Synthesis of 1,3-Dienes via Ligand-Enabled Sequential Dehydrogenation of Aliphatic Acids.

1,3-Dienes are common scaffolds in biologically active natural products as well as building blocks for chemical synthesis. Developing efficient methods for the synthesis of diverse 1,3-dienes from simple starting materials is therefore highly desirable. Herein, we report a Pd(II)-catalyzed sequential dehydrogenation reaction of free aliphatic acids via ß-methylene C-H activation, which enables one-step synthesis of diverse E,E-1,3-dienes. Free aliphatic acids of varying complexities, including the antiasthmatic drug seratrodast, were found to be compatible with the reported protocol. Considering the high lability of 1,3-dienes and lack of protecting strategies, dehydrogenation of aliphatic acids to reveal 1,3-dienes at the late stage of synthesis offers an appealing strategy for the synthesis of complex molecules containing such motifs.

Dual-Ligand Catalyst for the Nondirected C-H Olefination of Heteroarenes.

Pd(II)-catalyzed nondirected C-H functionalization of heteroarenes is a significant challenge for the following reasons: poor reactivity of electron-deficient heterocycles and the unproductive coordination of Lewis basic nitrogen atoms. Existing methodologies using palladium catalysis often employ a large excess of heterocycle substrates to overcome these hurdles. Despite recent advances in nondirected functionalization of arenes that allow them to be used as limiting reagents, the reaction conditions are incompatible with electron-deficient heteroarenes. Herein we report a dual-ligand catalyst that enables Pd(II)-catalyzed nondirected C-H olefination of heteroarenes without using a large excess of substrate. In general, the use of 1-2 equiv of substrates was sufficient to obtain synthetically useful yields. The reactivity was rationalized by the synergy between two types of ligands: a bidentate pyridine-pyridone ligand promotes C-H cleavage; the monodentate heterocycle substrate acts as a second ligand to form a cationic Pd(II) complex that has high affinity for arenes. The proposed dual-ligand cooperation is supported by a combination of X-ray, kinetics, and control experiments.

Catalyst-controlled site-selective methylene C-H lactonization of dicarboxylic acids.

Catalyst-controlled site-selective activation of ß- and γ-methylene carbon-hydrogen (C-H) bonds of free carboxylic acids is a long-standing challenge. Here we show that, with a pair of palladium catalysts assembled with quinoline-pyridone ligands of different chelate ring sizes, it is possible to perform highly site-selective monolactonization reactions with a wide range of dicarboxylic acids, generating structurally diverse and synthetically useful γ- and δ-lactones via site-selective ß- or γ-methylene C-H activation. The remaining carboxyl group serves as a versatile linchpin for further synthetic applications, as demonstrated by the total synthesis of two natural products, myrotheciumone A and pedicellosine, from abundant dicarboxylic acids.

Palladium-Catalyzed Enantioselective ß-C(sp3)-H Activation Reactions of Aliphatic Acids: A Retrosynthetic Surrogate for Enolate Alkylation and Conjugate Addition.

Enolate alkylation and conjugate addition into an α,ß-unsaturated system have served as long-standing strategic disconnections for the installation of α- or ß-substituents on carbonyl-containing compounds. At the onset of our efforts to develop C-H activation reactions for organic synthesis, we set our eye toward developing asymmetric ß-C-H activation reactions of aliphatic acids with the perspective that this bond-forming event could serve as a more flexible retrosynthetic surrogate for both canonical carbonyl-related asymmetric transformations.In this Account, we describe our early efforts using strongly coordinating chiral oxazolines to probe reaction mechanism and the stereochemical nature of the C-H cleavage transition state. The characterization of key reactive intermediates through X-ray crystallography and computational studies suggested a transition state with C-H and Pd-OAc bonds being approximately coplanar for optimum interaction. We then moved forward to develop more practical, weakly coordinating monodentate amide directing groups, a necessary advance toward achieving the ß-C-H activation of weakly coordinating native carboxylic acids. Throughout this journey, gradual deconvolution between a substrate's directing effect and its intimate interplay with ligand properties has culminated in the design of new ligand classes that ultimately allowed the competency of native carboxylic acids in ß-C-H activation. These efforts established the importance of ligand acceleration in Pd-catalyzed C-H activation, where the substrate's weak coordination is responsible for positioning the catalyst for C-H cleavage, while the direct participation from the bifunctional ligand is responsible for enthalpically stabilizing the C-H cleavage transition state.Building upon these principles, we developed five classes of chiral ligands (MPAA, MPAQ, MPAO, MPAThio, MPAAM) to enable enantioselective ß-C-H activation reactions, including carbon-carbon and carbon-heteroatom bond formation. The accumulated data from our developed enantioselective C-H activation reactions indicate that ligands possessing point chirality are most effective for imparting stereoinduction in the C-H activation step, the application of which enabled the desymmetrization and subsequent C-H functionalization of enantiotopic carbon and protons across a range of weakly coordinating arylamides and, more recently, free carboxylic acids. Progress in ligand design, in conjunction with the enabling nature of alkali metal countercations, led to the realization of a suite of ß-methyl and now methylene C(sp3)-H activation reactions. These advancements also enabled the use of economical oxidants, such as peroxides and molecular oxygen, to facilitate catalyst turnover. In the future, continued progress in designing more efficient bifunctional chiral ligands is likely to provide a myriad of enantioselective ß-C-H activation reactions of readily available native substrates.

Forwards and backwards - synthesis of Laurencia natural products using a biomimetic and retrobiomimetic strategy incorporating structural reassignment of laurefurenynes C-F.

Laurefurenynes C-F are four natural products isolated from Laurencia species whose structures were originally determined on the basis of extensive nuclear magnetic resonance experiments. On the basis of a proposed biogenesis, involving a tricyclic oxonium ion as a key intermediate, we have reassigned the structures of these four natural products and synthesized the four reassigned structures using a biomimetic approach demonstrating that they are the actual structures of the natural products. In addition, we have developed a synthesis of the enantiomers of the natural products laurencin and deacetyllaurencin from the enantiomer of (E)-laurefucin using an unusual retrobiomimetic strategy. All of these syntheses have been enabled by the use of tricyclic oxonium ions as pivotal synthetic intermediates.