Synthèses totales des mauritines A, B, C et F ; synthèse de macrocycles orientée pour la diversité structurale (conception et synthèse d'un cyclophane support d'un coude b)

DANS LA PREMIÈRE PARTIE DE CE MANUSCRIT, NOUS AVONS DECRIT LA PREMIÈRE SYNTHÈSE TOTALE DES MAURITINES A, B, C ET F, ALCALOÏDES CYCLOPEPTIDIQUES À 14 CHAÎNONS BIOLOGIQUEMENT ACTIFS. LA STRATÉGIE DE SYNTHÈSE QUE NOUS AVONS DÉVELOPPÉ EST BASÉE SUR UNE CYCLOÉTHERIFICATION PAR RÉACTION DE S(N)AR INTRAMOLÉCULAIRE ET MET EN JEU UN TRIPEPTIDE LINÉAIRE INTACT, CE QUI REND LA STRATÉGIE TRÈS CONVERGENTE. LE RENDEMENT GLOBAL DE CES SYNTHÈSES TOTALES EST DE 6.7-10.2 POUR CENT POUR 13-14 ÉTAPES. UNE ÉTUDE COMPLÈTE PAR SPECTROSCOPIE RMN A ÉTÉ RÉALISÉE SUR LES MAURITINES A, B, C ET F, PERMETTANT NOTAMMENT D'ATTRIBUER, POUR LA PREMIÈRE FOIS, TOUS LES SIGNAUX CORRESPONDANT AUX PROTONS MAIS AUSSI À TOUS LES CARBONES. DANS LA DEUXIÈME ET TROISIÈME PARTIE DE CE MANUSCRIT, NOUS AVONS DÉCRIT UNE NOUVELLE SÉQUENCE UGI-S(N)AR PERMETTANT DE SYNTHÉTISER EFFICACEMENT DES MACROCYCLES, ANALOGUES DE PRODUITS NATURELS BIOLOGIQUEMENT ACTIFS, QUI COMPORTENT SOIT UN MOTIF BIARYL ÉTHER SOIT UN MOTIF ARYL-X-ALKYL ENDOCYCLIQUE (X = NH, 0, S). CETTE SÉQUENCE PERMET D'INTRODUIRE UNE GRANDE DIVERSITÉ STRUCTURALE DANS LES MOLÉCULES CIBLES ET DES MACROCYCLES À 14, 15, 16 ET 17 CHAÎNONS ONT PU ÊTRE SYNTHÉTISÉS. ENFIN, LA SÉQUENCE UGI-S(N)AR PERMETTANT D'ACCÉDER AUX MACROCYCLES COMPORTANT UN MOTIF BIARYL ÉTHER A PU ÊTRE APPLIQUÉE AUSSI EFFICACEMENT SUR SUPPORT SOLIDE (RÉSINE DE WANG). DANS LA DERNIÈRE PARTIE DE CE MANUSCRIT, NOUS AVONS CONÇU ET SYNTHÉTISÉ UN NOUVEAU CYCLOPHANE DE TYPE CYCLOISODITYROSINE, SUPPORT EXTERNE POTENTIEL D'UN COUDE BÉTA. AINSI, QUATRE MOLÉCULES CIBLES ONT ÉTÉ SYNTHÉTISÉES PUIS ENTIÈREMENT CARACTÉRISÉES. UNE ANALYSE CONFORMATIONNELLE DÉTAILLÉE (RMN, DICHROÏSME CIRCULAIRE) A MONTRÉ QUE CETTE UNITÉ CYCLOISODITYROSINE CONSTITUE VRAISEMBLABLEMENT UN BON SUPPORT EXTERNE D'UN COUDE BÉTA DU TYPE II, QUI POURRAIT PERMETTRE LE DÉVELOPPEMENT D'UNE NOUVELLE CLASSE DE PEPTIDOMIMETIQUES.IN THE FIRST PART OF THIS MANUSCRIPT, WE HAVE DETAILLED THE FIRST TOTAL SYNTHESES OF MAURITINES A, B, C AND F, 14-MEMBERED CYCLOPEPTIDE ALKALOIDS WITH BIOLOGICAL ACTIVITY. OUR STRATEGY IS VERY CONVERGENT AND IS BASED ON THE INTRAMOLECULAR S(N)AR CYCLOETHERIFICATION WHICH INVOLVES AN INTACT LINEAR TRIPEPTIDE. THE OVERALL YIELD OF THESE TOTAL SYNTHESES IS 6.7-10.2 PER CENT FOR 13-14 STEPS. FOR THE FIRST TIME DETAILLED NMR STUDIES ALLOWED ALL PROTON AND CARBON SIGNALS TO BE ATTRIBUTED. IN THE SECOND AND THIRD PART OF THIS MANUSCRIPT, WE HAVE DETAILLED A NEW UGI-S(N)AR SEQUENCE WHICH ALLOW THE EASY ACCESS TO NATURAL PRODUCT-LIKE MACROCYCLES CONTAINING EITHER AN ENDOCYCLIC BIARYL ETHER OR AN ARYL-X-ALKYL PATTERN (X = NH, O, S). THIS SEQUENCE ALLOW THE INTRODUCTION OF BROAD STRUCTURAL DIVERSITY INTO THE TARGETTED MOLECULES AND 14 TO 17-MEMBERED MACROCYCLES HAVE BEEN SYNTHESIZED. A SOLID SUPPORTED VERSION OF THIS SEQUENCE WAS ALSO DEVELOPPED FOR THE SYNTHESIS OF BIARYL ETHER CONTAINING MACROCYCLES (WANG RESIN). IN THE LAST PART OF THIS MANUSCRIPT, WE HAVE DESIGNED AND SYNTHESIZED A NEW MACROCYCLIC BETA TURN SCAFFOLD. THUS FOUR CYCLOISODITYROSINE-LIKE MACROCYCLES HAVE BEEN SYNTHESIZED AND FULLY CHARACTERIZED. A DETAILLED CONFORMATIONAL STUDY (NMR, CIRCULAR DICHROÏSM) SHOWED THAT THESE TARGETTED MOLECULES ARE PROBABLY TYPE II BETA TURNS. THEREFORE THIS NEW SCAFFOLD COULD BE FURTHER CONSIDERED FOR THE DEVELOPPMENT OF A NEW CLASS OF PEPTIDOMIMETICS.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

