Zbigniew Pakulski

Synthesis of lupane-type saponins bearing mannosyl and 3,6-branched trimannosyl residues and their evaluation as anticancer agents

The saponins modified with mono- or trimannosyl residues can provide a convenient means of delivering drugs to certain human cells via interactions with mannose receptors. In the study reported therein, we developed a convenient approach for the synthesis of 3-O-mannoside and branched trimannoside derivatives of the saponin lupeol and of C-28 acyl esters of 3-O-acetyl-betulinic acid bearing the same mannosyl entities. Lupeol and 3-O-acetyl-betulinic acid were mannosylated with tetra-O-benzoyl- or tetra-O-acetyl-alpha-D-mannopyranosyl trichloroacetimidates. De-esterification followed by regioselective dimannosylation of the unprotected monosaccharide derivatives with 2equiv of tetra-O-benzoyl-alpha-D-mannopyranosyl trichloroacetimidate selectively yielded O-3,O-6-linked trimannosides. The cytotoxic activity of selected lupane-type saponins (derivatives of lupeol, betulinic acid, and betulin) toward normal human fibroblasts and various cancer cell lines was also compared.

Reaction of sugar thiocyanates with Grignard reagents. New synthesis of thioglycosides.

Abstract Glycosyl thiocyanates having hydroxyl groups protected with acetyl or benzoyl groups react readily at −40°C with Grignard reagents to afford the corresponding alkyl or aryl thioglycosides in good yields. Monosaccharide derivatives having the SCN grouping at other positions form under similar conditions thioethers. Axial thiocyanates do not react. Elevated temperatures induce side reactions leading to mercaptans.

The reaction of acetyliron [(η5-C5H5)Fe(CO)(PPh3)(COCH3)] with sugar aldehydes. New synthesis of deoxysugars

Abstract Aldol reactions of sugar aldehydes ( 5 – 13 ) with enolate 2 of racemic and both enantiomeric forms of acetyliron were investigated. The steric course of reactions depended strongly on the counterions used. High stereocontrol was achieved with the following cations: tin(II), diethylaluminum(I), zirconium(IV) and the triethylaluminum-containing cation. Matched pairs, particularly with the pentose- and hexose-derived aldehydes, yielded the corresponding aldol products with very high stereoselectivities. Products of aldol reactions were decomplexed with N-bromosuccinimide in methanol. From aldols 14a-d – 18a-d stereoisomeric methyl 2-deoxypentonates and 2-deoxyhexonates were obtained and their configuration was determined. Aldols obtained from acetyliron anion ( 2 ) and pentose- and hexose-derived aldehydes 8 – 13 led after decomplexation to pairs of stereoisomeric methyl 6-deoxy(7-deoxy)-hept(oct)uronates. These products were separated and their configuration was assigned on the basis of chemical transformations to free 6-deoxyheptoses. In case of D- and L-arabino aldehydes ( 9 and 10 )-because of low stability of products - the configuration was assigned by the synthesis of a model compound. A regularity was found in the 1 H NMR spectra of methyl 6-deoxy-hepturonates connecting coupling constants J α,β and J α ′, β of the methylene protons with the configuration of the β-carbon atom.

The chemical structure and genetic locus of Campylobacter jejuni CG8486 (serotype HS:4) capsular polysaccharide: the identification of 6-deoxy-D-ido-heptopyranose.

In line with our on-going efforts to create a multivalent anti-Campylobacter jejuni vaccine based on its capsule polysaccharides (CPSs), we report here the chemical structure and the genetic locus of the CPS produced by C. jejuni strain CG8486, which belongs to the serotype HS:4 CPS complex. C. jejuni CG8486 CPS was observed to be composed of approximately 17 disaccharide repeating blocks of 4-substituted N-acetyl-beta-D-glucopyranosamine and 3-substituted 6-deoxy-beta-D-ido-heptopyranose. A small number of 6-deoxy-beta-D-ido-heptopyranose units were observed to carry O-methyl phosphoramidate moieties at the O-2 or O-7 position. The gene content and organization of the CPS locus of C. jejuni CG8486 were comparable to those of C. jejuni strains NCTC 11168 and 81-176, but several CG8486 CPS genes were observed to be more divergent from those present in the CPS loci of NCTC 11168 and 81-176 CPS, which indicated that there are genetic characteristics specific to the C. jejuni HS:4 CPS complex. The efficacy of a glycoconjugate vaccine based on C. jejuni CG8486 CPS is presently being tested in an animal model, the results of which will be presented in future communications.

