Synthesis of Substituted Pyridines via Formal (3+3) Cycloaddition of Enamines with Unsaturated Aldehydes and Ketones.

An organocatalyzed, formal (3+3) cycloaddition reaction is described for the practical synthesis of substituted pyridines. Starting from readily available enamines and enal/ynal/enone substrates, the protocol affords tri- or tetrasubstituted pyridine scaffolds bearing various functional groups. This method was demonstrated on a 50 g scale, enabling the synthesis of 2-isopropyl-4-methylpyridin-3-amine, a raw material used for the manufacture of sotorasib.

Tandem Olefin Metathesis/Oxidative Cyclization: Synthesis of Tetrahydrofuran Diols from Simple Olefins.

A tandem olefin metathesis/oxidative cyclization has been developed to synthesize 2,5-disubstituted tetrahydrofuran (THF) diols in a stereocontrolled fashion from simple olefin precursors. The ruthenium metathesis catalyst is converted into an oxidation catalyst in the second step and is thus responsible for both catalytic steps. The stereochemistry of the 1,5-diene intermediate can be controlled through the choice of catalyst and the type of metathesis conducted.

Tandem Z-Selective Cross-Metathesis/Dihydroxylation: Synthesis of anti-1,2-Diols.

A stereoselective synthesis of anti-1,2-diols has been developed using a multitasking Ru catalyst in an assisted tandem catalysis protocol. A cyclometalated Ru complex catalyzes first a Z-selective cross-metathesis of two terminal olefins, followed by a stereospecific dihydroxylation. Both steps are catalyzed by Ru, as the Ru complex is converted to a dihydroxylation catalyst upon addition of NaIO4.

Enantioselective olefin metathesis with cyclometalated ruthenium complexes.

The success of enantioselective olefin metathesis relies on the design of enantioenriched alkylidene complexes capable of transferring stereochemical information from the catalyst structure to the reactants. Cyclometalation of the NHC ligand has proven to be a successful strategy to incorporate stereogenic atoms into the catalyst structure. Enantioenriched complexes incorporating this design element catalyze highly Z- and enantioselective asymmetric ring opening/cross metathesis (AROCM) of norbornenes and cyclobutenes, and the difference in ring strain between these two substrates leads to different propagating species in the catalytic cycle.

Dynamic kinetic resolution of allylic sulfoxides by Rh-catalyzed hydrogenation: a combined theoretical and experimental mechanistic study.

A dynamic kinetic resolution (DKR) of allylic sulfoxides has been demonstrated by combining the Mislow [2,3]-sigmatropic rearrangement with catalytic asymmetric hydrogenation. The efficiency of our DKR was optimized by using low pressures of hydrogen gas to decrease the rate of hydrogenation relative to the rate of sigmatropic rearrangement. Kinetic studies reveal that the rhodium complex acts as a dual-role catalyst and accelerates the substrate racemization while catalyzing olefin hydrogenation.

Rh-catalyzed intramolecular olefin hydroacylation: enantioselective synthesis of seven- and eight-membered heterocycles.

This communication describes the first rhodium-catalyzed intramolecular olefin hydroacylation to produce medium-sized heterocyclic ketones with high regio- and enantiocontrol. Both alpha- and beta-substituted ketones can be produced, depending on catalyst choice and substrate structure. In this stereoselective C-H bond functionalization, ethers, sulfides, and sulfoxides function as effective directing groups.

Mechanistic insights into the rhodium-catalyzed intramolecular ketone hydroacylation.

[Rh((R)-DTBM-SEGPHOS)]BF(4) catalyzes the intramolecular hydroacylation of ketones to afford seven-membered lactones in large enantiomeric excess. Herein, we present a combined experimental and theoretical study to elucidate the mechanism and origin of selectivity in this C-H bond activation process. Evidence is presented for a mechanistic pathway involving three key steps: (1) rhodium(I) oxidative addition into the aldehyde C-H bond, (2) insertion of the ketone CO double bond into the rhodium hydride, and (3) C-O bond-forming reductive elimination.

Atom efficient cyclotrimerization of dimethylcyanamide catalyzed by aluminium amide: a combined experimental and theoretical investigation.

A novel method for the cyclotrimerization of dimethylcyanamide to form hexamethylmelamine has been developed using an aluminium amide catalyst; detailed DFT modelling of the catalytic cycle supports a triple insertion, nucleophilic ring closure, deinsertion mechanism.

Determination of NMR lineshape anisotropy of guest molecules within inclusion complexes from molecular dynamics simulations.

Nonspherical cages in inclusion compounds can result in non-uniform motion of guest species in these cages and anisotropic lineshapes in NMR spectra of the guest. Herein, we develop a methodology to calculate lineshape anisotropy of guest species in cages based on molecular dynamics simulations of the inclusion compound. The methodology is valid for guest atoms with spin 1/2 nuclei and does not depend on the temperature and type of inclusion compound or guest species studied.

Free energies of carbon dioxide sequestration and methane recovery in clathrate hydrates.

Classical molecular dynamics simulations are used to compare the stability of methane, carbon dioxide, nitrogen, and mixed CO(2)N(2) structure I (sI) clathrates under deep ocean seafloor temperature and pressure conditions (275 K and 30 MPa) which were considered suitable for CO(2) sequestration. Substitution of methane guests in both the small and large sI cages by CO(2) and N(2) fluids are considered separately to determine the separate contributions to the overall free energy of substitution. The structure I clathrate with methane in small cages and carbon dioxide in large cages is determined to be the most stable.

Strain-release electrophilic activation via E-cycloalkenones.

UVA irradiation (ca. 350 nm) of a mixture of cyclic enones and nitrogen heterocycles leads to efficient formation of the 1,4-adducts in a variety of solvents, at room temperature. These reactions likely proceed through strained E-cycloalkenone intermediates, as suggested by low-temperature generation/trapping experiments monitored by 1H NMR.