Stereochemical Assignment of the 36-Membered Macrolide Ring Portion of Poecillastrin C.

Absolute configuration at 12 stereocenters in the 36-membered macrocyclic ring portion of poecillastrin C (1) was disclosed by chemical degradation and NMR analyses of 1, chemical synthesis, and molecular modeling techniques.

Absolute Configuration of 4-Chloroisoleucine in Cyclolithistide A: An Antifungal Peptide Lactone Discovered in Marine Lithistid Sponges.

Cyclolithistide A is a peptide lactone isolated from marine lithistid sponges. Its entire structure, including absolute configurations, has been reported except the relative and absolute configurations of its characteristic residue, 4-chloroisoleucine (4-CIle). We synthesized four isomers of 4-CIle from furfural-derived N-Boc imine and propionaldehyde. Analysis of the acid hydrolysate of cyclolithistide A and the synthetic samples of 4-CIle after derivatization with l- and d-FDAA permitted us to propose the absolute configuration of the 4-chloroisoleucine residue in cyclolithistide A as 2S,3R,4R.

Cobalt/Photoredox Dual-Catalyzed Cross-Radical Coupling of Alkenes via Hydrogen Atom Transfer and Homolytic Substitution.

Cobalt-catalyzed metal hydride hydrogen atom transfer (MHAT) in combination with photoredox catalysis has emerged as a powerful synthetic method, owing to its redox nature and applicability to various radical precursors. Herein, we describe a cross-radical coupling reaction under cobalt/photoredox dual catalysis. MHAT and homolytic substitution (SH2) processes enabled Markovnikov-selective hydrobenzylation of di/trisubstituted alkenes, affording products with a quaternary carbon center in a redox-neutral manner.

Enantioselective Synthesis of 1,2-Benzothiazine 1-Imines via RuII /Chiral Carboxylic Acid-Catalyzed C-H Alkylation/Cyclization.

Sulfondiimines are diaza-analogues of sulfones with a chiral sulfur center. Compared to sulfones and sulfoximines, their synthesis and transformations have so far been studied to a lesser extent. Here, we report the enantioselective synthesis of 1,2-benzothiazine 1-imines, i.e., cyclic sulfondiimine derivatives from sulfondiimines and sulfoxonium ylides via C-H alkylation/cyclization reactions. The combination of [Ru(p-cymene)Cl2 ]2 and a newly developed chiral spiro carboxylic acid is key to achieving high enantioselectivity.

Catalytic Enantioselective Amination of Enol Silyl Ethers Using a Chiral Paddle-Wheel Diruthenium Complex.

A chiral paddle-wheel dinuclear ruthenium catalyst was applied to a catalytic asymmetric nitrene-transfer reaction with enol silyl ethers. The ruthenium catalyst was applicable to aliphatic enol silyl ethers as well as aryl-containing enol silyl ethers. The substrate scope of the ruthenium catalyst was superior to that of analogous chiral paddle-wheel rhodium catalysts. α-Amino ketones derived from aliphatic substrates were obtained in up to 97% ee with the ruthenium catalyst, while analogous rhodium catalysts resulted in only moderate enantioselectivity.

Synthesis of Polysubstituted Enamides by Hydrogen Atom Transfer Alkene Isomerization Using Dual Cobalt/Photoredox Catalysis.

M-HAT isomerization is a highly reliable method to access thermodynamically stable alkenes with high functional group tolerance. However, synthesis of heteroatom-substituted alkenes by M-HAT isomerization reaction is still underdeveloped. Herein, we report an enamide synthesis using M-HAT via a combination of cobalt and photoredox catalysis. This method tolerates a variety of functional groups including haloarenes, heteroarenes, free hydroxy groups, non-protected indoles, and drug derivatives. Furthermore, this method can isomerize styrene derivatives in good yield and E/Z selectivity.

Formation of Isolable Dearomatized [4 + 2] Cycloadducts from Benzenes, Naphthalenes, and N-Heterocycles Using 1,2-Dihydro-1,2,4,5-tetrazine-3,6-diones as Arenophiles under Visible Light Irradiation.

We report that the dearomative [4 + 2] cycloaddition between 1,2-dihydro-1,2,4,5-tetrazine-3,6-diones (TETRADs) and benzenes, naphthalenes, or N-heteroaromatic compounds under visible light irradiation affords the corresponding isolable cycloadducts. Several synthetic transformations including transition-metal-catalyzed allylic substitution reactions using the isolated cycloadducts at room temperature or above were demonstrated. Computational studies revealed that the retro-cycloaddition of the benzene-TETRAD adduct proceeds via an asynchronous concerted mechanism, while that of the benzene-MTAD adduct (MTAD = 4-methyl-1,2,4-triazoline-3,5-dione) proceeds via a synchronous mechanism.

An Electron-Deficient CpE Iridium(III) Catalyst: Synthesis, Characterization, and Application to Ether-Directed C-H Amidation.

