Search

Ruthenium(II)-catalyzed enantioselective C–H functionalization reactions of sulfoximines with sulfoxonium ylides are described. The combination of [RuCl2(p-cymene)]2 and a pseudo-C 2-symmetric binaphthyl monocarboxylic acid furnished the S-chiral products in 76:24 to 92:8 er.

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 Ni

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

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.

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.

Myrindole A, a bis-indole alkaloid, was isolated from the deep-sea sponge Myrmekioderma sp. The high degree of unsaturation of the molecule complicated the assignment of its structure by standard 2D-NMR experiments but was ultimately achieved by a combination of 1H-15N-HMBC and 1,n-ADEQUATE experiments as well as the comparison of measured and calculated CD spectra. Myrindole A showed antimicrobial activity against Gram-positive and Gram-negative bacteria.

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.

Enantioselective C–H alkylation of ferrocene carboxamides with diazomalonates using an achiral Cp*Ir(III)/chiral carboxylic acid is described. The combination of an achiral Cp*Ir(III) complex and a binaphthyl-based chiral carboxylic acid provided planar chiral alkylated ferrocenes in good yields with moderate to good enantioselectivity (up to 94 : 6 er).

The enantioselective C-H alkylation of 8-ethylquinolines with enones or acrolein using a RhIII catalyst and a chiral carboxylic acid is described. Under mild reaction conditions, a binaphthyl-based chiral carboxylic acid enables the enantioselective cleavage of the 8-ethylquinoline C(sp3)-H bond. The obtained results demonstrate the utility of the combination of a high-valent group 9 metal catalyst and a chiral carboxylic acid for the enantioselective C(sp3)-H activation and the subsequent C-C bond formation.

Despite their unique potential as rare 1,1-dipole synthons, allyl sulfones are rarely used in target-oriented syntheses, likely due to the lack of a general catalytic method for their branch-selective allylic substitution. Herein, we identified allyl 4-chlorophenyl sulfone as a versatile linchpin for both base-mediated α-derivatization and subsequent cobalt-catalyzed allylic substitution. The sequential transformations allow for highly regioselective access to branched allylic substitution products with a variety of aliphatic side chains. The photoredox-enabled­ ­cobalt catalysis is indispensable for achieving high yields and regioselectivity­ for the desulfonylative substitution in contrast to traditional metal-catalyzed protocols, which lead to inferior outcomes in the corresponding transformations.

Transition-metal-catalyzed C-H functionalization reactions with Cp*MIII catalysts (M=Co, Rh, Ir) have found a wide variety of applications in organic synthesis. Albeit the intrinsic difficulties in achieving catalytic stereocontrol using these catalysts due to their lack of additional coordination sites for external chiral ligands and the conformational flexibility of the Cp ligand, catalytic enantioselective C-H functionalization reactions using the Group 9 metal triad with Cp-type ligands have been intensively studied since 2012. In this minireview, the progress in these reactions according to the type of the chiral catalyst used are summarized and discussed. The development of chiral Cpx ligands the metal complexes thereof, artificial metalloenzymes, chiral carboxylate-assisted enantioselective C-H activations, enantioselective alkylations assisted by chiral carboxylic acids or chiral sulfonates, and chiral transient directing groups are discussed.

An extensively N-methylated linear nonapeptide heptavalinamide A (1) was isolated from the marine cyanobacterium Symploca sp. collected at Kabira Reef of Ishigaki Island, Okinawa. The amino acid sequence of 1 was assigned by interpretation of 2D NMR and MS/MS data. The absolute configurations of the constituent amino acids were determined by the application of Marfey's method. A method to assign the configuration of N,N-dimethylvaline by LCMS is discussed.

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.

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 pi-allyl cobalt complex as a radicalophile that mediates C-C bond formation.

