Leveraging Electron Push-Pull Effect for Catalytic Polymerization and Degradation of a Cyclobutane Monomer System.

Ring-opening polymerization (ROP) offers a striking solution to solve problems encountered in step-growth condensation polymerization, including precise control over molecular weight, molecular weight distribution, and topology. This has inspired our interest in ROP of cycloalkanes with an ultimate goal to rethink polyolefins, which clearly poses a number of challenges. Practicality of ROP of cycloalkanes is actually limited by their low polymerizability and elusive mechanisms which arise from significantly varied ring size and non-polar C-C bonds in monomers. In this work, by using Lewis acid/Brønsted base/C(sp3)-H initiator system previously developed in our laboratory, we focus on cyclobutanes and explore the positional and electronic effects of substituents on the ring, namely electron push-pull effect, in promoting controlled polymerization to afford densely functionalized poly(cyclobutanes), as well as catalytic degradation of obtained polymers for upcycling. More importantly, experiments and DFT calculations unveil considerable population of Lewis-acid-induced thermostabilized 1,4-zwitterions, which distinguish cyclobutanes from cyclopropanes and others. All these findings would shed light on catalytic synthesis and degradation of saturated all-carbon main-chain polymers, as well as small molecule transformations of cyclobutanes.

Organo/Transition-Metal Combined Catalysis Rejuvenates Both in Asymmetric Synthesis.

Since its advent two decades ago, asymmetric organo/transition-metal combined catalysis (AOMC), including cooperative catalysis and relay catalysis, has leveraged redistribution of chemical bonds to build up molecular complexity and enantio-differentiation to form individual enantiomers with activations from versatile organocatalysts and transition-metal complexes. The goal of this perspective is to provide readers with the fundamental attributes of AOMC─orthogonality, kinetics, mechanism, and selectivity─to understand how an organocatalyst and a transition-metal complex would collaborate to enable fruitful new reaction development and what are the intrinsic pathways of unproductive events, such as catalyst self-quenching. In closing, future opportunities of AOMC have been directed toward the prediction of effective catalyst combination, introducing enzyme catalysis, and a focus on transient radical intermediate, to animate this area in the years to come.

Chiral Indoline-2-carboxylic Acid Enables Highly Enantioselective Catellani-type Annulation with 4-(Bromomethyl)cyclohexanone.

Chiral indoline-2-carboxylic acid has been identified to enable a highly enantioselective Catellani-type annulation of (hetero)aryl, alkenyl triflate and conjugated vinyl iodides with 4-(bromomethyl)cyclohexanone, directly assembling a diverse range of chiral all-carbon bridged ring systems. Control experiments and DFT calculations suggest that the coordinating orientation of the chiral amino acid to the arylpalladium(II) center allows for high levels of stereochemical control.

Organocatalyzed Birch Reduction Driven by Visible Light.

The Birch reduction is a powerful synthetic methodology that uses solvated electrons to convert inert arenes to 1,4-cyclohexadienes-valuable intermediates for building molecular complexity. Birch reductions traditionally employ alkali metals dissolved in ammonia to produce a solvated electron for the reduction of unactivated arenes such as benzene (Ered < -3.42 V vs SCE). Photoredox catalysts have been gaining popularity in highly reducing applications, but none have been reported to demonstrate reduction potentials powerful enough to reduce benzene. Here, we introduce benzo[ghi]perylene imides as new organic photoredox catalysts for Birch reductions performed at ambient temperature and driven by visible light from commercially available LEDs. Using low catalyst loadings (<1 mol percent), benzene and other functionalized arenes were selectively transformed to 1,4-cyclohexadienes in moderate to good yields in a completely metal-free reaction. Mechanistic studies support that this unprecedented visible-light-induced reactivity is enabled by the ability of the organic photoredox catalyst to harness the energy from two visible-light photons to affect a single, high-energy chemical transformation.

Bromine Radical Catalysis by Energy Transfer Photosensitization.

We report here a mild, safe, and user-friendly bromine radical catalysis system that enables efficient [3 + 2] cycloaddition of diversely substituted vinyl- and ethynylcyclopropanes with a broad range of alkenes, including drug-like molecules and pharmaceuticals. Key to the success is the use of photosensitizing triplet-state ß-fragmentation of a judiciously selected precatalyst, cinnamyl bromide, to generate bromine radicals in a controlled manner using parts per million-level photocatalyst (i.e., 4CzIPN) loading.

Organocatalyzed Photoredox Radical Ring-Opening Polymerization of Functionalized Vinylcyclopropanes.

Organocatalyzed photoredox radical ring-opening polymerization (rROP) of vinylcyclopropanes (VCPs) is employed for the synthesis of polymers with controlled molecular weight (MW), dispersity, and composition. Herein, we report the study on the rROP of a variety of VCP monomers bearing diverse functional groups (such as amide, alkene, ketal, urea, hemiaminal ether, and so on) under organocatalyzed conditions with varying light sources and temperature. Notably, VCP monomers bearing natural product functionality or their derivatives can be polymerized in a controlled manner to produce poly(VCPs) with predictable MW, low dispersity, tunable composition, high thermal stability, and tailored glass transition temperature (T g), ranging 39 to 107 °C. Lastly, successful "grafting through" synthesis of molecular brush copolymers containing 1.0 or 5.0 kDa polydimethylsiloxane (PDMS) side chains from readily accessible EtVCP-PDMS macromonomers further demonstrates the robustness of this organocatalyzed photoredox rROP.

