ABSTRACT
Successful biochemical studies of the natural products belactosin A and C and their acylated congeners have shown a ß-lactonecarboxamide moiety to be a possible core structure of powerful proteasome inhibitors. As a part of further investigations, variously decorated simplified ß-lactonecarboxamides have been synthesized in order to understand structure-biological activity relations in detail, to find ways of improving their biological activity and stability and to reduce the complexity of their preparation. Biological tests showed that the best compounds possess a high potential against phytopathogenic fungi in the greenhouse.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fungi/enzymology , Peptides/chemistry , Peptides/pharmacology , Proteasome Inhibitors , Acylation , Enzyme Inhibitors/chemical synthesis , Intercellular Signaling Peptides and Proteins , Peptides/chemical synthesis , Plants/microbiology , Streptomyces/chemistry , Structure-Activity RelationshipABSTRACT
A cationic ruthenium(II) complex enabled efficient oxidative alkenylations of anilides in water as a green solvent and proved applicable to double C-H bond functionalizations of (hetero)aromatic amides with ample scope. Detailed studies provided strong support for a change of ruthenation mechanism in the two transformations, with an irreversible metalation as the key step in cross-dehydrogenative alkenylations of benzamides.
ABSTRACT
Cationic ruthenium(II) complexes enabled oxidative C-H bond functionalizations with anilines bearing removable directing groups. The C-H/N-H bond cleavages occurred most efficiently in water as a sustainable solvent and provided general access to various bioactive indoles. Mechanistic studies provided strong support for a novel reaction manifold.
Subject(s)
Aniline Compounds/chemical synthesis , Indoles/chemistry , Ruthenium/chemistry , Water/chemistry , Catalysis , Cations/chemistry , Molecular Structure , Oxidation-ReductionABSTRACT
Successful biochemical studies of the natural products belactosin A and C as well as their more stable acylated derivatives have proved them to be powerful proteasome inhibitors and thereby potential candidates as pharmacologically relevant active compounds. In order to understand their structure-biological activity relations in detail and to find ways of improving their biological activity, four new modified belactosin congeners have been synthesized and tested. One of them (compound 6) turned out to be a more potent inhibitor against HeLa cells than the known proteasome inhibitor MG132.
Subject(s)
Cysteine Proteinase Inhibitors/pharmacology , Fibroblasts/drug effects , Peptides/chemical synthesis , Proteasome Inhibitors , Uterine Cervical Neoplasms/drug therapy , Acylation , Animals , Antineoplastic Agents , Blotting, Western , Crystallography, X-Ray , Dose-Response Relationship, Drug , Female , Fibroblasts/cytology , HeLa Cells , Humans , Leupeptins/pharmacology , Mice , Mice, Transgenic , Models, Molecular , Molecular Structure , Peptides/pharmacology , Proteasome Endopeptidase Complex/metabolism , Stereoisomerism , Structure-Activity Relationship , Uterine Cervical Neoplasms/pathologyABSTRACT
Ruthenium-catalyzed C-H bond arylations of indoles, thiophenes, and pyrroles were accomplished in a highly chemo- and site-selective manner through the use of removable directing groups.
Subject(s)
Carbon/chemistry , Hydrogen/chemistry , Ruthenium/chemistry , Catalysis , Indoles/chemistry , Molecular Structure , Pyrroles/chemistryABSTRACT
An inexpensive ruthenium catalyst enabled oxidative annulations of alkynes by acrylamides with ample scope, which allowed for the preparation of 2-pyridones employing various electron-rich and electron-deficient acrylamides as well as (di)aryl- and (di)alkyl-substituted alkynes.