The synthesis, characterization, and catalytic performance of an iridium(III) catalyst with an electron-deficient cyclopentadienyl ligand ([CpE IrI2 ]2 ) are reported. The [CpE IrI2 ]2 catalyst was synthesized by complexation of a precursor of the CpE ligand with [Ir(cod)OAc]2 , followed by oxidation, desilylation, and removal of the COD ligand. The electron-deficient [CpE IrI2 ]2 catalyst enabled C-H amidation reactions assisted by a weakly coordinating ether directing group. Experimental mechanistic studies and DFT calculations suggested that the high catalytic performance of [CpE IrI2 ]2 is due to its electron-deficient nature, which accelerates both C-H activation and IrV -nitrenoid formation.

Noble-Metal-Free C-H Allylation of Tetrahydroisoquinolines Using a Cobalt-Organophotoredox Dual Catalyst System.

Metallaphotoredox-catalyzed allylation represents an emerging synthetic methodology that enables allylic substitution using nucleophilic radical species. The C-H allylation of N-aryl tetrahydroisoquinolines is an innovative example in this area and allows access to synthetically useful precursors for the further derivatization of tetrahydroisoquinolines. However, previous methods have required the use of noble metals, which has hampered their application due to concerns over their sustainability. Here we report the C-H allylation of N-aryl tetrahydroisoquinolines using a cobalt/organophotoredox dual catalyst system. Based on precedent, control experiments and controlled irradiation experiments, a mechanism for the cobalt/photoredox-catalyzed allylation that involves a π-allyl cobalt complex is proposed.

Photoinduced Nickel-Catalyzed Carbon-Heteroatom Coupling.

Herein, we report visible light-promoted single nickel catalysis for diverse carbon-heteroatom couplings under mild conditions. This mild, general, and robust method to couple diverse nitrogen, oxygen, and sulfur nucleophiles with aryl(heteroaryl)/alkenyl iodides/bromides exhibits a wide functional group tolerance and is applicable to late-stage modification of pharmaceuticals and natural products. On the base of preliminary mechanistic studies, a NiI /NiIII cycle via the generation of active NiI complexes that appear from homolysis of NiII -I rather than NiII -aryl bond was tentatively proposed.

Photocatalytic Deuterium Atom Transfer Deuteration of Electron-Deficient Alkenes with High Functional Group Tolerance.

Due to its mild reaction conditions and unique chemoselectivity, hydrogen atom transfer (HAT) hydrogenation represents an indispensable method for the synthesis of complex molecules. Its analog using deuterium, deuterium atom transfer (DAT) deuteration, is expected to enable access to complex deuterium-labeled compounds. However, DAT deuteration has been scarcely studied for synthetic purposes, and a method that possesses the favorable characteristics of HAT hydrogenations has remained elusive. Herein, we report a protocol for the photocatalytic DAT deuteration of electron-deficient alkenes. In contrast to the previous DAT deuteration, this method tolerates a variety of synthetically useful functional groups including haloarenes. The late-stage deuteration also allows access to deuterated amino acids as well as donepezil-d2 . Thus, this work demonstrates the potential of DAT chemistry to become the alternative method of choice for preparing deuterium-containing molecules.

Native Amide-Directed C(sp3 )-H Amidation Enabled by Electron-Deficient RhIII Catalyst and Electron-Deficient 2-Pyridone Ligand.

Trivalent group-9 metal catalysts with a cyclopentadienyl-type ligand (CpMIII ; M=Co, Rh, Ir, Cp=cyclopentadienyl) have been widely used for directed C-H functionalizations, albeit that their application to challenging C(sp3 )-H functionalizations suffers from the limitations of the available directing groups. In this report, we describe directed C(sp3 )-H amidation reactions of simple amide substrates with a variety of substituents. The combination of an electron-deficient CpE Rh catalyst (CpE =1,3-bis(ethoxycarbonyl)-substituted Cp) and an electron-deficient 2-pyridone ligand is essential for high reactivity.

Iron/Photosensitizer Hybrid System Enables the Synthesis of Polyaryl-Substituted Azafluoranthenes.

Photosensitization of organometallics is a privileged strategy that enables challenging transformations in transition-metal catalysis. However, the usefulness of such photocatalyst-induced energy transfer has remained opaque in iron-catalyzed reactions despite the intriguing prospects of iron catalysis in synthetic chemistry. Herein, we demonstrate the use of iron/photosensitizer-cocatalyzed cycloaddition to synthesize polyarylpyridines and azafluoranthenes, which have been scarcely accessible using the established iron-catalyzed protocols. Mechanistic studies indicate that triplet energy transfer from the photocatalyst to a ferracyclic intermediate facilitates the thermally demanding nitrile insertion and accounts for the distinct reactivity of the hybrid system. This study thus provides the first demonstration of the role of photosensitization in overcoming the limitations of iron catalysis.

Genome-based discovery and total synthesis of janustatins, potent cytotoxins from a plant-associated bacterium.

