期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 27, 期 27, 页码 7525-7532出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202100059
关键词
amides; lactams; microreactors; peptides; synthetic methods
资金
- JSPS KAKENHI [20K21188]
- Grants-in-Aid for Scientific Research [20K21188] Funding Source: KAKEN
This study describes a rapid, mild, inexpensive, and less-wasteful lactamization method using highly electrophilic reagents in a microflow reactor, successfully synthesizing various lactams and cyclic peptides while suppressing undesired reactions.
Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventional lactamization includes acid-mediated and coupling-agent-mediated approaches that suffer from narrow substrate scope, much waste, and/or high cost. Inexpensive, less-wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein, a methods using highly electrophilic triphosgene in a microflow reactor that accomplishes rapid (0.5-10 s), mild, inexpensive, and less-wasteful lactamization are described. Methods A and B, which use N-methylmorpholine and N-methylimidazole, respectively, were developed. Various lactams and a cyclic peptide containing acid- and/or heat-labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimized by the use of microflow technology.
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