HETEROCYCLES

■ Contents

■ Editor’s Remark

HETEROCYCLES Contents*

*The Japan Institute of Heterocyclic Chemistry, 1-7-17, Motoakasaka, Minato-ku, Tokyo 107-0051, Japan

■ Synthetic Studies on Keramaphidin B: Formation of a Macrocyclic Ring by Intramolecular Diels-Alder Reaction

Hiroki Shimoda, Takahiro Shibata, Daisuke Sekine, and Masahisa Nakada*

*Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan

Abstract

The possibility of constructing the macrocyclic ring of keramaphidin B via an intramolecular Diels-Alder (IMDA) reaction has been investigated. The IMDA reaction of a substrate possessing dihydropyridone and diene moieties, which were tethered by an alkyl chain including a linear triple bond, was found to proceed in the presence of SnCl4 at 80 °C.

■ Alternative Chiral Preparations of a Swaminathan Ketone via Asymmetric Aldol Reactions Mediated by Chiral Amines Bearing a Pyrrolidine

Yuichi Akahane, Arisa Miura, and Kohei Inomata*

*Phamaceutical Department, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

We established a novel chiral route to provide a Swaminathan ketone (3) bearing a 7-membered ring via intramolecular aldol reaction of trione (7) mediated by chiral pyrrodinylmethylamine derivatives. Despite the moderate enantioselectivity of 3, we succeeded in increasing optical purities by using a lipase-mediated asymmetric esterification of an alcohol (16) at a later synthetic stage. The absolute configuration was determined by Mosher’s ester method, and relations between absolute configurations and optical rotations of 3 were clarified.

■ Synthesis of 4-Aroyl-5-arylpyrazoles and 4-Aroyl-3-arylpyrazoles via the Reaction of Enaminodiketones with Substituted Hydrazines

Rika Kotouge, Takashi Nishiyama, Akira Yamauchi, Kanako Ono, Noriyuki Hatae, Tsutomu Oikawa, Satoshi Hibino, and Tominari Choshi*

*Graduate School of Pharmacy & Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

Abstract

Pyrazole is a five-membered heterocyclic compound and is one of the important heterocycles in the fields of medicine and pharmacology. Here, we demonstrate the reactivity of symmetrical enaminodiketones 8–14 with substituted hydrazines. When using alkylhydrazines, if the substituent size of the alkyl group is small, it is possible to selectively synthesize 1-substituted 4-aroyl-5-arylpyrazoles and their regioisomers, 1-substituted 4-aroyl-3-arylpyrazoles, by choosing the solvent (EtOH or toluene). When they react with bulky substituted hydrazines (e.g., cyclohexyl, phenyl, or pyridyl), only 1-substituted 4-aroyl-5-arylpyrazoles are selectively obtained.

■ Synthetic Studies on Marineosins Based on a Direct Coupling Reaction of Pyrrole and δ-Lactone

Kohei Yamamoto, Yuki Morii, Akihisa Suga, Keita Komine, Hayato Fukuda, Jun Ishihara,* and Susumi Hatakeyama*

*Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

A promising precursor of marineosins A and B, unusual macrocyclic pyrrole and spiroiminal alkaloids isolated from marine microorganism has been synthesized employing a direct coupling of pyrrole and δ-lactone.

■ Artificial Intelligence-Designed Stereoselective One-Pot Synthesis of trans-β-Lactams and Its Application to Cholesterol Absorption Inhibitor SCH 47949 Synthesis

Tetsuhiko Takabatake, Takumi Yoneda, Jyo Otsuka, Natsuko Kagawa, and Masahiro Toyota*

*Department of Chemistry, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuencho, Sakai, Osaka 599-8531, Japan

Abstract

Cholesterol absorption inhibitor drug SCH 47949 is synthesized stereoselectively using an artificial intelligence design proposed by SYNSUP. The key step involves a stereoselective one-pot preparation of the trans-β-lactam system through thermal electrocyclization. The trans-β-lactam intermediate is converted to SCH 47949 by a series of functional group transformations proposed by SYNSUP.

■ Benzylic Oxidation and Functionalizations of Xanthenes by Ligand Trasfer Reactions of Hypervalent Iodine Reagents

Toshifumi Dohi,* Keina Komiyama, Shohei Ueda, Nobutaka Yamaoka, Motoki Ito, and Yasuyuki Kita*

*Research Organization of Science and Technology, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan

Abstract

The benzylic oxidation, amidation, and unprecedented heteroarylation proceed at room temperature using iodosobenzene, (sulfonylimido)iodobenzenes, and diaryliodonium(III) salts are described for the direct Csp3-H functionalizations of xanthene molecules. This study has demonstrated that hypervalent iodine reagents serve as unified synthetic tools for versatile xanthene Csp3-H transformations based on the radical and SET oxidation processes.