Recent Progress in Asymmetric Relay Catalysis of Metal Complex with Chiral Phosphoric Acid.

Asymmetric metal/organo relay catalysis, utilizing a metal complex and a chiral organocatalyst in a one-pot cascade reaction, is aimed to sequentially impart activation on multiple steps by distinct catalysts. Such a catalysis merges the advantages of both metal catalysis and organocatalysis, providing step-economy, and, more importantly, the potential to achieve inaccessible reactivity by a single catalyst. Chiral phosphoric acids are among the most robust organocatalysts, rendering a broad range of enantioselective bond-forming reactions. The combination of metal complexes and chiral phosphoric acids in a single vessel has been well documented. In particular, the asymmetric relay catalysis of metal complex with chiral phosphoric acid has grown rapidly since 2008. Several excellent reviews have been published to cover almost all examples in this area from 2008 to early 2014; therefore, in this chapter, we will mainly highlight progress from 2014 to mid-2019.

Controlling Polymer Composition in Organocatalyzed Photoredox Radical Ring-Opening Polymerization of Vinylcyclopropanes.

Although radical polymerizations are among the most prevalent methodologies for the synthesis of polymers with diverse compositions and properties, the intrinsic reactivity and selectivity of radical addition challenge the ability to impart control over the polymerization propagation and produce polymers with defined microstructure. Vinylcyclopropanes (VCPs) can be polymerized through radical ring-opening polymerization to produce polymers possessing linear (l) or cyclic (c) repeat units, providing the opportunity to control polymer structure and modify the polymer properties. Herein, we report the first organocatalyzed photoredox radical ring-opening polymerization of a variety of functionalized VCP monomers, where high monomer conversions and spatial and temporal control were achieved to produce poly(VCPs) with predictable molecular weight and low dispersity. Through manipulating polymerization concentration and temperature, tunable l or c content was realized, allowing further investigation of thermal and viscoelastic materials properties associated with these two distinct compositions. Unexpectedly, the photoredox catalysis enables a postpolymerization modification that converts l content into the c content. Combined experimental and computational studies suggested an intramolecular radical cyclization pathway, where cyclopentane and cyclohexane repeat units are likely formed.

Directed γ-C(sp3)-H Alkylation of Carboxylic Acid Derivatives through Visible Light Photoredox Catalysis.

Visible light photoredox catalysis enables direct γ- C(sp3)-H alkylation of saturated aliphatic carbonyl compounds. Electron-deficient alkenes are used as the coupling partners in this reaction. Distinguished site selectivity is controlled by the predominant 1,5-hydrogen atom transfer of an amidyl radical generated in situ.

N-Heterocyclic Carbene and Chiral Brønsted Acid Cooperative Catalysis for a Highly Enantioselective [4+2] Annulation.

A chiral NHC/Brønsted acid cooperative catalysis system has been developed for asymmetric annulation of functionalized benzaldehydes and activated ketones through dearomative generation of dienolate.

Organocatalytic Highly Enantioselective Substitution of 3-(1-Tosylalkyl)indoles with Oxindoles Enables the First Total Synthesis of (+)-Trigolutes B.

A highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)indoles with oxindoles has been established by using chiral bifunctional organocatalysts, providing an efficient entry to multiply functionalized 3,3'-disubstituted oxindoles, and was exploited as the key step to enable the first asymmetric total synthesis of optically pure (+)-trigolutes B to be accomplished in a concise manner, within seven steps with an 18% overall yield.

Quinine-catalyzed highly enantioselective cycloannulation of o-quinone methides with malononitrile.

2-Amino-3-cyano-4H-chromenes show great potential as novel anticancer agents. Here we report a quinine-catalyzed highly enantioselective formal 4 + 2 cycloaddition of ortho-quinone methides and malononitrile, providing a unique approach to 4-arylvinyl, 4-aryl and 4-vinyl 2-amino-3-cyano-4H-chromenes with excellent yields and enantioselectivities. Moreover, this reaction can be performed in up to 6 mmol scale without any noticeable loss of yield and stereoselectivity.

C-H functionalization/asymmetric Michael addition cascade enabled by relay catalysis: metal carbenoid used for C-C bond formation.

A combination of either ruthenium(II) or rhodium(II) complexes and quinine-derived squaramide enables 3-diazooxindoles, indoles, and nitroalkenes to undergo highly efficient asymmetric three-component reactions, thus affording optically active 3,3'-bis(indole)s through a consecutive C-C bond-forming sequence, which turned out to be applicable to the facile total synthesis of (-)-folicanthine.

