5-exo-Selective Asymmetric Bromolactonization of Stilbenecarboxylic Acids Catalyzed by Phenol-bearing Chiral Thiourea

We developed a novel thiourea Lewis-base catalyst with phenol moieties for the enantioselective 5--bromolactonization of stilbenecarboxylic acids to afford chiral 3-substituted phthalides. The phenol moieties are crucial for the enantio- and regio-selectivity.


Evaluation of Quantum Chemistry Calculation Methods for Conformational Analysis of Organic Molecules Using A-Value Estimation as a Benchmark Test.

A-values of 20 substituents were estimated by quantum chemistry calculations of different theoretical levels. Comparison with the reported experimental values provided a good benchmark to evaluate the theoretical levels for the conformational analysis of organic molecules.


Remote Electronic Effect of Chiral N-Heterocyclic Carbene Catalyst on an Asymmetric Benzoin Reaction

A remote electronic effect of chiral aminoindanol-derived N-heterocyclic carbene catalyst on an asymmetric benzoin reaction was investigated. The catalyst bearing remote electron-withdrawing substituents increased enantioselectivity of the reaction at the cost of the reaction rate. DFT calculations rationalized the increased enantioselectivity.


Remote electronic effect on the N-heterocyclic carbene-catalyzed asymmetric intramolecular Stetter reaction and structural revision of products


Preparation of N-2-Nitrophenylsulfenyl Imino Peptides and Their Catalyst-Controlled Diastereoselective Indolylation

N-2-Nitrophenylsulfenyl (Nps) imino dipeptides bearing various functional groups were successfully prepared via MnO2mediated oxidation and then subjected to diastereoselective indolylation. Each diastereomer of the adduct was selectively obtained from the same substrates using the appropriate chiral phosphoric acid catalysts. These transformations would be useful for synthesizing non-canonical amino acid-containing peptides as novel drug candidates.


Kinetic Resolution of α-Hydroxyamide via N-Heterocyclic Carbene-Catalyzed Acylation


Enhanced Molecular Recognition through SubstrateAdditive Complex Formation in N-Heterocyclic-Carbene-Catalyzed Kinetic Resolution of alpha-Hydroxythioamides.


The Rationale for Stereoinduction in Conjugate Addition to Alkylidenemalonates Bearing a Menthol-derived Chiral Auxiliary


Mechanistic Support for Intramolecular Migrative Cyclization of Propargyl Sulfones Provided by Catalytic Asymmetric Induction with a Chiral Counter Cation Strategy


Development of a 1,3a,6a-triazapentalene derivatives as a compact and thiol-specific fluorescent labeling reagent


Asymmetric Synthesis of α-Amino Phosphonic Acids Using Stable Imino Phosphonate as a Universal Precursor


Traceless synthesis of protein thioesters using enzyme-mediated hydrazinolysis and subsequent self-editing of cysteinyl prolyl sequence


Optical Resolution via Catalytic Generation of Chiral Auxiliary


A recyclable hydrophobic anchor-tagged asymmetric amino thiourea catalyst


Direct enantioselective indolylation of peptidyl imine for the synthesis of indolyl glycine-containing peptides


Resin-bound crypto-thioester for native chemical ligation


Chemical Biology for Pharmaceutical Sciences (Development of Practical Chemical Biotechnology)

薬学における生命指向型化学(実用的ケミカルバイオテクノロジーの開発を目指して)

Journal of the Pharmaceutical Society of Japan


Chemical synthetic platform for chlorpromazine oligomers that were reported as photo-degradation products of chlorpromazine

A synthetic platform for chlorpromazine (CPZ) oligomers, which could be generated via photo-reaction of CPZ, is essential to promote their biological and structural studies. In this paper, the first synthetic platform for CPZ oligomers is described. A photo-irradiation experiment of CPZ to confirm whether the structure of the CPZ dimer generated by the photo-irradiation was identical to that prepared by our synthetic method is also reported.


