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[Image: see text] The absolute structure of an indole alkaloid (+)-cinchonaminone by total synthesis of both (+)-cinchonaminone and its enantiomer was determined. The main focus of the study was the enantioselective synthesis of both enantiomers of a chiral cis-3,4-disubstituted piperidine. We also evaluated monoamine oxidase (MAO) inhibitory activities of these enantiomers. Furthermore, its structurally simplified derivatives were synthesized that did not have any chiral center. Two of these derivatives showed stronger MAO inhibitory activities than that of (+)-cinchonaminone.

Ketene acetal derivatives, such as 1-alkoxyvinyl esters and O-silyl ketene acetals, belong to the category of O-substituted enols of esters, which easily react with various types of nucleophiles, Nu-H, under neutral conditions to give the corresponding acylated and silylated products in excellent yields only by evaporation of the generated volatile esters. Silyl ketene acetals can be easily synthesized by various simple procedures, whereas 1-alkoxyvinyl esters require an equimolar or catalytic amount of a mercury salt to synthesize them. This drawback prevented the advancement of the chemistry of 1-alkoxyvinyl esters. In 1993, we developed a useful synthetic method of 1-alkoxyvinyl esters using a small amount (0.5-1 mol %) of a ruthenium catalyst. Encouraged by this discovery, we subsequently developed various reactions and applied them to the synthesis of natural products. It is noteworthy that the stereoselective total synthesis of fredericamycin A was achieved by the combined use of these reactions. Macrocyclization was variously utilized for the synthesis of natural macrolides by two types of approaches: direct macrolactonization of α,ω-hydroxy acids or intermolecular esterification between an acid and alcohol followed by a ring-closure step. Additionally, several new reactions using 1-alkoxyvinyl esters or their analogs as key intermediates on the basis of our methods were recently reported. In this paper, we introduce our efforts from the synthesis of 1-alkoxyvinyl esters to the application such as natural product syntheses and recent advancements.

α,β-Unsaturated esters were selectively protected in situ in the presence of α,β-unsaturated Weinreb amides using PEt3 and trimethylsilyl trifluoromethanesulfonate (TMSOTf) in toluene under reflux. Diisobutylaluminium hydride (DIBAL-H) reduction of the mixture followed by tetra-n-butylammonium fluoride (TBAF) treatment produced α,β-unsaturated aldehydes in good yields along with the recovered α,β-unsaturated esters.

Herein, we report an unprecedented thermal [2 + 2]-cycloaddition between silylalkynes and allenylphenols to form an aromatizing cyclobutachromene intermediate, followed by the nucleophilic addition of water to yield functionalized arylcyclobutenals. This reaction is atom- and pot-economical because all the atoms contained in the starting material are retained in the final product, no other reactants are required, and it proceeds in one-pot.

A hydrocarboxylation reaction of alkyne or styrene derivatives with CO2 proceeded smoothly by using an air-stable nano-sized nickel catalyst supported on sulfur-modified gold (SANi), giving functio...

The Pd-catalyzed migratory cycloisomerization of N-allyl- o-allenyl aniline derivatives is first reported to give indoles having a substituent at the 2-position.

Aromatic methoxymethyl (MOM) ethers behave differently from aliphatic MOM ethers upon treatment with trialkylsilyl triflate (R3SiOTf) and 2,2′-bipyridyl. The aromatic MOM ethers are first converted to silyl ethers and subsequently deprotected by hydrolysis to give the mother alcohols when the R3SiOTf used is trimethylsilyl triflate (TMSOTf). Conversely, direct conversion of aromatic MOM ethers to aromatic triethylsilyl (TES) ethers is possible when the R3SiOTf used is triethylsilyl triflate (TESOTf).

The synthesis of new N1,N8-diacetylspermidine (DiAcSpd) analogues having a linker with desired functional groups in the methylene skeleton, which have been designed by theoretical calculations, is described. We have also achieved the preparation of DiAcSpd supported on solid-phase resins, which have the potential to be used for the evolution of ligands by exponential enrichment (SELEX).

