A palladium-catalyzed oxidative cascade carbonylative carbocyclization of enallenols was developed. Under mild reaction conditions, a range of cis-fused [5,5] bicyclic gamma-lactones and gamma-lactams with a 1,3-diene motif were obtained in good yields with high diastereoselectivity. The obtained lactone/lactam products are viable substrates for a stereoselective Diels-Alder reaction with N-phenylmaleimide, providing polycyclic compounds with increased molecular complexity.

A highly selective and efficient oxidative carbocyclization/borylation of enallenols catalyzed by palladium immobilized on amino-functionalized siliceous mesocellular foam (Pd-AmP-MCF) was developed for diastereoselective cyclobutenol synthesis. The heterogeneous palladium catalyst can be recovered and recycled without any observed loss of activity or selectivity. The high diastereoselectivity of the reaction is proposed to originate from a directing effect of the enallenol hydroxyl group. Optically pure cyclobutenol synthesis was achieved by the heterogeneous strategy by using chiral enallenol obtained from kinetic resolution.

A palladium-catalyzed oxidative tandem process of enallenols was accomplished within a homogeneous/heterogeneous catalysis manifold, setting the stage for the highly chemodivergent and diaster-eoselective synthesis of gamma-lactones and gamma-lactams under mild conditions.

Oxidation reactions play a central role in organic synthesis, and it is highly desirable that these reactions are mild and occur under catalytic conditions. In Nature, oxidation reactions occur under mild conditions via cascade processes, and furthermore, they often occur in an enantioselective manner with many of them involving molecular oxygen or hydrogen peroxide as the terminal oxidant. Inspired by the reactions in Nature, we have developed a number of Pd(II)-catalyzed cascade reactions under mild oxidative conditions. These reactions have an intrinsic advantage of step economy and rely on selectivity control in each step. In this Account, we will discuss the control of chemo-, regio-, and diastereoselectivity in Pd(II)-catalyzed dehydrogenative cascade coupling reactions. The enantioselective version of this methodology has also been addressed, and new chiral centers have been introduced using a catalytic amount of a chiral phosphoric acid (CPA). Research on this topic has provided access to important compounds attractive for synthetic and pharmaceutical chemists. These compounds include carbocyclic, heterocyclic, and polycyclic systems, as well as polyunsaturated open-chain structures. Reactions leading to these compounds are initiated by coordination of an allene and an unsaturated pi-bond moiety, such as olefin, alkyne, or another allene, to the Pd(II) center, followed by allene attack involving a C(sp(3))-H cleavage under mild reaction conditions. Recent progress within our research group has shown that weakly coordinating groups (e.g., hydroxyl, alkoxide, or ketone) could also initiate the allene attack on Pd(II), which is essential for the oxidative carbocyclization. Furthermore, a highly selective palladium-catalyzed allenic C(sp(3))-H bond oxidation of allenes in the absence of an assisting group was developed, which provides a novel and straightforward synthesis of [3]dendralene derivatives. For the oxidative systems, benzoquinone (BQ) and its derivatives are commonly used as oxidants or catalytic co-oxidants (electron transfer mediators, ETMs) together with molecular oxygen. A variety of transformations including carbocyclization, acetoxylation, arylation, carbonylation, borylation, beta-hydride elimination, alkynylation, alkoxylation, and olefination have been demonstrated to be compatible with this Pd(II)-based catalytic oxidative system. Recently, several challenging synthetic targets, such as cyclobutenes, seven-membered ring carbocycles, spirocyclic derivatives, functional cyclohexenes, and chiral cyclopentenone derivatives were obtained with high selectivity using these methods. The mechanisms of the reactions were mainly studied by kinetic isotope effects (KIEs) or DFT computations, which showed that in most cases the C(sp(3))-H cleavage is the rate-determining step (RDS) or partially RDS. This Account will describe our efforts toward the development of highly selective and atom-economic palladium(II)-catalyzed oxidative transformation of allenes (including enallenes, dienallenes, bisallenes, allenynes, simple allenes, and allenols) with a focus on overcoming the selectivity problem during the reactions.

A highly selective palladium-catalyzed hydroborylative carbocyclization of bisallenes to afford seven-membered rings has been established. This ring-closing coupling reaction showed good functional group compatibility with high chemo- and regioselectivity, as seven-membered ring 3 was the only product obtained. The extensive use of different linkers, including nitrogen, oxygen, malononitrile, and malonate, showed a broad substrate scope for this approach. A one-pot cascade reaction was realized by trapping the primary allylboron compound with an aldehyde, affording a diastereomerically pure alcohol and a quaternary carbon center by formation of a new C-C bond. A comprehensive mechanistic DFT investigation is also presented. The calculations suggest that the reaction proceeds via a concerted hydropalladation pathway from a Pd(0)-olefin complex rather than via a pathway involving a defined palladium hydride species. The reaction was significantly accelerated by the coordination of the pendant olefin, as well as the introduction of suitable substituents in the bridge, due to the Thorpe-Ingold effect.

An enantioselective Pd^II/Brønsted acid-catalyzed carbonylative carbocyclization of enallenes ending with a cross-dehydrogenative coupling (CDC) with a terminal alkyne was developed. VAPOL phosphoric acid was found as the best co-catalyst among the examined 28 chiral acids, for inducing the enantioselectivity of α-chiral ketones. As a result, a number of chiral cyclopentenones were easily synthesized in good to excellent enantiomeric ratio with good yields.

A highly selective olefin-assisted palladium-catalyzed oxidative carbocyclization via remote olefin insertion to afford cyclohexenes has been developed. It was shown that the assisting olefin moiety was indispensable for the formation of the cyclohexene product. Furthermore, preliminary studies on chiral anion-induced asymmetrical carbocyclization-borylation of enallenes have been carried out.

An olefin-assisted, palladium-catalyzed oxidative alkynylation of enallenes for regio- and stereoselective synthesis of substituted trienynes has been developed. The reaction shows a broad substrate scope and good tolerance for various functional groups on the allene moiety, including carboxylic acid esters, free hydroxyls, imides, and alkyl groups. Also, a wide range of terminal alkynes with electron-donating and electron-withdrawing aryls, heteroaryls, alkyls, trimethylsilyl, and free hydroxyl groups are tolerated.

A highly selective palladium-catalyzed oxidative carbonylation/carbocyclization/alkoxycarbonylation of enallenols to afford spirolactones bearing an all-carbon quaternary center was developed. This transformation involves the overall formation of three C-C bonds and one C-O bond through a cascade insertion of carbon monoxide (CO), an olefin, and CO. Preliminary experiments on chiral anion-induced enantioselective carbonylation/carbocyclization of enallenols afforded spirolactones with moderate enantioselectivity.

A highly selective palladium-catalyzed allenic C-H bond oxidation was developed, and it provides a novel and straightforward synthesis of [3]dendralene derivatives. A variety of [3]dendralenes with diverse substitution patterns are accessible with good efficiency and high stereoselectivity. The reaction tolerates a broad substrate scope containing various functional groups on the allene moiety, including ketone, aldehyde, ester, and phenyl groups. Also, a wide range of olefins with both electron-donating and electron-withdrawing aryls, acrylate, sulfone, and phosphonate groups are tolerated.