With the intention of applying the Evans' chiral auxiliary to the solid phase organic synthesis, we prepared a new polymer-supported oxazolidinone 6 and examined its potential. As the starting material for the synthesis of 6, we selected an α-hydroxy-β-amino acid phenylnorstatine 1, containing a carboxyl substituent available for loading. Conveniently, 1 could be transformed to the oxazolidinone derivative 5 and immobilized to Wang resin successfully. After conversion to the corresponding carboximide, the solid phase asymmetric alkylations were performed. Lithium hydroperoxide mediated chemoselective hydrolysis yielded the desired chiral α-alkylatedcarboxylic acids 11 with high stereoselectivities. In conclusion, we synthesized a phenylnorstatine-derived new polymer-bound chiral auxiliary and it was found to be applicable to the solid phase asymmetric alkylation reactions with the results comparable to the liquid phase model experiments.

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The aldol reaction is one of the most powerful methods of forming carbon–carbon bonds. We found that lithium binaphtholates are effective catalysts for the aldol reaction of trimethoxysilyl enol ethers with aldehydes. The aldol reaction of trimethoxysilyloxycyclohexene and benzaldehyde catalyzed by lithium binaphtholate (10 mol%) prepared from (R)-3,3'-dichloro-2,2'-binaphthol and n-BuLi afforded the corresponding anti-adduct predominantly in high yield with 56% ee. Though the enantioselectivities are still modest, the present reaction is the first example of base-catalyzed enantioselective aldol reaction of trimethoxysilyl enol ethers with carbonyl compounds.

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A new method for asymmetric cyclization was developed based on dynamic chirality of enolates derived from α-amino acids. N-(ω-bromoalkyl)-amino acid derivatives, readily prepared from natural α-amino acids, gave cyclic amino acids with a quaternary stereo-center by the treatment with potassium hexamethyldisilazaide (KHMDS). Chirality of parent amino acids was almost completely preserved during enolate-formation and cyclization process, giving cyclic amino acids in up to 98% ee in retention of configuration. This method is applicable to the asymmetric synthesis of azetidine, pyrrolidine, piperidine, and azepane derivatives. Similarly, a route to highly substituted chiral nitrogen-containing heterocycles was developed through intramolecular conjugate addition of chiral enolates derived from α-amino acids.

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We describe the development of a new tridentate chiral ligand effective for the asymmetric catalysis of Nozaki—Hiyama allylation, methallylation and propargylation. Various aldehydes (aromatic and aliphatic) were generally allylated or methallylated with good to excellent enantioselectivity (86-96% ee). The enantioselective reaction catalyzed by this Cr-ligand complex has great potential for natural product synthesis, and a key intermediate of calcitriol lactone synthesis was obtained with excellent diastereoselectivity (97% de, 91%). Another remarkable feature of this ligand is the stability of the Cr-ligand complex which was recovered after the enantioselective reaction and recycled without diminishing the enantioselectivity and yield.

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We have developed an efficient methodology for the preparation of optically active adamantane derivatives. Thus, enantiomerically enriched (> 96% ee) 1,2,5- and 1,3,4- substituted adamantanes were constructed starting from the common meso symmetric 7-methylidenebicyclo[3.3.1]nonan-3-one by employing either an asymmetric aldol reaction or the kinetic resolution under Sharpless asymmetric epoxidation condition for the enantiomerization steps, and the following titanium(IV) chloride mediated cyclization. The utility of the methodology has been demonstrated by synthesizing pharmaceutically attractive chiral α-adamantyl-α-amino acids.

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Halichlorine and pinnaic acid are biologically active marine alkaloids, which have a unique azaspirocyclic framework with several stereogenic centers. The central interests are stereoselective construction of the azaspirocyclic core. We have developed a new methodology for stereoselective construction of azaspirocylic core of the natural products. The sequence involves cascade radical translocation/cyclization reaction, which allows creating azaspirocyclic frameworks from simple piperidine derivatives. It is noteworthy that a formal C-H activation by the radical intermediate is comprised in the cascade process. Furthermore, we achieved that the stereoselective installation of side chains at C(5) and C(14) positions was successful in good overall yields.

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Securinine is a member of the Securinega family of alkaloids, and it possesses CNS stimulating activity as a GABA_A receptor antagonist. In addition to its attractive biological activity, securinine with an α,β-unsaturated-γ-lactone unit and an indolizidine skeleton, is an interesting target in synthetic chemistry. We report here the total synthesis of (−)-securinine, in which dienyne metathesis was employed as a key reaction. The dienyne, a precursor for RCM reaction, was prepared from (+)-pipecolinic acid in several steps. The RCM reaction of this dienyne in the presence of Ru-carbene complex proceeded smoothly to give the cyclized product in good yield. This compound was further transformed to (−)-securinine by sequential oxidation, allylic bromination and amino-cyclization. We believe that this synthetic strategy is widely applicable to the synthesis of other Securinega family of alkaloids.

