Iterative synthesis of nitrogen-containing polyketide via oxime intermediates.

Typical polyketides consist of C, H, and O atoms, whereas several types of N-containing polyketides are known to show intriguing properties. Because conventional synthetic approaches for such compounds focus on only specific structures, a more general method is desirable. Here, we have developed an iterative synthesis of nitrogen-containing polyketide. Chain elongation of carboxylic acid via decarboxylative Claisen condensation with malonic acid half thioester was iteratively performed to construct carbon frameworks. ß-Keto groups formed by the chain elongation were appropriately converted to O-methyl oximes for incorporation of nitrogen atoms. Cyclization of the resulting oxime intermediates followed by reductive N-O cleavage afforded structurally diverse nitrogen-containing polyketides such as 2-pyridone, 4-aminopyrone, and 4-aminosalicylate. This method was finally applied to the synthesis of (R)-6-aminomellein, which is a nitrogen-substituted derivative of bioactive compound, (R)-6-methoxymellein. The versatility of the present method would enable the synthesis of diverse polyketides with nitrogen functional groups, which can be potentially utilized for the development of novel bioactive compounds.

Solid-Phase Biomimetic Synthesis of Polyketide.

Solid-phase biomimetic polyketide synthesis has been developed. This method is composed of (i) carbon chain elongation of resin-bound carboxylic acid via decarboxylative Claisen condensation with malonic acid half thioester, (ii) stepwise transformation of the resulting ß-ketothioester, and (iii) hydrolysis of thioester to regenerate the carboxylic acid for the next iteration cycle. Colorimetric tests were available for convenient monitoring of the solid-phase reactions; malachite green (basic dye) and iron(III) chloride successfully detected the carboxylic acid and the ß-ketothioester, respectively. In addition, gel-phase 13C NMR could be utilized to confirm the progress of substrate immobilization. The established method was applied to the synthesis of the natural products, xylapyrone C and kavain. The present method could be further extended to the synthesis of (R)-kavain with catalytic diastereoselective asymmetric transfer hydrogenation as a key step.

Iterative Polyketide Synthesis via a Consecutive Carbonyl-Protecting Strategy.

To address the difficulty in protecting a ß-polycarbonyl compound, a method for the sequential protection of elongating carbonyl groups was demonstrated. The iterative chain elongation of a carboxylic acid with malonic acid half thioester followed by the protection of the resulting ß-ketothioester was performed via the stepwise formation of an isoxazole ring using an O-protected oxime functionality. Yangonin and isosakuranetin were synthesized according to this procedure.

Development of Selective Peptide Catalysts with Secondary Structural Frameworks.

Enzymes are biogenic catalysts that enable the vital activity of organisms. Enzymes promote reactions in a selective manner with a high level of substrate recognition ability. The development of such a sophisticated catalyst has been one of the goals for chemists. A synthetic peptide is the prime candidate to realize an enzyme-like catalyst. Considering that the catalytic function of enzymes derives from their molecular structures, the key for the creation of a peptide catalyst might be the introduction of a specific three-dimensional structure. Our motivation was to find a peptide catalyst with a versatile secondary structural framework and apply the peptide to a variety of selective reactions. Although helical-peptide-catalyzed asymmetric epoxidation of enones is popular, no other highly enantioselective reaction with a helical peptide has been reported. It was found that resin-supported α-helical polyleucine promoted asymmetric conjugate addition of a carbon nucleophile to enones via the formation of an iminium intermediate at the N-terminal amino group. By changing the helical chain to a repetitive Leu-Leu-Aib (Aib = α-aminoisobutyric acid) sequence and introducing a few amino acids to the N-terminus, a highly enantioselective peptide catalyst was obtained. The helical peptide catalyst was applicable for a tandem enamine/iminium-mediated reaction and asymmetric epoxidation of enones. Although the extension of the helical peptide to conjugate addition of a nucleophile to an enal was not successful simply by attaching proline to the N-terminus of the helix, the incorporation of a ß-turn motif was effective to improve the catalytic performance. In the sequence of such a turn-helix-type peptide, the helical part was seemingly distant from the N-terminal amino group; however, the hydrophobicity, structure, and chirality of the helix largely affected the reaction. The turn-helix-type peptide promoted a wide range of asymmetric reactions: conjugated additions of hydride and carbon nucleophiles to enals via the iminium activation and α-oxyamination of aldehydes via the enamine activation. The peptides with turn-helix and helix frameworks were also employed for several reactions that were difficult to achieve with low-molecular-weight catalysts: enzyme-cocatalyzed asymmetric oxidation in water, diastereo- and enantioselective cyclopropanation, regioselective reduction of dienals, kinetic resolution of planar-chiral compounds, and desymmetrization to induce planar chirality. To explore other types of peptide catalysts, a combinatorial library screening was performed. On the way, it was revealed that a histidyl residue assisted to accelerate a reaction via reversible addition to an iminium intermediate. Through the screening of random peptide libraries, novel peptide sequences for efficient and enantioselective conjugate addition were discovered. Although we have no information about the molecular structure of the newly found peptides, they can be an entry point for establishing a versatile framework of peptide catalysts.

