Stereoselective α-glycosylation of C(6)-hydroxyl myo-inositols via nickel catalysis-application to the synthesis of GPI anchor pseudo-oligosaccharides.

Glycosylphosphatidyl inositol (GPI) anchors play a key role in many eukaryotic biological pathways. Stereoselective synthesis of GPI anchor analogues have proven to be critical for probing the biosynthesis, structure, and biological properties of these compounds. Challenges that have emerged from these efforts include the preparation of the selectively protected myo-inositol building blocks and the stereoselective construction of glucosamine α-linked myo-inositol containing pseudodisaccharide units. Herein, we describe the effectiveness of the cationic nickel(II) catalyst, Ni(4-F-PhCN)4(OTf)2, at promoting selective formation of 1,2-cis-2-amino glycosidic bonds between the C(2)-N-substituted benzylideneamino trihaloacetimidate donors and C(6)-hydroxyl myo-inositol acceptors. This catalytic coupling process allows rapid access to pseudosaccharides of GPI anchors in good yields and with excellent levels of α-selectivity (α:ß=10:1-20:1). In stark contrast, activation of trichloroacetimidate donors containing the C(2)-N-substituted benzylidene group with TMSOTf and BF3(.)OEt2 provided the desired pseudodisaccharides as a 1:1 mixture of α- and ß-isomers.

Nickel-catalyzed stereoselective glycosylation with C(2)-N-substituted benzylidene D-glucosamine and galactosamine trichloroacetimidates for the formation of 1,2-cis-2-amino glycosides. Applications to the synthesis of heparin disaccharides, GPI anchor pseudodisaccharides, and α-GalNAc.

The 1,2-cis-2-amino glycosides are key components found within a variety of biologically important oligosaccharides and glycopeptides. Although there are remarkable advances in the synthesis of 1,2-cis-2-amino glycosides, disadvantages of the current state-of-the-art methods include limited substrate scope, low yields, long reaction times, and anomeric mixtures. We have developed a novel method for the synthesis of 1,2-cis-2-amino glycosides via nickel-catalyzed α-selective glycosylation with C(2)-N-substituted benzylidene D-glucosamine and galactosamine trichloroacetimidates. These glycosyl donors are capable of coupling to a wide variety of alcohols to provide glycoconjugates in high yields with excellent levels of α-selectivity. Additionally, only a substoichiometric amount of nickel (5-10 mol %) is required for the reaction to occur at 25 °C. The current nickel method relies on the nature of the nickel-ligand complex to control the α-selectivity. The reactive sites of the nucleophiles or the nature of the protecting groups have little effect on the α-selectivity. This methodology has also been successfully applied to both disaccharide donors and acceptors to provide the corresponding oligosaccharides in high yields and α-selectivity. The efficacy of the nickel procedure has been further applied toward the preparation of heparin disaccharides, GPI anchor pseudodisaccharides, and α-GluNAc/GalNAc. Mechanistic studies suggest that the presence of the substituted benzylidene functionality at the C(2)-amino position of glycosyl donors is crucial for the high α-selectivity observed in the coupling products. Additionally, the α-orientation of the C(1)-trichloroacetimidate group on glycosyl donors is necessary for the coupling process to occur.

Comparison of zwitterionic N-alkylaminomethanesulfonic acids to related compounds in the Good buffer series.

Several N-alkyl and N,N-dialkylaminomethanesulfonic acids were synthesized (as zwitterions and/or sodium salts) to be tested for utility as biological buffers at lower pH levels than existing Good buffer compounds (aminoalkanesulfonates with a minimum of two carbons between amine and sulfonic acid groups as originally described by Norman Good, and in common use as biological buffers). Our hypothesis was that a shorter carbon chain (one carbon) between the amino and sulfonic acid groups should lower the ammonium ion pK(a) values. The alkylaminomethanesulfonate compounds were synthesized in aqueous solution by reaction of primary or secondary amines with formaldehyde/sodium hydrogensulfite addition compound. The pK(a) values of the ammonium ions of this series of compounds (compared to existing Good buffers) was found to correlate well with the length of the carbon chain between the amino and sulfonate moeties, with a significant decrease in amine basicity in the aminomethanesulfonate compounds (pK(a) decrease of 2 units or more compared to existing Good buffers). An exception was found for the 2-hydroxypiperazine series which shows only a small pK(a) decrease, probably due to the site of protonation in this compound (as confirmed by X-ray crystal structure). X-ray crystallographic structures of two members of the series are reported. Several of these compounds have pK(a) values that would indicate potential utility for buffering at pH levels below the normal physiological range (pK(a) values in the range of 3 to 6 without aqueous solubility problems) - a range that is problematic for currently available Good buffers. Unfortunately, the alkylaminomethanesulfonates were found to degrade (with loss of their buffering ability) at pH levels below the pK(a) value and were unstable at elevated temperature (as when autoclaving) - thus limiting their utility.

Nickel-catalyzed stereoselective formation of alpha-2-deoxy-2-amino glycosides.

The development of a new method for the stereoselective synthesis of alpha-2-deoxy-2-amino glycosides is described. This methodology relies on the nature of the cationic nickel catalyst, generated in situ from L(n)NiCl(2) and AgOTf, to direct the anomeric stereoselectivity. The new glycosylation reaction is highly alpha-selective and proceeds under mild conditions with 5-10 mol % of the nickel catalyst loading at ambient temperature. This new method has been applied to both D-glucosamine and galactosamine trichloroacetimidate donors as well as an array of primary, secondary, and tertiary alcohol nucleophiles to provide the desired glycoconjugates in good yields with excellent alpha-selectivity. Mechanistic studies of the present reaction are underway and will be reported in due course.

Palladium-controlled beta-selective glycosylation in the absence of the C(2)-ester participatory group.

The development of a new glycosylation method for the stereoselective synthesis of beta-glycosides in the absence of the traditional C(2)-ester neighboring group effect is described. This process relies on the ability of the cationic palladium catalyst, Pd(PhCN)(2)(OTf)(2) generated in situ from Pd(PhCN)(2)Cl(2) and AgOTf, to direct beta-selectivity. The new glycosylation reaction is highly beta-selective and proceeds under mild conditions with 1-2 mol % of catalyst loading. This beta-glycosylation method has been applied to a number of glucose donors with benzyl, allyl, and p-methoxybenzyl groups incorporated at the C(2)-position as well as tribenzylated xylose and quinovose donors to prepare various disaccharides and trisaccharides with good to excellent beta-selectivity. Mechanistic studies suggest that the major operative pathway is likely to proceed via a seven-membered ring intermediate, wherein the cationic palladium complex coordinates to both the C(1)-imidate nitrogen and C(2)-oxygen of the trichloroacetimidate donor. Formation of this seven-membered ring intermediate directs the selectivity, leading to the formation of beta-glycosides.

Cationic palladium(II)-catalyzed stereoselective glycosylation with glycosyl trichloroacetimidates.

The development of a new method for stereoselective glycosylation with glycosyl trichloroacetimidate donors employing cationic palladium(II), Pd(CH(3)CN)(4)(BF(4))(2), is described. This process employs Pd(CH(3)CN)(4)(BF(4))(2) as an efficient activator, providing access to a variety of disaccharides and glycopeptides. This reaction is highly stereoselective and proceeds under mild conditions with low catalyst loading. Interestingly, this palladium catalysis directs beta-glucosylations in the absence of classical neighboring group participation.