Synthesis of 3-Amino-4-substituted Monocyclic ß-Lactams—Important Structural Motifs in Medicinal Chemistry

Abstract

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.

Copper-Catalyzed Enantioconvergent Radical C(sp3)–N Cross-Coupling to Access Chiral α-Amino-β-lactams

“…Chiral β-lactams, an important class of heterocyclic compounds, are present in a wide range of natural products and pharmaceutical molecules. − Among them, chiral α-amino-β-lactams with pronounced biological activities have attracted the interest of synthetic organic chemists. − Notable examples of these chiral α-amino-β-lactams have attractive antibacterial activities, such as penicilliums, nocardicins, and sulfazecin (Scheme A). As a result, a variety of synthetic strategies have been elegantly developed for the construction of chiral α-amino-β-lactams. ,− Among them, the most popular strategy is the asymmetric Staudinger [2 + 2] cycloaddition, which has been successfully applied to the synthesis of antibiotic precursors containing chiral α-amino-β-lactams, such as loracarbef and Gram-negative strains (Scheme B, left). However, traditional approaches generally rely on the utilization of chiral auxiliaries.…”