Biomimetic iterative method for polyketide synthesis.

An iterative method for synthesizing polyketides was demonstrated, in which the chain elongation of a carboxylic acid was performed by decarboxylative dehydration condensation with a malonic acid half thioester. After transforming the resulting ß-ketothioester into an appropriate form, the carboxylic acid functionality was regenerated for the next elongation step.

Determination of the Absolute Configuration of Side Chains of Basic Amino Acid Residues Using the Water-Soluble Porphyrin-Based Exciton Chirality Method.

We demonstrated that the circular dichroism (CD) exciton chirality method, based on the supramolecular interactions of meso-tetra(4-sulfonatophenyl)porphyrin (MTPPS4, M = Zn or H2), was applicable for the determination of the absolute configuration between the side chains of two basic amino acid residues of stable monomeric ß-hairpin peptides (tryptophan zipper: Trpzip). When MTPPS4 was added to an aqueous solution containing Trpzip, a bisignate CD signal was detected in the Soret band region in addition to a decrease in absorbance. These spectral changes indicated the formation of a supramolecule consisting of Trpzip and MTPPS4 via electrostatic interactions between the positively charged lysine residue of Trpzip and the negatively charged sulfonate group of MTPPS4. On the basis of the Job plots, the supramolecular structure of Trpzip-ZnTPPS4 is ZnP-Tz-ZnP or ZnP-Tz-ZnP-Tz-ZnP, whereas that of Trpzip-H2TPPS4 is -(-H2P-Tz-)n- (MP and Tz denote MTPPS4 and Trpzip, respectively). To explain the bisignate CD spectra of the supramolecules, a plausible model, that is, ZnP-Tz-ZnP, was carefully analyzed by the CD exciton chirality method: two orthogonalized electric transition dipole moments of each MTPPS4 and the effects of free rotation of MTPPS4 around the electrostatic bonding axis were considered. The exciton-coupled CD spectral pattern based on ZnTPPS4 reflected the absolute configuration between the side chains of two lysine residues. Our approach can be used to determine the absolute configuration of side chains of other peptides with two basic amino acid residues in the amino acid sequences.

Exploration of Structural Frameworks for Reactive and Enantioselective Peptide Catalysts by Library Screenings.

By screening large-scale N-terminal l-prolyl peptide libraries, we explored efficient catalysts for asymmetric Michael addition of a malonate to an enal. The catalytically active peptides obtained by the screening could be categorized into two groups based on the similarity of amino acid sequences. One group of the peptides selectively gave an S-product, whereas the other gave an R-product, despite all of the peptides having a common N-terminal sequence, Pro-d-Pro. Further optimization by second-generation screenings afforded more reactive and enantioselective catalysts. It was found that the peptides having a histidine residue at the seventh position were good catalysts, and their reaction efficiencies were correlated with the abilities of entrapping a substrate into resin beads.

Helical-Peptide-Catalyzed Enantioselective Michael Addition Reactions and Their Mechanistic Insights.

Helical peptide foldamer catalyzed Michael addition reactions of nitroalkane or dialkyl malonate to α,ß-unsaturated ketones are reported along with the mechanistic considerations of the enantio-induction. A wide variety of α,ß-unsaturated ketones, including ß-aryl, ß-alkyl enones, and cyclic enones, were found to be catalyzed by the helical peptide to give Michael adducts with high enantioselectivities (up to 99%). On the basis of X-ray crystallographic analysis and depsipeptide study, the amide protons, N(2)-H and N(3)-H, at the N terminus in the α-helical peptide catalyst were crucial for activating Michael donors, while the N-terminal primary amine activated Michael acceptors through the formation of iminium ion intermediates.

Histidine-containing peptide catalysts developed by a facile library screening method.

Although peptide catalysts have a high potential for the use as organocatalysts, the optimization of peptide sequences is laborious and time-consuming. To address this issue, a facile screening method for finding efficient aminocatalysts from a peptide library has been developed. In the screening for the Michael addition of a malonate to an enal, a dye-labeled product is immobilized on resin-bound peptides through reductive amination to visualize active catalysts. This procedure allows for the monitoring of the reactivity of entire peptides without modifying the resin beads beforehand. Peptides containing histidine at an appropriate position were identified by this method. A novel function of the histidyl residue, which enhances the binding of a substrate to the catalyst by capturing an iminium intermediate, was indicated.

Peptide-catalyzed kinetic resolution of planar-chiral metallocenes.

Kinetic resolution of racemic planar-chiral metallocenes was performed through the conjugate addition of a nucleophile to the enal part of substrates. While no enantiomeric discrimination was found with low-molecular-weight organocatalysts, a properly designed resin-supported peptide catalyzed the reaction in a highly selective manner.

Peptide-catalyzed consecutive 1,6- and 1,4-additions of thiols to α,ß,γ,δ-unsaturated aldehydes.

Regio- and enantioselective addition of thiols to α,ß,γ,δ-unsaturated aldehydes was performed with a resin-supported peptide catalyst. It was shown that a 1,4-adduct was generated mainly at the initial stage of the reaction, and this was eventually converted to a thermodynamically stable 1,6- and 1,4-diadduct through retro-addition/addition reactions.

