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.

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.

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.

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.

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.

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.

Pre-steady-state kinetic studies of redox reactions catalysed by Bacillus subtilis ferredoxin-NADP(+) oxidoreductase with NADP(+)/NADPH and ferredoxin.

Ferredoxin-NADP(+) oxidoreductase ([EC1.18.1.2], FNR) from Bacillus subtilis (BsFNR) is a homodimeric flavoprotein sharing structural homology with bacterial NADPH-thioredoxin reductase. Pre-steady-state kinetics of the reactions of BsFNR with NADP(+), NADPH, NADPD (deuterated form) and B. subtilis ferredoxin (BsFd) using stopped-flow spectrophotometry were studied. Mixing BsFNR with NADP(+) and NADPH yielded two types of charge-transfer (CT) complexes, oxidized FNR (FNR(ox))-NADPH and reduced FNR (FNR(red))-NADP(+), both having CT absorption bands centered at approximately 600n m. After mixing BsFNR(ox) with about a 10-fold molar excess of NADPH (forward reaction), BsFNR was almost completely reduced at equilibrium. When BsFNR(red) was mixed with NADP(+), the amount of BsFNR(ox) increased with increasing NADP(+) concentration, but BsFNR(red) remained as the major species at equilibrium even with about 50-fold molar excess NADP(+). In both directions, the hydride-transfer was the rate-determining step, where the forward direction rate constant (~500 s(-1)) was much higher than the reverse one (<10 s(-1)). Mixing BsFd(red) with BsFNR(ox) induced rapid formation of a neutral semiquinone form. This process was almost completed within 1 ms. Subsequently the neutral semiquinone form was reduced to the hydroquinone form with an apparent rate constant of 50 to 70 s(-1) at 10°C, which increased as BsFd(red) increased from 40 to 120 µM. The reduction rate of BsFNR(ox) by BsFd(red) was markedly decreased by premixing BsFNR(ox) with BsFd(ox), indicating that the dissociation of BsFd(ox) from BsFNR(sq) is rate-limiting in the reaction. The characteristics of the BsFNR reactions with NADP(+)/NADPH were compared with those of other types of FNRs.

Chiral NHC Ligands Bearing a Pyridine Moiety in Copper-Catalyzed 1,2-Addition of Dialkylzinc Reagents to ß-Aryl-α,ß-unsaturated N-Tosylaldimines.

Asymmetric 1,2-addition of dialkylzinc reagents to α,ß-unsaturated N-tosylaldimines was catalyzed by copper salt in the presence of chiral imidazolium salts having a pyridine ring, which were derived from amino acid, to afford the corresponding chiral allylic amines with up to 91% ee in reasonably high yields. The chiral N-heterocyclic carbene (NHC) ligand played an important role in controlling chemoselectivity.

Phosphinic acid-promoted addition reaction of isocyanides to (Z)-hydroximoyl chlorides: efficient synthesis of α-(hydroxyimino)amides.

The reaction of (Z)-hydroximoyl chlorides with isocyanides promoted by phosphinic acid in the presence of triethylamine proceeds smoothly to afford α-(hydroxyimino)amides in good to high yields. Phosphinic acid plays an important role in effectively promoting the reaction. A wide range of (Z)-hydroximoyl chlorides and isocyanides were found to be suitable for this reaction.

(Z)-Selective Enol Triflation of α-Alkoxyacetoaldehydes: Application to Synthesis of (Z)-Allylic Alcohols via Cross-Coupling Reaction and [1,2]-Wittig Rearrangement.

The stereoselective transformation of α-alkoxyacetoaldehydes to the corresponding (Z)-vinyl triflates was achieved by treatment with phenyl triflimide and DBU. The stereochemistry was explained by the "syn-effect," which was attributed primarily to an σ → π* interaction. The ß-alkoxy vinyl triflates obtained were applied to the stereoselective synthesis of structurally diverse (Z)-allylic alcohols via transition metal-catalyzed cross-coupling reaction and [1,2]-Wittig rearrangement.

A one-pot O-sulfinative Passerini/oxidation reaction: synthesis of α-(sulfonyloxy)amide derivatives.

We have developed a one-pot O-sulfinative Passerini/oxidation reaction, in which a combination of an aldehyde, an isocyanide, and a sulfinic acid react, followed by the addition of mCPBA as an oxidant to give the corresponding α-(sulfonyloxy)amides in high yields. This reaction is the first reported demonstration of an isocyanide-based multicomponent reaction using a sulfinic acid in place of a carboxylic acid. A wide range of aldehydes and isocyanides are applicable to this reaction.

Chiral N-heterocyclic carbene ligands bearing a pyridine moiety for the copper-catalyzed alkylation of N-sulfonylimines with dialkylzinc reagents.

Amino acid-derived chiral imidazolium salts, each bearing a pyridine ring, were developed as N-heterocyclic carbene ligands. The copper-catalyzed asymmetric alkylation of various N-sulfonylimines with dialkylzinc reagents in the presence of these chiral imidazolium salts afforded the corresponding alkylated products with high enantioselectivity (up to 99 % ee). The addition of HMPA to the reaction mixture as a co-solvent is critical in terms of chemical yield and enantioselectivity. A wide range of N-sulfonylimines and dialkylzinc reagents were found to be applicable to this reaction.

Ring enlargement reaction of C,N-cyclic-N'-acyl azomethine imines with sulfonium ylide: an efficient synthesis of 3-benzazepine derivatives.

Highly efficient formation of 3-benzazepine derivatives has been achieved, based on the ring expansion reaction of C,N-cyclic-N'-acyl azomethine imines with sulfonium ylide generated in situ from the corresponding sulfonium salt. The reactions proceeded smoothly to afford the tricyclic 3-benzazepine derivatives in good to high yields. A wide range of C,N-cyclic N'-acyl azomethine imines were applicable to this reaction.

A one-pot O-phosphinative Passerini/Pudovik reaction: efficient synthesis of highly functionalized α-(phosphinyloxy)amide derivatives.

A one-pot O-phosphinative Passerini/Pudovik reaction has been developed, based on reacting aldehydes, isocyanides, and phosphinic acids followed by the addition of second aldehydes to form the corresponding α-(phosphinyloxy)amide derivatives. This is the first reported instance of a Passerini-type, isocyanide-based multicomponent reaction using a phosphinic acid instead of a carboxylic acid. The nucleophilicity of the phosphinate group allows a subsequent catalytic Pudovik-type reaction, affording the highly functionalized α-(phosphinyloxy)amide derivative in high yield. A wide range of aldehydes and isocyanides are applicable to this reaction.

Carboxylic acid free novel isocyanide-based reactions.

In order to develop a practical method for the construction of drug-like and heterocyclic compounds, we have designed a novel Passerini- or Ugi-type reaction system where a compound (which we write in the general form as Z-X) composed of an electrophilic (Z) and a nucleophilic group (X) could essentially perform the same function as the carboxylic acid. Based on this concept, we have developed the O-silylative Passerini reaction and the borinic acid catalyzed α-addition of isocyanides to aldehydes and water. In addition, we have designed and demonstrated the addition reaction of isocyanides to nitrones in the presence of TMSCl to afford the corresponding 1,2,3,4-tetrahydroisoquinoline-1-carboxyamides. Furthermore, a novel [5 + 1] cycloaddition of isocyanide was explored with C,N-cyclic N'-acyl azomethine imines as a "1,5-dipole" via a strategy involving intramolecular trapping of the isocyanide.