Subject(s)
Pyridones/chemical synthesis , Ruthenium/chemistry , Alkynes/chemistry , Catalysis , Chemistry, Organic/economics , Chemistry, Organic/methods , Molecular Structure , Oxidation-Reduction , Pyridones/chemistry , StereoisomerismABSTRACT
Isocyanides have long proved themselves to be irreplaceable building blocks in modern organic chemistry. The unique features of the isocyano group make isocyanides particularly useful for the synthesis of a number of important classes of nitrogen heterocycles, such as pyrroles, indoles, and quinolines. Several cocyclizations of isocyanides via zwitterions and radical intermediates as well as transition-metal-catalyzed syntheses of different types of heterocycles have recently been developed. Methods starting from isocyanides often have distinct advantages over alternative approaches to the same heterocycles because of their enhanced convergence, the great simplicity of most of the operations with them, and the great variety of isocyanides readily available for use. Isocyanides have also been used in some enantioselective syntheses of chiral heterocyclic compounds, including natural products as well as precursors thereof.
ABSTRACT
A sequence of Michael addition of a primary amine onto methyl 2-chloro-2-cyclopropylidene-acetate (1), acylation of the adduct with alpha-bromo acid chlorides under modified Schotten-Baumann conditions and ring-closing twofold nucleophilic substitution on the thus formed bishalides 3a-e with aliphatic or aromatic amines according to a very simple protocol with final acid/base extraction or filtration over silica gel for purification leads to the 3-spirocyclopropanated 5-oxopiperazine-2-carboxylates 2 or in two cases, after intermolecular transesterification of 2, to bicyclic oxopiperazines 6, with a remarkable variability of the substituents R1-R3 in 39-99% yields (20 examples). Starting with alpha-bromophenylacetic acid chloride, the trans-configured 6-phenyl-5-oxopiperazine-2-carboxylates are formed preferentially.
Subject(s)
Carboxylic Acids/chemical synthesis , Dipeptides/chemical synthesis , Molecular Mimicry/physiology , Amines/chemistry , Biomimetics/methods , Carboxylic Acids/chemistry , StereoisomerismABSTRACT
ortho-Lithiophenyl (-hetaryl) isocyanides react with aldehydes and ketones providing isocyanoalcohols 8 (36-89%, nine examples), 4H-3,1-benzoxazines 9 (45-78%, six examples) or, after two types of rearrangements, isobenzofuran-1(3H)-imines (iminophthalanes) 18 (52-75%, four examples), or indolin-2-ones 19 (42-79%, two examples), depending on the reaction conditions and substitution patterns. Isocyanoalcohols 8, in turn, were converted to 9 or 18 under Cu(I) catalysis (66-86%, eight examples). 4H-3,1-Benzoxazin-4-ones 39-Nu and isatoic anhydride 40 were obtained by the reaction of 2 with carbon dioxide followed by trapping of the lithiated intermediate with iodine and subsequent reactions with nucleophiles (45-60%, three examples).
Subject(s)
Aldehydes/chemistry , Benzoxazines/chemistry , Benzyl Alcohols/chemical synthesis , Cyanides/chemistry , Ketones/chemistry , Lithium/chemistry , Organometallic Compounds/chemistry , Benzofurans/chemical synthesis , Benzofurans/chemistry , Benzoxazines/chemical synthesis , Benzyl Alcohols/chemistry , Imines/chemical synthesis , Imines/chemistry , Indoles/chemical synthesis , Indoles/chemistryABSTRACT
ortho-Lithiophenyl isocyanide has been generated from ortho-bromophenyl isocyanide and successfully employed toward the synthesis of 2-substituted phenyl isocyanides as well as 2,3-disubstituted 3H-quinazoline-4-ones and 3H-quinazolin-4-thiones.
ABSTRACT
The formal cycloaddition of alpha-metallated methyl isocyanides 1 onto the triple bond of electron-deficient acetylenes 2 represents a direct and convenient approach to oligosubstituted pyrroles 3. The scope and limitations of this reaction (24 examples, 25-97% yield) are reported along with an optimization of the reaction conditions and a rationalization of the mechanism. In addition, a related newly developed Cu(I)-mediated synthesis of 2,3-disubstituted pyrroles by the reaction of copper acetylides derived from unactivated terminal alkynes with substituted methyl isocyanides is described (11 examples, 5-88% yield).
