Green/red light-sensing mechanism in the chromatic acclimation photosensor.

Certain cyanobacteria alter their photosynthetic light absorption between green and red, a phenomenon called complementary chromatic acclimation. The acclimation is regulated by a cyanobacteriochrome-class photosensor that reversibly photoconverts between green-absorbing (Pg) and red-absorbing (Pr) states. Here, we elucidated the structural basis of the green/red photocycle. In the Pg state, the bilin chromophore adopted the extended C15-Z,anti structure within a hydrophobic pocket. Upon photoconversion to the Pr state, the bilin is isomerized to the cyclic C15-E,syn structure, forming a water channel in the pocket. The solvation/desolvation of the bilin causes changes in the protonation state and the stability of π-conjugation at the B ring, leading to a large absorption shift. These results advance our understanding of the enormous spectral diversity of the phytochrome superfamily.

Directing-Group-Assisted Non-Strained Ether C-O Bond Homolysis Mediated by Low-Valent Titanium.

Ether C-O bonds are typical constituents of organic molecules that are seldom regarded as reactive functional groups except when highly strained. With the assistance of appropriate directing groups, low-valent titanium was found to homolytically cleave non-strained C-O bonds. In particular, a newly designed catechol monoether directing group rendered a route toward the activation of non-benzylic C(sp3)-O bonds. This method has been applied to conventional radical addition reactions to alkenes.

Silylacetate-promoted addition reaction of isocyanides to nitrones: effective synthesis of C(1)-carboxamide derivatives.

We report an efficient method for the synthesis of C(1)-carboxamide derivatives by adding isocyanides to 3,4-dihydroisoquinoline N-oxides and 3,4-dihydro-ß-carboline 2-oxide in the presence of TMSOAc. 3,4-Dihydroisoquinoline-1-carboxylamide derivatives and 9-dihydro-3H-pyrido[3,4-b]indole-1-carboxamide derivatives were obtained in reasonable yields. The method could be used to synthesize alangiobussine, an alkaloid, in 61% yield.

Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

Divergent transformation of C,N-cyclic-N'-acyl azomethine imines by reaction with diazo compounds.

C,N-cyclic-N'-acyl azomethine imines with isoquinoline skeletons were investigated for their reactivity with diazo compounds via two different pathways. During the reaction with ethyl diazoacetate, an α-diazoacetate moiety was introduced at the C1-position of the resulting tetrahydroisoquinolines. Alternatively, diazomethane or trimethylsilyldiazomethane was used to synthesize 3-benzazepine derivatives via ring expansion.

Molecular Assembly and Gelating Behavior of (l)-Alanine Derivatives.

In this study, a low-molecular-weight organogelator derived from (l)-amino acids was designed and synthesized. Gelation assays using (l)-amino acid derivatives were performed to confirm the gelation ability, which was found to be high in several compounds. The (l)-alanine derivatives were determined to be excellent gelators, forming good gels even when smaller amounts were added. These results led to a library of amino acid-derived organogelators. In addition, the thermal properties of the (l)-alanine derivatives with high gelation performance were measured. Differential scanning calorimetry measurements revealed that the thermal stability of the gels could be controlled by changing the gelator concentration. The surface states of the obtained gels were observed by field-emission scanning electron microscopy and atomic force microscopy measurements, which confirmed the structure of the self-molecular aggregates. Self-molecular aggregates were observed to be helical or sheet-like, and the gels were constructed by forming aggregates by self-molecular recognition.

Cyclopropenes for the Stepwise Synthesis of 1,2,4,5-Tetraarylbenzenes via 1,4-Cyclohexadienes.

This paper describes a synthetic approach to the synthesis of 1,2,4,5-tetraarylbenzene derivatives from cyclopropenes. The Lewis acid-mediated dimerization of cyclopropenes gives tricyclo[3.1.0.02,4]hexane derivatives. The subsequent thermal ring-opening reaction under solvent-free conditions gives 1,4-cyclohexadienes bearing quaternary carbons. The novel Br2-mediated oxidative rearrangement of 1,4-cyclohexadienes takes place to give 1,2,4,5-tetraarylbenzene derivatives in high to excellent yields.

Highly (E)-Selective Trisubstituted Alkene Synthesis by Low-Valent Titanium-Mediated Homolytic Cleavage of Alcohol C-O Bond.

Ti-mediated homolytic C-O bond cleavage was useful for cascade radical-ionic reactions. Benzyl alcohols treated with TiCl4(col) (col = 2,4,6-collidine) and Mn powder generated the corresponding benzyl radicals; in addition, their reaction with 2-carboxyallyl acetates and the subsequent elimination of the acetoxy group yielded α,ß-unsaturated carbonyl compounds with exclusive (E)-stereoselectivity. The simplicity of the procedure and its wide substrate scope represent a solution to the drawbacks associated with the reactions.

Direct and Unified Access to Carbon Radicals from Aliphatic Alcohols by Cost-Efficient Titanium-Mediated Homolytic C-OH Bond Cleavage.

Low-valent Ti-mediated homolytic C-O bond cleavage offers unified access to carbon radicals from ubiquitous non-activated tertiary, secondary, and even primary alcohols. In contrast to the representative Ti reagents, which were ineffective for this purpose, "TiCl2 (cat)"/Zn (cat=catecholate) was found to be specifically active. This method was applied to the addition reactions of radicals to alkenes and exhibited high generality and yields. More than 50 combinations were examined. The excellent cost-efficiency and accessibility of "TiCl2 (cat)"/Zn further enhance its applicability. Control experiments proved the presence of a carbon radical intermediate and excluded the pathway via alkyl chlorides. Further mechanistic study indicated that the 1 : 2 complex of alkoxide (R-O- ) and TiIII is an active species in the C-O cleavage.