A Rapid Access to Biaryl Ether Containing Macrocycles by Pairwise Use of Ugi 4CR and Intramolecular SNAr-Based Cycloetherification

An Ugi reaction promoted by ammonium chloride in aprotic solvent is documented here for the first time. From readily accessible starting materials, macrocycles with an endo aryl-aryl ether bond are synthesized in only two steps, Ugi four-component reaction (Ugi 4CR) and an intramol. SNAr reaction. The nitro group serves as an activator for the macrocyclization and provides a handle for the introduction of functional group diversity. For example, dipeptide amide I was obtained in an Ugi 4CR from isonitrile II, PhCHO, PhCH2NH2 and 3-hydroxyphenylacetic acid in the presence of NH4+Cl- in toluene at 0 Deg for 20 h. Cycloetherification of I took place in the presence of K2CO3 in DMF for 3 h to give macrocycle III in 80% yield. [on SciFinder (R)

Rapid and diverse route to natural product-like biaryl ether containing macrocycles

A two-step sequence involving an Ugi four-component reaction and an intramol. nucleophilic arom. substitution (SNAr) has been developed for the rapid access to biaryl-ether contg. macrocycles. For example, reacting heptanal with butylamine, (3-hydroxyphenyl)acetic acid, and isonitrile I in dry toluene in the presence of NH4Cl gave dipeptide II. II was then cyclized using an intramol. SNAr sequence to give cyclic ether III as a mixt. of 4 diastereomers. In the course of this study, we documented that ammonium chloride can promote the Ugi-4CR in non-polar aprotic solvent (toluene) without the interference of an alternative Passerini reaction. Solid phase synthesis of macrocycles by this two-step sequence was also developed using polymer (Wang resin) supported alpha -(4'-fluoro-3'-nitro)phenethyl isocyanoacetate as one of the inputs. [on SciFinder (R)

Paramétrisation des données radiocristallographiques relatives à la phénothiazine et à ses dérivés de substitution

Les auteurs décrivent à partir des données radiocristallo-graphiques connues, la variation de la géométrie moléculaire de la phénothiazine et de ses dérivés de substitution à l’aide de paramètres (pour la plupart stériques) auxquels ils ont appliqué une analyse statistique de corrélation.Les deux faits les plus marquants concernent l’angle de pliage et le mode de déploiement de la chaîne substituant l'azote du noyau phénothiazinique : quelle que soit la nature, le nombre, la place des radicaux fixés, la substitution a pour effet de diminuer l'angle de pliage, phénomène qui est analysé comme une perturbation de la conjugaison du noyau tricyclique.Quant au substituant en N10 on constate, sauf contrainte stérique particulière, qu'il a tendance à prendre une position de « fuite » l'éloignant au maximum du noyau phénothiazinique

Total synthesis of an atropdiastereomer of RP-66453 and determination of its absolute configuration

A convergent synthesis of all S-configurated diastereoisomer of RP-66453 (aS,S,S,S,S,S), a peptide secondary metabolite, has been developed. The synthesis is notable for its brevity, partly because functionalized amino acids can be used directly. By combination of chem. evidence and NMR data, the abs. configuration of RP-66453 was detd. to be (aR,S,S,S,S,S). It is interesting to note that nature created RP-66453 with a thermodynamically less stable atropisomer, while lab. synthesis using intramol. Suzuki-Miyarura coupling as the last ring-closure step produced the thermodynamically more stable isomer. [on SciFinder (R)

Total synthesis of mauritines A, B, C, and F: Cyclopeptide alkaloids with a 14-membered paracyclophane unit

A unified strategy for the synthesis of mauritines A (I), B, C, and F has been developed based on a key intramol. nucleophilic arom. substitution reaction (SNAr) for the formation of the strained 14-membered paracyclophane. It was demonstrated that the outcome of the cycloetherification is independent of the stereochem. of the peptide backbone. On the other hand, dehydration of the secondary benzylic alc., via the phenylselenide intermediate, is configuration dependent. A modified reductive deamination procedure via the diazonium intermediate was developed. A complete assignment of proton and carbon NMR spectroscopy signals for these natural products is reported for the first time. [on SciFinder (R)

Synthesis of alpha,alpha'-Disubstituted alpha-Acetoxy Esters and alpha,alpha'-Disubstituted alpha-hydroxy Acids by Baeyer-Villiger Oxidation of the Corresponding béta-Ketoesters

International audienceThe regioselective Baeyer-Villiger oxidation of a wide range of α,α−disubstituted β-ketoesters has been developed to synthesize, in good yields, α,α-disubstituted α-acetoxy esters. The reactions were performed using m-chloroperbenzoic acid in the presence of triflic acid. The rearrangement was shown to occur with retention of configuration of the migrating group. The corresponding α,α−disubstituted α-hydroxy acids were obtained in good yields, after hydrolysis

On the Use of N-Carboxyanhydrides as Interesting Starting Materials in Organic Synthesis

International audienc

On the Use of N-Carboxyanhydrides as Interesting Starting Materials in Organic Synthesis

International audienc

On the use of Amino Acids as Starting Material for the Synthesis of Biomolecules

National audienc