1-Oxabicyclic beta-lactams as new inhibitors of elongating MPT--a key enzyme responsible for assembly of cell-surface phosphoglycans of Leishmania parasite

New iminosugars (1-oxabicyclic beta-lactam disaccharides) have been synthesized as inhibitors of elongating alpha-D-mannosyl phosphate transferase (eMPT), a key enzyme involved in the iterative biosynthesis of cell-surface phosphoglycans of the Leishmania parasite. The design is based on a transition-state model for this remarkable enzyme that transfers intact alpha-D-mannosyl-phosphate from GDP-Man. Since these phosphoglycans are unique to Leishmania and are essential for its infectivity and survival, their biosynthetic pathway has emerged as a novel target for anti-leishmanial drug and vaccine design.     

Iterative synthesis of Leishmania phosphoglycans by solution,solid-phase,and polycondensation approaches without involving any glycosylation

A general strategy (solution, solid-phase, and polycondensation) for the synthesis of antigenic phosphoglycans (PG) of the protozoan parasite Leishmania is presented. Phosphoglycans constitute the variable structural and functional domain of major cell-surface lipophosphoglycan (LPG) and secreted proteophosphoglycan (PPG), the molecules involved in infectivity and survival of the Leishmania parasite inside human macrophages. We have shown that the chemically labile, anomerically phosphodiester-linked phosphoglycan repeats can be assembled in an iterative and efficient manner from a single key intermediate, without involving any glycosylation steps. Furthermore, the phosphoglycan chain can be extended toward either the nonreducing (6'-OH) or the reducing (1-OH) end. We also describe a new and efficient solid-phase methodology to construct phosphoglycans based on design and application of a novel cis-allylphosphoryl solid-phase linker that enabled the selective cleavage of the first anomeric-phosphodiester linkage without affecting any of the other internal anomeric-phosphodiester groups of the growing PG chain on the solid support. The strategy to construct larger phosphoglycans in a one-pot synthesis by polycondensation of a single key intermediate is also described, enabling CD spectrometric measurements to show the helical nature of phosphoglycans. Our versatile synthetic approach provides easy access to Leishmania phosphoglycans and the opportunity to address key immunological, biochemical, and biophysical questions pertaining to the phosphoglycan family (LPG and PPG) unique to the parasite.     

Efficient synthesis of 3, 6-dideoxy-beta-D-arabino-hexopyranosyl-terminated LacdiNac glycan chains of the Trichinella spiralis parasite

The synthesis of a linear trisaccharide epitope of the Trichinella spiralis N-linked glycan, in a form amenable to glycoconjugate formation, is reported. The trisaccharide contains the synthetically challenging LacdiNAc [beta-GalpNAc(1-->4)-beta-GlcpNAc] element, as well as a terminal 3,6-dideoxy-beta-D-arabino-hexopyranose (tyvelose) residue. An orthogonal protection strategy is described, which permits the protection and manipulation of three amino groups present in the disaccharide beta-GalNAc(1-->4)-beta-GlcNAc and the tether used to prepare neoglycoconjugates. The beta-linked dideoxyhexose was generated in excellent yield by the introduction of the dideoxyhexose unit as a beta-D-ribo-hexopyranoside (paratose) followed by an oxidation-reduction sequence to generate the beta-D-arabino configuration in high diastereomeric excess. The required dideoxyhexose donor was synthesized in a series of high-yielding steps from glucose utilizing the p-methoxyphenyl glycoside.     

Synthetic fragments of antigenic lipophosphoglycans from Leishmania major and Leishmania mexicana and their use for characterisation of the Leishmania elongating alpha-D-mannopyranosylphosphate transferase

The phosphorylated branched heptasaccharides 7 and 8, the octasaccharide 9 and the phosphorylated trisaccharides 5 and 6, which are fragments of the phosphoglycan portion of the surface lipophosphoglycans from Leishmania mexicana (5) or L. major (6-9), were synthesised by using the glycosyl hydrogenphosphonate method for the preparation of phosphodiester bridges. The compounds were tested as acceptor substrates/putative inhibitors for the Leishmania elongating alpha-D-mannosylphosphate transferase.     

Efficient synthesis of scutellarein

Scutellarein is a component of Scutellaria, recently known as a potent cytotoxic agent on human leukaemia cells. The aim of this study was the synthesis of scutellarein and its methylated derivative. The new features are the innovating method to afford flavones from flavanones and the A-ring regioselective bromination step that lead to the target molecule by a facile and high-yielding pathway.     

Efficient synthesis of carbohydrate thionolactones

Carbohydrate thionolactones may be efficiently synthesized from the corresponding 1-thio sugars via a two-step procedure involving formation of a glycosyl phenylthiosulfinate by treatment with either phenylsulfinyl chloride or 1-(phenylsulfinyl)piperidine (BSP), and subsequent thermal elimination in toluene.     

Efficient synthesis of 2'-C-beta-methylguanosine

2'-beta-Methyl nucleosides have potential value as therapeutic agents and as nucleoside analogues for exploring RNA biology. Here we develop a strategy for efficient synthesis for 2'-C-beta-methylguanosine (3). Starting from 1,2,3,5-tetra-O-benzoyl-2-C-beta-methyl-d-ribofuranose (1) and N2-acetylguanine, we obtained the title compound in two steps (78% overall yield) with high stereoselectivity (beta/alpha > 99:1) and high regioselectivity (N9/N7 > 99:1). Extension of this strategy to the classic synthesis of guanosine also resulted in high stereoselectivity (beta/alpha = 99:1) and improved regioselectivity (N9/N7 = 97:3).     

