The 4-imidazolidinone structure is an important motif that exists in many bioactive natural products. Medicinal and biologically active compounds also have the 4-imidazolidinone structure. The introduction of 4-imidazolidinone structures changes the activity and stability of peptides, such as Leu-enkephalin, vancomycin, and cyclic peptides. Additionally, 4-imidazolidinones have also been used as chiral organocatalysts, ligands, and synthetic intermediates. Thus, there are numerous synthetic methods available to access 4-imidazolidinones. The most general and straightforward method is via the condensation of ɑ-amino amides with aldehydes and ketones. However, this reaction generally requires harsh reaction conditions as well as the removal of water and multiple steps.

Recently, due to our interest in the development of the reaction with hypervalent iodine compounds, we reported the synthesis of cis-β-amide-vinylbenziodoxolones from sulfonamide, including amino acid derivatives, with an ethynyl benziodoxolone-chloroform complex. Based on the results of the aforementioned studies, we present the synthesis of 4-imidazolidinones from various diamides with ethynyl benziodoxolones through double Michael-type addition, which is an unprecedented reaction mode for hypervalent alkynyl iodine compounds (Scheme 1). cis-2,5-Disubstituted 4-imidazolidinones were diastereoselectively synthesized from peptides.

研究成果 Scheme1 JPEG.jpeg

It is noteworthy that glycine-derived 4-imidazolidinone was further derivatized by reduction, Sonogashira reaction, and deprotection. Several experiments were conducted to elucidate the reaction mechanism. To gain further insight into the reaction mechanism of the cyclization step, density functional theory (DFT) calculations were performed using Gaussian16, Revision C.01. Those results indicate that 5-exo-trig cyclization, that is, intramolecular Michael-type addition, was the most likely pathway (Scheme 2). In conclusion, we achieved the efficient synthesis of 4-imidazolidinones from a variety of diamides by double Michael-type addition, a novel reaction mode for hypervalent alkynyl iodine compounds, and a formal reductive elimination sequence using in situ generated EBX from TMS-EBX or EBX-MeCN.

研究成果 Scheme2 JPEG.jpeg

This work was supported by JSPS KAKENHI Grant Nos. 19K06977 and 22K06530 and Grants for Research from SIS (The Society of Iodine Science) and OGAWA Science and Technology Foundation.

Article information

Literature name : Organic Letters
Article title : A Synthesis of 4-Imidazolidinones from Diamides and Ethynyl Benziodoxolones via Double Michael-type Addition: Ethynyl Benziodoxolones as Electrophilic Ynol Synthons
Author list : Ayaka Shimizu, Atsushi Shibata, Takashi Kano, Yuuichi Kumai, Ryouhei Kawakami, Hiroyoshi Esaki*, Kazuaki Fukushima, Norihiro Tada*, Akichika Itoh*
Volume and number : Vol. 24, No. 48
Page : 8859-8863
DOI: 10.1021/acs.orglett.2c03648

Lab name

Laboratory of Pharmaceutical Synthetic Chemistry