Two synthetic routes for the synthesis of amino-triazolodiazepine (Ata) scaffolds are presented. The scope of both of these proceeding through key intra- and intermolecular Huisgen cycloaddition reactions is discussed. The replacement of the His-Pro dipeptide segment in angiotensin IV by the dipeptide mimetic Ata-Gly and subsequent biological evaluation in two inhibitory enzyme assays validated the use of the Ata moiety as a His mimic given the equipotency of both peptidic analogs.

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Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. Inhibiting the catalytic activity of these proteins has become one of the major therapeutic concepts in contemporary drug discovery. We report here the design and the synthesis of novel 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential inhibitors of Src kinase. The synthesis of these derivatives and the preliminary results of biological activity will be discussed.

A novel and efficient synthesis of precursors of a-amino acids is described. The key step involves a carbolithiation reaction on acyclic ene-carbamates generated from the corresponding vinylphosphates via a palladium cross-coupling reaction followed by a spontaneous internal N→C alkyloxycarbonyl migration.The development of new synthetic approaches to nonnatural amino acids is a blossoming field of research since such compounds find applications in the synthesis of pharmacologically useful molecules, analogues of bioactive peptides mimetics. 1 Our goal was to devise a new route to a-amino acids based on a vinyl carbolithiation performed on acyclic ene-carbamates as the original key synthetic step. Carbolithiation has seen increasing use as a powerful method for complex ring synthesis. 2 However, very few teams have reported the intermolecular nucleophilic addition of organolithium reagents to an alkene, an addition generally difficult to control since it may lead to polymerization of the olefin. 3 To obtain synthetically useful carbolithiation reactions, the final organometallic adduct must be stabilized 4 or must differ markedly from the starting one. 5 In a previous work, we reported a successful carbolithiation approach on seven-membered ring enecarbamates. 6 In this paper, we want to explore the scope of our method and to this purpose, study carbolithiation on acyclic ene-carbamates in order to develop a process that would give easy access to a-amino acids bearing a quaternary carbon next to the nitrogen (cf. Scheme 1). The first part of this work concerns the preparation of acyclic enecarbamates from the corresponding vinylphosphates via a palladium cross-coupling reaction. Carbolithiation on the latter will be investigated in a second stage. Scheme 1 Access to a-amino acidsIn connection with our efforts to develop synthetic routes to nitrogen-containing derivatives, we have undertaken a research program directed towards expanding the range of lactam-derived vinyl phosphates available to the organist chemist. 6,7 Taking advantage of our previous results, a synthesis of the original acyclic amide-derived vinylphosphates 3 was envisaged. Starting from aromatic primary amines 1, after protection of the nitrogen, the amide 2 was treated with LDA (1.2 equiv) at -78°C in THF providing the desired lithium enolate that was quenched with diphenylchlorophosphate (1.2 equiv, cf. Table 1). After workup and purification by silica gel chromatography, the required acyclic amide-derived vinylphosphates 3a-c were isolated in good yields. A Pd-catalyzed Suzuki-Miyaura coupling reaction was then investigated. By using classical conditions, a range of acyclic ene-carbamates 4a-f, substituted a to nitrogen by different aryl or heteroaryl groups, was isolated in fair to good yields (cf. Table 2). 8Carbolithiation was then considered, and acyclic ene-carbamates 4a-f were submitted to reaction with a small range of commercially available organolithium reagents. Treatment of 4a-f in THF at -78°C with an excess of RLi followed by war...

Aminocarboxylic acids (hydrazinocarboxylic acids) and esters Q 0440 Synthesis of α-Amino Acids via a Carbolithiation Reaction on Acyclic Ene-Carbamates and an Internal N→C AlkyloxycarbonylMigration. -(COTTINEAU, B.; GILLAIZEAU*, I.; FARARD, J.; AUCLAIR, M.-L.; COUDERT, G.; Synlett