Cysteine-free intramolecular ligaiton of N-sulfanylethylanilide peptide using 4-mercaptobenzylphosphonic acid: Synthesis of cyclic peptide, trichamide


Inside Front Cover: Elucidation of inhibitor-binding pocket of D-amino acid oxidase using docking simulation and N-sulfanylethylanilide-based labeling technology


Elucidation of inhibitor-binding pocket of D-amino acid oxidase using docking simulation and N-sulfanylethylanilide-based labeling technology


A convenient method for preparation of -imino carboxylic acid derivatives and application to the asymmetric synthesis of unnatural -amino acid derivative

We describe herein a manganese(IV) oxide-mediated oxidation of N-p-methoxyphenyl (PMP)-protected glycine derivatives for the synthesis of -imino carboxylic acid derivatives. Using this methodology, utilization of unstable glyoxic acid derivatives was avoided. Furthermore, using this methodology we synthesized novel -imino carboxylic acid derivatives such as -imino phenyl ester, perfluoroalkyl etsers, imides, and thioester. The asymmetric Mannich reaction of those novel imine derivatives with 1,3-dicarbonyl compound is also described, and the novel -imino imide gave improved chemical yield and stereoselectivity compared with those obtained by the use of the conventional -imino ester-type substrate.


Development of an anilide-type scaffold for the thioester precursor N-sulfanylethylcoumarinyl amide

N-Sulfanylethylcoumarinyl amide (SECmide) peptide, which was initially developed for use in the fluorescence-guided detection of promoters of N-S acyl transfer, was successfully applied to a facile and side reaction-free protocol for N-S acyl-transfer-mediated synthesis of peptide thioesters. Additionally, 4-mercaptobenzylphosphonic acid (MBPA) was proven to be a useful catalyst for the SECmide or N-sulfanylethylanilide (SEAlide)-mediated NCL reaction.


Back Cover: Tailored synthesis of 162-residue S-monoglycosylated GM2-activator protein (GM2AP) analogues that allows access to protein library


Tailored synthesis of 162-residue S-monoglycosylated GM2-activator protein (GM2AP) analogues that allows access to protein library


Labelling of endogenous target protein via N-S acyl transfer-mediated activation of N-sulfanylethylanilide


An N-Sulfanylethylanilide-based traceable linker for enrichment and selective labelling of target proteins


Identification of SNAIL1 Peptide-Based Irreversible Lysine Specific Demethylase 1-Selective Inactivators

Inhibition of lysine-specific demethylase 1 (LSD1), a flavin-dependent histone demethylase, has recently emerged as a new strategy for treating cancer and other diseases. LSD1 interacts physically with SNAIL1, a member of the SNAIL/SCRATCH family of transcription factors. This study describes the discovery of SNAIL1 peptide-based inactivators of LSD1. We designed and prepared SNAIL1 peptides bearing a propargyl amine, hydrazine, or phenylcyclopropane moiety. Among them, peptide 3, bearing hydrazine, displayed the most potent LSD1-inhibitory activity in enzyme assays. Kinetic study and mass spectrometric analysis indicated that peptide 3 is a mechanism-based LSD1 inhibitor. Furthermore, peptides 37 and 38, which consist of cell-membrane-permeable oligoarginine conjugated with peptide 3, induced a dose-dependent increase of dimethylated Lys4 of histone H3 in HeLa cells, suggesting that they are likely to exhibit LSD1-inhibitory activity intracellularly. In addition, peptide 37 decreased the viability of HeLa cells. We believe this new approach for targeting LSD1 provides a basis for development of potent selective inhibitors and biological probes for LSD1.


Development of an intein-inspired amide cleavage chemical device

A photoresponsive amide cleavage device was developed based on the asparagine imidation-mediated cleavage of peptide bonds during intein-mediated protein splicing. The chemical environment of the protein splicing process was mimicked by the incorporation of geminal dimethyl groups and a secondary amine unit in asparagine scaffold. Furthermore, the resulting photoresponsive device could induce the phototriggered cleavage of an amide bond by the protection of the secondary amine unit with an o-nitrobenzyloxycarbonyl group.


One-pot/sequential native chemical ligation using photo-caged crypto-thioester

A practical and efficient methodology for the chemical synthesis of peptides/proteins using a one-pot/sequential ligation is described. It features the use of photocleavable S-protection on an N-sulfanylethylaniline moiety. Removal of the S-protecting ligated materials under UV irradiation provides a readily usable mixture for subsequent native chemical ligation.