A nanoparticle (NP)-based precatalyst has been developed for organic synthesis: sulfur-modified Au-supported Fe (SAFe). The SAFe was easily prepared through a three-step procedure involving simultaneous in situ metal NP and nanospace organization (PSSO). This method avoids the need for preformed templates for immobilizing and stabilizing the metal nanoparticles. On account of the relative safety and enormous earth abundance of iron, SAFe potentially represents an ideal precatalyst for carbon–carbon bond-forming cross-coupling reactions. As such, it has been applied as a precatalyst to Kumada coupling under ligand-free conditions, proving to be capable of being recycled and used repeatedly for this reaction. Analysis of SAFe and of reaction mixtures suggested that the active species in these reactions are produced in situ by assemblies of iron-based NPs.

Oxygen atoms have a lone pair of electrons, so they have high chelation ability, high nucleophilic ability, stabilizing ability of adjacent cations, and take a chelate or oxocarbenium ion structure with Lewis acids and metals. I took advantage of these properties to develop three new reactions, 1) asymmetric synthesis of chiral quaternary carbon centers, 2) asymmetric synthesis using acetal functions, and 3) organic chemistry using acetal-type reactive salt chemical species, and applied them to biologically active natural products synthesis. New reactions described here are all innovative and useful for natural products synthesis. In particular, the first asymmetric synthesis of fredericamycin A, and concise asymmetric synthesis of anthracycline antibiotics, scyphostatin, (+)-Sch 642305, (-)-stenine, clavolonine, (+)-rubrenolide, (+)-rubrynolide, (+)-centrolobine, and decytospolide A and B, etc., are noteworthy. Furthermore, since reactions using acetal-type reactive salt chemical species allow the coexistence of functional groups that normally cannot coexist, the reactions using reactive salts have potential to change the retrosynthesis planned based on conventional reactions.

Acetals are the most useful protecting groups for carbonyl functional groups. In addition to the role of protection, they can also be used as synthons of carbonyl functions. Previously, we developed a chemoselective deprotection and nucleophilic substitution of acetals from aldehydes in the presence of ketals. This article describes the highly discriminative and chemoselective transformations of acetals bearing different substitution patterns, different types of acetals, as well as mixed acetals. These reactions can achieve the transformations that cannot be attained by conventional methods, and their results strongly suggest the combination of R3SiOTf/2,4,6-collidine to promote such unprecedented phenomena.

We developed novel one-pot multiple Diels-Alder reactions, which are frequently used in the construction of six-membered rings in functional molecular synthesis. We report triple and double Diels-Alder reactions with styrene derivatives, where the secondary Diels-Alder reaction takes place at a different position from that of the conventional Wagner-Jauregg reaction.

A hypervalent iodine(III) reagent mediated oxidative skeletal rearrangement reaction of secondary amines is reported. The transformation, which uses PhI(OAc)2 in CF3CH2OH, was found to be highly efficient at inducing the direct 1,2-C-to-N migration of secondary amines. This method offers facile and divergent access to polycyclic and macrocyclic indole-fused compounds. The synthetic potential of the method is also demonstrated through its application to several substrates, including secondary as well as primary amines.

A palladium-catalyzed hydroxycyclization reaction of 1,7-enynes to afford seven-membered silacycles (1 H-benzo[ b]silepine skeletons) is developed. This is the first example of both seven-membered ring construction from enynes using a palladium catalyst and hydroxycyclization of enynes to give seven-membered silacycles.

The aldol reaction using aldehyde-derived silyl enolates as nucleophiles with aromatic aldehydes chemoselectively proceeded in the presence of silyl triflate and 2,2'-bipyridyl to produce β-siloxy aldehydes, while the aliphatic aldehydes were completely recovered. The unprecedented chemoselectivities depend on the reactivities of the pyridinium-type intermediates derived from the aromatic and aliphatic aldehydes.

The first enantio- and diastereoselective Betti/intramolecular aza-Michael sequence carried out using a C3-symmetric chiral trisimidazoline organocatalyst is reported. The reaction of phenols and N-tosylimines bearing a Michael acceptor moiety afforded densely functionalized 1,3-disubstituted isoindolines bearing two stereogenic centers as single diastereomers in high yields (≤93%) and excellent enantioselectivities (≤99.9%).

