A Reverse Strategy for synthesis of nucleosides based on n-pentenyl orthoester donors.

Strategically derivatized NPOE glycosyl donors, are able to efficiently glycosylate silylated nucleobases under mild conditions, even as low as -78 °C if necessary. Ensuring trans-1,2 glycosylation, thus permitting, unlike classical procedures, a Reverse Strategy for the synthesis of ribonucleosides, where glycosylation occurs late, rather than early, and convergency is optimized.

Ready access to a branched Man5 oligosaccharide based on regioselective glycosylations of a mannose-tetraol with n-pentenyl orthoesters.

A branched Man(5) oligosaccharide has been synthesized by sequential regioselective glycosylations on a mannose-tetraol with n-pentenyl orthoester glycosyl-donors promoted by NIS/BF(3)·Et(2)O, in CH(2)Cl(2). An extended n-pentenyl chain was incorporated into the tetraol acceptor to facilitate (a) the solubility of the starting tetraol in CH(2)Cl(2), and (b) future manipulations at the reducing end of the Man(5) oligosaccharide.

Unexpected stereocontrolled access to 1α,1'β-disaccharides from methyl 1,2-ortho esters.

Mannopyranose-derived methyl 1,2-orthoacetates (R = Me) and 1,2-orthobenzoates (R = Ph) undergo stereoselective formation of 1α,1'β-disaccharides, upon treatment with BF(3)·Et(2)O in CH(2)Cl(2), rather than the expected acid-catalyzed reaction leading to methyl glycosides by way of a rearrangement-glycosylation process of the liberated methanol.

Ready preparation of furanosyl n-pentenyl orthoesters from corresponding methyl furanosides.

The 3,5-di-O-benzoyl n-pentenyl orthoesters of the four pentofuranoses have been prepared. The first key intermediate in each case is the methyl pentofuranoside(s), and a user-friendly procedure for the preparation of each, based on the Callam-Lowary precedent, is described, whereby formation of the crucial α/β anomeric mixture is optimized. The mixture is used directly to prepare the corresponding perbenzoylated pentofuranosyl bromide(s) and then the title compounds.

Armed-disarmed effects in carbohydrate chemistry: history, synthetic and mechanistic studies.

This chapter begins with an account of the serendipitous events that led to the development of n-pentenyl glycosides (NPGs) as glycosyl donors, followed by the chance events that laid the foundation for the armed-disarmed strategy for oligosaccharide assembly. A key mechanistic issue for this strategy was that, although both armed and disarmed entities could function independently as glycosyl donors, when one was forced to compete with the other for one equivalent of a halonium ion, the disarmed partner was found to function as a glycosyl acceptor. The phenomenon was undoubtedly based on reactivity, but further insight came unexpectedly.

Reaction of 1,2-orthoesters with HF-pyridine: a method for the preparation of partly unprotected glycosyl fluorides and their use in saccharide synthesis.

Glycosyl fluorides can be prepared in an efficient manner by treatment of pyranose- or furanose-derived 1,2-orthoesters, with hydrogen fluoride pyridine (HF-py). The method is compatible with the presence of a variety of protecting groups, including tert-butyldiphenyl silyl ethers, and can be applied to sugar derivatives with free hydroxyl groups, thus avoiding the need for the protection-deprotection steps.

Efficient chemical synthesis of a dodecasaccharidyl lipomannan component of mycobacterial lipoarabinomannan.

Lipomannan (LM) is one of the domains of lipoarabinomannan (LAM) glycolipids, the latter being one of several cell surface organic molecules that fortify mycobacterial species against external attack. Some members of mycobacterial families are pathogenic, most notably Mycobacterium tuberculosis and Mycobacterium leprae, while others are nonpathogenic, and used in the clinic, such as Mycobacterium smegmatis. Additional biological significance arises from the fact that LM has been implicated in several health disorders outside of those associated with mycobacterial pathogens, notably for treatment of bladder cancer.

Regioselective strategies mediated by lanthanide triflates for efficient assembly of oligomannans.

Readily prepared mannosyl n-pentenylorthoesters (NPOEs) serve as donors in themselves and as convenient intermediates for other glycosyl donors, such as n-pentenyl glycosides (NPGs), thioglycosides, and trichloroacetimidates. These various donors are activated by different reagents, and are therefore amenable to versatile, discriminate use. Scandium and ytterbium triflates respond very differently to these donors, with the result that chemoselective discrimination between NPOEs, NPGs, trichloroacetimidates as well as ethyl and phenyl thioglycosides can be achieved.

A study of n-pentenylorthoesters having manno, gluco and galacto configurations in regioselective glycosylations.

Kochetkov's extensive investigations of glycosyl orthoester and their analogs as glycosyl donors revealed that the alkyl derivatives were plagued by competition between the departing alcohol and the incoming acceptor. n-Pentenyl orthoesters (NPOEs) obviate competition by sequestering the departing pentenyl alcohol as a 2-halomethyl tetrahydrofuran. Exquisitely regioselective glycosidations of diol acceptors can be carried out with NPOEs triggered specifically with Yb(OTf)(3)/NIS.

Relevance of the glycosyl donor to the regioselectivity of glycosidation of primary-secondary diol acceptors and application of these ideas to in situ three-component double differential glycosidation.

[reaction: see text] Three pairs of primary-secondary diol acceptors have been exposed to armed, disarmed, and n-pentenyl ortho ester glycosyl donors in glycosidation reactions. It is shown that the regioselectivity of those glycosylations is greatly influenced by the armed, disarmed, or ortho ester nature of the glycosyl donors. The selectivities observed have been used to devise efficient in situ three-component glycosylations involving two donors and one acceptor.

