HETEROCYCLES

■ Contents

■ Heterocycles Award

HETEROCYCLES Announcement*

*The Japan Institute of Heterocyclic Chemistry, 1-1-7, 503 Motoakasaka, Minato-ku, Tokyo
107-0051, Japan

■ Synthesis of Multisubstituted Benzofurans/Indoles Using Multichlorinated Phenols/Anilines via Palladium-Catalyzed Site-Selective Sonogashira Coupling

Miyuki Yamaguchi and Kei Manabe*

*School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga, Shizuoka 422-8526, Japan

Abstract

Multisubstituted benzofurans/indoles are a critical class of compounds in the fields of pharmaceuticals and natural products. A useful method of preparing 2-substituted benzofurans/indoles is the Pd-catalyzed Sonogashira coupling of 2-halophenols/2-haloanilines and terminal alkynes, followed by cyclization. For the syntheses of multisubstituted benzofurans/indoles, the use of multichlorinated phenols/anilines as coupling partners is powerful because the synthetic steps required are reduced and all dichlorophenol and dichloroaniline positional isomers are commercially available and inexpensive. However, their use in benzofuran/indole synthesis is limited because of their low reactivity compared with those of the corresponding iodo or bromo compounds. Furthermore, site-selective Sonogashira coupling at the 2-position of the multihalogenated phenols/anilines is sterically and electronically challenging. To overcome these problems, dihydroxyterphenylphosphine (DHTP) has been developed as a ligand that enables the highly ortho-selective Sonogashira coupling of 2-chlorophenols/2-chloroanilines with terminal alkynes. Using the Pd–DHTP catalyst, chlorinated benzofurans/indoles are successfully obtained, which are easily converted to other derivatives by substitution of the chloro group. In this review, we summarize this and related studies to demonstrate the utility of this method.

■ Recent Progress on Synthesis of Spirochromanone and Spirochromane Derivatives

S. Chakroborty,* P. Panda, S. C. Ramírez-Lopìez, M. A. Garcia Eleno, E. C. Yañez, L. Strekowski, and M. V. B. Unnamatla*

*School of Sciences, Auro University, earthspace, Hazira Road, opp. ONGC, Surat, Gujarat 394510, India

Abstract

Nature offers plenty of opportunities to the researchers of different communities to explore heterocyclic compounds. Among the various magic heterocyclic scaffolds, chromane and chromanone are the most privileged heterocycles due to their omnipresence in most value-added chemical entities. On the other hand, spirocyclic heterocyclic moieties offer unique three-dimensional frameworks which can fit into the cavity of the proteins, including enzymes, thereby enhancing the biological properties. Considering the remarkable significance of spirocyclic systems of chromanes and chromanones, various novel strategies such as Kabbe condensation, organocatalyzed reactions, oxa/sulfa-Michael-Aldol cascade reaction, oxa-Michael/addition and 1,3-dipolar cycloaddition, among others, have emerged to access this precious heterocyclic architecture in good to excellent yields. This review summarizes the synthesis of a variety of spirochromane and spirochromanone derivatives covering the literature from 1991-2020.

■ Nucleophilic Substitution of 2,2-Bis(arylthio)-4,4,6,6-tetrachlorocyclotriphosphazene with Ammonia, Phenoxide, and Thiophenoxide

Manabu Kuroboshi,* Ayako Ueno, Ayane Kawano, and Hideo Tanaka

*Division of Chemsitry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

Nucleophilic substitution of hexachlorocyclotriphosphazene (HCCP) with arylthiol gave 2,2-bis(arylthio)-4,4,6,6-tetrachlorocyclotriphosphazene. Aminolysis of 2,2,4,4-teterachloro-6,6-bis(4-methoxyphenylthio)-
cyclotriphosphazene with gaseous ammonia gave gem-disubstituted 2,2-diamino-4,4-dichloro-6,6-bis(4-methoxyphenylthio)cyclotriphosphazene in Et2O and tetrasubstituted 2,2,4,4-tetraamino-6,6-bis(4-methoxyphenylthio)-
cyclotriphosphazene in acetonitrile, respectively. The reaction of 2,2,4,4-teterachloro-6,6-bis(4-methoxyphenylthio)cyclotriphosphazene
with 4-chlorophenol gave a mixture of gem-disubstituted 2,2-dichloro-4,4-bis(4-chlorophenoxy)-6,6-bis(4-methoxyphenylthio)cyclotriphosphazene and tetrasubstituted 2,2,4,4-tetrakis(4-chlorophenoxy)-6,6-bis(4-
methoxyphenylthio)cyclotriphosphazene, whose ratio depended on the reaction solvent. On the other hand, in reaction of 2,2-bis(arylthio)-4,4,6,6-tetrachlorocyclotriphosphazene with another arylthiol, ArS-groups were scrambled