Preparation of peptide thioesters from naturally occurring sequences using reaction sequence consisting of regioselective S-cyanylation and hydrazinolysis

The vital roles of peptide/protein thioesters in protein chemistry, including chemical or semi-synthesis of proteins, have encouraged studies on the development of methods for the preparation of such chemical units. Biochemical protocols using intein or sortase have proved to be useful in protein chemistry as methods suitable for naturally occurring sequences, including recombinant proteins. Although chemical protocols are potential options for thioester preparation, only a few are applicable to naturally occurring sequences, because standard chemical protocols require an artificial chemical device for producing thioesters. In this context, the chemical preparation of thioesters based on a reaction sequence consisting of regioselective S-cyanylation and hydrazinolysis was investigated. Regioselective S-cyanylation, which is required for cysteine-containing thioesters, was achieved with the aid of a zinc-complex formation of a CCHH-type zinc-finger sequence. Free cysteine residues that are not involved in complex formation were selectively protected with a 6-nitroveratryl group followed by S-cyanylation of the zinc-binding cysteine. Hydrazinolysis of the resulting S-cyanopeptide and subsequent photo-removal of the 6-nitroveratryl group yielded the desired peptide hydrazide, which was then converted to the corresponding thioester. The generated thioester was successfully used in N-to-C-directed one-pot/sequential native chemical ligation using an N-sulfanylethylanilide peptide to give a 64-residue peptide toxin. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 531-546, 2016.


Efficient one-pot synthesis of CXCL14 and its derivative using an N-sulfanylethylanilide peptide as a peptide thioester equivalent and their biological evaluation

CXCL14 is a CXC-type chemokine that exhibits chemotactic activity for immature dendritic cells, activated macrophages, and activated natural killer cells. However, its specific receptor and signaling pathway remain obscure. Recently, it was reported that CXCL14 binds to CXCR4 with high affinity and inhibits CXCL12-mediated chemotaxis. Furthermore, the CXCL14 C-terminal -helical region is important for binding to its receptor. In this context, we chemically synthesized CXCL14 and its derivative with a one-pot method using N-sulfanylethylanilide peptide as a thioester equivalent. The synthetic CXCL14 proteins possessed inhibitory activities to CXCL12-mediated chemotaxis comparable with that of recombinant CXCL14. Moreover, we proved that chemically biotinylated CXCL14 binds to CXCR4 on cells by flow cytometry analysis.


Design and synthesis of a hydrogen peroxide-responsive amino acid that induces peptide bond cleavage after exposure to hydrogen peroxide


The total chemical synthesis of the monoglycosylated GM2 ganglioside activator using a novel cysteine surrogate

We describe a novel peptide ligation/desulfurization strategy using a -mercapto-N-glycosylated asparagine derivative. The newly developed procedure was successfully applied to the total chemical synthesis of the GM2 ganglioside activator protein bearing a monosaccharide on the native glycosylation site.


Synthesis of lactam-bridged cyclic peptides by using olefin metathesis and diimide reduction


Development of chemical methodology for preparation of peptide thioesters applicable to naturally occurring peptides using a sequential quadruple acyl transfer system


N-Sulfonyl-β-lactam hapten as an effective labeling reagent for aldolase mAb

Utilization of chemically programmed antibodies (cpAbs) is regarded to be one of the most efficient methods for the development of therapeutic systems. cpAbs can extend the half-life of programming reagents, activate immune systems via the Fc region of antibodies and achieve universal vaccination by attaching varieties of small, programmed molecules. In the current study, we aimed to develop a novel labeling reagent for the preparation of cpAbs and found that N-sulfonyl-β-lactams (NSBLs) were optimal. NSBL can be synthesized from readily available 4-(bromomethyl)benzenesulfonyl chloride via few simple manipulations and can label the aldolase monoclonal antibody (mAb) 84G3, which could not be labeled effectively by the conventional labeling reagent, N-acyl-β-lactam (NABL). We also demonstrated that the conjugate, which consists of mAb 84G3 and an NSBL bearing a biotin moiety, maintained strong binding activity to streptavidin. In addition, the stability assay of NSBL revealed that NSBLs can tolerate aqueous media without significant decomposition over 24h.

