Microwave-assisted diastereoselective two-step three-component synthesis for rapid access to drug-like libraries of substituted 3-amino-β-lactams

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 1; pp. 41 - 49
• Main Authors: Janssen, Guido V., van den Heuvel, Joyce A.C., Megens, Rik P., Benningshof, Jorg C.J., Ovaa, Huib
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2018; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Combinatorial Chemistry Techniques; Dose-Response Relationship, Drug; Lactams - chemical synthesis; Lactams - chemistry; Library synthesis; Life Sciences & Biomedicine; Microwave synthesis; Microwaves; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Saccharines; Science & Technology; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Staudinger reaction; Stereoisomerism; Structure-Activity Relationship; β-Lactams; Microwave synthesis; Staudinger reaction; Saccharines; β-Lactams; Library synthesis; SACCHARIN DERIVATIVES; ANTIBIOTICS; DESIGN; COMPOUND; beta-Lactams; KETENE; TARGETS; GENERATION; STEREOSELECTIVE-SYNTHESIS; INHIBITORS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.11.014

[Display omitted] Large, diverse compound libraries are an essential requisite in target-based drug development. In this work, a robust microwave-assisted synthesis for the diastereoselective generation of 3-saccharinyl-trans-β-lactams is reported. The method is optimised for combinatorial library synthesis in which decoration of the scaffold is varied on both the β-lactam and the saccharine moiety. Within the European Lead Factory (ELF) consortium, a library of 263 compounds was efficiently produced using the developed methodology.