A versatile and chemoselective route has been developed for the synthesis of aliphatic fluorinated methyl ethers (ROCH 2 R F ), specifically monofluoromethyl ethers (ROCH 2 F) and trifluoromethylthiomethyl ethers (ROCH 2 SCF 3 ), through pyridinium-type salt intermediates derived from methoxymethyl (MOM) ethers. The addition of a fluorine source (F − or SCF 3 − ) to the pyridinium-type salts afforded the corresponding fluorinated methyl ethers in good yields under mild conditions. Notably, the synthesis of monofluoromethyl ethers proceeded within just 5 min.

(+)-Laurenidificin has a fused bis-THF skeleton and an enyne structure in its side chain. It is known that the bis-THF skeleton is cis,cis fused, and the absolute configuration at the C6 position is R, but the whole structure has not been determined. We synthesized one possible isomer of (+)-laurenidificin by using intramolecular double bromoetherification as a key step. Treatment of a protected (E,E)-diene diol with 2,4,4,6-tetrabromo-2,5-cyclohexadienone as the halogenating agent afforded a cis,cis-fused bis-THF derivative in good yield with high stereoselectivity. Several additional transformations, including introduction of a hydroxy group at the C6 position and construction of the enyne structure, gave a possible isomer of (+)-laurenidificin. The 1H NMR and 13C NMR spectroscopy data of this isomer are in complete agreement with those of natural (+)-laurenidificin, and its optical rotation and that of natural laurenidificin have the same positive sign.

Metal-catalyzed cycloisomerization reactions of 1,n-enynes have become conceptually and chemically attractive processes in the search for atom economy, which is a key subject of current research. However, metal-catalyzed cycloisomerization between aryl enol ether and silylalkynes has not been developed. The ruthenium hydride complex catalyzed cycloisomerization between aryl enol ether and silylalkynes is reported to give benzofurans having useful functional groups, vinyl and trimethylsilylmethyl, on the 2- and 3-positions, respectively.

Recent progress in the chemoselective reduction and alkylation of carbonyl functions using our in situ protection method is described. Methods that enable reversal or control of the reactivity of a carbonyl functional group are potentially useful. They open up new areas of synthetic organic chemistry and change the concept of retrosynthesis because they remove the need for complicated protection/deprotection sequences. In this account, we discuss the strategy and applications of our in situ protection method using phosphonium salts.

We developed a conceptually and methodologically novel ruthenium(0) nanoparticle catalyst, sulfur-modified Au-supported ruthenium nanoparticles (SARu). SARu is easily prepared through a three-step procedure involving simultaneous in situ metal nanoparticle and nanospace organization. This unique method does not require any conventional preformed template to immobilize and stabilize metal nanoparticles. SARu is an ideal ruthenium catalyst for liquid-phase combinatorial synthesis because it repeatedly catalyzes ligand-free Suzuki–Miyaura coupling of aryl halides, including aryl chlorides, with arylboronic acids with low Ru leaching. Physical analysis of SARu showed that the active species in these reactions were ruthenium (0) nanoparticles with a size of 1–3 nm. Also, we developed a continuously irradiating microwave methodology, which can first time discriminate the heating effect and the microwave effect in microwave experiments.

The development of a novel chemoselective functionalization can diversify the strategy for synthesizing the target molecules. The perfect chemoselectivity between aromatic and aliphatic aldehydes is difficult to achieve by the previous methods. The aromatic aldehyde-selective nucleophilic addition in the presence of aliphatic aldehydes was newly accomplished. Namely, the aromatic aldehyde-selective nucleophilic addition using arenes and allyl silanes proceeded in the presence of trialkylsilyl triflate and 2,2′-bipyridyl, while the aliphatic aldehydes completely remained unchanged. The reactive pyridinium-type salt intermediate derived from an aromatic aldehyde chemoselectively underwent the nucleophilic substitution. Moreover, the aromatic acetals as the protected aldehydes could be directly transformed into similar pyridinium salt intermediates, which reacted with various nucleophiles coexisting with the aliphatic aldehydes.