Host-associated bacteria are increasingly being recognized as underexplored sources of bioactive natural products with unprecedented chemical scaffolds. A recently identified example is the plant-root-associated marine bacterium Gynuella sunshinyii of the chemically underexplored order Oceanospirillales. Its genome contains at least 22 biosynthetic gene clusters, suggesting a rich and mostly uncharacterized specialized metabolism. Here, in silico chemical prediction of a non-canonical polyketide synthase cluster has led to the discovery of janustatins, structurally unprecedented polyketide alkaloids with potent cytotoxicity that are produced in minute quantities. A combination of MS and two-dimensional NMR experiments, density functional theory calculations of 13C chemical shifts and semiquantitative interpretation of transverse rotating-frame Overhauser effect spectroscopy data were conducted to determine the relative configuration, which enabled the total synthesis of both enantiomers and assignment of the absolute configuration. Janustatins feature a previously unknown pyridodihydropyranone heterocycle and an unusual biological activity consisting of delayed, synchronized cell death at subnanomolar concentrations.

Design and Synthesis of Cyclopropane Congeners of Resolvin E3, an Endogenous Pro-Resolving Lipid Mediator, as Its Stable Equivalents.

Resolvins are pro-resolving lipid mediators with highly potent anti-inflammatory effects. Because of their polyunsaturated structures, however, they are unstable to oxygen as a drug prototype. To address this issue, we designed and synthesized CP-RvE3 as oxidatively stable congeners of RvE3 by replacing the cis-olefin with a cis-cyclopropane to avoid the unstable bisallylic structure. Although the oxidative stabilities of CP-RvE3 were not improved, ß-CP-RvE3 was 3.7 times more metabolically stable than RvE3. Thus, we identified ß-CP-RvE3 as a metabolically stable equivalent.

Cobalt(III)/Chiral Carboxylic Acid-Catalyzed Enantioselective Synthesis of Benzothiadiazine-1-oxides via C-H Activation.

Among sulfoximine derivatives containing a chiral sulfur center, benzothiadiazine-1-oxides are important for applications in medicinal chemistry. Here, we report that the combination of an achiral cobalt(III) catalyst and a pseudo-C2 -symmetric H8 -binaphthyl chiral carboxylic acid enables the asymmetric synthesis of benzothiadiazine-1-oxides from sulfoximines and dioxazolones via enantioselective C-H bond cleavage. With the optimized protocol, benzothiadiazine-1-oxides with several functional groups can be accessed with high enantioselectivity.

Achiral Cp*Rh(III)/Chiral Lewis Base Cooperative Catalysis for Enantioselective Cyclization via C-H Activation.

An enantioselective [4+3] cyclization via C(sp2)-H activation with a cooperative catalytic system consisting of a Cp*Rh(III) complex and a chiral Lewis base is described. An α,ß-unsaturated acyl ammonium intermediate is generated from a chiral isochalcogenurea catalyst and an acyl fluoride reacts with a metallacycle generated from the Cp*Rh catalyst and a benzylamine derivative. This cooperative catalytic system gives a variety of benzolactams in good yields with excellent enantioselectivities (up to 99:1 er). The results demonstrated that chiral Lewis base catalysis is a powerful tool for controlling the enantioselectivity of transition metal-catalyzed C-H functionalizations.

Regioselective Deaminative Allylation of Aliphatic Amines via Dual Cobalt and Organophotoredox Catalysis.

Despite the rapid progress in C-C bond-forming reactions using Katritzky salts, their deaminative allylation remains a challenge. Inspired by the metallaphotoredox-catalyzed allylic substitution regime, here, we report the deaminative allylation of Katritzky salts via cobalt/organophotoredox dual catalysis. This cross-electrophile coupling enables regioselective allylation using a variety of allylic esters, overcoming the substrate limitations of reported protocols. Mechanistic studies indicate the involvement of a π-allyl cobalt complex as a radicalophile that mediates C-C bond formation.

Intramolecular Hydrogen Atom Transfer Hydroarylation of Alkenes toward δ-Lactams Using Cobalt-Photoredox Dual Catalysis.

Intramolecular hydroarylation of alkenes through hydrogen atom transfer (HAT) represents a robust method to prepare benzo-fused heterocycles. However, the reported methods have limitations in a variety of accessible cyclic scaffolds. Here we report a dual cobalt- and photoredox-catalyzed HAT hydroarylation of alkenes that is characterized by higher efficiency in the synthesis of a δ-lactam compared to established protocols. The proposed mechanism is supported by experiments and DFT calculations.

1,2-Disubstituted 1,2-Dihydro-1,2,4,5-tetrazine-3,6-dione as a Dynamic Covalent Bonding Unit at Room Temperature.

Dynamic covalent bonds are useful tools in a wide range of applications. Although various reversible chemical reactions have been studied for this purpose, the requirement for harsh conditions, such as high temperature and low or high pH, to activate generally stable covalent bonds limits their potential applications involving biomolecules or household utilization. Here, we report the design, synthesis, characterization, and dynamic covalent bonding properties of 1,2-disubstituted 1,2-dihydro-1,2,4,5-tetrazine-3,6-dione (TETRAD). Hetero-Diels-Alder reactions of TETRAD with furan derivatives and their retro-reactions proceeded rapidly at room temperature under neutral conditions, enabling a chemically induced sol-gel transition system.