Nouvelles réactions d'hétéroannélation palladocatalysées à partir d'acyloximes

Ce manuscrit est consacré au développement de nouvelles réactions d'hétéroannélation palladocatalysées et à leur utilisation en synthèse totale. La première partie de ce manuscrit est dédiée au développement de nouvelles voies d'accès aux phénantridines, aux isoquinoléines, aux oxadiazolones et aux benzimidazoles à partir de dérivés d'oximes. Nous avons développé une nouvelle voie d'accès palladocatalysée aux phénantridines et aux isoquinoléines en utilisant une séquence domino aminopalladation/arylation directe. Cette approche est nouvelle et originale, car elle est basée sur l'insertion du palladium dans la liaison N-O d'une acyloxime. L'espèce aza-palladium (II) qui se forme est ensuite piégée de manière intermoléculaire par une aryne pour former un second intermédiaire Pd(II) qui subit finalement une arylation directe. Cette réaction s'avère générale sur les acyloximes dérivées de la benzophénone, et des arynes ou des alcynes très activés peuvent être utilisés pour former des phénantridines ou des isoquinoléines. Nous avons également noté que des substrats de type amidoximes secondaires, placés en présence de chlorure de pentafluorobenzoyle, pouvaient subir une rupture de liaison C-C inattendue pour former des oxadiazolones. Cette réaction a été étudiée et nous avons pu montrer qu'elle était générale pour la formation d'oxadiazolones et que dans ce cas, le chlorure de pentafluorobenzoyle pouvait être considéré comme un équivalent du phosgène. Enfin nous présentons également des résultats préliminaires pour la synthèse de benzimidazoles à partir d'acyloximes. La seconde partie de ce manuscrit présente à la première synthèse totale de l'alstoscholarine (Z et E), de manière concise et efficace. Cet alcaloïde, récemment isolé des feuilles d'Alstonia Scholaris, présente une structure pentacyclique inédite, avec un noyau indole et un noyau pyrrole placés de part et d'autre d'un bicycle ponté [3-1-3]. Notre synthèse est basée sur la formation tardive du noyau indole, en utilisant une méthode palladocatalysée développée au laboratoire. Elle est effectuée en l'absence de tout groupement protecteur et fait intervenir d'autres étapes clés comme une désymétrisation organocatalytique énantiosélective, une coupure oxydante avec formation régiosélective d'un hémiaminal à six chaînons qui permet de différencier les deux fonctions aldéhydiques formées ou encore une alkylidénation de Takeda, évitant l'épimérisation. Le rendement global de la synthèse est bon (13,5%) et le nombre d'étapes peu élevé. Enfin, la synthèse est modulable et devrait permettre la préparation de nombreux analogues.This PhD thesis is dedicated to the development of palladium-catalyzed heteroannulation reactions and their use in total synthesis. ln the first part, a new access to phenantridines, isoquinolines, oxadiazolones and benzimidazoles from oximes derivatives is presented. We have developed a new domino palladium-catalyzed process involving an aminopalladation and a direct arylation step, based on the oxidative addition of palladium into N-O bonds. This aza-palladium (II) species is then intermolecularly trapped by an aryne or an alkyne. We have also noticed that secondary amidoxime, placed in the presence of pentafluorobenzoyl chloride could undergo an unexpected C-C bond cleavage to form oxadiazolones. This reaction has also been studied and we have found that it was general for the formation of oxadiazolones and that in this case pentafluorobenzoyl chloride couId be considered as a "CO" equivalent. Finally, we also present preliminary results for the formation of benzimidazoles from acyloximes. ln the second part, we present the first total synthesis of alstoscholarine (Z and E). This alkaloid, recently isolated from the leaves of A lston ia Scholaris have an atypical pentacyclic structure, characterized by a bridged [3.1.3] bicycle fused with an indole ring on a side and a pyrrole ring on the other side. Our synthesis is based on a late-stage palladium-catalyzed indole formation developed in our laboratory. The synthesis is concise (8 steps), efficient (13.5% overall yield), and protecting group free. It also features an enantioselective desymmetrization, a regioselective hemiaminal cyclisation and a Takeda olefination to avoid epimerization. We are currently exploiting these results for the synthesis of analogues.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Palladium-catalyzed annulation of acyloximes with arynes (or alkynes): synthesis of phenanthridines and isoquinolines

A palladium-catalyzed domino aminopalladation/C-H functionalization sequence has been developed, and provides access to functionalized phenanthridines and isoquinolines. The use of butyronitrile as the solvent is determinant to the success of the domino process. [on SciFinder (R)

