Design, Synthesis, and Monoamine Oxidase Inhibitory Activity of (+)-Cinchonaminone and Its Simplified Derivatives.

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.

1-Alkoxyvinyl Ester as an Excellent Acyl Donor: Efficient Macrolactone Synthesis.

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.

Selective Reduction of α,ß-Unsaturated Weinreb Amides in the Presence of α,ß-Unsaturated Esters.

α,ß-Unsaturated esters were selectively protected in situ in the presence of α,ß-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,ß-unsaturated aldehydes in good yields along with the recovered α,ß-unsaturated esters.

Development of New Innovative Synthetic Organic Chemistry Using Lone Pairs of Oxygen Atoms.

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.

Direct synthesis of dialkylarylvinylsilane derivatives: metathesis of dialkylaryl-iso-propenylsilane and its application to tetracyclic silacycle dye synthesis.

The metathesis of dialkylarylvinylsilane, which has not been accomplished to date, is achieved using dialkylaryl-iso-propenylsilane as a substrate. In addition, we discovered that the reason why the metathesis of a ruthenium carbene complex and dialkylarylvinylsilane is difficult is the formation of a carbide complex.

Metal-Free Nitrogen-Containing Polyheterocyclic Near-Infrared (NIR) Absorption Dyes: Synthesis, Absorption Properties, and Theoretical Calculation of Substituted 5-Methylisoindolo[2,1-a]quinolines.

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.

Chemoselective Transformations of Aromatic Methoxymethyl Ethers Using Trialkylsilyl Triflate and 2,2'-Bipyridyl.

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).

Pd-Catalyzed Migratory Cycloisomerization of N-Allyl- o-allenylaniline Derivatives.

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.

Chemoselective Nucleophilic Functionalizations of Aromatic Aldehydes and Acetals via Pyridinium Salt Intermediates.

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.

Design and synthesis of N1,N8-diacetylspermidine analogues having a linker with desired functional groups.

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).

Discovery and structure-activity relationship of imidazolinylindole derivatives as kallikrein 7 inhibitors.

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.

Cascade Multiple Diels-Alder Reactions of Styrene Derivatives with Maleimide or Maleic Anhydride.

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.

Highly Discriminative and Chemoselective Deprotection/Transformations of Acetals with the Combination of Trialkylsilyl Triflate/2,4,6-Collidine.

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.

Oxidative Rearrangement of Secondary Amines Using Hypervalent Iodine(III) Reagent.

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.

Palladium-Catalyzed Seven-Membered Silacycle Construction: 1,7-Enyne Hydroxycyclization To Give a Benzosilepine Skeleton.

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.

Aromatic aldehyde-selective aldol addition with aldehyde-derived silyl enol ethers.

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 ß-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.

Enantio- and Diastereoselective Betti/aza-Michael Sequence: Single Operated Preparation of Chiral 1,3-Disubstituted Isoindolines.

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%).

Ruthenium-Catalyzed 1,6-Aromatic Enamide-Silylalkyne Cycloisomerization: Approach to 2,3-Disubstituted Indoles.

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.

Transformation of Methylene Acetals to Bromoformates with a Combination of Trimethyl(phenylthio)silane and N-Bromosuccinimide.

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.

Concise synthesis of oxacyclic compounds using highly discriminative two-way transformations of α,ß-unsaturated esters in the presence of enones.

Highly discriminative transformation of α,ß-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.