We have synthesized and theoretically calculated 5-methylisoindolo[2,1-a]quinoline derivatives as novel near-infrared absorption dyes via a ruthenium-catalyzed one-pot metathesis/oxidation/1,3-dipolar cycloaddition protocol. The reactivity in 1,3-dipolar cycloaddition was governed by the electronic effect of aromatic ring substituents. Substrates with an electron-withdrawing group on the aromatic ring afforded higher yields. The maximal absorption wavelength of 3,5-dimethyl-11-phenylisoindolo[2,1-a]quinoline-7,10-dione and 11-(4-methoxyphenyl)-5-methylisoindolo[2,1-a]quinoline-7,10-dione in MeOH increased to 736 and 737 nm, although that of 3a was 727 nm.

The synthesis of new N1,N8-diacetylspermidine (DiAcSpd) analogues having a linker with desired functional groups in the methylene skeleton, which have been designed by theoretical calculations, is described. We have also achieved the preparation of DiAcSpd supported on solid-phase resins, which have the potential to be used for the evolution of ligands by exponential enrichment (SELEX).

Selective one-pot alkylation or allylation of ketones in the presence of α,β-unsaturated ketones (enones) were accomplished by using our in situ protection methodology. Enones selectively react with a combination of PPh3 and silyl triflates in the presence of ketones to produce phosphonium silyl enol ethers, which act as protective groups for the enones during the alkylation or allylation of ketones, and can be easily deprotected to regenerate the parent enones on work-up.

We have developed a conceptually and methodologically novel self-assembled multilayer nickel nanoparticle (NP) catalyst – sulfur-modified gold-supported Ni NPs (SANi) – for organic synthesis. The SANi catalyst was easily prepared through a three-step procedure involving simultaneous in situ metal NP and nanospace organization. This unique method does not require any conventional preformed template for immobilizing and stabilizing NPs. SANi catalyzes carbon-carbon bond-forming cross-coupling, Kumada coupling, and Negishi coupling reactions under ligand-free conditions and can be used repeatedly for these reactions. Physical analysis of SANi showed that the active species in these reactions are self-assembled multilayer zerovalent Ni NPs with a size of ∼3 nm.

We have developed a novel nonmetathesis reaction, namely, ruthenium-catalyzed intramolecular [2 + 2] cycloaddition of allenamide-enes, to give heterocycles (i.e., azabicyclo[3.1.1]heptanes). This is the first example of [2 + 2] cycloaddition using a ruthenium carbene catalyst. The reaction proceeds at room temperature, but not under thermal or radical conditions.

The intermediates formed during the Beckmann fragmentation of α-alkoxy and α-alkoxy-α-alkyl oxime acetates have been successfully trapped as phosphonium salts, which were subsequently reacted with a variety of Grignard reagents to give the corresponding substituted products in good yields. Notably, this reaction proceeded smoothly even from α-alkoxy-α-alkyl oxime acetates.

with promoted the enantioselective organocatalytic oxidation of to afford oxaziridines bearing a tetrasubstituted carbon stereogenic center in high yields with up to 87% ee.

N-Alkyl-N-(2-vinylbenzyl)prop-2-en-1-amine derivatives undergo a one-pot olefin isomerization/aliphatic enamine ring-closing metathesis (RCM)/oxidation/1,3-dipolar cycloaddition sequence with the ruthenium complex, Ru(CO)HCl(PPh3)3, a second generation Hoveyda–Grubbs catalyst, and a 1,3-dipolarophile. Overall, in a single operation the reaction sequence converts simple benzylamine derivatives into isoindolo[1,2-a]isoquinolines with a π-conjugated four-ring system, through three unique ruthenium-catalyzed transformations.

A series of imidazolinylindole derivatives were discovered as novel kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Structure-activity relationship (SAR) studies led to the identification of potent human KLK7 inhibitors. By further modification of the benzenesulfonyl moiety to overcome species differences in inhibitory activity, potent inhibitors against both human and mouse KLK7 were identified. Furthermore, the complex structure of 25 with mouse KLK7 could explain the SAR and the cause of the species differences in inhibitory activity.