Correction: Peptide-catalyzed kinetic resolution of planar-chiral metallocenes.

Correction for 'Peptide-catalyzed kinetic resolution of planar-chiral metallocenes' by Midori Akiyama et al., Chem. Commun., 2014, 50, 7893-7896.

Peptide-catalyzed diastereo- and enantioselective cyclopropanation of aromatic α,ß-unsaturated aldehydes.

Highly diastereo- and enantioselective cyclopropanation of aromatic α,ß-unsaturated aldehydes was achieved using a resin-supported peptide catalyst under aqueous conditions. In the peptide sequence, the residue possessing an oxygen atom with the appropriate length of the side chain was essential for attaining good diastereoselectivity.

Peptide-catalyzed regio- and enantioselective reduction of α,ß,γ,δ-unsaturated aldehydes.

A resin-supported peptide catalyst (see box in the scheme) was used in the title reaction. The inherent regioselectivity was overcome by the peptide catalyst to promote the 1,6-selective reaction prior to 1,4-reduction. High stereoconvergence was also achieved when using a mixture of geometric isomers of the starting aldehydes. Ach=1-amino-1-cyclohexanecarboxylic acid.

Asymmetric one-pot sequential Friedel-Crafts-type alkylation and α-oxyamination catalyzed by a peptide and an enzyme.

In the presence of a peptide catalyst and the oxidative enzyme laccase, a one-pot sequential reaction including a Friedel-Crafts-type alkylation of α,ß-unsaturated aldehydes followed by an α-oxyamination was realized. The reaction in aqueous solvent to promote the enzymatic oxidation, and the use of a peptide catalyst compatible with such conditions, were essential. The present sequential reaction afforded oxygen-functionalized indole or pyrrole derivatives in a highly enantioselective manner.

Asymmetric Michael addition of boronic acids to a γ-hydroxy-α,ß-unsaturated aldehyde catalyzed by resin-supported peptide.

A resin-supported peptide catalyst effective for the asymmetric Michael addition of boronic acids to (E)-4-hydroxybut-2-enal was developed. From a spectral study, it was revealed that the optimum peptide consisted of both a ß-turn and helix. Such a combination of secondary structures was essential for achieving a high catalytic ability.

Preparation and characterization of nanoporous thin films from fully aliphatic polyimides.

Fully aliphatic polyimides (APIs) were prepared from rel-(1'R,3S5'S)-spiro[furan-3(2H),6'-[3]oxabicyclo[3.2.1]octane]-2,2',4',5(4H)-tetrone (DAn) as unsymmetrical spiro dianhydride, and either cis-trans-1,4-diaminocyclohexane (mix-DACH) or trans-1,4-diaminocyclohexane (trans-DACH) as diamine. Structure of all prepared monomers and polymers was confirmed via 1H-NMR and FT-IR. The solubility, optical transparency, and thermal properties of the full APIs were investigated. The solubility and decomposition temperature of the full APIs were found to be correlated with their intermolecular regularity confirmed via wide-angle X-ray diffraction (WAXD). Triblock copolyimides were synthesized through the incorporation of a thermally labile polymer, poly(propylene glycol) (PPG), into the full APIs, and their thermal properties were studied via thermogravimetric analysis (TGA). Nanoporous thin films of the full APIs were prepared via thermolysis of the labile block in the copolyimide films. Phase separation and nanopore formation in the copolymer films were confirmed via atomic force microscopy (AFM) and scanning electron microscopy (SEM), respectively. Nanoporous pores were successfully prepared inside the films.

Peptide/laccase cocatalyzed asymmetric α-oxyamination of aldehydes.

An asymmetric α-oxyamination could be successfully performed by a peptide catalyst and laccase. The combination of peptide catalysis and enzymatic air oxidation promoted the reaction smoothly in water without employing a metal reagent. The oxyaminated compounds could be obtained as both aldehyde and carboxylic acid products depending on the reaction conditions.

Cadmium sorption to plasma membrane isolated from barley roots is impeded by copper association onto membranes.

The present study was designed to examine the effect of copper (Cu) on sorption of cadmium (Cd) to plasma membrane (PM) preparations as one of the models of competition between metals on root PM. Plasma membrane preparations were obtained from roots of barley (Hordeum vulgare L. cv. Minorimugi) and 50 µM CdSO4 with or without 50 µM CuSO4 were added to the PM suspensions. The sorption of Cd to PM vesicles increased with time within 15 min while Cu sorption to the PM occurred instantaneously. The sorption of Cd to PM vesicles was inactivated immediately after the addition of Cu into the reaction mixture. Results indicate that Cu association to PM vesicles occurs quicker than Cd, and, as a result, impedes the access of Cd to PM vesicles. The present study suggests that the competition between Cd and other minerals at root PM of plants can be demonstrated by employing isolated PM preparations. We consider that the difference in the capacity among some minerals for impeding Cd sorption to PM may also be characterized by investigating the interaction between Cd and other minerals on the PM.