Development of Environmentally Benign Organometallic Catalysis for Drug Discovery and Its Application

Abstract

We have developed a novel organometallic catalysis and applied it to drug discovery. Two new catalysts were found, ruthenium hydride with a nitrogen-containing heterocyclic carbene (A) and an organopalladium catalyst supported on a sulfur-terminated semiconductor, gallium arsenide (001) (B). Both catalysts are environmentally benign, because A can yield indole derivatives with good atom economy, and B can catalyze the Mizoroki-Heck reaction more than 10 times with only trace amounts of leached palladium (ppb level). We also describe our synthetic study of nitrogen-containing heterocycles using ring-closing metathesis (RCM), such as chiral bicyclic lactams, azacycloundecenes, axially chiral macrolactams, 1,2-dihydroquinolines and indoles, including the development of silyl-enol ether ene metathesis, selective isomerization of terminal olefin, enamide metathesis and cycloisomerization and its application to the syntheis of 4 natural products, (؊)-coniceine, (S)-pyrrolam A, angustureine, and fistulosin.

Novel Cyclic Biphalin Analogues by Ruthenium-Catalyzed Ring Closing Metathesis: in Vivo and in Vitro Biological Profile

“…For the preparation of the cyclic Boc-protected analogue 4 via RCM, the reaction conditions were extensively optimized; ruthenium carbene complexes are easier to prepare and handle than molybdenum complexes. Their remarkable stability to air, water, acid, and functional group tolerance render this group of catalysts suitable for applications in peptide chemistry. , We first explored RCM using Zhan-1B and Grubbs I generation catalyst under several reaction conditions, leading to major recovery of the starting material and undetermined byproducts, probably due to the low solubility of the linear compound in the reaction solvent. The desired cyclic product 4 was finally obtained in good yield as a mixture of cis / trans isomers, using the more stable and reactive Grubbs II generation catalyst in DCE under reflux for 78 h. The ring closure was achieved with a catalytic amount of catalyst (10%) to a solution of peptide 3 in DCE at reflux, monitored by TLC (AcOEt/MeOH = 97:3) until reaction completion.…”

Preparation of Nonsymmetrically Substituted Stilbenes in a One-Pot Two-Step Heck Strategy Using Ethene As a Reagent

“…The palladium-catalyzed C−C coupling between aryl halides or vinyl halides and activated alkenes in the presence of a base is well-known now as the Heck reaction. , There have been a number of recent reviews of the scope and versatility of the reaction. – It finds wide applications from natural product to fine chemicals synthesis as well as in the preparation of functional polymers and their precursors. – When looking in the literature, the vast majority of the publications citing the Heck reaction involve the reaction of aryl halides with monosubstituted alkenes such as styrene and butyl acrylate. Generally the alkene coupling partner is used in a stoichiometric excess relative to the aryl halide component and a wide range of catalyst systems have been developed for obtaining the Heck products in good yields.…”

Efficient synthesis of 3‐sulfonyl‐1,2‐dihydroquinolines via tandem aza‐Michael addition/cyclizations of N‐acyl‐protected 2‐aminobenzaldehyde with vinyl sulfones

“…The 1,2-dihydroquinolines (1,2-DHQs) are an important class of compounds widely present in natural products [1,2], synthetic pharmaceutical molecules, and biologically active compounds [3][4][5][6]. 1,2-DHQs have increasingly gained special attention due to a number of pharmaceutical drugs containing a 1,2-dihydroquinoline moiety which plays a crucial role in the core pharmacophore, and structurally similar synthetic analogs also have the potential to be biologically active.…”