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An efficient synthetic entry to the ABC and ACE ring systems common to the madangamine alkaloids has been developed. Acidic treatment of the cyclohexanone derivatives bearing the aminophenol afforded the corresponding cyclic N,O-acetals containing the AC ring. The N,O-acetal obtained underwent successive C-O bond cleavage with AlH₃ and intramolecular S_N2 displacement of the mesylate to yield the ABC ring. On the other hand, treatment of the azabicyclononanone derived from another N,O-acetal provided the ACE ring via novel intramolecular aldol-type condensation along with silyl group migration.

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An enantioselective total synthesis of aspidophytine is reported. The indole fragment was prepared by indole synthesis using 2-alkenylphenyl isocyanide. The 2-stannylindole product, which is generated after indole formation, was treated with iodine to provide 2-iodoindole. The optically active terminal acetylene unit was prepared through enzymatic resolution of the cyclopentenol derivative and Claisen rearrangement. Union of these two unites was achieved by Sonogashira-coupling. After formation of the 11-membered cyclic secondary amine by means of the Ns protocol, the aspidosperma skeleton and the lactone ring were constructed to complete the total synthesis.

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We have developed a new and efficient synthetic method for functionalized dihydrobenzofurans and benzofurans via the route involving [3, 3]-sigmatropic rearrangement of O-aryl enehydroxylamine.The acylation of 5a with TFAA proceeded at 0°C to give the dihydrobenzofuran 9a in 99% yield via possible intermediate 7a. In the case of trichloroacetic anhydride, a high reaction temperature was required. The substituent effect on imine part was investigated. Treatment of substrates 5b-d with TFAA gave dihydrobenzofurans 9b–d while the reaction with trifluoroacetyl triflate in the presence of base gave the benzofurans 12b-d in good yields. This successive method involving acylation, [3, 3]-sigmatropic rearrangement, and intramolecular cyclization was applied to the synthesis of Stemofuran A and Eupomatenoid 6.

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We have developed a new organozincate-mediated anionic polymerization (ZAP) using ^tBu₄ZnLi₂ as an initiator. This method possesses great versatility and high chemoselectivity, and multi-functionalized monomers, such as NIPAm, AN, and HEMA, could be polymerized in high yields. Furthermore, the current anionic polymerization by using ^tBu₄ZnLi₂ has high compatibility with protic solvents, which accelerate the reactions significantly. The polymer growth was also well-regulated, and the terminal zincate of the polymer end could be modified by electrophilic traps.

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Palladium-catalyzed allylic substitution with carbon nucleophiles is one of the most important reactions in transition metal-catalyzed synthetic methods. In most cases, allyl esters or allyl carbonates have been used as allylating agents. If allyl alcohols can be used as allylating agents, the overall process of the allylation would become highly efficient and atom economical. On the other hand, organic reactions in water have recently attracted much attention, not only because unique reactivity is often observed in water but also because water is a safe and economical substitute for conventional organic solvents. Here, we disclose a new catalytic system for palladium-catalyzed allylic substitution of allyl alcohols in water as a dispersion medium. The key is the use of a catalytic amount of a carboxylic acid such as 1-AdCO₂H, which dramatically accelerates the palladium-catalyzed allylic substitution.

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Development of water-soluble chiral ketones designed for efficient asymmetric dioxirane oxidation was achieved. The water-soluble chiral quarternary bis(ammonium)ketones (S,S-1, S,S-2, S,S-3, S,S-4) having C₂-symmetry were synthesized in several steps from (S,S)-1,2-cyclohexanediamine. Enantioselective epoxidation of a variety of olefins was examined by chiral dioxiranes generated in situ from catalytic amount of these chiral ketones (0.05 eq.), Oxone^®(5 eq.), and NaHCO₃(15.5 eq.) in CH₃CN–aq. Na₂EDTA solution at 20°C. Epoxidation of a variety olefins proceeded very smoothly to give optically active epoxides inmoderate to excellent chemical yield.

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New axially dissymmetric ligands, 2,2'-bis((R^*)-2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-1-hydroxyoctyl)-(R^*)- biphenyl, were synthesized. A chiral catalyst prepared by mixing the ligand and Ti(Oi-Pr)₄ in toluene at 50°C for 30 min catalyzed an ethyl addition to benzaldehyde to give the product quantitatively and up to 98% ee. The high reactivity and enantioselectivity of the catalyst are attributed to the electron-withdrawing and sterically large R_f groups. Another advantage of this ligand is easy recoverability by using a fluorous solvent. The ligand was recovered quantitatively by a three-phase extraction (using FC-72, CH₂Cl₂ and water) directly after the reaction. The ligand recovered could be used in the next reaction without further purification and its asymmetric induction did not decrease at all even after several recycling.

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The Bfp and Hfb groups, a novel fluorous tag, were able to be easily prepared. The Bfp and Hfb groups were readily introduced to carbohydrate, removed in high yield, and were recyclable after cleavage. The use of the fluorous tags made it possible to synthesize rapidly an oligosaccharide by minimal column chromatography purification. Each synthetic intermediate was able to be easily purified only by simple fluorous-organic solvent extraction, and monitored by TLC, NMR, and MS.

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