During these fourty years, we have pursued new methodologies in organic synthesis and developed many synthetically useful reactions. Among them, four topics are introduced in this lecture. (1) Regio- and stereoselective silylmetalation of acetylenes, (2) Triethylborane induced radical addition of Ph₃SnH to acetylenes, (3) Preparation of three types of organometallic ate complexes, R₃MnMgBr, R₃MgLi, and R₃Co(L₂)MgBr, and their synthetic use, (4) Metal-mediated or –catalyzed retro-allylation of homoallyl alcohol.

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Highly regio- and stereoselective anti-carboalumination of TMS-alkynes having a tethered ether group has been achieved by using the cationic scandium alkyl species as a catalyst. Comparing with the conventional carboalumination catalysts, this system exhibits significantly higher activities. The reaction could be carried out under mild conditions, and the resultant vinylalanes could be easily transformed into tetrasubstituted alkynes in one-pot via stereospecific carbon-carbon bond formation. The same catalyst system was also effective for regioselective carboalumination of alkenes having a tethered ether group. In the present anti-carboalumination, a tethered ether group played an important role in controlling the stereo- and regiochemistry, possibly through its coordination to the metal center. As a ether group, bulky tert-butyldimethylsilyl or tert-butyldiphenylsilyl ether group could be used without loss of the selectivity.

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Organozinc reagents have been widely used as soft nucleophiles in organic synthesis and the control of nucleohilicity is highly important for desired selective transformations. Various methods have been utilized for promotion of the reactivity, and conventionally ate complexation or transmetalation has been employed. In connection with our recent studies on the reactivity control of organozinc reagents, we focused our interest on electron donative activation for promoting the reactivity of organozinc reagents. In this research, we disclosed that the t-Bu-P4 base promoted 1,2-reaction of aldehyde and ketones and S_N2 ′ reaction of α , β -unsaturated esters bearing a γ -chlorlide with various organolzinc reagents and that DMSO accelerated the S_N2 ′ reaction of propargyl electrophile with organozinc reagents dramatically.

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The first efficient method for kinetic resolution of racemic-aminoaldehydes which is based on recognition by copper(II) ion associated with (R,R)-Ph-BOX complex is achieved, i.e; coordinated aminoaldehydes were transformed into optically active amino acid methyl esters, and non-coordinated aminoaldehydes converted into optically active aminoaldehydes dimethyl acetals. Previously, we have reported asymmetric electrochemical oxidation of 1,2-aminoaldehydes to afford optically active amino acid methyl esters with low yield but good enantioselectivity. In line with our previous work, use of chiral copper catalyzed oxidation with N-iodosuccinimide (NIS) afforded optically active amino acid methyl esters in high enantioselectivity. The oxidation using NIS was applicable to various cyclic/acyclic aminoaldehydes (s value : up to 368). Since several commonly-used N-protecting groups on aminoaldehydes could be applied, these results might enhance the value of this oxidative kinetic resolution.

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The glycosyl onium ions are interesting species in carbohydrate chemistry. For instance, the well-known solvent effect in glycosylation reaction is explained by glycosyl onium ion intermediates. But, the investigation examples of characterization and reactivity of unstable glycosyl onium ions are few. We generated glycosyl sulfonium ions form highly reactive glycosyl triflate, generated by electrochemical oxidation method quantatively. The both alfa- and beta- glycosyl sulfonium ions were characterized by NMR and cold-spray MS. Furthermore, it is revealed that the alfa-glycosyl sulfonium ion has higher reactivity than beta-glycosyl sulfonium ion by time-course NMR analysis. From the stereochemical outcome observed in the glycosylation of glycosyl sulfonium ion with MeOH indicates that a simple SN2 attack on the glycosyl sulfide can be excluded as a reaction pathway.

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Protein kinase C (PKC), which is included in serine/threonine protein kinases and has 11 isozymes, is an important protein in the signal transductions related to cell growth, differentiation, apoptosis, etc. The PKC activation is mediated by binding of ligands such as diacylglycerol(DAG)/phorbol esters (tumor promoter) to C1 domains. PKC is also a receptor for ligands such as phrbol esters that are known as tumor promoters. Thus, PKC is one of important targets of drug discovery. To date, several different ligands targeted to PKC C1 domains, such as DAG-lactones, have been synthesized. Thus, in this study, we synthesized C1B domain analogs containing fluorescent groups that can be used as screening-tools for PKC-specific ligands. Furthermore, we synthesized caged DAG-lactones, which are inactive but activated by photo-irradiation, to investigate functions of PKC in cells.