■ Synthesis of Cycloalkyl/Steroidal Heteroaryl Sulfides Using Rhodium-Catalyzed Heteroaryl Exchange Reaction

Mieko Arisawa,* Katsuya Nakai, Tomoki Yamada, Ren Suzuki, and Masahiko Yamaguchi*

*Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, sendai 980-8578, Japan

Abstract

Cycloalkyl heteroaryl sulfides are efficiently synthesized by the single-bond cleavage and exchange reaction of S-cycloalkyl thioesters and heteroaryl ethers without using a base. The method is applicable to steroids at the A- and D-rings, and provides diverse heteroarylthiolated steroids with five- and six-membered heteroarenes.

■ Synthesis of 1,2-Benzothiazole-3(2H)-thione 1,1-Dioxides by DBU-Promoted Cyclization of 2-(Aminosulfonyl)-N-methylbenzothioamide Derivatives

Kazuhiro Kobayashi* and Daiki Fujiwara

*Applied Chemistry Field, Chemistry and Biotechnology Course, Department of Engineering, Graduate School of Sustainability Science, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

An efficient method for the preparation of 2-alkyl-1,2-benzothiazole-3(2H)-thione 1,1-dioxides has been developed. Thus, the reaction of 2,N-dilithio derivatives of N-alkylbenzenesulfonamides with methyl isothiocyanate affords 2-[(alkylamino)sulfonyl]-N-methylbenzothioamides, which are treated with a catalytic amount of DBU in refluxing toluene to provide the desired products in moderate to good yields.

■ Syntheses of Indirubins by Aldol Condensation of Isatins with Indoxyl Anion Generated in situ by Lipase-Catalyzed Deacetylation of Indoxyl Acetate

Takeshi Sugai,* Kengo Hanaya, and Shuhei Higashibayashi

*Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shiba-Kouen, Minato-ku, Tokyo, Japan

Abstract

The syntheses of indirubin (76% yield), 6-bromoindirubin (82% yield), and 6-bromoindirubin-3′-oxime (78% yield in two steps) were achieved via the lipase-triggered aldol condensation between isatins and an indoxyl anion in tetrahydrofuran under anhydrous and anaerobic conditions as the key step. The aldol donor was generated in situ by Burkholderia cepacia lipase (Amano PS-IM)-catalyzed deacetylation of commercially available and stable indoxyl acetate in the presence of triethylamine and with 2-propanol as the transesterification reagent. The scale-up of the presently developed reactions is easier than that in the previously reported chemical aldol condensations, because of the simplicity of the isolation procedure and suppression of the oxidative byproduct formation from indoxyl acetate.

■ An Improved Synthesis of a Salicylated Divinylcarbinol Derivative as a Part of Salicylic Macrolides

Aki Kohyama, Yoshihito Oguma, Takumi Yamagishi, Kenji Sugimoto, and Yuji Matsuya*

*Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan

Abstract

An improved enantioselective synthesis of (R)-salicylated divinyl carbinol derivative (4), the key intermediate for the total synthesis of natural salicyclic macrolides, has been achieved. Key steps of the synthesis involve the introduction of the chirality by reliable Sharpless asymmetric epoxidation, carbon-carbon bond formation via Heck reaction and the regeneration of a terminal alkene structure via deoxygenation. The efficient route shortened the reaction sequence and enabled the preparation of (R)-4 in 4 steps in 28% overall yield from divinyl carbinol.

■ Platinum on Carbon–Catalyzed and Chemoselective Aqueous Oxygen Oxidation of Aromatic Acetals to Benzoic Acids

Naoki Yasukawa, Takumi Matsuda, Eisho Shimizu, Hironao Sajiki,* and Yoshinari Sawama*

*Laboratory of Organic Chemistry, Department of Pharmaceutical Sciences, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan

Abstract

Novel chemoselective transformations can diversify the synthetic pathways of the target molecules. The chemoselective oxidation of aromatic acetals to benzoic acid derivatives under platinum on carbon (Pt/C)–catalyzed oxygen oxidation conditions has been newly developed with a tolerance of aliphatic acetals and ketals. The present oxidation was clean and useful from the viewpoint of the easy removal of Pt/C and the use of molecular oxygen as a green oxidant in water as an abundant, non-toxic and environmentally friendly solvent.