ABSTRACT
The importance of amides as a component of biomolecules and synthetic products motivates the development of catalytic, direct amidation methods employing free carboxylic acids and amines that circumvent the need for stoichiometric activation or coupling reagents. ortho-Iodophenylboronic acid 4a has recently been shown to catalyze direct amidation reactions at room temperature in the presence of 4A molecular sieves as dehydrating agent. Herein, the arene core of ortho-iodoarylboronic acid catalysts has been optimized with regards to the electronic effects of ring substitution. Contrary to the expectation, it was found that electron-donating substituents are preferable, in particular, an alkoxy substituent positioned para to the iodide. The optimal new catalyst, 5-methoxy-2-iodophenylboronic acid (MIBA, 4f), was demonstrated to be kinetically more active than the parent des-methoxy catalyst 4a, providing higher yields of amide products in shorter reaction times under mild conditions at ambient temperature. Catalyst 4f is recyclable and promotes the formation of amides from aliphatic carboxylic acids and amines, and from heteroaromatic carboxylic acids and other functionalized substrates containing moieties like a free phenol, indole and pyridine. Mechanistic studies demonstrated the essential role of molecular sieves in this complex amidation process. The effect of substrate stoichiometry, concentration, and measurement of the catalyst order led to a possible catalytic cycle based on the presumed formation of an acylborate intermediate. The need for an electronically enriched ortho-iodo substituent in catalyst 4f supports a recent theoretical study (Marcelli, T. Angew. Chem. Int. Ed.2010, 49, 6840-6843) with a purported role for the iodide as a hydrogen-bond acceptor in the orthoaminal transition state.
Subject(s)
Boron Compounds/chemistry , Carboxylic Acids/chemistry , Halogens/chemistry , Iodobenzenes/chemistry , Catalysis , Hydrogen Bonding , Molecular StructureABSTRACT
A series of neamine derivatives were prepared from the cyclic carbonate and sulfate of 1,3,2',6'-tetraazido-3',4',-di-O-acetylneamine. Ring opening reactions with diversely substituted amines result in the formation of the corresponding carbamates or sulfonic acids with good overall yields. The antibacterial activities of the synthesized products against E. coli (DH5α) and S. aureus (RN4220) were evaluated. With isolated single regioisomers, the preponderant effect of the 5-positions of the carbamate substituent on the neamine core was demonstrated.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Framycetin/chemistry , Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Framycetin/pharmacology , Microbial Viability/drug effects , Molecular Structure , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
Hepatitis C virus (HCV) translation initiation is mediated by a highly structured and conserved RNA, termed the Internal Ribosome Entry Site (IRES), located at the 5'-end of its single stranded RNA genome. It is a key target for the development of new antiviral compounds. Here we made use of the recently developed HCV cell culture system to test the antiviral activity of artificial ribonucleases consisting of imidazole(s) linked to antisense oligodeoxynucleotides targeting the HCV IRES. Results from the cell culture model indicate that the naked antisense oligodeoxynucleotide displayed an efficient antiviral activity. Despite the increased activity observed with the addition of imidazole moieties when tested with the cell-free system, it appears that these improvements were not reproduced in the cellular model.