Protecting-Group-Free Total Synthesis of (E) and (Z)-Alstoscholarine

Looking for hidden symmetry: The first asymmetric total synthesis of pentacyclic (E)- and (Z)-alstoscholarines is accomplished starting from cyclic meso-anhydride 9. The absolute configuration was set by an organocatalytic desymmetrization of 9. Other key steps involved a regioselective hemiaminal formation to differentiate two aldehydes with concurrent creation of the D-ring, a chemoselective palladium-catalyzed indole synthesis and a Takeda olefination to install the ethylidene moiety. Each step of this eight-stage synthesis led to the constructive C-C, C-N or C-O bond formation. The synthesis is protecting-group-free, with high synthetic economy, and confirms the absolute configuration assigned to the natural products

Unexpected C–C Bond Cleavage: Synthesis of 1,2,4-Oxadiazol-5-ones from Amidoximes with Pentafluorophenyl or Trifluoromethyl Anion Acting as Leaving Group

An unexpected C-C bond cleavage has been observed on pentafluorobenzoylamidoxlmes under mild basic conditions. This observation has been exploited to develop a new synthesis of 1,2,4-oxadiazol-5-ones from amidoximes using pentafluorobenzoyl chloride or trifluoroacetic anhydride (TFAA) as a double acylating agent. The pentafluorophenyl anion and the trifluoromethyl anion acted as leaving groups in this transformation

Unexpected C–C Bond Cleavage: Synthesis of 1,2,4-Oxadiazol-5-ones from Amidoximes with Pentafluorophenyl or Trifluoromethyl Anion Acting as Leaving Group

An unexpected C–C bond cleavage has been observed on pentafluorobenzoylamidoximes under mild basic conditions. This observation has been exploited to develop a new synthesis of 1,2,4-oxadiazol-5-ones from amidoximes using pentafluorobenzoyl chloride or trifluoroacetic anhydride (TFAA) as a double acylating agent. The pentafluorophenyl anion and the trifluoromethyl anion acted as leaving groups in this transformation

Injectable Self-Healing Hydrogels Based on Boronate Ester Formation between Hyaluronic Acid Partners Modified with Benzoxaborin Derivatives and Saccharides

International audienc

Enantioselective, Chromatography-Free Synthesis of β³-Amino Acids with Natural and Unnatural Side Chains

β³-Amino acids are key components of some pharmaceuticals, excellent surrogates for metabolically labile α-amino acids, and building blocks for chiral heterocycles. Unfortunately they are not easily accessible in enantiomerically pure form, especially when possessing unnatural side chains. A flexible, chromatography-free process for the synthesis of enantiopure β³-amino acids possessing natural and unnatural side chains is described. The procedure uses inexpensive starting materials and reagents and offers a good alternative to the hazardous and expensive Arndt–Eistert homologation of enantiopure α-amino acids. Its utility has been demonstrated with the preparative scale synthesis of two valuable β³-amino acids possessing unnatural side chains

Self-crosslinking smart hydrogels through direct complexation between benzoxaborole derivatives and diols from hyaluronic acid

International audienceBoronate ester cross-linked hydrogels have emerged as promising injectable scaffolds for biomedical applications given their rapid self-healing ability. For a rational design of such networks, all variables influencing their dynamic rheological properties, especially the boronic acid and the diol-containing molecule selected as molecular crosslinkers have to be carefully considered. Herein, by tailoring the structure of benzoboroxole (BOR), self-crosslinking hydrogels based on hyaluronic acid (HA) modified with BOR derivatives are obtained for the first time through the direct BOR-HA diol complexation at physiological pH. Among the different HA-BOR conjugates investigated, those prepared from 6-amino-7-fluoro-3,3-dimethyl benzoboroxole (HA-DMF6ABOR) and 7-amino-3,3-dimethyl benzoboroxole (HA-DM7ABOR) show unprecedented self-crosslinking properties, leading to the formation of self-healing hydrogels with extremely slow dynamics. These networks also exhibit remarkable pH-and glucose-responsive behaviors. These properties are related to the peculiar structure of these two BOR moieties, having as the common feature, a gem-dimethyl group in the oxaborole ring and an ortho-substituent in the phenyl ring. Molecular dynamic simulations are used to provide insight in the role of these substituents in the outstanding capability of DMF6ABOR and DM7ABOR to crosslink HA. They show that BOR complexation induces changes in conformation of HA favoring formation of a highly entangled 3D networ