Methods for site-selective transformations of hydroxyl groups in carbohydrate derivatives are reviewed. The construction of oligosaccharides of defined connectivity hinges on such transformations, which are also needed for the preparation of modified or non-natural sugar derivatives, the installation of naturally occurring postglycosylation modifications, the selective labeling or conjugation of carbohydrate derivatives, and the preparation of therapeutic agents or research tools for glycobiology. The review begins with a discussion of intrinsic factors and processes that can influence selectivity in reactions of unprotected or partially protected carbohydrate derivatives, followed by a description of transformations that engage two OH groups in cyclic adducts (acetals, ketals, boronic esters, and related species). An overview of the various classes of site-selective transformations of OH groups in sugars is then provided: the reactions discussed include esterification, thiocarbonylation, alkylation, glycosylation, arylation, silylation, phosphorylation, sulfonylation, sulfation, and oxidation. Emphasis is placed on recently developed methods that employ reagent or catalyst control to achieve otherwise challenging transformations or site-selectivities.

Site-Selective Functionalization of Hydroxyl Groups in Carbohydrate Derivatives.

A highly convergent total synthesis of the anthelmintic macrolide avermectin B1a 1 is described. The key features of this synthesis include the introduction of the C(11)–C(15) portion by selective ring opening of a symmetrical 1,4-bis-epoxide 4 followed by reaction with the anion derived from the 3-methyl-2-(1-methylpropyl)-6-phenylsulphonylpyran 3 to afford the ‘northern’ C(11)–C(25) fragment 39. Coupling of the derived C(11)–C(25) aldehyde unit 42 with a C(1)–C(10)‘southern’ fragment 2 was achieved via a novel deconjugative vinyl sulphone anion sequence. Macrolactonisation and subsequent introduction of the 3,4-double bond gave the aglycone portion 51. The oleandrosyloleandrose disaccharide was introduced by a novel silver-mediated coupling between the 5-acetylated aglycone 70 and the thiocarbonylimidazolide 69. Final deacetylation was accomplished using Super-Hydride to give the natural product 1.

Total synthesis of the anthelmintic macrolide avermectin B1a

A highly convergent total synthesis of the spiroacetal macrolide (+)-milbemycinβ1

Avermectins and milbemycins Part I

Gangliosides are cell-surface sialic acid containing glycolipids. They are found in high concentration on the surface of central nervous system cells. Gangliosides are believed to play a role in important biological events such as cell growth regulation, cell-cell adhesion, and malignancy.1-3 GM4 (1, Scheme 1) is structurally the simplest ganglioside and has been isolated as a minor component from brain, rat kidney, mouse erythrocytes, and chicken egg yolk.4-6 GM4 is an important cell adhesion molecule in cell growth and tissue regeneration and promotes neuron adhesion through its interaction with myelin-associated glycoprotein.7 GM3 (2, Scheme 1) was first isolated from equine erythrocytes8 and is known to modulate the epidermal growth factor (EGF) and the platelet-derived growth factor (PDGF) receptors.9,10 Tumors, such as those involved in brain cancer, overexpress EGF receptor. GM4 and GM3 are also found in high concentration in tumor cells.11 N-Acetylneuraminic acid is often found at the nonreducing end of the oligosaccharide component of these gangliosides. N-Acetylneuraminic acid is involved in a number of important biological events, including intracellular interactions such as adhesion, aggregation and agglutination; masking antigenic oligosaccharides and suppression of undesired immune reactions; influence on the cell membrane permeability for ions, amino acids, and proteins; and protection of glycoproteins against proteolysis.12-15 Terminal N-acetylneuraminic acid is an attachment site of pathogens to the cells, and often, the removal of this carbohydrate initiates catabolic and inflammatory processes.16,17 In vivo, sialic acid containing glycoconjugates are catabolized by the removal of the terminal sialic acid residue through the action of hydrolase-type enzymes called neuraminidases that cleave the glycosidic bond of N-acetylneuraminic acid.18 The design of nonhydrolyzable analogues of N-acetylneuraminic acid glycosides is an attractive approach to control, at the molecular level, events of crucial importance to glycobiology and immunology. Thus, the replacement of the interglycosidic oxygen atom by a hydroxymethylene group generates a new class of hydrolytically and metabolically inert “C”glycosides. We are interested in the synthesis of the C-glycoside analogues of GM4 and GM3 (3 and 4, Scheme 1) because such glycoconjugates are expected to be resistant to catabolism and to have increased biological half-lives, leading to derivatives with significant therapeutic potential. For example, the C-glycoside of GM4 is expected to demonstrate stable cell adhesion over a prolonged period of time,7 while the C-analogue of GM3 (4, Scheme 1) is expected to inhibit EGF receptor mediated signal transduction.9 Both analogues 3 and 4 are also potential candidates as cancer vaccines. Recently, our laboratory developed a method for the synthesis of C-glycosides of N-acetyneuraminic acid using samarium iodide.19 We now report the use of this method for the synthesis of a common C-glycoside precursor of GM4 and GM3 (22(S), (Scheme 3), this precursor being also versatile for the synthesis of C-glycoside analogues of other related gangliosides such as GM2 or GM1. This C-glycoside precursor was obtained through samarium(II) iodide coupling of the 3-formyl derivative 15 (Scheme 2) with the N-acetyneuraminic acid phenyl sulfone derivative 17 (Scheme 3).

Synthesis of a versatile neuraminic acid c -disaccharide precursor for the synthesis of c-glycoside analogues of gangliosides

Avermectin chemistry: problems of conjugation, deconjugation, and epimerization

Stereoselectivity in the Hydroboration of C4-C-Methylene Groups

A ready route to a functionalized anhydro derivative of 1,6-anhydro-β-D-glucopyranose (levoglucosan)

Avermectin Chemistry: Problems of Conjugation, Deconjugation, and Epimerization.

Conditions for the hydroxylation of an exocyclic methylene group at C4 of a pyranoside ring via hydroboration have been examined with a view to determining the optimum procedure for obtaining the axially-oriented C4-CH2OH group. The regio- and stereochemical outcome of the reactions rely not only on the hydroborating reagent used, but, to a surprising degree, on the nature of the protecting group at the “remote” C6-OH. Silyl ethers are preferred because the only by-product formed is the tertiary alcohol, which can be recycled through dehydration to the starting alkene by treatment with thionyl chloride.

R. Faghih

Papers

Avermectin chemistry: problems of conjugation, deconjugation, and epimerization

Stereoselectivity in the Hydroboration of C4-C-Methylene Groups

A ready route to a functionalized anhydro derivative of 1,6-anhydro-β-D-glucopyranose (levoglucosan)

Avermectin Chemistry: Problems of Conjugation, Deconjugation, and Epimerization.

Stereoselectivity in the Hydroboration of C4-C-Methylene Groups.