Iterative, orthogonal strategy for oligosaccharide synthesis based on the regioselective glycosylation of polyol acceptors with partially unprotected n-pentenyl-orthoesters: further evidence for reciprocal donor acceptor selectivity (RDAS).

An efficient iterative, orthogonal protocol based on the regioselective glycosyl coupling of D-mannose polyols with, partially unprotected, n-pentenyl orthoester donors permits the synthesis of linear and branched oligosaccharides with minimal protecting group tampering.

A strategy for ready preparation of glycolipids for multivalent presentation.

The olefinic residue of n-pentenyl glycosides serves as the trigger for regioselective construction of higher saccharides and then for elaboration in multivalent glycolipids. [reaction: see text]

The antituberculosis, antitumor, multibranched dodecafuranoarabinan of Mycobacterium species has been assembled from a single n-pentenylfuranoside source.

An n-pentenyl furanosyl-1,2-orthoester can function as a donor or be rearranged leading to an n-pentenyl furanoside acceptor which is glycosylated by its progenitor, regioselectively or doubly, thereby enabling rapid fabrication of a multibranched dodecasaccharide, known to possess a wide variety of biological interactions.

One-pot chemo-, regio-, and stereoselective double-differential glycosidation mediated by lanthanide triflates.

Nuanced activation of n-pentenyl, thioglycoside, and trichloroacetimidate donors by lanthanide salts coupled with donor/acceptor matching can simplify oligosaccharide assembly. Thus, a one-pot, double-differential glycosidation process can be designed, in which an n-pentenyl acceptor-diol is chemo- and regioselectively glycosidated by using an n-pentenyl ortho ester under the agency of Yb(OTf)(3)/NIS followed by in situ addition of a 2-O-acylated trichloroacetimidate or ethyl thioglycoside to effect stereoselective glycosidation at the remaining OH.

Preparation, properties, and applications of n-pentenyl arabinofuranosyl donors.

[reaction: see text] The development of n-pentenyl furanosyl donors has been tested using arabinose as a model. The readily prepared ortho ester (NPOE) is converted into disarmed (NPG(AC)) and thence armed (NPG(ALK)) n-pentenyl arabinofuranosides. The reactivities of these furanosyl donors and pyranosyl counterparts have been assessed by allowing pairs of both to compete for an acceptor.

Synthesis of a key Mycobacterium tuberculosis biosynthetic phosphoinositide intermediate.

Regioselective mannosylations of a myoinositol acceptor diol are readily achieved by Lewis acid mediated iodinolysis of n-pentenyl ortho-esters. The procedure affords a psuedotrisaccharide to which the phosphoglyceryl and other lipid residues are added leading to the key biosynthetic intermediate of Mycobacterium species.

Synthesis of a malaria candidate glycosylphosphatidylinositol (GPI) structure: a strategy for fully inositol acylated and phosphorylated GPIs.

A congener of the glycosylphosphatidylinositol (GPI) membrane anchor present on the cell surface of the malaria pathogen Plasmodium falciparum has been synthesized. This GPI is an example of a small number of such membrane anchors that carry a fatty acyl group at O-2 of the inositol. Although the acyl group plays crucial roles in GPI biosynthesis, it rarely persits in mature molecules.

Orthoesters versus 2-O-acyl glycosides as glycosyl donors: theorectical and experimental studies.

n-Pentenyl orthoesters (NPOEs) undergo routine acid catalyzed rearrangement into 2-O-acyl n-pentenyl glycosides (NPGs). The reactant and product can both function as glycosyl donors affording 1,2-trans linked glycosides predominantly. However, both donors differ in their rates of reactions, the yields they produce, and the nature of their byproducts, indicating that the NPOE/NPG pair may not be reacting through the same intermediates.

Synthetic approaches to heavily lipidated phosphoglyceroinositides.

[reaction: see text] Naturally occurring phosphoinositide glycoconjugates are equipped with varied acyl residues that are important for their biological activity and biosynthesis. This paper reports that acylation at O2 of the myo-inositol moiety can be achieved by stereocontrolled ortho ester rearrangement. Coupling to homo- or heterodiacylated glycerols was achieved via phosphoramidite methods, and exhaustive debenzylation by transfer hydrogenation afforded the deprotected phosphoglyceroinositides.

One pot/two donors/one diol give one differentiated trisaccharide: powerful evidence for reciprocal donor-acceptor selectivity (RDAS).

Three component, one-pot reactions involving equimolar amounts of the acceptor diol and both armed and disarmed donors presented simultaneously, produce a single double-differential glycosidation product; this phenomenon provides evidence for Reciprocal Donor Acceptor Selectivity (RDAS).

Unexpected role of O-2 "protecting" groups of glycosyl donors in mediating regioselective glycosidation.

Glycosidation of several vicinal diols reveals that exquisite regioselectivity can be achieved by using 2-O-benzoyl n-pentenyl glycoside donors and/or their cyclic 1,2-ortho ester counterparts. The regioselective preferences for both are the same, although ratios and yields may differ. In stark contrast, glycosidation of the diols with the corresponding 2-O-benzylated donors gives poor, if any, regioselectivity.

Armed/Disarmed Effects and Adamantyl Expansion of Some Caged Tricyclic Acetals en Route to Tetrodotoxin(1)(,)(2).

Transformation of the previously prepared tricyclic ketone 4 into an advanced intermediate, 2a, of the Kishi-Goto synthesis of tetrodotoxin requires, among other things, cleavage of the internal acetal. In our attempts to carry this out, we were confronted by two major obstacles, one resulting from armed/disarmed effects encountered during acid-catalyzed acetolyses. Thus ester protecting groups proximal to the acetal moiety inhibited cleavage, e.