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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Chemoselective Cleavage of Si-C(sp3) Bonds in Unactivated Tetraalkylsilanes Using Iodine Tris(trifluoroacetate).

Organosilanes are synthetically useful reagents and precursors in organic chemistry. However, the typical inertness of unactivated Si-C(sp3) bonds under conventional reaction conditions has hampered the application of simple tetraalkylsilanes in organic synthesis. Herein we report the chemoselective cleavage of Si-C(sp3) bonds of unactivated tetraalkylsilanes using iodine tris(trifluoroacetate). The reaction proceeds smoothly under mild conditions (-50 °C to room temperature) and tolerates various polar functional groups, thus enabling subsequent Tamao-Fleming oxidation to provide the corresponding alcohols. NMR experiments and density functional theory calculations on the reaction indicate that the transfer of alkyl groups from Si to the I(III) center and the formation of the Si-O bond proceed concertedly to afford an alkyl-λ3-iodane and silyl trifluoroacetate. The developed method enables the use of unactivated tetraalkylsilanes as highly stable synthetic precursors.

Transition-metal-free nucleophilic 211At-astatination of spirocyclic aryliodonium ylides.

The transition-metal-free 211At-astatination of spirocyclic aryliodonium ylides via a nucleophilic aromatic substitution reaction is described. This method enables the preparation of 211At-radiolabeled compounds derived from multi-functionalized molecules and heteroarenes in good to excellent radiochemical yields.

Oshimalides A and B, Sesterterpenes of the Manoalide Class from a Luffariella sp. Deep-Sea Marine Sponge: Application of Asymmetric Dihydroxylation in Structure Elucidation.

Oshimalides A (1) and B (2) were isolated from a Luffariella sp. marine sponge. The absolute configurations of the stereogenic centers in the cyclohexenone ring were determined by the modified Mosher's analysis of the reduction product. The absolute configuration of the stereogenic center in the dihydropyran ring was assigned by analysis of the 1H NMR data of the vicinal diols which were prepared by AD-mix reagents stereoselectively.

Homophymamide A, Heterodetic Cyclic Tetrapeptide from a Homophymia sp. Marine Sponge: A Cautionary Note on Configurational Assignment of Peptides That Contain a Ureido Linkage.

A previously unreported heterodetic cyclic peptide, homophymamide A (1), was isolated from a Homophymia sp. marine sponge. The structure of homophymamide A was determined to be a lower homologue of anabaenopeptins by spectroscopic analysis, chemical degradation, and chemical synthesis. Analysis of the acidic hydrolysate showed that the racemization of Lys took place, leading us to pose a cautionary note on the configurational assignment of peptides that contain a ureido bond.

Structure Elucidation of Calyxoside B, a Bipolar Sphingolipid from a Marine Sponge Cladocroce sp. through the Use of Beckmann Rearrangement.

Marine sponges are an excellent source of biologically active secondary metabolites. We focus on deep-sea sponges for our discovery study. A marine sponge Cladocroce sp. exhibited cytotoxic activity in the bioactivity screening. From this sponge a previously unreported cytotoxic glycosphingolipid, calyxoside B, was isolated and the structure of this compound was elucidated by analyses of MS and NMR spectra and chemical derivatization. We converted the ketone in the middle of a long aliphatic chain into an oxime to which was applied Beckmann rearrangement to afford two positional isomers of amides. The products were subjected to acidic hydrolysis followed by LC-MS analysis, permitting us to assign unequivocally the position of the ketone. Calyxoside B shows cytotoxicity against HeLa cells with an IC50 value of 31 µM and also weakly stimulated the production of cytokines in mice.

Single-bacterial genomics validates rich and varied specialized metabolism of uncultivated Entotheonella sponge symbionts.

Marine sponges are prolific sources of unique bioactive natural products. The sponge Theonella swinhoei is represented by several distinct variants with largely nonoverlapping chemistry. For the Japanese chemotype Y harboring diverse complex polyketides and peptides, we previously provided genomic and functional evidence that a single symbiont, the filamentous, multicellular organism "Candidatus Entotheonella factor," produces almost all of these compounds. To obtain further insights into the chemistry of "Entotheonella," we investigated another phylotype, "Candidatus Entotheonella serta," present in the T. swinhoei WA sponge chemotype, a source of theonellamide- and misakinolide-type compounds. Unexpectedly, considering the lower chemical diversity, sequencing of individual bacterial filaments revealed an even larger number of biosynthetic gene regions than for Ca E. factor, with virtually no overlap. These included genes for misakinolide and theonellamide biosynthesis, the latter assigned by comparative genomic and metabolic analysis of a T. swinhoei chemotype from Israel, and by biochemical studies. The data suggest that both compound families, which were among the earliest model substances to study bacterial producers in sponges, originate from the same bacterium in T. swinhoei WA. They also add evidence that metabolic richness and variability could be a more general feature of Entotheonella symbionts.