Yutaka Ukaji

Sulfoxonium ylides can react with nitrosoarenes to produce nitrones under catalyst-free conditions; however, prolonged heating conditions are required. In this study, MgBr2•OEt2 was employed to promote the reaction of nitroso compounds with α-carbonyl sulfoxonium ylides, affording the corresponding nitrones. When conducted in the presence of magnesium salts, the one-pot tandem nitrone formation/1,3-dipolar cycloaddition to allyl alcohol afforded the corresponding isoxazolidines diastereoselectively. Furthermore, the magnesium salt of tartramide was used to realize chiral induction in the 1,3-dipolar cycloaddition reaction, resulting in the optically active isoxazolidine. Our approach represents a promising one-pot strategy for synthesizing optically active isoxazolidines.

A radical coupling reaction between non-activated alcohols and 2-arylallyl pivalates was discovered. The reaction involves the dual function of low-valent titanium in cleaving both C–OH and C–OPiv bonds.

A novel method for preparing 4-membered azetidine nitrones, starting from isolable nitrile oxides, has been developed. The reaction of diazomethane with the bulky nitrile oxides proceeds via double nucleophilic incorporation of the methylene moiety to produce 4-membered cyclic nitrones in yields up to 74%. A reaction pathway involving the formation of a strained azirine N-oxide intermediate is discussed.

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.

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-β-carboline 2-oxide in the presence of TMSOAc.

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.

A Ni-catalyzed radical cross-coupling reaction between benzyl alcohols and alkenyl triflates was discovered. A benzyl radical was generated directly from alcohols by low-valent Ti-mediated alcohol C–O bond homolysis and was successfully utilized in a Ni-catalyzed cross-coupling reaction. The addition of tetrabutylammonium iodide (n-Bu₄NI) facilitated the reaction. n-Bu₄NI was found to be instrumental in transforming alkenyl triflates into iodides, which are more reactive in the subsequent cross-coupling process.

Divergent transformation of C,N-cyclic-N′-acyl azomethine imines by ethyl diazoacetate and trimethylsilyldiazomethane was achieved to give α-diazoacetate moiety-introduced tetrahydroisoquinolines and 3-benzazepine derivatives respectively.

A reductive radical coupling reaction between non‐activated aliphatic alcohols and styrenes has been discovered through the use of low‐valent Ti‐mediated C−O bond homolysis. A general application of styrene derivatives in radical coupling reactions remains a challenge in organic synthesis. The preliminary investigation revealed that the resulting benzyl radical intermediate behaves differently depending on minor steric differences around the spin center, which results in a lack of generality. The addition of 1,3,5‐trimethyl‐2,5‐cyclohexadiene uniformly hydrogenated the benzyl radicals irrespective of the steric environments of the attacking radicals. Under the optimal reaction conditions, all tertiary, secondary, and primary alcohols were applicable. In this study, alcohols were successfully used directly as radical sources and reacted with a large number of styrenes.

The enantioselective hetero-Diels–Alder reaction of the cyclic azo compound 4-phenyl-1,2,4-triazole-3,5-dione with 2,4-dienyl carboxylic acids was performed using tartaric acid ester as the chiral auxiliary. The corresponding cycloadducts were obtained with enantioselectivities of up to 76% ee. The cis-carboxylic acid produced could be converted into the corresponding cis- and trans-methyl esters by varying the reaction conditions.