Bioorganic & Medicinal Chemistry Letters


Liquid-phase synthesis of bridged peptides using olefin metathesis of protected peptide with long aliphatic chain anchor

Bridged peptides including stapled peptides are attractive tools for regulating protein-protein interactions (PPIs). An effective synthetic methodology in a heterogeneous system for the preparation of these peptides using olefin metathesis and hydrogenation of protected peptides with a long aliphatic chain anchor is reported.


Catalytic asymmetric synthesis of the pentacyclic core of (-)-nakadomarin A via oxazolidine as an iminium cation equivalent

A facile and catalytic asymmetric synthesis of the pentacyclic core of (-)-nakadomarin A, containing all the stereogenic centers of the natural product was achieved. The key intermediate involves the oxazolidine moiety as an iminium cation equivalent. An efficient method for the removal of the N-hydroxyethyl group is also described.


A Dual Arylboronic Acid-Aminothiourea Catalytic System for the Asymmetric Intramolecular Hetero-Michael Reaction of a,b-Unsaturated Carboxylic Acids

A bifunctional aminoboronic acid has been used to facilitate for the first time the intramolecular aza- and oxa-Michael reactions of α,β-unsaturated carboxylic acids. The combination of an arylboronic acid with a chiral aminothiourea allowed for these reactions to proceed successfully in an enantioselective manner to afford the desired heterocycles in high yields and ee's (up to 96% ee). The overall utility of this dual catalytic system was demonstrated by a one-pot enantioselective synthesis of (+)-erythrococcamide B, which proceeded via sequential Michael and amidation reactions.


Development of caged non-hydrolyzable phosphoamino acids and application to photo-control of binding affinity of phosphopeptide mimetic to phosphopeptide-recognizing protein

The design and synthesis of caged non-hydrolyzable phospho-serine, -threonine, and -tyrosine derivatives that generate parent non-hydrolyzable phosphoamino acids, containing a difluoromethylene unit instead of the oxygen of a phosphoester, after UV-irradiation are described. The caged non-hydrolyzable amino acids were incorporated into peptides by standard Fmoc solid-phase peptide synthesis, and the obtained peptides were successfully converted to the parent non-hydrolyzable phosphopeptides by UV-irradiation. Application of the caged non-hydrolyzable phosphoserine-containing peptide to photo-control the binding affinity of the peptide to 14-3-3 protein is also reported.


A Powerful Hydrogen-Bond-Donating Organocatalyst for the Enantioselective Intramolecular Oxa-Michael Reaction of ,-Unsaturated Amides and Esters

Tuning the organocatalyst: An unprecedented enantioselective intramolecular oxa-Michael reaction of unactivated α,β-unsaturated amides and esters catalyzed by a powerful hydrogen-bond-donating organocatalyst has been developed. Furthermore, the products obtained from this reaction have been used for the straightforward asymmetric synthesis of several natural products and biologically important compounds.


Chemically Programmed Antibodies As HIV-1 Attachment Inhibitors

Herein we describe the design and application of two small-molecule anti-HIV compounds for the creation of chemically programmed antibodies. N-acyl-β-lactam derivatives of two previously described molecules BMS-378806 and BMS-488043 that inhibit the interaction between HIV-1 gp120 and T-cells were synthesized and used to program the binding activity of aldolase antibody 38C2. Discovery of a successful linkage site to BMS-488043 allowed for the synthesis of chemically programmed antibodies with affinity for HIV-1 gp120 and potent HIV-1 neutralization activity. Derivation of a successful conjugation strategy for this family of HIV-1 entry inhibitors enables its application in chemically programmed antibodies and vaccines and may facilitate the development of novel bispecific antibodies and topical microbicides.


Facile and Stabile Linkages through Tyrosine: Bioconjugation Strategies with the Tyrosine-Click Reaction

The scope, chemoselectivity, and utility of the click-like tyrosine labeling reaction with 4-phenyl-3H-1,2,4-triazoline-3,5(4H)-diones (PTADs) is reported. To study the utility and chemoselectivity of PTAD derivatives in peptide and protein chemistry, we synthesized PTAD derivatives possessing azide, alkyne, and ketone groups and studied their reactions with amino acid derivatives and peptides of increasing complexity. With proteins we studied the compatibility of the tyrosine click reaction with cysteine and lysine-targeted labeling approaches and demonstrate that chemoselective trifunctionalization of proteins is readily achieved. In particular cases, we noted that PTAD decomposition resulted in formation of a putative isocyanate byproduct that was promiscuous in labeling. This side reaction product, however, was readily scavenged by the addition of a small amount of 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) to the reaction medium. To study the potential of the tyrosine click reaction to introduce poly(ethylene glycol) chains onto proteins (PEGylation), we demonstrate that this novel reagent provides for the selective PEGylation of chymotrypsinogen, whereas traditional succinimide-based PEGylation targeting lysine residues provided a more diverse range of PEGylated products. Finally, we applied the tyrosine click reaction to create a novel antibody-drug conjugate. For this purpose, we synthesized a PTAD derivative linked to the HIV entry inhibitor aplaviroc. Labeling of the antibody trastuzumab with this reagent provided a labeled antibody conjugate that demonstrated potent HIV-1 neutralization activity demonstrating the potential of this reaction in creating protein conjugates with small molecules. The tyrosine click linkage demonstrated stability to extremes of pH, temperature, and exposure to human blood plasma indicating that this linkage is significantly more robust than maleimide-type linkages that are commonly employed in bioconjugations. These studies support the broad utility of this reaction in the chemoselective modification of small molecules, peptides, and proteins under mild aqueous conditions over a broad pH range using a wide variety of biologically acceptable buffers such as phosphate buffered saline (PBS) and 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) buffers as well as others and mixed buffered compositions.


NHC-catalyzed thioesterification of aldehydes by external redox activation

The NHC-catalyzed thioesterification of aromatic or aliphatic aldehydes with a range of thiols was developed in the presence of a stoichiometric amount of an organic oxidant. Among the oxidants examined, phenazine was shown to give the best results in terms of chemical yield and compatibility with thiols.


Organocatalyzed Isomerization of a-Substituted Alkynoates into Trisubstituted Allenoates by Dynamic Kinetic Resolution


Organocatalytic asymmetric Neber reaction for the synthesis of 2H-azirine carboxylic esters

The first enantioselective Neber reaction of β-ketoxime sulfonates catalyzed by a bifunctional thiourea has been developed. The reaction proceeds stereoselectively with 5 mol % of the catalyst to give the 2H-azirine carboxylic esters in good yields with up to 93% ee. In addition, the resulting azirines can be successfully employed in the stereoselective synthesis of di- and trisubstituted aziridines.


Bifunctional Hydrogen-Bond Donors That Bear a Quinazoline or Benzothiadiazine Skeleton for Asymmetric Organocatalysis

Hydrogen-bond (HB)-donor catalysts that bear a 2-aminoquinazolin-4-(1H)-one or a 3-aminobenzothiadiazine-1,1-dioxide skeleton have been developed, and it has been shown that these catalyst motifs act similarly to other HB-donor catalysts such as thioureas. The highly enantioselective hydrazination of 1,3-dicarbonyl compounds was realized even at room temperature with up to 96% ee for 2-aminoquinazolin-4-(1H)-one-type catalysts, which were more effective than the corresponding urea and thiourea catalysts. In addition, benzothiadiazine-1,1-dioxide-type catalysts were shown to promote the isomerization of alkynoates to allenoates with high enantioselectivity. To overcome the problem that the products were obtained as mixtures with the starting alkynoates, we developed the tandem isomerization and cycloaddition of alkynoates for the synthesis of advanced chiral compounds such as bicyclo[2.2.1]heptenes and 3-alkylidene pyrrolidine without a significant loss of enantioselectivity.


Effects of Bolus Injection of 5-Fluorouracil on Steady-State Plasma Concentrations of 5-Fluorouracil in Japanese Patients with Advanced Colorectal Cancer

The irinotecan (CPT-11) + 5-fluorouracil (5-FU)/leucovorin (LV) + UFT/LV chemotherapy, in which repetitive oral administration of UFT/LV replaces the infusion of 5-FU/LV in the FOLFIRI regimen, has been proposed previously. In this study, five of 10 patients were injected with a bolus of 5-FU and the other were not injected with it in order to examine the effect of omitting it in terms of pharmacokinetics of 5-FU. The treatment consisted of the intravenous infusions of CPT-11 at 100 mg/m(2 )and l-LV at 15 mg/m(2), and the injection of a bolus of 5-FU at 500 mg/m(2) on day 1, and the repetitive oral administration of UFT/LV (300 mg/m(2)/day as tegafur + 75 mg/day of LV) on days 1-5. A total of 13 measurements of the plasma concentrations of uracil, 5-FU and tegafur were made per patient within 48 hr after the start of chemotherapy and the value of area under the concentration-time curve (AUC(0-48)) was evaluated. The plasma concentration was also determined at 2 weeks to assess long-term exposure to 5-FU. The plasma concentrations of 5-FU at 24 hr after the start of treatment were 27.4 ng/mL and 9.4 ng/mL in the patients with and without the bolus injection, respectively. At 48 hr, they were 31.3 ng/mL and 10.4 ng/mL with the AUC(0-48) values of 22.16 mg h/L and 0.65 mg h/L, respectively. The 5-FU was detected in the plasma at 226 hr after the last administration of UFT/LV for the patients with the bolus injection, but not for those without. A bolus of 5-FU on day 1 provided long-term exposure to 5-FU.

International Journal of Medical Sciences


Synthesis of Optically Active N-Aryl Amino Acid Derivatives through the Asymmetric Petasis Reaction Catalyzed by a Novel Hydroxy-Thiourea Catalyst


Catalytic asymmetric synthesis of both enantiomers of 4-substituted 1,4-dihydropyridines with the use of bifunctional thiourea-ammonium salts bearing different counterions

Organoammonium salts composed of a Brønsted acid and an anilinothiourea promoted the Michael addition of ß-keto esters and α,ß-unsaturated aldehydes in the presence of primary amines to give functionalized 1,4-dihydropyridines enantioselectively. With the use of the different Brønsted acids such as DFA and HBF(4) with the same bifunctional thiourea, both enantiomers of 4-substituted 1,4-dihydropyridine were synthesized from the same starting materials.


Effect of dose-escalation of 5-fluorouracil on circadian variability of its pharmacokinetics in Japanese patients with Stage III/IVa esophageal squamous cell carcinoma

The effects of dose-escalation of 5-fluorouracil (5-FU) on the clinical outcome and pharmacokinetics of 5-FU were investigated in Japanese patients with Stage III/IVa esophageal squamous cell carcinoma. Thirty-five patients with Stage III/IVa were enrolled, who were treated with a definitive 5-FU/cisplatin-based chemoradiotherapy. A course consisted of continuous infusion of 5-FU at 400 mg/m(2)/day (the standard dose group, N=27) or 500-550 mg/m(2)/day (the high dose group, N=8) for days 1-5 and 8-12, infusion of cisplatin at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course repeated after a 2-week interval. Plasma concentrations of 5-FU were determined by high performance liquid chromatography at 5:00 PM on days 3, 10, 38 and 45, and at 5:00 AM on days 4, 11, 39 and 46. No patient with Stage IVa achieved a complete response in the standard dose group, whereas a complete response was observed at a rate of 50% in the high dose group, and this can be explained by a higher plasma concentration of 5-FU. The circadian rhythm in the concentrations found at the standard dose was not observed for a higher dose.


Brønsted acid-thiourea co-catalysis: asymmetric synthesis of functionalized 1,4-dihydropyridines from b-enamino esters and a,b-unsaturated aldehydes


Replacement of cisplatin with nedaplatin in a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma

The effects of replacing cisplatin (CDDP) with cis-diammineglycolatoplatinum (nedaplatin, NDP), a second-generation platinum complex, on the pharmacokinetics of 5-fluorouracil (5-FU) were investigated in Japanese patients with esophageal squamous cell carcinoma, who were treated with a definitive 5-FU/CDDP-based chemoradiotherapy. Fifty-six patients were enrolled, 49 treated with CDDP and 7 treated with NDP. A course consisted of continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, infusion of CDDP or NDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course repeated after a 2-week interval. Plasma concentrations of 5-FU were determined by high performance liquid chromatography at 5 PM on days 3, 10, 38 and 45, and at 5 AM on days 4, 11, 39 and 46. The circadian rhythm in plasma concentrations of 5-FU observed in the case of CDDP was altered when NDP was used instead. The clinical response can be predicted by monitoring plasma concentrations of 5-FU in the CDDP group, but not in the NDP group.


