Joël Poncet

Formation of oxazolines and thiazolines in peptides by the mitsunobu reaction

Abstract The Mitsunobu reaction was efficiently used to introduce oxazolines and thiazolines in the peptide backbone. The reaction proceeded from β-hydroxy α-amino acid-containing peptides at room temperature in 58-72% isolated yields.

Synthése de la dolastatine 10 et de la [R-doe]-dolastatine 10

Abstract A stepwise synthesis of dolastatin 10 starting from the dolaphenine residue is described. The chiral dola isoleuine and dolaproine residues were obtained by 5-step procedures from the corresponding N -Boc amino acid. The key steps are respectively the NaBH 4 reduction of an allylic ketone and the addition of an achiral Z-crotylboronate on the N -Boc- L -prolinal. Peptidic couplings were efficiently realised with reagents developed in the laboratory.

Stereocontrolled synthesis of N,O-dimethyl-γ-amino-β-hydroxy acids : analogues of the (R)-MeIle-ψ(CHOMe)-Gly residue of the cytotoxic marine pseudopeptide dolastatin 10

Abstract The stereocontrolled synthesis of the N,O-dimethylated-γ-amino-β-hydroxy acid (R)-MeVal-ψ(CHOMe)-Gly ( 3b ) is reported; the key step is the formation of the nonmethylated allylic precursor with the anti configuration 20 by reduction of the keto analogue 16 .

N-methyl N-carboxyanhydride : an unexpected by-product when coupling boc-N-methyl amino acids

Abstract Activation of Boc-amino acids and Boc-N-methyl amino acids leads to the corresponding NCA. This side reaction explains the low yields obtained when coupling N-methyl amino acids. It was not observed with the Z-or Fmoc-protective groups.

Total synthesis of the proposed structure of Dolastatin 15

Abstract Efficient synthesis of dolastatin 15 (1) was accomplished following a convergent strategy. The pyrrolidinone cycle of 5 was obtained by thermic cyclization of the corresponding Meldrums adduct 4. The methylation of the enol function was performed under Mitsunobu conditions. On the other hand, the peptide part 10 was elongated by using PyCloP as coupling reagent. The ester linkage between both segments was efficiently performed under conditions we previously described by using a mixed anhydride activation with isopropenyl chlorocarbonate. Final compound 12 was found to exhibit physical properties slightly different from those recently reported by Pettit and co-workers for the natural dolastatin 15 and their synthesis product.

Isopropenyl chlorocarbonate (IPCC)1 in amino acid and peptide chemistry: Esterification of N-protected amino acids; Application to the synthesis of the depsipeptide valinomycin☆

Abstract Esterification of N-protected α-amino acids was achieved via isopropenyl chlorocarbonate (IPCC) activation. In situ alcoholysis of the unstable mixed anhydride intermediate was catalyzed by 4-(dimethylamino)pyridine (DMAP). Competing isopropenyl ester formation was negligible when using methylene chloride as the solvent. A variety of esters from primary and secondary alcohols were obtained with good yields (60 to 96 %), and even the more hindered tertiobutyl alcohol gave acceptable yields under more drastic conditions. The improvement in depsipeptide synthetic methodology is illustrated by preparation of the antibiotic valinomycin, using IPCC for ester bond formation, and BOP reagent for peptidic coupling and the last-step cyclization.

Didemnin B : comparative study and conpormational approach in solution

Abstract A comparative study of isodideimnine-1 and didemnin B is presented using spcctroecopic methods, partial degradation and partial synthesis. This leads to the conclusion of the presence of a single depsipeptide, namely didemnin B, with (3S,4R,5S) isostatine instead of the previous statine residue. An attempt to determine the whole conformation in solution of didemnin B by using 2D-NMR is also described.

Conformational study of dolastatin 10

Abstract The potent antineoplasic pseudopeptide dolastatin 10 isolated from the sea hare Dolabella auricularia was examined by a combination of one and two dimensional NMR techniques (DQF-COSY, HOHAHA, ROESY, HMQC, and HMBC) followed by restrained molecular-dynamics (MD) simulations to elucidate its conformation in solution (DMSO). The study showed that dolastatin 10 exists in two different conformations corresponding to a cistrans isomerisation of the Dil-Dap amide bond.

TRH-induced antinociception: Interaction with the opioid systems?

Mice were chronically treated with morphine or ethylketocyclazocine in order to induce a marked tolerance to their antinociceptive effect in the phenyl-p-benzoquinone writhing test. TRH (2 mg kg-1 i.p.) significantly reduced the number of writhes in non-tolerant mice, but did not alter the response of morphine- or ethylketocyclazocine-tolerant mice. TRH did not modify the binding of [3H]naloxone in mouse brain either in vitro (TRH: 10(-10)-10(-4) M) or ex vivo (TRH: 1-40 mg kg-1 i.p.). There was no dose-dependent modification of the in vivo binding of [3H]lofentanil in any of the mouse brain areas studied after TRH (1-40 mg kg-1 i.p.).