Synthesis of (−)-Epi-Indolactam V by an Intramolecular Buchwald–Hartwig C–N Coupling Cyclization Reaction

The synthetic efforts toward the concise synthesis of (−)-indolactam V from simple and commercially available starting materials using palladium- and copper-catalyzed intramolecular N-arylation strategy for the elaboration of the requisite nine-membered lactam ring as the key step are described. The incorporation of a turn-inducing structural element along the linear precursor was fundamental to achieve the heterocyclization step as well as obtain the correct regio- and chemoselectivity. The stereoselective nature in the C–N coupling cyclization reaction is interpreted in terms of minimization of allylic strain at the transition state for the palladium-amido complex formation. Meanwhile, the synthesis of the (−)-epi-indolactam V and its enantiomer have been accomplished

Organocatalytic synthesis of α-quaternary amino acid derivatives via aza-Friedel–Crafts alkylation of indoles with simple α-amidoacrylates

none4The first (organo)catalytic method for regio- and chemoselective aza-Friedel-Crafts (FC) alkylation of indoles and pyrroles with commercially available methyl alpha-acetamidoacrylates has been discovered. It minimizes/eliminates common competing reactions that occur due to the high and multiatom-nucleophilic character of indole and pyrrole. Diverse quaternary alpha-amino acids were successfully prepared in good yield and high selectivity using low catalyst loading. The enantioselective variant using BINOL-derived phosphoric acids was also explored with indole providing the desired F-C alkylation product with moderate enantioselectivities.openRIGHI M.; BARTOCCINI F.; LUCARINI S.; PIERSANTI G.Righi, M.; Bartoccini, Francesca; Lucarini, Simone; Piersanti, Giovann

Asymmetric Total Synthesis of All Rugulovasine Stereoisomers and Preliminary Evaluation of Their Biological Properties

A unified enantioselective synthesis and the biological evaluation of all rugulovasine stereoisomers are reported. The syntheses are centered on the divergent and stereochemical modular combination of each enantiomer of 4-amino Uhle's ketone and a methacrylate derivative to build the unsaturated oxaspirolactone moiety by the Dreiding-Schmidt reaction, followed by Fukuyama alkylation to afford the required N-methyl secondary amine in excellent yield. The modularity of this divergent approach, the diastereoselectivities of the reactions, and the late-stage site-selective methylation permit the rapid asymmetric syntheses of all rugulovasine stereoisomers, including the first total syntheses of optically pure (+)- and (−)-rugulovasine B and their trideuteromethylated derivatives. All enantiopure stereoisomers of rugulovasine were tested for their binding affinities to dopamine, serotonin, and adrenergic neuroreceptors, revealing their preferred selectivity for the serotonin 1 A receptor

Palladium(II)-Catalyzed Cross-Dehydrogenative Coupling (CDC) of N-Phthaloyl Dehydroalanine Esters with Simple Arenes: Stereoselective Synthesis of Z-Dehydrophenylalanine Derivatives

Pd(II)-catalyzed cross-dehydrogenative coupling (CDC) of methyl N-phthaloyl dehydroalanine esters with simple aromatic hydrocarbons is reported. The reaction, which involves the cleavage of two sp(2) C-H bonds followed by C-C bond formation, stereoselectively generates highly valuable Z-dehydrophenylalanine skeletons in a practical, versatile, and atom economical manner. In addition, a perfluorinated product was expediently converted into important nonproteinogenic amino acid building blocks through copper-catalyzed conjugate additions of boron, silicon, and hydride moieties

Enantioselective organocatalytic strategies to noncanonical α‐amino acids

Organocatalytic asymmetric synthesis has evolved over the years and continues to attract the interest of many researchers worldwide. Enantiopure noncanonical amino acids (ncAAs) are valuable building blocks in organic synthesis, medicinal chemistry, and chemical biology. They are employed in the elaboration of peptides and proteins with enhanced activities and/or improved properties compared to their natural counterparts, as chiral catalysts, in chiral ligand design, and as chiral building blocks for asymmetric syntheses of complex molecules, including natural products. The linkage of ncAA synthesis and enantioselective organocatalysis, the subject of this perspective, tries to imitate the natural biosynthetic process. Herein, we present contemporary and earlier developments in the field of organocatalytic activation of simple feedstock materials, providing potential ncAAs with diverse side chains, unique three-dimensional structures, and a high degree of functionality. These asymmetric organocatalytic strategies, useful for forging a wide range of C–C, C–H, and C–N bonds and/or combinations thereof, vary from classical name reactions, such as Ugi, Strecker, and Mannich reactions, to the most advanced concepts such as deracemisation, transamination, and carbene N−H insertion. Concurrently, we present some interesting mechanistic studies/models, providing information on the chirality transfer process. Finally, this perspective highlights, through the diversity of the amino acids (AAs) not selected by nature for protein incorporation, the most generic modes of activation, induction, and reactivity commonly used, such as chiral enamine, hydrogen bonding, Brønsted acids/bases, and phase-transfer organocatalysis, reflecting their increasingly important role in organic and applied chemistry

