Our main research aims include development of innovative chemical reactions, and design and creation of new functional molecules. We are conducting fundamental and applied research in these areas not only by means of experimental approaches based on synthetic organic chemistry, elements chemistry, and spectroscopy, but also from a theoretical viewpoint based on computational chemistry. We understand that rational and accurate designs of new reactions and novel materials based only on past experiences are often difficult because excellent estimates of transition state structures, reactive intermediates and functions by means of experimental techniques are almost impossible. For example, catalytic reactions and multicomponent reactions (MCRs) that chemically combine three or more molecules into a new product are faster and generate less waste, making them invaluable in efforts to improve efficiency and sustainability; however, a full understanding of those processes has eluded researchers because its multipart workings are difficult to detect experimentally. We believes a dual approach combining the benefits of theoretical and experimental chemistry should be encouraged: an approach that will result in breakthrough synthetic processes and functional molecules, use fewer chemicals and be more cost effective.
Geranyl resorcylates isolated from the fruiting bodies of Hericium erinaceum exhibit a variety of biological activities including stimulation of nerve growth factor (NGF) synthesis, inhibition of collagen-induced platelet aggregation, suppression of endoplasmic reticulum (ER) stress-dependent cell death, plant growth regulation, and so on. This paper describes the divergent total synthesis of the members of geranyl resorcylates with the intention to clarify the structure-activity relationship (SAR) and to supply compounds for further research. The synthesis commenced with preparation of the phthalide core by the newly-developed CuBr2-mediated one-pot multi-functionalization reaction. The C5'-oxidized side chain was synthesized via alkylation with the protected cyanohydrin. Two fragments were assembled by the modified Stille coupling reactions, which were followed by functional group manipulations to furnish the target molecules. From the common intermediates, eleven natural products including hericenones A, B, J and I, hericene A, hericerin, hericenols B-D, and erinacerins A and B were synthesized. Among them, the structures of hericerin and hericenone B were revised as the carbonyl regioisomers of the original assignments. Futhermore, it was suggested that hericenols C and D were artifacts resulting from degradation of hericenol B. This study affords not only the natural product library for SAR study but information to deduce the biosynthetic pathways of geranyl resorcylates.
A new strategy for the design of a chiral ligand for asymmetric transition-metal catalysis has been developed. Our strategy is based on the development of achiral cationic ammonium-phosphine hybrid ligands paired with readily available chiral anions. These ion-paired chiral ligands impart a remarkable stereocontrolling ability to their palladium complexes, which catalyze highly enantioselective allylic alkylations of prochiral carbon nucleophiles. Moreover, the exploitation of ion-paired chiral ligands in combinatorial screening has enabled the rapid identification of the optimal ligand for the palladium-catalyzed new asymmetric allylation reaction. We also developed a highly enantio- and diastereoselective [3+2] annulation reaction of 5-vinyloxazolidinones and activated trisubstituted alkenes catalyzed by a palladium complex bearing a different type of ion-paired ligand, which allows for the single-step construction of three contiguous stereocenters, including vicinal all-carbon quaternary stereocenters.
Actin is an essential cytoskeletal protein for the regulation of various cellular functions. A number of actin-stabilizing and depolymerizing agents have been discovered in marine invertebrates, and they show potent cytotoxicity. Among them, a polyketide macrolide aplyronine A has antitumor effects against xenograft in mice. However, the potent cytotoxicity and apoptogenic effect of aplyronine A was not entirely accounted for by its actin filament-severing properties, and its molecular targets and mechanisms of action remained unclear. We developed aplyronine A acetylene or biotin derivatives that bear an aryldiazirine group at the C34 terminus, which formed a covalent bond with actin. By using these chemical probes, we have showed that aplyronine A synergistically binds to tubulin in association with actin, and prevents spindle formation and mitosis in tumor cells. Our findings of aplyronine A will provide further insights into the molecular mechanisms of structurally diverse natural products that regulate cytoskeletal dynamics.
We achieved biomimetic type total syntheses of various carotenoids by using oxirane-ring cleavage as a key reaction. The fascinating point of this strategy is as follows; selective preparation of tetrasubstituted olefinic compounds, cyclopentyl ketones, or 3,6-epoxides could be attained by optimization of side chain lengths and the terminal functional groups at the C-6-position of 5,6-epoxides as a result of regioselective oxirane-ring cleavage and subsequent reactions. In particular, Lewis acid-treatment of epoxide carrying an acetoxypropyl group at C-6 preferably provided tetrasubstituted olefinic compound. On the other hand, Lewis acid or aminium salt-treatment of epoxides carrying an acetoxyethyl or a siloxymethyl group at C-6, and epoxy dienal preferentially afforded cyclopentyl ketones. Treatment of epoxy dienoate and epoxy dienonitrile, possessing a free hydroxy group at the C-3-position with aminium salt preferentially afforded 3,6-epoxides. These resulting compounds were successfully utilized for the total syntheses of crassostreaxanthin B, mytiloxanthin, capsanthin, capsorubin, cucurbitaxanthin A, and cycloviolaxanthin, respectively. Total syntheses of amarouciaxanthin A and B, salmoxanthin, and deepoxysalmoxanthin utilizing oxirane-ring cleavage are also described.
An electrochemical method to synthesize cationic palladium complexes has been developed. Their counter anions could be changed readily by the electrolyte. The reaction could be incorporated into electro-oxidative palladium catalyzed reactions, such as Wacker-type reaction, homo-coupling of arylboronic acids, oxidative Sonogashira-type coupling, and Glaser-type coupling of terminal alkynes. These reactions exhibited a wide scope and a variety of products were obtained in high yields due to high activity of electrogenerated palladium species. We also developed site-selective sequential reactions by the integration of the electro-oxidative coupling reactions with non-electrochemical reactions. The reaction site could be controlled completely by the on/off application of electricity.
Photocycloaddition reaction is one of the most useful reactions to afford the unique structures, such as cyclobutanes, which are difficult to construct by a thermal reaction. Nevertheless, there are a few reports of the enantioselective photocyclization because of the difficulty of controlling racemic background reactions that occur by just excitation of substrates. This review focuses on two reports about the enantioselective catalytic intermolecular [2+2] photocycloaddition using visible light to afford chiral functionalized cyclobutenes and cyclobutanes.
Catalytic asymmetric epoxidation is one of the most important methods to synthesize chiral building blocks. However, catalytic reactions directed by a remote functional group, several bonds distal to the reactive site of the substrates, are rare. Here, I review the asymmetric epoxidation of homo- or bishomoallylic alcohols by using metal-BHA ligand systems and regioselective epoxidation for polyene compounds by using peptide catalysts.