Synthesis of Pyridobenzazepines Using a One-Pot Rh/Pd-Catalyzed Process.

In recent years, our group has been developing multicatalytic reactions for the synthesis of biologically relevant heterocyclic compounds. An efficient dual-metal catalyzed reaction of electron-deficient o-chlorovinylpyridines with o-aminophenylboronic esters to access pyridobenzazepines is described. Combining a RhI-catalyzed arylation followed by a Pd0-catalyzed C-N coupling, in a one-pot procedure, provides a simplified method to access heterocycles without workup and purification after each step. The substrate scope encompasses a variety of N-H and N-alkylated pyridobenzazepine variants with yields up to 93%.

Synthesis of Fused Pyrimidinone and Quinolone Derivatives in an Automated High-Temperature and High-Pressure Flow Reactor.

Fused pyrimidinone and quinolone derivatives that are of potential interest to pharmaceutical research were synthesized within minutes in up to 96% yield in an automated Phoenix high-temperature and high-pressure continuous flow reactor. Heterocyclic scaffolds that are either hard to synthesize or require multisteps are readily accessible using a common set of reaction conditions. The use of low-boiling solvents along with the high conversions of these reactions allowed for facile workup and isolation. The methods reported herein are highly amenable for fast and efficient heterocycle synthesis as well as compound scale-ups.

Combining Ru-Catalyzed C-H Functionalization with Pd-Catalyzed Asymmetric Allylic Alkylation: Synthesis of 3-Allyl-3-aryl Oxindole Derivatives from Aryl α-Diazoamides.

Ruthenium-catalyzed C-H functionalization was successfully combined with palladium-catalyzed asymmetric allylic alkylation in one pot. The novel dual-metal-catalyzed reaction provides a variety of 3-allyl-3-aryl oxindoles from the corresponding α-diazoamides in up to 99% yield with up to 85% ee. The appropriate ligand choice is important to promote the sequential reaction, avoiding undesired metal interaction or ligand exchange.

Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs.

Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of HIV integrase (IN) while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of enterohepatic recirculation in the rat is minimized. Desymmetrization of the C4 substituent allowed for potency optimization against virus having the N124 variant of integrase. Combination of these lessons led to the discovery of compound 20, having balanced serum-shifted antiviral potency and minimized excretion in to the biliary tract in rat, potentially representing a clinically viable starting point for a new treatment option for individuals infected with HIV.

Multicomponent-multicatalyst reactions (MC)(2)R: efficient dibenzazepine synthesis.

A Rh(I)/Pd(0) catalyst system was applied to the multicomponent synthesis of aza-dibenzazepines from vinylpyridines, arylboronic acids, and amines in a domino process with no intermediate isolation or purification.

Formation of substituted oxa- and azarhodacyclobutanes.

The preparation of substituted oxa- and azarhodacyclobutanes is reported. After exchange of ethylene with a variety of unsymmetrically and symmetrically substituted alkenes, the corresponding rhodium-olefin complexes were oxidized with H2O2 and PhINTs (Ts=p-toluenesulfonyl) to yield the substituted oxa- and azarhodacyclobutanes, respectively. Oxarhodacyclobutanes could be prepared with excellent selectivity for incorporation of the oxygen atom on the more substituted carbon atom of the alkene. At the same time, azarhodacyclobutanes showed good-to-excellent selectivity for heteroatom incorporation on the less substituted carbon. Furthermore, it was shown that steric modifications of the ancillary ligand have a significant influence on the selectivity of Rh-olefin complex formation as well as formation of the substituted azametallacycles.

One-pot synthesis of chiral dihydrobenzofuran framework via Rh/Pd catalysis.

A one-pot synthesis of the chiral dihydrobenzofuran framework is described. The method utilizes Rh-catalyzed asymmetric ring opening (ARO) and Pd-catalyzed C-O coupling to furnish the product in excellent enantioselectivity without isolation of intermediates. Systematic metal-ligand studies were carried out to investigate the compatibility of each catalytic system using product enantiopurity as an indicator.

Diastereoselective Friedel-Crafts alkylation of hydronaphthalenes.

An efficient and versatile synthesis of chiral tetralins has been developed using both inter- and intramolecular Friedel-Crafts alkylation as a key step. The readily available hydronaphthalene substrates were prepared via a highly enantioselective metal-catalyzed ring opening of meso-oxabicyclic alkenes followed by hydrogenation. A wide variety of complex tetracyclic compounds have been isolated with high levels of regio-, diastereo-, and enantioselectivity.