N 6-Isopentenyladenosine (i6A) was isolated from a marine sponge Oceanapia sp. as the major cytotoxic constituent along with N6-isopentenyladenosine 5ʹ-monophosphate (i6AP) which was inactive. The structures of i6A and i6AP were assigned by a combination of the analysis of NMR spectroscopy and mass spectrometry. This is the first isolation of i6A and i6AP from a marine sponge.

Homoallylic amines are important synthetic targets in organic synthesis. Compared to other conventional allylation reactions using pre-functionalized allylic compounds, the allylation of imines usi...

Cobalt-catalyzed C-H allylation reactions of NH-free benzimidates using vinylcyclopropanes or allyl carbonate are reported. The reactive and relatively unstable imidate groups remain intact during the C-H allylations to afford functionalized imidates without dealcoholizations. The thus obtained allylated imidate was subsequently converted into other heterocyclic structures through a following C-H functionalization reaction, demonstrating the synthetic utility of this method.

Enantioselective C–H functionalization reactions using trivalent group 9 metals (Co, Rh, Ir) have been investigated mainly on the basis of the development of well-designed chiral cyclopentadienyl (...

This account describes Cp*CoIII-catalyzed C–H functionalization reactions developed in our group between 2013 and 2018. Cp*CoIII catalysts not only serve as inexpensive alternatives to Cp*RhIII catalysts but also exhibit unique reactivity and selectivity in several transformations. In the latter part of this review, we introduce catalytic asymmetric C–H functionalization reactions using achiral RhIII or CoIII catalysts with chiral disulfonates or carboxylic acids as external chiral sources.1 Introduction and Overview2 Cp*CoIII-Catalyzed C–H Functionalization Reactions2.1 C–H Addition Reactions to Polar Double Bonds2.2 Cp*Co(CO)I2 and [Cp*CoI2]2 Precursors for the C2-selective C–H Amidation of Indoles2.3 C–H Functionalization of Carbamoyl-Protected Indoles Using Alkynes2.4 C–H Allylation Using Allyl Alcohols2.5 Cyclization Reactions of O-Acyloximes and Alkynes2.6 Other Miscellaneous Reactions3 Enantioselective C–H Functionalization Reactions by Hybrid Catalysis3.1 Cp*RhIII/Chiral Disulfonate Catalysts for the Enantioselective C–H Addition to Enones3.2 Enantioselective C–H Cleavage Using Chiral Carboxylic Acids4 Summary and Perspective

The photocatalyst-free C-H γ,γ,γ-trifluoroalkylation of quinolines under visible light irradiation is reported. By the combination of readily available alkenes and Umemoto's reagent II, a variety of γ,γ,γ-trifluoroalkyl groups were installed into quinolines via chemoselective sequential radical processes. This transformation provides rapid access to a variety of quinoline derivatives with scarcely explored fluoroalkyl groups, affording a novel library of N-heteroaromatic compounds and versatile building blocks for applications in medicinal chemistry.

Monoaryl-λ3 -iodanes are potentially attractive arylating agents. They are generally synthesized from aryl iodides via oxidation, which can cause functional group incompatibility, especially when polyfunctionalized derivatives are desired. This work describes the direct synthesis of monoaryl-λ3 -iodanes through a chemoselective ipso-substitution reaction of arylgermanes and arylstannanes with iodine tris(trifluoroacetate). The generated iodanes were converted to iodonium ylides or used for further transformations in one pot. The presented method enables the preparation of polyfunctionalized monoaryl-λ3 -iodanes.

There are several examples of marine organisms whose metabolic profiles differ among conspecifics inhabiting the same region. We have analyzed the metabolic profile of each colony of a Theonella swinhoei marine sponge with a yellow interior and noticed the patchy distribution of one metabolite. This compound was isolated and its structure was studied by a combination of spectrometric analyses and chemical degradation, showing it to be a congener in the theonellamide class of bicyclic peptides. Theonellamides had previously been isolated by us only from T. swinhoei with a white interior and not from those with a yellow interior.

