Synthesis of 3-amino-4-substituted monocyclic ß-lactams—important structural motifs in medicinal chemistry

Grabrijan, Katarina (author), Strašek Benedik, Nika (author), Gobec, Stanislav (author)

Monocyclic ß-lactams (azetidin-2-ones) exhibit a wide range of biological activities, the most important of which are antibacterial, anticancer, and cholesterol absorption inhibitory activities. The synthesis of decorated monocyclic ß-lactams is challenging because their ring is highly constrained and consequently reactive, which is also an important determinant of their biological activity. We present the optimized synthesis of orthogonally protected 3-amino-4-substituted monocyclic ß-lactams. Among several possible synthetic approaches, Staudinger cycloaddition proved to be the most promising method for initial ring formation, yielding monocyclic ß-lactams with different substituents at the C-4 position, a phthalimido-protected 3-amino group, and a (dimethoxy)benzyl protected ring nitrogen. Challenging deprotection methods were then investigated. Oxidative cleavage with cerium ammonium nitrate and ammonia-free Birch reduction was found to be most effective for selective removal of ring nitrogen protection. Hydrazine hydrate was used for deprotection of the phthalimido group, and the procedure had to be modified by the addition of HCl in the case of aromatic substituents at the C-4 position. The presented methods and the synthesized 3-amino-4-substituted monocyclic ß-lactam derivatives are an important step toward new ß-lactams with potential pharmacological activities.

• Language: English
• Keywords: monocyclic ß-lactam, Staudinger [2+2] cyclocondensation, cerium ammonium nitrate, hydrazine hydrate, 3-amino-4-substituted azetidin-2-one, inhibitory activities
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: 26 str.
• Numbering: Vol. 23, iss. 1, art. 360
• PID: 20.500.12556/RUL-136778
• UDC: 615.4:54
• ISSN on article: 1422-0067
• DOI: 10.3390/ijms23010360
• COBISS.SI-ID: 92152323
• Publication date in RUL: 20.05.2022

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 01.01.2022

Secondary language

• Language: Slovenian
• Keywords: monociklični ß-laktam, Staudingerjeva [2+2] ciklokondenzacija, cerijev amonijev nitrat, hidrazin hidrat, 3-amino-4-substituiran azetidin-2-on, inhibitorna aktivnost, farmacevtska kemija

Projects

• Funder: ARRS - Slovenian Research Agency
• Funding programme: Young researchers

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0208
• Name: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin