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.

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.

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.

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.

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.

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).

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.

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.

Chemoselective Reduction and Alkylation of Carbonyl Functions Using Phosphonium Salts as an in Situ Protecting Groups.

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.

Enantioselective organocatalytic oxidation of ketimine.

C3-Symmetric chiral trisimidazolines with m-chloroperbenzoic acid promoted the organocatalytic oxidation of N-sulfonyl ketimine. The present imidazoline catalysis produced oxaziridines bearing a tetrasubstituted carbon stereogenic center in high yields with up to 87% ee.

Beckmann Fragmentation and Successive Carbon-Carbon Bond Formation Using Grignard Reagents via Phosphonium Salt Intermediates.

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.

Development of a Sulfur-Modified Glass-Supported Pd Nanoparticle Catalyst for Suzuki-Miyaura Coupling.

A safe, facile and low-leaching (up to 0.17 ppm) sulfur-modified glass-supported palladium nanoparticle catalyst has been developed for the Suzuki-Miyaura coupling of aryl halides with aryl boronic acids. Most notably, this catalyst was highly recyclable and could be used up to 10 times without any discernible decrease in its activity.

Development of an Enyne Metathesis/Isomerization/Diels-Alder One-Pot Reaction for the Synthesis of a Novel Near-Infrared (NIR) Dye Core.

N-Alkyl-N-allyl-2-alkynylaniline derivatives undergo a tandem ring-closing enyne metathesis/isomerization/Diels-Alder cycloaddition sequence in the presence of a second-generation Grubbs catalyst and dienophiles. In practice, the acyclic enyne in the presence of the ruthenium alkylidene first undergoes ring-closing metathesis to generate cyclic 4-vinyl-1,2-dihydroquinolines; following diene isomerization and then the addition of a dienophile, these ring-closing metathesis products are selectively converted into a 7-methyl-4H-naphtho[3,2,1-de]quinoline-8,11-dione core. Overall, the reaction sequence converts simple aniline derivatives into π-conjugated small molecules, which have characteristic absorption in the near-infrared region, in a single operation through three unique ruthenium-catalyzed transformations.

Stereoselective Construction of 2,7-Disubstituted fused-Bis Tetrahydrofuran Skeletons: Biomimetic-Type Synthesis and Biological Evaluation of (±)- and (-)-Aplysiallene and Their Derivatives.

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.

Oxidative rearrangement of cyclobutanone derived N,O-ketals leading to pyrrolidone derivatives.

A halogen-induced oxidative rearrangement of N,O-ketals prepared from cyclobutanones, leading to pyrrolidone derivatives, is developed. The reaction proceeds via an iminium ether intermediate and, depending on the reaction medium, two types of pyrrolidone derivative, containing a halogen atom or hydroxyl group, can be obtained.

C3-Symmetric chiral trisimidazoline-catalyzed Friedel-Crafts (FC)-type reaction.

Imidazoline-catalyzed enantioselective Friedel-Crafts (FC)-type reactions were established using C3-symmetric chiral trisimidazolines. The imidazoline catalysts promoted the FC-type reaction of aldimines with 2-naphthols to produce the corresponding adducts in high yields with up to 99% ee.

In situ protection methodology in carbonyl chemistry.

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.

Asymmetric dearomatizing spirolactonization of naphthols catalyzed by spirobiindane-based chiral hypervalent iodine species.

This report details the development of a spirobiindane-based chiral hypervalent iodine reagent, especially focusing on its structural elucidation for effective asymmetric induction of the chiral spiro center during the oxidative dearomatizing spirolactonization of naphthols. In this study we synthesized a new series of ortho-functionalized spirobiindane catalysts and demonstrated that the enantioselectivity can be dramatically improved by the presence of the substituents ortho to the iodine atom. The structural elucidation of a spirobiindane-based hypervalent iodine catalyst has led to further improvement in the stereoselective construction of the spiro center during the oxidative dearomatizing spirolactonization of naphthols. Thus, catalytic oxidation with the highest reported level of enantioselectivity in hypervalent iodine chemistry has been achieved with also an excellent level of asymmetric induction (92% ee for substrate 3a). As a result, this study, dealing with a series of modified iodine catalysts, can provide important clues about the transition state and reaction intermediate to help scientists understand the origin of the stereoselectivity. A plausible transition-state model and intermediate in the reaction for the stereoselective formation of spirolactone products are postulated by considering the ortho-substituent effect and the results of X-ray analysis. In this reaction model, the high enantiomeric excess obtained by using the spirobiindane catalysts could be well explained by the occupation of the equatorial site and extension of the surroundings around the hypervalent iodine bonds by the introduced ortho-substituent. Thus, this study would contribute to estimation of the chiral hypervalent iodine compounds in asymmetric reactions.