Stellatolide H (1) was isolated from a deep-sea sponge Discodermia sp. as the cytotoxic constituent. The planar structure of 1 was elucidated on the basis of the NMR spectroscopic and mass spectrometric data. The absolute configurations of the constituent amino acid residues were determined by the Marfey’s method. Stellatolide H (1) is a peptide lactone of the callipeltin class with its N-terminus blocked by 3-hydroxy-6,8-dimethyldeca-(4Z,6E)-dienoic acid (Hdda).

Palladium-catalyzed germylation of aryl bromides and aryl triflates using commercially available hexamethyldigermane is described. Optimized reaction conditions afforded various functionalized aryltrimethylgermanes, including drug-like molecules, in moderate to good yields, demonstrating the versatility of the presented protocols.

Poecillastrin H (1), a chondropsin-type macrolide with a conjugated pentaene moiety, was isolated from the Characella sp. marine sponge. The planar structure of 1 was elucidated by analysis of spectroscopic data. The absolute configuration of the β-hydroxyaspartic acid residue (β-OHAsp) was determined to be d-threo by Marfey’s analysis, and the mode of lactone ring formation through the OHAsp residue was determined by chemical degradation. Poecillastrin H was extremely sensitive toward light and showed potent cytotoxic activity against 3Y1 cells with an IC50 value of 4.1 nM.

Morphology-guided cell-based screening of the extract of a Mycale sp. marine sponge led to the isolation of two trisoxazole macrolides, miuramides A (1) and B (2), which induced characteristic morphological changes in 3Y1 cells. The structure of 1 including absolute configuration was elucidated by a combination of the analysis of spectroscopic data, derivatization, and degradation. Both compounds exhibit potent cytotoxicity against 3Y1 cells.

Poecillastrin E (1), F (2), and G (3) were isolated from a marine sponge Poecillastra sp. as the cytotoxic constituents. Their planar structures were determined by analyzing the MS and NMR spectra. They are closely related to the known poecillastrin C (4). The absolute configuration of the β-hydroxyaspartic acid (OHAsp) residue was determined to be D-threo by Marfey's analysis of the hydrolysate. The mode of lactone ring formation of OHAsp residue in 1–3 was determined by selective reduction of the ester linkage followed by acid hydrolysis.

Direct comparison of authentic ciliatamide A with four synthetic isomers (1-4) by means of NMR and chiral-phase HPLC revealed that ciliatamide A possesses the 12R (d-N-MePhe residue) and 22S (l-Lys residue) configurations, which were not identical with either our previous assignment or those proposed by others through total synthesis. The absolute configuration of the methionine sulfoxide residue in ciliatamide D was also revised to be d.

The first total synthesis of brasilicardins A and C, novel diterpenoid-saccharide-amino acid hybrid metabolites with unique immunosuppressive activity, is described. The key step is a Diels-Alder/reductive angular methylation sequence capitalizing on a trans-fused bicyclic α-cyano-α,β-enone as its precursor to construct the 8,10-dimethyl-trans/syn/trans-perhydrophenanthrene skeleton. Other notable features include an anti-selective aldol reaction, a stereocontrolled glycosylation of a C2 alcohol, and a one-pot, two-step global deprotection sequence that did not damage these sensitive molecules.

A novel indole-2,3-epoxide equivalent, 2-hydroxyindoline-3-triethylammonium bromide, was found to be a convenient reagent for formal C3-electrophilic reactions of indoles with various nucleophiles. By taking advantage of the nucleophilic character of the oxygen of the 2-hydroxyindoline, the interrupted retro-Claisen and interrupted Feist-Bénary reactions with 1,3-dicarbonyl compounds were efficiently achieved.