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Although catechin oligomers are attracting considerable biological interests, detailed studies are hampered by scarce availability of pure samples from natural sources, because of the co-production of various closely related congeners, hardly separable and unstable. We report synthetic studies on oligocatechins based on the "sugar-flavonoid analogy" inferred by the S_N1 reactivity shared by carbohydrates at C(1) and catechins at C(4). The keys for enabling rapid, high-yield oligomerization include, (1) the orthogonal synthetic strategy for iterative catechin-chain extension, (2) bromo-capping of the C(8) position of flavan skeleton, enabling equimolar coupling of electrophilic/nucleophilic units. In addition to homo-oligomers, hetero-oligomers are interesting, although synthesis has not been addressed so far, because of the limited availability of monomers. Flexible routes to various catechin/epicatechin monomers will also be discussed.

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The addition of alkenylzirconocene chloride to quinoline and isoquinoline derivatives proceeded efficiently in the presence of a stoichiometric amount of an acylating agent to give alkenylation-acylation products in high yields. On the other hand, the addition to 3,4-dihydroisoquinoline was accelerated by a catalytic amount of Cu(I) (10 mol%) in the presence of an acylating agent. The enantioselective addition of alkenylzirconocene chloride to 3,4-dihydroisoquinoline was also achieved by the use of a Cu(I) / chiral amine catalytic system (56-75%ee).

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We have disclosed the enantioselective desymmetrization of prochiral σ-symmetric 1,3-diols in the presence of catalytic amount of cinchona alkaloid derivative and diethyl zinc. The asymmetric acetylation of 2-benzyloxy-2-methylpropane-1,3-diol with acetic anhydride in the presence of 10 mol% of quinidine derivative and 5 mol% of diethyl zinc proceeded at 0 ºC to give the corresponding (S)-mono-acetate in 64% yields with 82% ee. On the other hand, the use of quinine derivative instead of quinidine derivative in the asymmetric acetylation of 2-benzyloxy-2-methylpropane-1,3-diol furnished the corresponding (R)-mono-acetate in 57% yields with 79% ee. Optically active mono-acetates were also obtained from the asymmetric acetylation of other 2-alkyl-2-benzyloxypropane-1,3-diols.

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Migration of silicon is a ubiquitous process. The Brook rearrangement is an intramolecular migration of silicon from carbon to oxygen. The reverse process - migration of silicon from oxygen to carbon - is referred to as the retro- or reverse-Brook rearrangement and has turned out to be a common feature. The general trend of the ease of silyl migration has been reported to be [1,2] > [1,3] >> [1,4] > [1,5] based on the logic of the shorter transfer distance being more favored, and this order of migration has long been accepted without question. We have investigated the relative ease of comparable [1,2]- and [1,4]-migrations in an alpha,gamma-disilyloxy organolithium system and clarified for the first time that the relative ease of the rearrangements is [1,2] << [1,4], a reversal of the accepted order, and that a larger-size silyloxy group at the gamma-position relative to that at the alpha-position induces a higher [1,4]-selectivity.

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Enamide is recognized as one of the important fragments found in some biologically active natural products as well as a valuable substrate for the synthesis of optically active amines via asymmetric hydrogenation. Therefore, many protocols for enamide synthesis have been developed to date. Here, we report a new method for the synthesis of functionalized enamides by a nickel-catalyzed multicomponent coupling of ynamides, aldehydes, and silane. The coupling reaction proceeded through carbon-carbon bond formation between beta-carbon of ynamides and carbonyl carbon of aldehydes to give an oxanickelacycle in a highly regio- and stereoselective manner. The cleavage of nickel-oxygen bond by sigma-bond metathesis with silane afforded gamma-silyloxyenamide derivatives in good yields.

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Disubstituted amino acids restrict the conformational freedom of their peptides, and induce helical secondary structures. We have studied various helical secondary structures of homopeptides composed of chiral cyclic disubstituted amino acids, and reported that L-Leu-hexapeptide containing (S,S)-Ac(5)c(dOM) preferentially formed an alpha-helix in the crystal state. This result stimulated us to use the cyclic amino acid containing alpha-helical short-peptides as asymmetric catalysts. Alpha-helical polypeptide-catalyzed asymmetric epoxidation of chalcone was discovered by S. Julia and co-workers. Herein, we synthesized several L-Leu-oligopeptides having cyclic amino acids, analyzed their preferred secondary structures, and studied an enantioselective epoxidation of chalcone using alpha-helical oligopeptides as chiral catalysts.

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