Jason S. Kingsbury

Ru complexes bearing bidentate carbenes: from innocent curiosity to uniquely effective catalysts for olefin metathesis

The discovery and development of a new class of Ru-based catalysts for olefin metathesis is described. These catalysts, particularly those that do not bear a phosphine ligand, have been demonstrated to promote unique levels of reactivity in a variety of olefin metathesis reactions. The design and development of supported and chiral optically pure variants of this class of Ru catalysts for use in enantioselective metathesis are discussed as well. All catalysts are air stable, reusable, and can be employed with unpurified solvents.

Catalytic Homologation of Cycloalkanones with Substituted Diazomethanes. Mild and Efficient Single-Step Access to α-Tertiary and α-Quaternary Carbonyl Compounds

Though volatile, toxic, and unstable, diazomethane is an indispensable one-carbon reagent with manifold uses in chemical synthesis. In this work, known protocols for hydrazone oxidation were adapted to permit facile access to a range of mono- and disubstituted aryl- or alkyldiazomethanes in pure form in solution; such procedures proceed in 30-60% overall yield starting from inexpensive carbonyl compounds. More important is the discovery that commercial Sc(III) salts are efficient catalysts for net insertion of the diazoalkyl carbon in these nucleophiles into the carbonyl C-C bond of simple cycloalkanones. In a single step, these reactions (1) forge two new C-C bonds under mild conditions, (2) produce molecular nitrogen as the sole stoichiometric byproduct, and (3) afford high yields of complex alpha-tertiary and -quaternary cyclic ketones that are typically accessible only through multistep procedures.

Diverse alkanones by catalytic carbon insertion into the formyl C-H bond. Concise access to the natural precursor of achyrofuran.

Over a century ago, the first reactions of diazomethane with aldehydes delivered methyl ketones. In the interim, aldehydes have been homologated with trimethylsilyldiazomethane, diazoacetates, and aryldiazomethanes, on rare occasion with catalysis. This work describes a mild procedure for convergent ketone assembly from nonstabilized diazoalkanes, including examples of chiral ketone synthesis with disubstituted (internal) nucleophiles. The methods remarkable tolerance to steric crowding is showcased in a simple approach to achyrofuran, a complex dibenzofuran.

Catalytic and Regioselective Ring Expansion of Arylcyclobutanones with Trimethylsilyldiazomethane. Ligand-Dependent Entry to β-Ketosilane or Enolsilane Adducts

Divergent reactivity is uncovered in the homologation of arylcyclobutanones with trimethylsilyldiazomethane. With Sc(OTf)(3) as catalyst, enolsilanes are obtained with a high preference for methylene migration. By contrast, Sc(hfac)(3) gives beta-ketosilanes with both regio- and diastereocontrol. Each adduct affords the cyclopentanone upon hydrolysis.

A Practical Synthesis of 3-Acyl Cyclobutanones by [2 + 2] Annulation. Mechanism and Utility of the Zn(II)-Catalyzed Condensation of α-Chloroenamines with Electron-Deficient Alkenes

New conditions for the conversion of simple tertiary amides to α-chloroenamines and their use in Zn(II)-catalyzed cycloaddition reactions with commercial α,β-unsaturated carbonyl compounds allows rapid, regiocontrolled access to 3-acyl cyclobutanones. Reactions take place at ambient temperature without solvent, giving strained [2 + 2] adducts with all-carbon-substituted quaternary carbon atoms. Ab initio calculations of the putative keteniminium intermediate and studies with styrenyl olefins suggest a dual role for Zn(OTf)(2) during catalysis.

Synthesis of Acyclic Ketones by Catalytic, Bidirectional Homologation of Formaldehyde with Nonstabilized Diazoalkanes. Application of a Chiral Diazomethyl(pyrrolidine) in Total Syntheses of Erythroxylon Alkaloids

This work offers a catalytic approach to convergent ketone assembly based upon formal and tandem C-H insertion of diazoalkanes in the presence of limiting amounts of monomeric formaldehyde, which is easily generated as a gas by thermolysis of the inexpensive and abundant paraformaldehyde (∼30 USD/kg). The method forms di-, tri-, and even tetrasubstituted acetones with high efficiency, and it has streamlined a synthesis of (-)-dihydrocuscohygrine in which the absolute stereochemistry of a proline-based starting material is preserved. Assisted by the advent of new protocols for hydrazone oxidation, we also provide full details on handling non-carbonyl-stabilized diazo compounds.

Titration of nonstabilized diazoalkane solutions by fluorine NMR.

A new protocol for titrating nonstabilized diazoalkane solutions by quantitative (19)F NMR is reported. An excess of 2-fluorobenzoic acid dissolved in CDCl(3) is treated with the diazoalkane solution at a low temperature, immediately forming the corresponding 2-fluorobenzoate ester upon warming. A significant difference in the (19)F chemical shift between the ester and acid is seen, allowing facile and accurate integration to determine titer. The procedure is safe, rapid, and indicates the active diazoalkane concentration with high precision.

General Methodologies Toward cis-Fused Quinone Sesquiterpenoids. Enantiospecific Synthesis of the epi-Ilimaquinone Core Featuring Sc-Catalyzed Ring Expansion

A stereocontrolled approach to the cis-decalin framework of clerodane diterpenes and biologically active quinone sesquiterpenes is reported. Starting from an inexpensive optically pure tetrahydroindanone, Birch reductive alkylation builds two new contiguous chiral centers—one of which is quaternary and all-carbon-substituted. Also featured is a highly regioselective diazoalkane—carbonyl homologation reaction to prepare the 6,6-bicyclic skeleton. Therein, the utility of Sc(OTf)3 as a mild catalyst for formal 1C insertion in complex settings is demonstrated.

Diastereoselective Synthesis of Complex cis-Hexahydroindanes by Reductive Alkylation

An efficient and operationally simple approach to complex cis-hexahydroindanes is reported. Upon Birch reduction of unprotected, C4-alkylated tetrahydroindanols and electrophilic trapping of the tetrasubstituted enolate, cis-fused products are formed with a new stereogenic quaternary carbon. The reaction is convergent, completely diastereoselective, and shows a broad scope with regard to the electrophile.