The Cp*CoIII-catalyzed C–H functionalization reaction of indoles with alkynes was examined using M06-level DFT calculations. The C≡C bond in the alkyne was inserted into the Co–C bond of an intermediate alkenyl–Co complex given by the acetate-assisted C–H bond activation step. Then the reaction pathway bifurcated into alkenylation and annulation pathways. In the case where AcOH, which was eliminated by ligand exchange for the alkyne, recoordinated to the Co atom, alkenylation proceeded via proton transfer. On the other hand, the annulation pathway to give pyrroloindolone became significant in the case where the ring-closure C–C bond formation was followed by the attachment of AcOH. At a high temperature (393 K), the difference in the Gibbs free energy between the transition state for proton transfer in the alkenylation pathway and that for the ring-closure C–C bond formation in the annulation pathway was relatively small, so both reactions could proceed. In addition, we also found another pathway to provi...

High-valent (pentamethylcyclopentadienyl)cobalt(III) [Cp*Co(III)] catalysts were found as inexpensive alternatives to (pentamethylcyclopentadienyl)rhodium(III) [Cp*Rh(III)] catalysts in the field of C—H bond functionalization, and applied to a variety of transformations. In this review, after the discovery and early examples of Cp*Co(III)-catalyzed C—H bond functionalization are summarized, the unique reactivity and selectivity of Cp*Co(III) and the differences between the cobalt and rhodium catalysis are intensively discussed. Such differences are assumed to be caused by the lower electronegativity, hard nature, and smaller ionic radius of cobalt.

New sesquiterpene quinones, metachromins X (1) and Y (2), together with the known metachromins C (3), J (4), and T (5), were isolated as inhibitors of cell cycle progression in the HeLa/Fucci2 cells. The structure of 1 was assigned by spectroscopic data and confirmed by a total synthesis. The planar structure of 2 was determined by interpretation of spectroscopic data, whereas its absolute configuration was analyzed by a combination of chiral HPLC and CD spectroscopy. Metachromins X (1) and C (3) arrested the cell cycle progression of HeLa/Fucci2 cells at S/G2/M phase.

SurE is a new, stand-alone thioesterase (TE) offloading the non-ribosomal peptide (NRP) assembly line found in surugamide biosynthesis. It is homologous to penicillin binding protein (PBP) and capable of cyclizing two structurally unrelated substrates derived from two different NRP assembly lines, highlighting the broad substrate tolerance of the SurE offloading cyclase.

Theonellamide A (TNM-A) is an antifungal bicyclic dodecapeptide isolated from a marine sponge Theonella sp. Previous studies have shown that TNM-A preferentially binds to 3β-hydroxysterol-containing membranes and disrupts membrane integrity. In this study, several 1H NMR-based experiments were performed to investigate the interaction mode of TNM-A with model membranes. First, the aggregation propensities of TNM-A were examined using diffusion ordered spectroscopy; the results indicate that TNM-A tends to form oligomeric aggregates of 2-9 molecules (depending on peptide concentration) in an aqueous environment, and this aggregation potentially influences the membrane-disrupting activity of the peptide. Subsequently, we measured the 1H NMR spectra of TNM-A with sodium dodecyl sulfate-d25 (SDS-d25) micelles and small dimyristoylphosphatidylcholine (DMPC)-d54/dihexanoylphosphatidylcholine (DHPC)-d22 bicelles in the presence of a paramagnetic quencher Mn2+. These spectra indicate that TNM-A poorly binds to these membrane mimics without sterol and mostly remains in the aqueous media. In contrast, broader 1H signals of TNM-A were observed in 10mol% cholesterol-containing bicelles, indicating that the peptide efficiently binds to sterol-containing bilayers. The addition of Mn2+ to these bicelles also led to a decrease in the relative intensity and further line-broadening of TNM-A signals, indicating that the peptide stays near the surface of the bilayers. A comparison of the relative signal intensities with those of phospholipids showed that TNM-A resides in the lipid-water interface (close to the C2' portion of the phospholipid acyl chain). This shallow penetration of TNM-A to lipid bilayers induces an uneven membrane curvature and eventually disrupts membrane integrity. These results shed light on the atomistic mechanism accounting for the membrane-disrupting activity of TNM-A and the important role of cholesterol in its mechanism of action.