Hydroxyl Group-Directed Organocatalytic Asymmetric Michael Addition of ,-Unsaturated Ketones with Alkenylboronic Acids

The organocatalytic asymmetric Michael addition of organoboronic acids to gamma-hydroxy enones in the presence of an iminophenol-type thiourea catalyst is demonstrated. The hydroxyl group in the substrates plays a critical role in this reaction.


Enantioselective nitrocyclopropanation of α,β-unsaturated α-cyanoimides catalyzed by bifunctional thiourea


Asymmetric synthesis of 4-substituted 2,6-dioxopiperidine-3-carbonitrile by using thiourea-catalyzed asymmetric Michael addition


Thiourea-Catalyzed Asymmetric Michael Addition of Activated Methylene Compounds to ,-Unsaturated Imides: Dual Activation of Imide by Intra- and Intermolecular Hydrogen Bonding

A thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to alpha,beta-unsaturated imides derived from 2-pyrrolidinone and 2-methoxybenzamide has been developed. In the case of 2-pyrrolidinone derivatives, the reaction with malononitrile proceeded in toluene with high enantioselectivity, providing the Michael adducts in good yields. However, the nucleophiles that could be used for this reaction were limited to malononitrile due to poor reactivity of the substrate. Further examination revealed that N-alkenoyl-2-methoxybenzamide was the best substrate among the corresponding benzamide derivatives bearing different substituents on the aromatic ring. Indeed, several activated methylene compounds such as malononitrile, methyl alpha-cyanoacetate, and nitromethane could be employed as a nucleophile to give the Michael adducts in good to excellent yields with up to 93% ee. The results of spectroscopic experiments clarified that this enhanced reactivity can be attributed to the intramolecular hydrogen-bonding interaction between the N-H of the imide and the methoxy group of the benzamide moiety. Thus, the key to the success of the catalytic enantioselective Michael addition is dual activation of the substrate by both intramolecular hydrogen bonding in the imide and intermolecular hydrogen bonding with thiourea 1a, as well as the activation of a nucleophile by the tertiary amine of the bifunctional thiourea.

Journal of the American Chemical Society


Stereoselective Synthesis of 3-Alkylideneoxindoles via Palladium-Catalyzed Domino Reactions

We have developed efficient catalytic methods for the stereoselective and diversity synthesis of various (E)-, (Z)-, and disubstituted 3-alkylideneoxindoles and 3-alkylidenebenzofuran-2-ones via palladium-catalyzed Heck/Suzuki-Miyaura, Heck/Heck, and Heck/carbonylation/Suzuki-Miyaura domino reactions.


Stereoselective Synthesis of 3-Alkylideneoxindoles using Tandem Indium-Mediated Carbometallation and Palladium-Catalyzed Cross-Coupling Reactions


Lossen rearrangement-mediated preparation of N-glyoxylyl peptide without addition of oxidant


Preparation of protein thioesters enabled by carboxypeptidase-mediated C-terminal specific hydrazinolysis


Development and application of novel protein labeling reagent "SEAL"


Development of methodology for producing thioesters from naturally occurring peptide sequence


N-S-acyl-transfer-mediated On-resin Formation of Thioester with Practical Application to Peptide Synthesis


Design, synthesis and biological evaluation of SNAIL1 peptide-based lysine specific demethylase 1 inhibitors


One-pot sequential native chemical ligations using photocaged crypto-thioester


Development of N-sulfanyltehylanilide (SEAlide)-based traceable linker for enrichment and selective labeling of target proteins


Tailored Synthesis of 162-Residue S-Monoglycosylated GM2-Activator Protein (GM2AP) Analogues Applicable to the Preparation of a Protein Library


Intein-inspired amide bond processing device


Second-generation synthetic strategy of GM2-activator protein (GM2AP) analogues applicable to the preparation of a protein library


One-pot/sequential native chemical ligation using photo-responsive crypto-thioester


Preparation of peptide thioesters from naturally occuring sequences using a chemical protocol


Development of intein-inspired peptide bond processing device


N-Sulfanylethylanilide (SEAlide) peptide as a versatile intermediate for protein chemical synthesis using native chemical ligation