Synthesis and Biological Evaluation of Metabolites of 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine (ST1535), A Potent Antagonist of the A2AAdenosine Receptor for the Treatment of Parkinson’s Disease

none9The synthesis and preliminary in vitro evaluation of five metabolites of the A2A antagonist ST1535 (1) are reported. The metabolites, originating in vivo from enzymatic oxidation of the 2-butyl group of the parent compound, were synthesized from 6-chloro-2-iodo-9-methyl-9H-purine (2) by selective C–C bond formation via halogen/magnesium exchange reaction and/or palladium-catalyzed reactions. The metabolites behaved in vitro as antagonist ligands of cloned human A2A receptor with affinities (Ki 7.5–53 nM) comparable to that of compound 1 (Ki 10.7 nM), thus showing that the long duration of action of 1 could be in part due to its metabolites. General behavior after oral administration in mice was also analyzed.openGiovanni Piersanti;Francesca Bartoccini;Simone Lucarini;Walter Cabri;Maria Antonietta Stasi;Teresa Riccioni;Franco Borsini;Giorgio Tarzia;Patrizia MinettiPiersanti, Giovanni; Bartoccini, Francesca; Lucarini, Simone; Walter, Cabri; Maria Antonietta, Stasi; Teresa, Riccioni; Franco, Borsini; Tarzia, Giorgio; Patrizia, Minett

An Italian Multicenter Perspective Harmonization Trial for the Assessment of MET Exon 14 Skipping Mutations in Standard Reference Samples

Lung cancer remains the leading cause of cancer deaths worldwide. International societies have promoted the molecular analysis of MET proto-oncogene, receptor tyrosine kinase (MET) exon 14 skipping for the clinical stratification of non-small cell lung cancer (NSCLC) patients. Different technical approaches are available to detect MET exon 14 skipping in routine practice. Here, the technical performance and reproducibility of testing strategies for MET exon 14 skipping carried out in various centers were evaluated. In this retrospective study, each institution received a set (n = 10) of a customized artificial formalin-fixed paraffin-embedded (FFPE) cell line (Custom METex14 skipping FFPE block) that harbored the MET exon 14 skipping mutation (Seracare Life Sciences, Milford, MA, USA), which was previously validated by the Predictive Molecular Pathology Laboratory at the University of Naples Federico II. Each participating institution managed the reference slides according to their internal routine workflow. MET exon 14 skipping was successfully detected by all participating institutions. Molecular analysis highlighted a median Cq cut off of 29.3 (ranging from 27.1 to 30.7) and 2514 (ranging from 160 to 7526) read counts for real-time polymerase chain reaction (RT-PCR) and NGS-based analyses, respectively. Artificial reference slides were a valid tool to harmonize technical workflows in the evaluation of MET exon 14 skipping molecular alterations in routine practice

Synthesis and Reactivity of Uhle’s Ketone and Its Derivatives

Uhle's ketone and its derivatives are highly versatile intermediates for the synthesis of a variety of 3,4-fused tricyclic indole frameworks, i.e. indole alkaloids of the ergot family, that are found in various bioactive natural products and pharmaceuticals. Therefore, the development of a convenient preparative method for this structural motif as well as its opportune/useful derivatization have been the subject of longstanding interest in the fields of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent and less recent methods for the preparation of Uhle's ketone and its derivatives as well as its main reactivity towards the synthesis of bioactive substances. Regarding the preparation, it can be roughly classified into two categories: (a) using 4-unfunctionalized and 4-functionalized indole derivatives as starting materials to construct a fused six-member ring, and (b) constructing the indole ring through intramolecular cycloaddition. Principally, the reactivity of the cyclic Uhle's ketone shown here is derived from the classical electrophilicity of the carbonyl carbon or the acidity of the alpha-hydrogen and, though less intensively investigated, chemical reactions that induce ring expansion to form novel ring skeletons

A Short Synthesis of (−)‐6,7‐Secoagroclavine via Metal‐Free Reductive Coupling

A concise, convergent, and enantioselective synthesis of (−)-6,7-secoagroclavine, a pivotal intermediate in the synthesis of both clavine and ergot alkaloids, was accomplished from a derivative of the renowned Uhle's ketone. The synthesis is centered on metal-free reductive coupling of the tosylhydrazone derivative of protected 4-amino Uhle's ketone and commercially available 2,2-dimethylethenylboronic acid, which is used as a four-carbon building block. This novel approach directly sets the stereochemistry on the difficult-to-access aryl vinyl methane carbon stereogenic center of (−)-6,7-secoagroclavine

C3-Alkylation of indoles and oxindoles by alcohols by means of borrowing hydrogen methodology

Transition metal‐catalyzed C3‐alkylation of indoles and oxindoles with nonderivatized alcohols, by means of borrowing hydrogen (BH) activation of the alcohol substrates, avoids the use of environmentally unfriendly alkylating agents. Only water is formed as the byproduct, thus making the BH process atom‐economical and environmentally benign. Diverse homogeneous and heterogeneous transition‐metal catalysts, indoles and oxindoles, and nonderivatized alcohols can be used for this transformation, hence rendering the BH process promising for replacing those procedures that use traditional alkylating agents. Although some earlier literature is discussed, this review mainly covers the literature published since 2015