Asymmetric organocatalysis combined with metal catalysis: concept, proof of concept, and beyond.

Asymmetric catalysis has been considered to be the most intriguing means for building collections of functionalized optically active compounds. In particular, metal and organocatalysis have been well established to allow many fundamentally different reactions. Metal catalysis has enabled the participation of a much broader scope of chemical bonds in organic transformations than are allowed by organocatalysis, while organocatalysis permits a broader scope of functional groups to undergo a diverse range of enantioselective transformations, individually, simultaneously, or sequentially. Theoretically, the combination of organocatalysts and metal complexes could probably render new transformations through the simultaneous or sequential activation and reorganization of multiple chemical bonds if the superior features of both the catalysts are adopted. In 2001, both our research group and Takemoto's group separately described an asymmetric allylation of glycine imino esters with allyl acetate catalyzed by palladium complexes and chiral ammonium salts. In these cases, the oxidative addition of palladium complexes to allyl acetate formed the π-allylic fragments, while the chiral ammonium salts were actually responsible for controlling the stereoselectivity. These reactions in fact marked the beginning of asymmetric organo/metal combined catalysis. Since then, asymmetric organocatalysis combined with metal catalysis, including cooperative catalysis, relay catalysis, and sequential catalysis, has been a versatile concept for the creation of unknown organic transformations. Sequential catalysis describes a one-pot reaction involving two or more incompatible catalytic cycles. Alternatively, cooperative and relay catalyses require high compatibility of principally distinct catalysts and will be the focus of this Account. The catalysts in cooperative catalytic reactions must be able to simultaneously and individually activate both substrates to drive a bond-forming reaction, while relay catalysis is basically defined as a cascade process in which two or more sequential bond-forming transformations are independently catalyzed by distinct catalysts. In the past decade, we have discovered a variety of binary catalytic systems consisting of metals, including Rh(II), Pd(0), Au(I), and Mg(II), and chiral organocatalysts, including chiral phosphoric acids and quinine-based bifunctional molecules, for cooperative catalysis and relay catalysis, allowing the accomplishment of many unprecedented asymmetric transformations. In this Account, these achievements will be summarized, particularly focusing on the description of the concept and proof of the concept, to demonstrate the robustness of combined organo/metal catalysis in the creation of efficient enantioselective transformations. In addition, elegant studies from other laboratories using chiral phosphoric acid/Au(I) for the establishment of asymmetric cascade reactions involving the carbon-carbon triple bond functionality and typical combined organo/metal catalytic systems, very recently disclosed, will also be highlighted.

Enantioselective construction of [6,5,6]-carbocyclic systems by organo/metal-catalyzed sequential reactions.

An efficient strategy for the enantioselective construction of [6,5,6]-carbocyclic compounds has been established via one-pot reaction of (E)-4-(2-ethynylphenyl)but-3-en-2-ones with maleimide sequentially catalyzed by cinchona alkaloid-based primary amine and gold complex (Ph3PAuNTf2). This methodology provided a facile approach to access the [6,5,6]-tricyclic skeleton in fairly good yield and with perfect enantioselectivities (98% to >99% ee).

Rhodium/chiral urea relay catalysis enables an enantioselective semipinacol rearrangement/Michael addition cascade.

The combined use of rhodium and cinchona-based squaramide has first been introduced for asymmetric relay catalysis, enabling a highly enantioselective semipinacol rearrangement/Michael addition cascade.

Pd-catalyzed asymmetric allylic alkylation of pyrazol-5-ones with allylic alcohols: the role of the chiral phosphoric acid in C-O bond cleavage and stereocontrol.

The combination of a palladium complex with a chiral phosphoramidite ligand and a chiral phosphoric acid enables the first highly efficient asymmetric allylic alkylation of pyrazol-5-ones with allylic alcohols, affording multiply functionalized heterocyclic products in high yields with excellent enantioselectivities that would be of great potential in the synthesis of pharmaceutically interesting molecules.

Cascade hydroamination/redox reaction for the synthesis of cyclic aminals catalyzed by a combined gold complex and Brønsted acid.

Relay catalysis: An unprecedented protocol for the synthesis of cyclic aminals has been realized under the relay catalysis of a gold(I)/Brønsted acid binary system to generate cyclic aminals in excellent yields of up to 99 % with moderate to high diastereoselectivity (see scheme; up to 95:5 d.r.).

Hybrid metal/organo relay catalysis enables enynes to be latent dienes for asymmetric Diels-Alder reaction.

The hybrid Au(I)/Brønsted acid binary catalyst system enables enynes to serve as latent 1,3-silyloxydienes capable of participating in the first cascade hydrosiloxylation of an enynyl silanol/asymmetric Diels-Alder reaction. A variety of polycyclic compounds bearing multistereogenic centers were obtained in high yields and excellent enantioselectivities from the relay catalytic cascade reaction between (2-(but-3-en-1-ynyl)phenyl) silanols and quinones catalyzed by the combined achiral gold complex and chiral N-triflyl phosphoramide.