Cobalt-Catalyzed C(sp2)-C(sp3) Suzuki-Miyaura Cross-Coupling Enabled by Well-Defined Precatalysts with L,X-Type Ligands.

Cobalt(II) halides in combination with phenoxy-imine (FI) ligands generated efficient precatalysts in situ for the C(sp2)-C(sp3) Suzuki-Miyaura cross coupling between alkyl bromides and neopentylglycol (hetero)arylboronic esters. The protocol enabled efficient C-C bond formation with a host of nucleophiles and electrophiles (36 examples, 34-95%) with precatalyst loadings of 5 mol%. Studies with alkyl halide electrophiles that function as radical clocks support the intermediacy of alkyl radicals during the course of the catalytic reaction. The improved performance of the FI-cobalt catalyst was correlated with decreased lifetimes of cage-escaped radicals as compared to diamine-type ligands. Studies of the phenoxy(imine)-cobalt coordination chemistry validate the L,X interaction leading to the discovery of an optimal, well defined, air-stable mono-FI cobalt(II) precatalyst structure.

Hydrazone and Oxime Olefination via Ruthenium Alkylidenes.

We describe the development of an efficient method for the olefination of hydrazones and oximes. The key design approach that enables this transformation is tuning of the energy/polarity of C=N π-bonds by employing heteroatom functionalities (NR2 , OR). The resulting hydrazones or oximes facilitate olefination with ruthenium alkylidenes. Through this approach, we show that air-stable, commercially available ruthenium alkylidenes provide access to functionalized alkenes (20 examples) in ring-closing reactions with yields up to 88 %.

Cobalt-Catalyzed C(sp2)-C(sp3) Suzuki-Miyaura Cross Coupling.

A cobalt-catalyzed method for the C(sp2)-C(sp3) Suzuki-Miyaura cross coupling of aryl boronic esters and alkyl bromides is described. Cobalt-ligand combinations were assayed with high-throughput experimentation, and cobalt(II) sources with trans-N,N'-dimethylcyclohexane-1,2-diamine (DMCyDA, L1) produced optimal yield and selectivity. The scope of this transformation encompassed steric and electronic diversity on the aryl boronate nucleophile as well as various levels of branching and synthetically valuable functionality on the electrophile. Radical trap experiments support the formation of electrophile-derived radicals during catalysis.

Catalytic Carbonyl-Olefin Metathesis of Aliphatic Ketones: Iron(III) Homo-Dimers as Lewis Acidic Superelectrophiles.

Catalytic carbonyl-olefin metathesis reactions have recently been developed as a powerful tool for carbon-carbon bond formation. However, currently available synthetic protocols rely exclusively on aryl ketone substrates while the corresponding aliphatic analogs remain elusive. We herein report the development of Lewis acid-catalyzed carbonyl-olefin ring-closing metathesis reactions for aliphatic ketones. Mechanistic investigations are consistent with a distinct mode of activation relying on the in situ formation of a homobimetallic singly bridged iron(III)-dimer as the postulated active catalytic species. These "superelectrophiles" function as more powerful Lewis acid catalysts that form upon association of individual iron(III)-monomers. While this mode of Lewis acid activation has previously been postulated to exist, it has not yet been applied in a catalytic setting. The insights presented are expected to enable further advancement in Lewis acid catalysis by building upon the activation principle of "superelectrophiles" and to broaden the current scope of catalytic carbonyl-olefin metathesis reactions.

Interrupted carbonyl-olefin metathesis via oxygen atom transfer.

Some of the simplest and most powerful carbon-carbon bond forming strategies take advantage of readily accessible ubiquitous motifs: carbonyls and olefins. Here we report a fundamentally distinct mode of reactivity between carbonyls and olefins that differs from established acid-catalyzed carbonyl-ene, Prins, and carbonyl-olefin metathesis reaction paths. A range of epsilon, zeta-unsaturated ketones undergo Brønsted acid-catalyzed intramolecular cyclization to provide tetrahydrofluorene products via the formation of two new carbon-carbon bonds. Theoretical calculations and accompanying mechanistic studies suggest that this carbocyclization reaction proceeds through the intermediacy of a transient oxetane formed by oxygen atom transfer. The complex polycyclic frameworks in this product class appear as common substructures in organic materials, bioactive natural products, and recently developed pharmaceuticals.

GaCl3-Catalyzed Ring-Opening Carbonyl-Olefin Metathesis.

The development of a Lewis acid-catalyzed ring-opening cross-metathesis reaction which enables selective access to acyclic, unsaturated ketones as the carbonyl-olefin metathesis products is described. While catalytic amounts of FeCl3 were previously identified as optimal to catalyze ring-closing metathesis reactions, the complementary ring-opening metathesis between cyclic alkenes and carbonyl functionalities relies on GaCl3 as the superior Lewis acid catalyst.

Mechanistic Investigations of the Iron(III)-Catalyzed Carbonyl-Olefin Metathesis Reaction.

Iron(III)-catalyzed carbonyl-olefin ring-closing metathesis represents a new approach toward the assembly of molecules traditionally generated by olefin-olefin metathesis or olefination. Herein, we report detailed synthetic, spectroscopic, kinetic, and computational studies to determine the mechanistic features imparted by iron(III), substrate, and temperature to the catalytic cycle. These data are consistent with an iron(III)-mediated asynchronous, concerted [2+2]-cycloaddition to form an intermediate oxetane as the turnover-limiting step. Fragmentation of the oxetane via Lewis acid-activation results in the formation of five- and six-membered unsaturated carbocycles.

Lewis Acid Catalyzed Carbonyl-Olefin Metathesis.

Olefin-olefin metathesis has led to important advances in diverse fields of research, including synthetic chemistry, materials science and chemical biology. The corresponding carbonyl-olefin metathesis also enables direct carbon-carbon bond formation from readily available precursors, however, currently available synthetic procedures are significantly less advanced. This Synpacts article provides an overview of recent achievements in the field of Lewis acid-mediated and Lewis-acid catalyzed carbonyl-olefin metathesis reactions.

Iron(III)-catalysed carbonyl-olefin metathesis.

The olefin metathesis reaction of two unsaturated substrates is one of the most powerful carbon-carbon-bond-forming reactions in organic chemistry. Specifically, the catalytic olefin metathesis reaction has led to profound developments in the synthesis of molecules relevant to the petroleum, materials, agricultural and pharmaceutical industries. These reactions are characterized by their use of discrete metal alkylidene catalysts that operate via a well-established mechanism. While the corresponding carbonyl-olefin metathesis reaction can also be used to construct carbon-carbon bonds, currently available methods are scarce and severely hampered by either harsh reaction conditions or the required use of stoichiometric transition metals as reagents. To date, no general protocol for catalytic carbonyl-olefin metathesis has been reported. Here we demonstrate a catalytic carbonyl-olefin ring-closing metathesis reaction that uses iron, an Earth-abundant and environmentally benign transition metal, as a catalyst. This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, mild reaction conditions, high functional-group tolerance, and amenability to gram-scale synthesis. We anticipate that these characteristics, coupled with the efficiency of this reaction, will allow for further advances in areas that have historically been enhanced by olefin metathesis.

Inhibition of the human proteasome by imidazoline scaffolds.

The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors such as bortezomib. Herein, we describe the optimization of noncompetitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound 49, IC50 130 nM) toward proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of noncompetitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors.