Kiyosei Takasu

Gold(I)-Catalyzed Polycyclizations of Polyenyne-Type Anilines Based on Hydroamination and Consecutive Hydroarylation Cascade

A hydroamination-double hydroarylation cascade using aniline derivatives bearing a trienyne moiety as the substrate was efficiently promoted by a gold(I) catalyst to produce benzo[a]naphtho[2,1-c]carbazole derivatives in good yields. This reaction is applicable to various substituted trienyne-type anilines, including 2,3-diethynylthiophene derivatives. The reaction of anilines bearing a tetraenyne and pentaenyne moiety allows direct construction of highly fused carbazoles by tetra- and pentacyclization, respectively, through hydroamination and consecutive hydroarylation without producing any theoretical waste products from the substrates.

Auto-Tandem Catalysis in the Synthesis of Substituted Quinolines from Aldimines and Electron-Rich Olefins: Cascade Povarov−Hydrogen-Transfer Reaction

We demonstrated a catalytic cascade inverse electron demand hetero-Diels-Alder reaction (Povarov reaction) and hydrogen-transfer process. The reaction of electron-rich olefins and excess amount of imines in the presence of acid catalysts under appropriate conditions affords substituted quinolines in a single operation. In the cascade process, the catalysts, such as Tf2NH, TfOH, and Lewis acids, catalyze two mechanistically distinct reactions (auto-tandem catalysis). We also describe the synthetic utility of the prepared quinolines.

Enhanced Rate and Selectivity by Carboxylate Salt as a Basic Cocatalyst in Chiral N-Heterocyclic Carbene-Catalyzed Asymmetric Acylation of Secondary Alcohols

The rate and enantioselectivity of chiral NHC-catalyzed asymmetric acylation of alcohols with an adjacent H-bond donor functionality are remarkably enhanced in the presence of a carboxylate cocatalyst. The degree of the enhancement is correlated with the basicity of the carboxylate. With a cocatalyst and a newly developed electron-deficient chiral NHC, kinetic resolution and desymmetrization of cyclic diols and amino alcohols were achieved with extremely high selectivity (up to s = 218 and 99% ee, respectively) at a low catalyst loading (0.5 mol %). This asymmetric acylation is characterized by a unique preference for alcohols over amines, which are not converted into amides under the reaction conditions.

Hydroxyl group-directed organocatalytic asymmetric Michael addition of alpha,beta-unsaturated ketones with alkenylboronic acids.

The organocatalytic asymmetric Michael addition of organoboronic acids to gamma-hydroxy enones in the presence of an iminophenol-type thiourea catalyst is demonstrated. The hydroxyl group in the substrates plays a critical role in this reaction.

Catalyst-Controlled Torquoselectivity Switch in the 4π Ring-Opening Reaction of 2-Amino-2-azetines Giving β-Substituted α,β-Unsaturated Amidines

The torquoselectivity of the 4π electrocyclic ring-opening reaction of 2-azetines can be controlled by the Brønsted acidity of the catalyst and the polarity of the solvent. DFT calculations provided insight into the mechanism of this remarkable switch. Anti and syn stereoisomers of α,β-unsaturated amidines were selectively synthesized from ynamides and aldimines in the presence of Tf(2)NH and CSA, respectively.

Atropisomerism of α,β‐Unsaturated Amidines: Stereoselective Synthesis by Catalytic Cascade Reaction and Optical Resolution

Atropisomerism, a stereochemical property resulting from restricted rotation around a single bond where the steric strain barrier is high enough, has been the subject of much attention in organic chemistry. Well-studied biaryls, along with several classes of atropisomeric compounds including ortho-substituted anilides, N-arylimides, and diaryl ethers have been identified and their stereoselective synthesis has been explored. In particular, axially chiral biaryls have been well studied because they provide an effective chiral environment for asymmetric reaction when they act as chiral ligands of metal catalysts or organocatalysts. Moreover, axially chiral anilides are utilized as useful chiral building blocks for N-heterocycles with axial-to-center chirality transfer. In contrast to the above atropisomers whose rotationally-restricted single bond is directly connected to one or two aryl group(s), atropisomerism in acyclic p-systems such as 1,3-dienes and a,b-unsaturated carbonyl derivatives have rarely been studied. To the best of our knowledge, there is only one example of the optical resolution of a,b-unsaturated carboxylic acid derivatives. Mannschreck and his co-workers reported the optical property of atropoisomeric thioamide derivatives of acrylic acid. However, atropisomerism of a,b-unsaturated amidine derivatives, which would be potential synthetic precursors for heterocyclic compounds, is unexplored. We envisioned that highly substituted amidines 1 would provide a comparable stable atropisomer on axial chirality around a C2 C3 single bond (Figure 1). Herein, we report the optical resolution of atropisomeric a,b-unsaturated amidines and a novel stereoselective synthetic method of a,b-unsaturated amidines with bulky substituents. At the outset of this study, we considered the preparation of steric hindered a,b-unsaturated amidines. We thought that efficient synthesis of 1 by a coupling reaction to make a C2 C3 single bond or direct addition or substitution reaction to introduce a bulky substituent would be difficult. To achieve stereoselective synthesis of a,b-unsaturated amidines, we focused on the cascade reaction, consisting of [2+2] cycloaddition and successive electrocyclic ring-opening reaction (cycloreversion) of nitrogen-substituted alkynes and imines (Scheme 1). The cascade reaction corresponds to formal aza–enyne metathesis. In the [2+2] cycloaddition, the repulsive steric interaction of bulky substituents on both substrates would decrease owing to the linear geometry of the alkyne substrate. We expected that cycloreversion of the resulting azetine intermediate 2 would proceed in a geometrical selective manner. As a related study, cycloreversion of cyclobutenes has been well explored to give the corresponding 1,3-butadienes. In the thermal cycloreversion of fourmembered rings, the geometry of the product is ruled out by conrotatory rotation of the s-orbital of the central single bond and torquoselectivity (inward vs outward rotation in the conrotatory rotation). The torquoselectivity of 2-amino2-azetines 2 can be controlled by the bulkiness of the substituent at the 3-position (Scheme 1). That is, when the R group at the C(3) position is comparatively small, outward [a] N. Shindoh, Prof. Dr. Y. Takemoto, Prof. K. Takasu Graduate School of Pharmaceutical Sciences Kyoto University Yoshida, Sakyo-ku, Kyoto 606-8578 (Japan) Fax: (+81) 75-753-4610 E-mail : kay-t@pharm.kyoto-u.ac.jp takemoto@pharm.kyoto-u.ac.jp Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200901103. Figure 1. Representative atropisomers (biaryls, anilides and 1,3-dienes) and putative atoropisomeric a,b-unsaturated amidines 1.

Chiral sulfur-containing 1,2-disubstituted ferrocenes

Abstract Enantiopure 1 -t- butylsulfinyl-2-subsituted ferrocenes were synthesized in reactions of (SR,1S,2R)-1-t-butylsulfinyl-2-lithioferrocene (11) with various electrophiles in good yields. (SR,1S,2R)-1-t-Butylsulfinyl-2-formylferrocene (19), prepared this way, underwent complete stereoselective addition reactions with Grignard reagents under chelation controlled conditions with titanium tetraisopropoxide. 1,4-Addition reactions of selected α,β-unsaturated esters with cuprate reagents gave mixtures of two diastereomers. The lack of stereoselectivity in these 1,4-addition reactions is due presumably to the remote reactive site (C-3′) and the flexibility of the side chain of the ester. A stereoselective cationic displacement reaction of (1S,2R,1′S)-1-(t-butylsulfonyl)-2-[α-(2-propenoyl)oxybenzyl]ferrocene (44) with 1-acetoxy-1,3-butadiene was found to produce (1S,2R,1′S)-1-(t-butylsulfonyl)-2-(5′-oxo-1′-phenyl-3′-pentenyl)ferrocene (45).

Development of a Brønsted Acid-Promoted Arene–Ynamide Cyclization toward the Total Syntheses of Marinoquinolines A and C and Aplidiopsamine A

A Brønsted acid-promoted arene-ynamide cyclization has been developed to construct the 3H-pyrrolo[2,3-c]quinolines. This reaction consists of the generation of a highly reactive keteniminium intermediate from arene-ynamide activated by a Brønsted acid and electrophilic aromatic substitution reaction to give arene-fused quinolines in high yields. This methodology enabled facile access to marinoquinolines A and C and aplidiopsamine A.

Fluorinated rhodacyanine (SJL-01) possessing high efficacy for visceral leishmaniasis (VL)

Anti-Leishmania in vitro and in vivo activities of various rhodacyanine derivatives have been examined. Among them, the fluorinatied variant SJL-01 (8) showed IC(50) of 0.011 microM against Leishmania donovani strain MHOM/ET/67/L82 (selective index of >15000) and 95-97% inhibition against L. donovani strain MHOM/ET/67/HU in female BALB/c mice by 1.3-12.5 mg/kg x 5 iv administrations. Negative results on chromosomal aberration test and in vitro micronucleus test suggest that compound 8 is a hopeful candidate for visceral leishmaniasis (VL).

Auxiliary induced asymmetric Michael-aldol reaction under kinetic and thermodynamic conditions

Asymmetric intramolecular Michael-aldol reaction of (−)-phenylmenthyl enoates 1 affords tricyclic cyclobutanes 2 in excellent diastereoselectivity. It is made clear that Michael-aldol reaction is reversible under conditions using trimethylsilyl iodide (TMSI) in the presence of hexamethyldisilazane (HMDS) at ambient temperature. The difference of stereoselectivity under kinetic or thermodynamic conditions are reported.