Noriki Kutsumura

Palladium-catalyzed highly regio- and stereoselective synthesis of 4-alkylidene-4H-3,1-benzoxazines from N-acyl-o-alkynylanilines.

The highly regio- and stereoselective 6-exo-dig mode cyclization of N-acyl-o-alkynylanilines producing 4-alkylidene-3,1-benzoxazines occurred unpredictably by use of a proper catalyst [Pd(OAc)(2)] and an effective additive (acetic acid) under suitable reaction conditions.

Novel one-pot method for chemoselective bromination and sequential Sonogashira coupling.

An efficient one-pot method for bromination-elimination of allyl alcohol derivatives and sequential Sonogashira coupling has been developed. A highlight of the method is chemoselective DBU-promoted elimination of vicinal dibromoalkanes having an adjacent O-functional group.

Synthesis of 2,3,4-tri-substituted 3,4-dihydroquinazolines via tandem nucleophilic addition/epoxy ring-opening cyclization methodology using N-(2-oxiranylphenyl)carbodiimides with nucleophiles

N-(2-Oxiranylphenyl)carbodiimides, which were synthesized via an aza-Wittig reaction of the corresponding functionalized iminophosphoranes with aromatic and aliphatic isocyanates, underwent O-, S-, C-, or N-nucleophilic addition onto a cumulene, followed by an epoxy ring-opening cyclization with the newly formed NH-nucleophile in a one-pot reaction to furnish 2,3-disubstituted 4-(hydroxymethyl)-3,4-dihydroquinazolines in a highly stereospecific manner.

A HETERO PAUSON-KHAND REACTION OF KETENIMINES: A NEW SYNTHETIC METHOD FOR γ-EXOMETHYLENE-α,β-UNSATURATED γ-LACTAMS

A novel ketenimine Pauson-Khand reaction has been described for the first time. C,C,N-Triarylketenimines reacted with alkyne-dicobalthexacarbonyl complexes upon heating in toluene in the presence of dimethyl sulfoxide as a promoter to afford γ-lactams, 5-(diphenylmethylene)-1H-pyrrol-2(5H)-ones, in good yields.

Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies

Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OX1R, Ki = 1.36 nM; OX2R, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine. Furthermore, all of the active nalfurafine derivatives in this study had almost no activity for OX2R, which led to high OX1R selectivity. These results suggest that nalfurafine derivatives could be a useful series of lead compounds to develop highly selective OX1R antagonists.

Synthetic Studies of N‐demethylossamine and Elaboration of its Glycosylation

An amino‐sugar, N‐demethylossamine, was efficiently synthesized from D‐threonine, two stereogenic centers of which were directly used as those at the C‐4 and 5 positions of the target sugar. In addition, the glycosylation study indicated that reaction of the acetate 7 with cyclopentanol under Lewis acid conditions, provided the desired α‐L‐glycoside 9α.

Synthesis of novel triplets with a 1,3,5-trioxazatriquinane skeleton and their pharmacologies for opioid receptors.

We designed and synthesized novel triplet molecules with 1,3,5‐trioxazatriquinane skeletons. One class comprises double‐capped triplets with a morphinan skeleton; the other class comprises simple phenol derivatives with phenethylamine moieties. One compound with m‐phenolic hydroxyl group, called SYK‐146, is a highly selective, potent agonist for the κ receptor, with activity nearly equivalent to that of U‐50488H. The o‐phenolic isomer of SYK‐146, called SYK‐524, showed potent but non‐selective agonistic activity for the opioid receptors. We also added several simple phenol derivatives to a library of compounds that target opioid receptors, and they showed high hit rates for the receptor. This library might also be expected to show high hit rates for other receptors.

Investigation of 7-benzylidenenaltrexone derivatives as a novel structural antitrichomonal lead compound

We evaluated antitrichomonal effects of δ opioid receptor (DOR) agonists and antagonists. Although all the agonists were inactive, the DOR antagonists BNTX (2a) and its derivatives 2b-d showed antitrichomonal activity with MIC of 20-40 μM. In addition, the development of a more effective synthetic method for the BNTX derivatives was achieved by using the Knoevenagel condensation.

Dibenzopyrrolo[1,2-a][1,8]naphthyridines: Synthesis and Structural Modification of Fluorescent L-Shaped Heteroarenes

The L-shaped, π-extended pentacycle dibenzopyrrolo[1,2-a][1,8]naphthyridine and its derivatives were synthesized using two methods: fully intramolecular [2 + 2 + 2] cycloaddition and oxidative aromatization using substituted carbodiimide and modification of an electron-rich indole ring of an L-shaped skeleton via electrophilic reaction and cross-coupling. These L-shaped compounds emitted fluorescence in high quantum yield. The position of substituents affected the fluorescence color through two different mechanisms, π-conjugation and skeletal distortion, which caused the substituted L-shaped compounds to emit fluorescence in a variety of colors and to exhibit solvato-fluorochromism.

Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor

The essential structure of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) was clarified, particularly the roles to OX1R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX1R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX1R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX1R ligands.