Jean Verducci

NEW SYNTHESIS OF THE CYCLIC TETRAPEPTIDE TENTOXIN EMPLOYING AN AZLACTONE AS KEY INTERMEDIATE

Abstract An improved preparation of the cyclic tetrapeptide Tentoxin is reported employing an azlactone as key intermediate. This new synthetic route offers the advantage over existing methodologies that the dehydro amino acid would easily be varied, thus allowing the simple preparation of analogues.

How to perform small peptide cyclizations

Abstract Small cyclopeptides of four to six residues are very interesting for their biological properties. Unfortunately, the synthesis of the linear precursor is generally fastidious and the cyclization often occurs in low yields. Molecular modeling used through the genmol program is a powerful tool for predicting the best precursor, as was shown in a previous paper about five tetrapeptides. However, sometimes all the linear precursors of a cyclopeptide can be unfavorable for cyclization when no structural feature (N-Me amino acid. Pro, D-amino acid) is present in the peptide. This led us to develop a method using a reversible chemical modification of the peptide main chain in order to favor the cisoid conformation able to cyclize easily. Tetraphenylalanine was used as a model, with the tert-butyloxycarbonyl (Boc) group as substituent on the main-chain nitrogen atoms. The cyclization yield increases from less than 1 % to 27% after this chemical modification and cleavage of the Boc groups. Molecular modeling on such molecules shows that this yield increase is due to a preferred conformation having the terminal functions close together induced by the Boc substituents.

A first approach to asymmetric protonation via a polymer supported chiral proton donor

Abstract Asymmetric protonation of achiral silyl enol ethers employing chiral proton donors is described for the first time. We have obtained modest enantiomeric excesses by carrying out these reactions in homogeneous solution. The subject of this paper is to report in a preliminary fashion the substantially improved asymmetric induction that can be achieved by supporting the proton donor on a polymeric resin (up to 94% ee). A temperature effect is observed and discussed.

Natural cyclopeptides as leads for novel pesticides: tentoxin and destruxin†

Difficulties in synthesis make natural cyclopeptides challenging targets for chemists. Our interest focused on two natural toxic cyclopeptide series produced by pathogenic fungi: tentoxin, [cyclo-(N-MeAla 1 -Leu 2 -N-MeΔ z Phe 3 -Gly 4 )] and the destruxins [cyclo-(Pro 1 -Ile 2 -N-MeVal 3 -N-MeAla 4 -β-Ala 5 -HA 6 )]. The total syntheses of these two bioactive series were optimised, and several analogues were designed and synthesised to establish structure-activity relationships. The importance of synthetic analogues in the identification of molecular targets and the explanation of mechanisms of action was demonstrated. Such systematic investigations can determine the crucial features responsible for the activity of the natural compound and help the design of more powerful or more selective products.

Deracemization of silyl enol ethers

Abstract The deracemization by enantioselective protonation of silyl enol ethers was tested using 2,2-dimethyl 5-phenyl 1,3-dioxolan 4-one 1 . The results obtained, especially with pantolactone as a chiral proton donor, are better than when the deracemization is carried out with the lithium enolate of 1 .

N-bis-silylation of α-amino acids: “benzostabases” as amino protecting group

Abstract N-Bis-trimethylsilylation of α-amino acids using the powerful trimethylsilyl triflate reagent is difficult, and is rendered impossible in the case of bulky side-chains (valine). However, favorable entropy changes resulting from a cyclization reaction allow the formation of “benzostabase” N-diprotections regardless of the side-chain bulk.

Anomeric effects in non-carbohydrate compounds: conformational differences between the oxazolidine rings of a cis-fused bicyclic system

Tris(hydroxymethyl)aminomethane (Tris) can react with benzaldehyde (1:2 molar ratio) to produce cis-2,8-diphenyl-5-hydroxymethyl-1-aza-3,7-dioxabicyclo[3.3.0]octa ne, the structure of which has been confirmed by nuclear magnetic resonance spectroscopy and X-ray crystallography. The crystal structure showed that both oxazolidine rings A and B are puckered in opposite directions. Ring A exists in an E3 envelope form with 0-3 noticeably down (0.65 A) the plane of the remaining atoms, whereas ring B adopts the 7E envelope conformation with the 0-7 atom displaced up from the mean reference plane by 0.70 A. Comparison of bond angles and bond distances showed that both oxazolidine rings A and B exhibit cross endo-anomeric effects resulting from electron delocalization over the bond sequence O-3-C-2-N-1-C-8-O-7.

DESTRUXIN ANALOGUES : DEPSI PEPTIDIC BOND REPLACEMENT BY AMIDE BOND

Abstract In order to determine the importance of the depsi bond present in natural destruxins, we have investigated the replacement of this ester bond by an amide bond, leading to a new family of analogues. Synthesis of six specific members of this new class of compounds is reported. Since none of these cyclopeptides showed any biological activity, we undoubtedly proved that the depside group is a requisite for insecticide effect.

Determination of the enantiomeric excess of α-hydroxy acids

Abstract This work describes a convenient and accurate method for optical purity determination of α-hydroxy acids. Their derivatization with commercially available valine methyl ester affords diastereoisomers easily separable by HPLC using achiral C 18 columns.

Synthesis of a [14C]-labelled photoactivatable cyclic tetrapeptide: [carbonyl-14C]-4-benzoylbenzoyl MeSer1-tentoxin

The synthesis of a new photochemical probe for labelling tentoxin 1 binding sites in the soluble part of chloroplast F0F1 ATPsynthase is described. [Carbonyl-14C]-4-benzoylbenzoyl MeSer1-tentoxin 6 was synthesised by coupling MeSer1-tentoxin 2 with [carbonyl-14C]-4-benzoylbenzoic acid 3, itself obtained by coupling [1-14C]-benzoyl chloride with the dilithio derivative of 4-bromobenzoic acid (9 ). Photolysis of the probe in methanolic solution occurs readily upon irradiation with UV light at 366 nm. Copyright