The molecular structures and chemical reactivity of boron compounds are characterized by the electron deficiency and low electronegativity of boron. Based on simple molecular design strategy taking advantage of the unique properties of boron, we have developed new chemical species and new organic transformations. This article describes our recent studies of (i) a two-coordinate boron cation (borinium ion) and (ii) a 9-borafluorene-mediated benzannulation reaction of alkyne derivatives. In the former, we successfully isolated a diarylborinium ion (Mes₂B⁺), which had been considered impossible to be isolated as a stable species without introducing particular electron-donating groups to boron. We found several unique small-molecule activation reactions mediated by Mes₂B⁺ such as C=O double bond cleavage of CO₂. Moreover, we revealed that Mes₂B⁺ serves as an excellent hole-doping reagent for carbon nanotube, graphene, and transition metal dichalcogenide. In the latter topic, we discovered a new efficient boron-mediated benzannulation reaction of alkyne derivatives, which enables the synthesis of a wide variety of extended π-conjugated molecules and polymers. The boron compounds used in these studies are simple but enable powerful organic transformations.

The tethered Diels-Alder reaction is one of the most powerful and versatile methods for formation of functionalized cyclohexene derivatives with high regio- and stereoselectivity. Many advantages of the intramolecular Diels-Alder reaction have been extended to the intermolecular counterpart by linking the diene to the dienophile with a temporary tether. This account describes some highlights of template-mediated Diels-Alder reactions, together with our asymmetric Diels-Alder reaction of 2,4-dienols and methyl acrylate utilizing a bimetallic Lewis acid template derived from (R)-5,5’,6,6’,7,8,8’-octahydro-1,1’-bi-2-naphthol. The bimetallic Lewis acid-template Diels-Alder reaction is feasible to hetero-Diels-Alder reaction of 4-siloxy-2,4-penta-dienols and aldehydes to provide substituted dihydropyrans with good enantioselectivities. The synthetic application for biologically active compounds is also demonstrated.

Chemotaxis of sperm toward an egg is a critical step in reproduction, particularly in aquatic environments, where sperm frequently travel long distances to contact an egg. Chemoattractants called sperm activating and attracting factors (SAAFs) were isolated from eggs of the ascidians Ciona intestinalis and Ascidia sydneiensis, and the structures of SAAFs were determined to be novel polyhydroxysterol sulfates, Ciinte-SAAF and Assydn-SAAF, respectively. However, the absolute configuration at C25 of the side chain remained unknown. For the complete structure elucidation of SAAFs, their two possible diastereomers with respect to C25 were synthesized. Ciinte-SAAF was synthesized starting from chenodeoxychoric acid. The steroid backbone was constructed via reductive 1,3-transposition of an allylic alcohol and the axial opening of an epoxide as key steps, and the side chain was introduced by Wittig olefination. Assydn-SAAF was synthesized starting from ergosterol. The steroid backbone was constructed by using an intramolecular pinacol coupling reaction and stereoselective reduction of a hydroxyketone as key steps, and the side chain was introduced by Julia-Kocienski olefination. Comparison of the NMR data of the synthetic specimens with those of the natural products, Ciinte-SAAF and Assydn-SAAF, led to the elucidation of the both absolute configurations at C25 as S. Thus, the complete structures were determined and the first syntheses of Ciinte-SAAF and Assydn-SAAF were achieved. Furthermore, structure-activity relationship studies of Ciinte-SAAF was carried out by using synthetic analog molecules, and molecular probes were prepared for elucidating the mode-of-action.

1,2-cis-Glycosides are frequently found in many biologically active natural products and pharmaceutical compounds. Therefore, to elucidate the precise biological roles of these carbohydrates and structure-activity relationships, the development of efficient glycosylation methods for the stereoselective synthesis of 1,2-cis-glycosides is becoming increasingly important in synthetic organic chemistry. In this review article, development of boronic-acid-catalyzed regioselective and 1,2-cis-stereoselective glycosylation that was recently developed in our laboratory, is introduced. This glycosylation method was successfully applied to the regioselective and stereoselective formation of 1,2-cis-β-glycosidic linkages, to the efficient synthesis of complex glycosides, and to the direct regioselective and 1,2-cis-stereoselective glycosylation of unprotected glycosides. Furthermore, mechanistic studies were consistent with a highly dissociative concerted S_Ni mechanism.

Several single metal and bimetallic nanoparticle catalysts immobilized on polymer supports have been developed for selective hydrogenation of quinones to hydroquinones. Au-Pt bimetallic nanoparticle catalyst showed the best reactivity and selectivity for this purpose. Though slight over-reduction proceeded under batch conditions, higher reactivity, selectivity, and robustness of the catalysts were confirmed under continuous-flow conditions with polydimethylsilane-supported catalysts. Various direct derivatizations of quinones, such as methylation, acetylation, trifluoromethanesulfonylation, and benzoylation were successfully performed under sequential-flow conditions to afford the desired products in good to excellent yields. Especially, air-sensitive hydroquinones, such as anthrahydroquinones and naphthohydroquinones, could be successfully generated and derivatized under closed sequential-flow conditions without decomposition. This sequential-flow systems showed various benefits of flow systems; suppression of over reactions by controlling residence time, facile use of unstable intermediates, continuous production and robustness of the system.

Continuous flow process provides a lot of advantages, such as high process safety, productivity and scalability, compared to conventional batch process. Although most of active pharmaceutical ingredients and its intermediates have been manufactured in batch mode, many researchers including medicinal and process chemists in pharmaceutical companies have great attention to this emerging and innovative technology to apply into their manufacturing process. Herein, we successfully established safe and efficient plug flow reactor system for phosgenation reactions employing less toxic triphosgene as well as simple and practical packed-bed reactor system for deacylation reactions with inexpensive anion-exchange resin as a catalyst by taking the advantages of continuous flow methodologies. In addition, we demonstrated that these continuous flow systems are applicable to the preparation of a wide variety of pharmaceutical intermediates in good to excellent yield and our flow technologies are readily scaled-up while increasing the safety and efficiency of the overall manufacturing process.

A rhodium(III)-catalyzed cyclopropanation of alkenes with N-enoxyphthalimides, the imide moiety of which works as an oxidizing directing group for C-H activation, has been developed. Careful tuning of reaction conditions such as the N-enoxyphthalimides, ligands, and bases lead to stereodivergent results. The reaction mechanism including the stereoselectivity was discussed through detailed control experiments and multivariate analysis. This protocol has also been applied to cis-selective cyclopropanation of allyl alcohols. These approaches provide various cyclopropanes not accessible by other routes.