Robert Jacquier

Asymmetric synthesis of cis and trans 2-methyl and 2-ethyl 1-amino cyclopropanecarboxylic acids

Abstract A new four step asymmetric synthesis of 2-methyl and 2-ethyl 1-amino cyclopropane carboxylic acids resulted from the cycloaddition of diazomethane to the corresponding chirally derivatized dehydro-aminoacid.

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.

New biocatalysts for peptide synthesis :Gels of copolymerized acrylic derivatives of α-chymotrypsin and polyoxyethylene

Abstract Copolymers of acrylated derivatives of α-chymotrypsin and polyethylene glycol (PEG*) have been prepared and used as biocatalysts for the synthesis of model peptides in organic solvent. AcTyrLeuNH 2 is quantitatively obtained even after a dozen of cycles.

Asymmetric synthesis of ketoprofen : A surprising base catalyst effect during asymmetric addition of pantolactone to methyl (3-benzoylphenyl) ketene

Abstract The best diastereoselectivity of addition of a chiral alcohol to the ketene derived from ketoprofen was obtained with R or S pantolactone (ed=99%). Depending on the tertiary amine used both for ketene formation and as catalyst during addition, the diastereoisomeric ratio of esters could be strongly modified and even inverted. Mild saponification afforded R or S ketoprofen in enantiomeric excess of up to 99%.

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.

Supramolecular asymmetric induction : A new concept applied to the supported enantioselective synthesis of α-amino acids

Abstract A polyacrylic resin with pendant chirality has been used as a chiral auxiliary. The prochiral ester enolate, reversibly linked to the polymer chain via a Schiff base, is surrounded by chiral pendants, allowing supramolecular asymmetric induction to occur. Amino acids with enantiomeric excesses up to 88–89% could be synthesized from supported glycine t-butyl ester enolate by reaction with alkyl halides. Enantioselective protonation depends on the initial configuration of the supported aminoacid. Alanine was obtained in 90% ee by repetitive asymmetric protonation.

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.