■ Synthesis and Reactivity of Novel 5-Imino-1,2-oxazole

Khalid Widyan*

*Department of Chemistry, Tafila Technical University, P.O Box 179, Tafila-Jordan, Jordan

Abstract

A convenient synthetic approach towards 5-imino-1,2-oxazoles beginning from N-substituted C-benzotriazolated nitrones and Reformatsky reagent is developed. The conversion of trisubstituted 5-imino-1,2-oxazoles into the corresponding 5-functionalized 1,2-oxazoles by interactions with phenyl isocyanates and 20% HCl is provided. In addition, one-pot synthesis of 1,2-oxazole-5-ones is achieved with yield of 85-90%

■ Optimization of NAMPT (Nicotinamide Phosphoribosyltransferase) Activators: Discovery of N,N-Diethyl-1,2-benzoxazole-3-carboxamide Derivatives as Potent NAMPT Activators with Mitigated Mutagenic Risks

Mayuko Akiu,* Takashi Tsuji, Yoshitaka Sogawa, Koji Terayama, Mika Yokoyama, Daigo Asano, Tomohiro Honda, Tomomichi Ishizaka, Tomoko Hasegawa, Anthony B. Pinkerton, and Tsuyoshi Nakamura

*Group I, Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

Abstract

DS68702229, a potent NAMPT activator developed from HTS followed by a hit-to-lead campaign, is a promising candidate compound that significantly reduced body weight when orally administered to mice with high fat diet-induced obesity. However, in vitro toxicology profiling of DS68702229 revealed bacterial mutagenicity using Salmonella typhimurium TA98 and TA100 strains upon S9 activation. Hypothesizing that DNA intercalation is the likely cause, we employed several approaches to disrupt the putative DNA intercalation, including modulation of the molecular shape. Our efforts culminated in the discovery of compounds 20k and 20l, which increased intracellular NAD+ levels in a cell-based assay without inducing mutagenicity, along with acceptable plasma exposure in mice after oral administration.

■ Chiral 1,2-Diaminocyclohexane-α-Amino Acid-Derived Amidphos/Ag(I)-Catalyzed Divergent Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Ylides

Haifei Wang, Chuliang Gong, Zhipeng Zhou, Qingxia Zhou, Youshi Liu,* and Jie Luo*

*College of Packaging and Materials Engineering, Hunan University of Technology, Zhuzhou 412007, China

Abstract

A series of chiral 1,2-diaminocyclohexanes-α-amino acids-derived amidophosphanes in combination with silver(I) salts, have been developed to cooperatively catalyze the azomethine ylides-involved 1,3-dipolar cycloaddition with different electron-deficient alkenes. Among these, the (1S,2S)-1,2-cyclohexanediamine-L-tert-leucine-derived amidphos/Ag(I) has been demonstrated as being a highly efficient catalytic system in the cis-1,2-disubstituted electron-deficient olefins-involved 1,3-dipolar cycloaddition of azomethine ylides, including a series of aromatic, heteroaromatic, aliphatic, and 2-substituted azomethine ylides, affording various fully substituted pyrrolidines in high to excellent yields (up to 97% yield) and enantioselectivities (up to 97% ee). Interestingly, the (1R,2R)-1,2-cyclohexanediamine-L-tert-leucine-derived amidphos/Ag(I) can efficiently catalyze terminal electron-deficient olefin-involved 1,3-dipolar cycloaddition, giving a series of 2,4,5-tri-substituted pyrrolidines with up to 92% yield and 92% ee.

