Ammonia Synthons for the Multicomponent Assembly of Complex Y-Lactams
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Five-membered ring lactams, known as γ-lactams, are important structural motifs in biologically active natural products, but γ-lactams that are substituted at the 1-position (nitrogen) are less common in drug leads. Although the substituted γ-lactams and the unsubstituted γ-lactams share the main γ-lactam core, a major difference between the two is the substitution at the nitrogen; the unsubstituted γ-lactams are also known as N-H lactam. This difference is substitution is seen in Figure 1 through a natural product Heliotropamide, a γ-lactam substituted at the 1-position and Salinosporamide, a γ-lactam unsubstituted at the 1-position. A survey of γ-lactams in preclinical and clinical development showed a nearly two-to-one ratio of N-H lactams over their substituted counter parts.  This is perhaps due to synthetic limitations.
HO CO2H O
HN HO Cl
H3CO HN HO2C
O OH HO CH OCH3 OO3
Figure 1: Examples of N-substituted γ-lactam and an “N-H” γ-lactams Jared Shaw and co-workers at the University of California- Davis, USA, have reported a multicomponent methodology for the synthesis of unsubstituted γ-lactams and their subsequent N-functionalization. By employing ammonium acetate as their starting material in a previously reported four-component reaction (4CR), the research team demonstrated a range of N-H lactam structures that could be produced. These substrates could then be functionalized at the nitrogen through acylation or arylation to provide the structural diversity unavailable through the original 4CR.  The mechanistically distinct four-component reaction previously reported in another study by Shaw enables the assembly of γ-lactams in a single synthetic step in high yield and dias...
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...g and attractive because it demonstrates that their previously established lactam-forming 4CR serves as a useful starting reaction in the preparation of unsubstituted γ-lactams. Additionally, these substrates can be further functionalized through acylation or arylation processes. The distinct products are useful starting blocks for the discovery of biological probes and medicinal leads.
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