl thioglycoside derivative of the nonulosonic acid KDN, carrying a 4,5‐O‐carbonate protecting group, is a highly efficient and α‐selective KDN donor when activated using N‐iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH). Glycosylations conducted with this protecting group do not suffer from competing glycal formation.
Nitrosation of peracetylated NeuAc glycosides followed by treatment with sodium trifluoroethoxide and then a suitable nucleophile enables late stage modification of sialic acid glycosides with stereospecific replacement of the acetamido functionality.
Reaction of propargylmagnesium bromide with 2,3;5,6-di-O-isopropylidene-D-mannonolactone followed by highly stereoselective reduction of the so-formed lactol with sodium borohydride gives a syn-diol from which practical syntheses of 2-keto-3-deoxy-D-glycero-D-galactononulosonic acid (KDN) and various partially protected derivatives have been achieved all of which feature the oxidative unmasking of the α-keto acid moiety from the alkyne.
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