The classical Kagan's amides are still practical NMR chiral shift reagents: determination of enantiomeric purity of P-chirogenic phospholene oxides

Abstract Application of the (S)-(+)-N-(3,5-dinitrobenzoyl)-1-phenylethylamine 1 and (S)-(+)-N-(3,5-dinitrobenzoyl)-1-(1-naphthyl)ethylamine 2 as chiral NMR shift agents for a variety of phospholene derivatives is described. 1H and 31P NMR spectra recorded in the presence of Kagans amides 1 or 2 show well resolved signals of vinylic protons as well as 31P signals and allow effective measurement of the enantiomeric excesses. The experimental rule for determination of the absolute configuration at P is also proposed.

Synthesis, crystal structure, and conformation of methyl 6-deoxy-2,3-O-isopropylidene-α-d-manno-heptofuranoside

Abstract Methyl 6-deoxy-2,3-O-isopropylidene-α- d -manno-heptofuranoside (9) has been synthesised from the acetyliron complex 2 by a sequence of reactions involving deprotonation of 2, its reaction with aldehyde 5, decomplexation, isolation of 7, and reduction to 9. Compound 9 crystallises in the orthorhombic system, space group P212121, with cell dimensions: a = 6.097(1), b = 7.942(1), c = 26.862(3) A. The intensity data were collected with a Syntex P21 diffractometer. The structure was solved by direct methods and refined by the full-matrix, least-squares procedure, resulting in R = 0.049. The furanoside and 2,3-O-isopropylidene rings are characterised by envelop conformations 5E and E3, respectively. Relatively strong intermolecular hydrogen bonss were observed in the crystal structure.

Application of [Mo2(OAc)4] for determination of absolute configuration of pyranoid and furanoid vic-diols by circular dichroism

Abstract The in situ complexes of [Mo 2 (OAc) 4 ] with vic-diols obtained from monosaccharides gave CD spectra suitable for determination of absolute configuration in this group. Positive (negative) torsional angle in the OCCO moiety leads to a positive (negative) Cotton effect at around 300 nm. This rule was also extended to vic-diols containing an amino group in the same molecule. Protection of the amino group as a carbamate inhibits the formation of a chiral complex with the NH 2 moiety and enables determination of absolute configuration of the diol fragment.

Synthesis of S-glycosyl thiophosphates, thiophosphonates and thiophosphinates by the Michaelis-Arbuzov rearrangement of anomeric thiocyanates.

Reaction of anomeric thiocyanates with a series of O-alkyl or O-trimethylsilyl phosphite, phenylphosphonite and diphenylphosphinite derivatives afforded the corresponding S-glycosyl thiophosphates, thiophosphonates and thiophosphinates in good yields. These derivatives had been previously applied as glycosyl donors in the synthesis of benzyl glycosides and disaccharides with excellent stereoselectivity.

Diastereoselective propargylation of sugar aldehydes. New synthesis of 6-deoxyheptoses

Abstract Propargylation of pentofuranose aldehydes by treatment with propargyl bromide in the presence of zinc dust yielded homopropargylic alcohols with a good isolated yield and, in many cases, excellent anti/syn selectivity. Catalytic hydrogenation of the triple bond afforded homoallylic alcohols, valuable substrates for the synthesis of 6-deoxyheptoses. Direct ozonolysis of the triple bond yielded uronic acid esters.

Enantioselective desymmetrization of a phospholene meso-epoxide

Cinchona alkaloids serve as effective chiral bases in the enantioselective rearrangement of 3-phospholene epoxide. The reaction results in the formation of a P,C-chirogenic 3-hydroxy-2-phospholene derivative with up to 52% e.e. A stereochemical course for the epoxide rearrangement involving anti-β-proton abstraction is implied.