Alpha-N-acetylmannosamine (ManNAc) synthesis via rhodium(II)-catalyzed oxidative cyclization of glucal 3-carbamates.

[reaction: see text] Glucal 3-carbamates 1 and 7 underwent oxidative cyclization with iodobenzene diacetate or iodosobenzene in the presence of Rh2(OAc)4, providing mannosamine 2-N,3-O-oxazolidinones. With iodosobenzene, incorporation of 4-penten-1-ol provided a readily separable anomeric mixture of n-pentenyl glycosides, with the anomers exhibiting pronounced differences in reactivity as glycosyl donors. N-acylation of the sugar oxazolidinones led to alpha-selective glycosyl donors for the elaboration of various 2-mannosamine frameworks. Alternatively, the anomeric n-pentenyl glycosides of N-Cbz 2-mannosamine oxazolidinones were converted separately to oxazolidinone-opened derivatives 28alpha and 28beta. These served as stereoconvergent glycosyl donors, and the alpha-linked products were readily advanced to a variety of N-acetylmannosamine (ManNAc) frameworks, using an intramolecular O-->N acetyl transfer as the final step.

Preparation of alpha-C-glycosides from glycals.

[reaction: see text]. A novel approach to simple C-glycosides is reported. Reductive ring opening of 1,2-anhydro sugars with titanocene(III) chloride produces an anomeric radical that can be trapped with a variety of agents. The reaction stereospecifically affords alpha-glycosides and produces a free C-2 hydroxyl group allowing for further elaboration.

Substituted glycals as probes of glycosidase mechanisms.

D-Glucal and a series of substituted derivatives have been tested as substrates, inhibitors and inactivators of the Agrobacterium faecalis beta-glucosidase in order to probe structure/function relationships in this enzyme. D-Glucal is shown to be a substrate (kcat = 2.3 min-1, Km = 0.85 mM) undergoing hydration with stereospecific protonation from the alpha-face to yield 2-deoxy-beta-D-glucose. 1-Methyl-D-glucal surprisingly serves as only a poor substrate (kcat = 0.056 min-1, Km = 57 mM), also undergoing protonation from the alpha-face. 2-Fluoro-D-glucal, however is completely inert, as a result of inductive destabilisation of the oxocarbenium ion-like transition state for protonation, and functions only as a relatively weak (Ki = 24 mM) inhibitor. Similar behaviour was seen with almond beta-glucosidase and yeast alpha-glucosidase and for the interaction of 2-fluoro-D-galactal with Escherichia coli beta-galactosidase. A series of of alpha, beta-unsaturated glucal derivatives was also synthesised and tested as potential substrates, inhibitors or inactivators of A. faecalis beta-glucosidase. Of these only 1-nitro-D-glucal functioned as a time dependent, irreversible inactivator (ki = 0.011 min-1, Ki = 5.5 mM), presumably acting as a Michael acceptor. Electrospray mass spectrometric analysis revealed multiple labeling of the enzyme by this inactivator, lessening its usefulness as an affinity label. Less reactive Michael acceptor glycals which might have been more specific (1-cyano-, 2-cyano-, 1-carboxylic acid, 1-carboxylic acid methyl ester) unfortunately did not function as inactivators or substrates, only as relatively weak reversible inhibitors (Ki = 3-96 mM).

Synthesis of C-glycopyranosyl compounds by a palladium-catalyzed coupling reaction of 1-tributylstannyl-D-glucals with organic halides.

1-Tributylstannyl-D-glucals, prepared from the corresponding 1-phenylsulfonyl-D-glucals, were coupled efficiently to various organic halides in the presence of a palladium(0) catalyst. This mild reaction is specially useful for the preparation of 1-C-aryl-D-glucals and compatible with unprotected hydroxy groups or hindered aromatic bromides. It has been shown that the resulting 1-C-aryl(alkyl)-D-glucals are suited for further synthetic manipulation of the enol ether group, including stereoselective hydrogenation, hydroboration-oxidation, or epoxidation. All compounds formed resulted from the attack of the alpha-face of the glucal derivatives by the reagent. The reaction, extended to 1,3-, 1,4-di-, and 1,3,5-tri-bromobenzenes, leads to the corresponding symmetrical di-(tri)-C-glucosylbenzenes. Finally, a sequential di-C-glucosylation of 1,3-dibromobenzene with two different 1-stannylated glucals was obtained.

A one-step C-linked disaccharide synthesis from carbohydrate allylsilanes and tri-O-acetyl-D-glucal.

The reaction of protected glucuronic esters 2 and 7, as well as D-glucuronolactone derivative 11, with (trimethylsilyl)methylmagnesium chloride in ether led to the corresponding stable bis-silyl adducts 3, 8, and 12, respectively. In Peterson-type reactions catalysed with mild acid, these compounds yielded carbohydrate allylsilanes 4, 9, and 13, respectively. Synthons 4 and 9 were coupled with tri-O-acetyl-D-glucal in a boron trifluoride-catalysed "carbon-Ferrier rearrangement" reaction to give C-linked disaccharides i.e., so-called "C-disaccharides" 16 and 17, respectively, in fair yields. Structural assignments of the anomeric configuration at the C-glycosylic carbon in the 2,3-unsaturated ring of these coupling products with the aid of n.m.r. spectroscopic methods unambiguously showed that alpha-D-C-linked disaccharides had been formed.