■ A New Template of MIitsunobu Acylate Cleavable in Non-Alkaline Conditions

Yoshimichi Sakakibara, Yusuke Sai, Yasumitsu Uraki, Makoto Ubukata, and Kengo Shigetomi*

*Research Faculty of Agriculture, Hokkaido University, Kita 9 Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0589, Japan

Abstract

The Mitsunobu inversion is one of the reliable methods for stereospecific substitution of chiral alcohols, but its deacylation step has limited the substrate scope. Here, we propose a new template of the Mitsunobu acylate that can be deacylated in non-alkaline treatments. The 3,4-dihydroxy-2-methylenebutanoate was selected as a template structure, and its acetonide- or bisTBS derivatives were synthesized. The latter especially showed excellent inversion efficiency (up to >99% ee) and good elimination performance for a series of secondary alcohols in near-neutral conditions. The results demonstrated the applicability of the new template for the substrates labile in alkaline conditions, such as α-hydroxyesters.

■ MS 4A-Promoted Aqueous Phospho-Aldol-Brook Rearrangement Reaction of Isatins

Fan Liu, Wei Han,* and Takeshi Oriyama*

*Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Ibaraki 310-8512, Japan

Abstract

An efficient, simple, environment-friendly, and low-cost protocol for the hydrophosphonation of isatins using inexpensive and non-toxic MS 4A as a recyclable additive in water has been developed. This protocol is also suitable for the aldol reaction of isatin with acetone or acetophenone.

■ Design and Synthesis of 1,3-Bis(3-(trifluoromethyl)diazirin-3-yl)phenylalanine for Efficient Photo Cross-Linking

Yuta Murai,* Takuma Yoshida, Zetryana Puteri Tachrim, and Makoto Hashimoto*

*Faculty of Advanced Life Science, Hokkaido University, Kita 21 Nishi 11, Sapporo 001-0021,

Abstract

Photoreactive α-amino acids are powerful chemical tools for elucidating interactions in protein networks. Typically, photophores are required for stability and generation of high-reactive species. Additionally, orientation of photophores is one of the significant issues for performing photoaffinity labeling. Therefore, we rationally designed a bis-diazirinyl-phenylalanine for which photo cross-linking efficiency could be increased. In this study, we synthesized a new 1,3-bis(3-(trifluoromethyl)diazirin-3-yl)phenylalanine and demonstrated further study in terms of photoactivation.

■ A New Natural Butenolide, (5R)-3-Tetradecyl-5-methyl-2(5H)-furanone, from Octocoral Cladiella conifera

Jhao-Syuan Zeng, Shun-Hua Chen, Yi-Hao Lo, Nan-Fu Chen, Zhi-Hong Wen, Jih-Jung Chen, Chia-Ching Liaw,* and Ping-Jyun Sung*

*Department of Planning and Research, National Museum of Marine Biology and Aquarium, 2 Houwan Road, Checheng, Pingtung, Taiwan 944, Taiwan

Abstract

A chemical examination of Cladiella conifera, octocoral collected in the waters of Taiwan, resulted in isolation of a new natural butenolide, (5R)-3-tetradecyl-5-methyl-2(5H)-furanone (1). The structure, including the absolute configuration, of 1 was established by spectroscopic analysis and 1 was found to inhibit the generation of COX-2 from RAW 264.7 stimulated by LPS.

■ Isolation of Peptidolipin NA Derivatives from the Culture of Nocardia arthritidis IFM10035T in the Presence of Mouse Macrophage Cells

Yasumasa Hara,* Daiki Tanimura, Teruhisa Manome, Midori A. Arai, Takashi Yaguchi, and Masami Ishibashi*

*Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba, Japan

Abstract

We isolated two peptidolipin NA derivatives, L-Val (6) peptidolipin NA and peptidolipin NA, named as compounds 1 and 2, respectively. These compounds were produced in the co-culture extracts of Nocardia arthritidis IFM10035T and the mouse macrophage cell line J774.1, but not in the single culture of N. arthritidis. Among the two compounds along with nocarjamide (3) isolated from the co-culture of N. tenerifensis and J774.1, compounds 1 and 3 showed higher cytotoxicity against J774.1, with IC50 values of 116 μM and 25 μM, respectively. In addition, compound 1 showed a TRAIL-resistance-overcoming activity in the human gastric adenocarcinoma AGS cells.