A series of trans/trans and cis/cis fused-bis tetrahydrofuran compounds have been obtained stereoselectively in high yields via a one-pot operation involving the intramolecular haloetherification of (Z,Z)-diene diol 19a and (E,E)-diene disilylether 19d, respectively. This method was subsequently applied to the biomimetic-type synthesis of (±)- and (-)-aplysiallene. The inhibitory activities of these compounds and their bromodiene isomers toward Na(+)/K(+) ATPase were determined in vitro, and gave IC50 values of approximately 15 μM in all cases.

Cycloisomerization is an atom economic procedure that converts dienes and enynes into cyclic molecules. To date, cycloisomerization between enamides and silylalkynes has not been explored. We found that N-acyl-N-vinyl-2-silylalkynylaniline derivatives undergo a cycloisomerization in the presence of a well-defined ruthenium hydride to give a 2,3-disubstitued indole. The vinyl and silylmethyl substituents on the 2- and 3-positions of the indole can be easily converted to other functional groups.

A novel transformation reaction of methylene acetals, using a combination of trimethyl(phenylthio)silane (PhSTMS) and N-bromosuccinimide (NBS) under mild reaction conditions, is described. Various methylene acetals were converted to their corresponding bromoformates in good to high yields. Under the given conditions, the reaction proceeded via a radical pathway. Further transformation of bromoformates to their corresponding epoxides was achieved by treatment with NaOMe.

Highly discriminative transformation of α,β-unsaturated esters in the presence of enones using two types of phosphonium salts, and their application to the synthesis of oxacyclic compounds in six steps in one pot have been achieved.

Polycyclic compounds containing a six-membered silacycle are important. However, we have limited knowledge of the nature of these six-membered silacycles because methodologies for their synthesis remain under-developed. Here, we have developed a one-pot enyne metathesis/Diels–Alder/oxidation methodology for the synthesis of six-membered silacycles. Some of these compounds are novel fluorophores.

Recent progress in the chemoselective reduction and alkylation of carbonyl functions using our in situ protection method is described. Methods that enable reversal or control of the reactivity of a carbonyl functional group are potentially useful. They open up new areas of synthetic organic chemistry and change the concept of retrosynthesis because they remove the need for complicated protection/deprotection sequences. In this account, we discuss the strategy and applications of our in situ protection method using phosphonium salts.

The results of studies leading to the development of enantioselective desymmetrizing, bromolactonization reactions of symmetric olefinic dicarboxylic acids, which are promoted by a C3 -symmetric trisimidazoline catalyst, are described. These processes generated carboxylic-acid-containing bromolactones in moderately high enantiomeric excesses. The results of optimization studies showed that reactions in a mixed solvent system of toluene and acetone proceeded with the highest levels of enantioselectivity. NMR studies probing the interactions between the catalyst and dicarboxylic acid substrates, as well as the effect of acetone on the stereochemistry of the process, are also described.

Enones selectively react with a combination of PPh(3) and TMSOTf to produce phosphonium silyl enol ethers, which work as protective groups of enones during the reduction of other carbonyl functions and can be easily deprotected to regenerate parent enones at workup. Furthermore, the first ketone selective alkylations in the presence of enones were also accomplished. This in situ protection method was applied to concise asymmetric total syntheses of decytospolides A and B.

An enantioselective iodolactonization reaction of allenoic acids has been developed using a trisimidazoline catalyst and I2. Our mechanistic study suggests the involvement of a π-allyl cation intermediate in this reaction system.

Recent progress in selective transformation of carbonyl groups using in situ protection methodology is described. These techniques which enable reversing reactivity of functional groups have potential usefulness because they can remove complicated protection-deprotection sequences. In this review, we discuss various in situ protection strategies and their synthetic applications.

The intermediate formed during the Beckmann fragmentation was successfully trapped as a collidinium salt, which was subsequently reacted with a variety of different Gilman reagents to give the corresponding addition products in good yields. Reaction mechanism was also investigated.