N-Heterocyclic Carbene-Catalyzed Chemoselective Monoacylation of 1,n-Linear Diols.

This paper discusses the N-heterocyclic carbene (NHC)-catalyzed redox monoacylation of 1,n-linear diols using α-benzoyloxyaldehydes. The reactions afforded monoacylated diols in moderate to good selectivities and chemical yields. Our original NHC bearing a pyridine moiety plays an important role in achieving good chemoselectivities. A wide range of 1,n-linear diols were successfully applied to this reaction.

Discovery of Selective Transforming Growth Factor ß Type II Receptor Inhibitors as Antifibrosis Agents.

Historically, modulation of transforming growth factor ß (TGF-ß) signaling has been deemed a rational strategy to treat many disorders, though few successful examples have been reported to date. This difficulty could be partially attributed to the challenges of achieving good specificity over many closely related enzymes that are implicated in distinct phenotypes in organ development and in tissue homeostasis. Recently, fresolimumab and disitertide, two peptidic TGF-ß blockers, demonstrated significant therapeutic effects toward human skin fibrosis. Therefore, the selective blockage of TGF-ß signaling assures a viable treatment option for fibrotic skin disorders such as systemic sclerosis (SSc). In this report, we disclose selective TGF-ß type II receptor (TGF-ßRII) inhibitors that exhibited high functional selectivity in cell-based assays. The representative compound 29 attenuated collagen type I alpha 1 chain (COL1A1) expression in a mouse fibrosis model, which suggests that selective inhibition of TGF-ßRII-dependent signaling could be a new treatment for fibrotic disorders.

Synthesis of 3,6-Dihydro-2H-1,2-oxazines via Dimethylsulfoxonium Methylide Addition to α,ß-Unsaturated Nitrones.

A unique and efficient formation of 3,6-dihydro-2H-1,2-oxazines starting from α,ß-unsaturated nitrones has been achieved. The nucleophilic addition of dimethylsulfoxonium methylide to the C═N bond of an α,ß-unsaturated nitrone to form an aziridine N-oxide followed by the Meisenheimer rearrangement affords 3,6-dihydro-2H-1,2-oxazine in up to 70% yield. Methylene was confirmed to be incorporated at the C3 position of the ring. A wide range of ß-aryl-substituted α,ß-unsaturated nitrones were applicable to this reaction.

Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class.

A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC50 values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC50 values in the low nanomolar range.

Discovery of a novel unsymmetrical structural class of HCV NS5A inhibitors with low picomolar antiviral activity.

A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC50 values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC50 in the low nanomolar range.

Nickel-Catalyzed Cross-Electrophile Coupling between Benzyl Alcohols and Aryl Halides Assisted by Titanium Co-reductant.

A nickel-catalyzed cross-electrophile coupling reaction between benzyl alcohols and aryl halides has been developed using a homolytic C-O bond cleavage protocol that has recently been established. The treatment of a benzyl alcohol and aryl halide with a nickel catalyst and low-valent titanium reagent generated from TiCl4(lutidine) (lutidine = 2,6-lutidine) and manganese powder afforded the cross-coupled product in high yield. A mechanistic study indicated the intermediacy of the benzyl radicals that originate from the benzyl alcohols.

Synthesis of Sterically Fixed Phytochrome Chromophore Derivatives Bearing a 15 E- Fixed or 15 E- Anti- Fixed CD-Ring Component.

To analyze the structure and function of phytochrome chromophores, we have been synthesizing natural and unnatural bilin chromophores of phytochromes. In this manuscript, we report the synthesis of sterically fixed 15 E- fixed 18Et-biliverdin (BV) and 15 E- anti-fixed 18Et-BV derivatives. The key reaction is the introduction of an sp3 carbon alkyl chain bearing a leaving group at the meso-position of the CD-ring component by using the corresponding Grignard reagents in the presence of LiCl.

Low-Valent Titanium-Mediated Radical Conjugate Addition Using Benzyl Alcohols as Benzyl Radical Sources.

A concise method to directly generate benzyl radicals from benzyl alcohol derivatives has been developed. The simple and inexpensive combination of TiCl4(collidine) (collidine = 2,4,6-collidine) and manganese powder afforded a low-valent titanium reagent, which facilitated homolytic cleavage of benzylic C-OH bonds. The application to radical conjugate addition reactions demonstrated the broad scope of this method. The reaction of various benzyl alcohol derivatives with electron-deficient alkenes furnished the corresponding radical adducts.

Development of a Synthetic Method for Multifunctionalized Pyrroles Using Isocyanide Dichloride as a Key Intermediate.

Multifunctionalized pyrrole derivatives were synthesized using a highly efficient method based on the Michael addition of carbanions generated in situ from isocyanide dichloride to α,ß-unsaturated carbonyl compounds. The reactions proceeded smoothly to afford the pyrrole derivatives in good to high yields. A wide range of Michael acceptors, such as α,ß-unsaturated carbonyl compounds and nitroolefin, were successfully applied to this reaction.

Development of a One-Pot Synthetic Method for Multifunctional Oxazole Derivatives Using Isocyanide Dichloride.

A one-pot synthetic method was developed for multifunctional dihydrooxazole and oxazole derivatives. New reaction sequences were developed involving the formation of isocyanide dichloride, an aldol-type reaction with aldehydes, and a nucleophilic addition-elimination reaction, which efficiently afforded the dihydrooxazole and oxazole scaffolds.

Formal Total Synthesis of Manzacidin C Based on Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Imines.

An enantioselective formal total synthesis of (+)-manzacidin C is described. A key feature of the synthesis is the construction of two chiral centers via the asymmetric 1,3-dipolar cycloaddition of an azomethine imine to methallyl alcohol by the use of (S,S)-DIPT as a chiral auxiliary.