Efficient synthesis of unsymmetrical disulfides

A novel way of synthesizing unsymmetrical disulfides from thiols with DDQ is presented here. This procedure ran in a straightforward manner to give high product yields. Unsymmetrical disulfides were directly synthesized from the corresponding mixture of thiols in equimolar amounts under mild conditions.     

Efficient synthesis of thiazoloquinazolinone derivatives

An original route to the rare 8H-thiazolo[5,4-f]quinazolin-9-one 1 and the novel 7H-thiazolo[4,5-h]quinazolin-6-one 2 is described. Access to the regioisomers was realized by fusion of a thiazole and a quinazoline ring via Appel's salt chemistry. Thermal reactions were carried out using a focused microwave reactor, reducing the overall time of the multi-step synthesis.     

Efficient synthesis of ningalin C

[reaction: see text] A concise and efficient synthesis of the permethyl derivative of the marine alkaloid ningalin C (2) has been accomplished. The key step involves the formation of a pyrrolinone from an aminoquinone in one pot. An efficient route for the synthesis of the key aminoquinone has also been developed.     

Efficient synthesis of alkyl beta-diketimines

A general synthesis for the preparation of alkyl N,N'-beta-diketimines has been developed. The method reported here demonstrates the use of dimethyl sulfate for conversion of enaminoketones to beta-diketimines. The reaction can be performed without solvent, providing good yields.     

Efficient solid-phase synthesis of sulfahydantoins

A novel solid-phase strategy allows the efficient preparation of "traceless" sulfahydantoins. A total of 28 derivatives, with crude purity generally higher than 85%, were prepared by parallel synthesis. Through reductive alkylations, Mitsunobu reactions, and sulfamoylation reactions on oxime resin, the synthetic strategy affords sulfahydantoin derivatives selectively substituted at N(2), N(5) and N(2), N(5) positions, although yields of disubstituted compounds are lower. The mild reaction conditions involved lead to sulfahydantoins without racemization.     

Efficient synthesis of substituted dihydrotetraazapentacenes

We describe a versatile and very efficient synthesis of previously unknown substituted 5,14-dihydro-5,7,12,14-tetraazapentacenes (DHTAPs). A structural study by NMR spectroscopy showed that the conjugated pi-system of the pentacyclic skeleton rearranges depending on the electronic effect of the substituent(s).     

Efficient synthesis of spiroisoxazoline oxindoles

The synthesis of spiroisoxazoline oxindoles containing ester groups at position 4′ and aromatic or ester groups at position 3′ of the isoxazoline ring is reported. The compounds were synthesized in yields up to 94% by 1,3-dipolar cycloaddition of 3-methylene indolin-2-ones and chlorooximes in the presence of triethylamine or zinc.     

Efficient BOP-mediated synthesis of fulgimides

A mild and efficient method for the synthesis of fulgimides is presented in which the peptide coupling reagent BOP is employed for dehydratation of fulgenic acid monoamides (succinamic acids). The disclosed method proved to be superior to those described in the literature.     

Efficient synthesis of naphthodiazacrown ethers

A benign and efficient synthesis of naphthodiazacrown ethers has been described. Reaction of simple dialdehyde precursor with α,ω-diamines followed by sodium borohydride reduction leads to 16-27 membered naphthodiazacrown ethers in 80-90% yields.     

Efficient synthesis of cyclopropylhydrazine salts

An efficient procedure for the synthesis of cyclopropylhydrazine in the form of its salts is reported. The copper salt-catalyzed addition of cyclopropylboronic acid to the azo group of di-tert-butyl azodicarboxylate and subsequent deprotection gave the cyclopropylhydrazine salts in high yields.     

A facile and novel route to the antigenic branched phosphoglycan of the protozoan Leishmania major parasite

A novel approach for the iterative synthesis of the antigenic branched phosphoglycan of the protozoan parasite Leishmania major is presented that exploits remarkable dual selectivity in the functionalization of d-lactal, providing flexibility to extend the PG chain either towards the reducing or nonreducing end.     

Efficient chromatography-free synthesis of the oxy-analogue of fingolimod

Fingolimod (FTY720) and its analogue derivatives are not only promising therapeutics in sphingolipid signaling but also valuable tools for understanding the roles of sphingolipids in (patho)physiological conditions. A practical method for the synthesis of the ether analogue of FTY720 is described. Our final synthetic approach allows high yield and efficient synthesis of O-FTY in only four steps without chromatographic purifications.     

Efficient solid-phase-based total synthesis of the bisintercalator TANDEM

[reaction: see text] In this article, the first solid-phase-based total synthesis of TANDEM, a synthetic analogue of triostin A, is described. In initial studies, the synthesis incorporated depsipeptide formation, introduction of chromophores, and disulfide bond formation on the solid phase, prior to a final solution-phase macrolactamization, to give the target molecule. Although pure TANDEM was obtained in an overall yield comparable to those for all syntheses to date, the yield of the final cyclization was low (11%). A more efficient approach involved removal from the solid phase prior to disulfide bond formation. The resulting linear peptide underwent macrolactamization under mild conditions and high dilution. Final disulfide bond formation was essentially quantitative and gave the target molecule, TANDEM, in an overall yield of 18%. The final compound was assessed for its ability to bind to 5'-TpA sequences on DNA by DNase I footprinting. This efficient synthesis sets the stage for a study of the structure-activity relationship of TANDEM and the natural product triostin A, with analogues containing "point mutations" at every site within the cyclic compounds.