Five-membered ring lactams, known as γ-lactams, are important structural motifs in biologically active natural products, but the γ-lactams that are replaced in the position 1 (nitrogen) are less common in drug derivations. Although substituted γ-lactams and unsubstituted γ-lactams share the main γ-lactam core, one major difference between the two is nitrogen substitution; Unsubstituted γ-lactams are also known as NH lactams. This difference is the substitution seen in Figure 1 across a natural product, heliotropamide,[1] a γ-lactam substituted at position 1, and salinosporamide,[2] an unsubstituted γ-lactam at position 1. An investigation of the gamma-lactams in preclinical and clinical development showed a nearly two-to-one ratio of NH lactams to their substituted counterparts. [3] This is perhaps due to synthetic limitations.HO CO2H ONHOHN HO ClH3CO HN HO2CO OH HO CH OCH3 OO3OHSalinosporamideHeliotropamideFigure 1: Examples of N-substituted γ-lactams and "NH" γ-lactams Jared Shaw and colleagues at the University of California -Davis, USA, reported a multicomponent methodology for the synthesis of unsubstituted γ-lactams and their subsequent N-functionalization. By employing ammonium acetate as the starting material in a previously reported four-component reaction (4CR), the research team demonstrated a range of lactam NH structures that could be produced. These substrates could then be nitrogen-functionalized via acylation or arylation to provide the structural diversity not available via the original 4CR. [3] The mechanically distinct four-component reaction previously reported in another study by Shaw allows the assembly of γ-lactams in a single synthetic step in high yield and diameter......half of paper..... .ge attractive because it demonstrates that their previously established lactam-forming 4CR serves as a useful starting reaction in the preparation of unsubstituted γ-lactams. Furthermore, these substrates can be further functionalized through acylation or arylation processes. The distinct products constitute useful starting points for the discovery of biological probes and medicinal leads. Works Cited1) Younai, A.; I lie, girlfriend; Shaw JTJOrg. Chemistry. 2010, 75, 8333-8337. 2) Satoh, N.; Yokoshima, South; Fukuyama T.Org. Lett. 2011, 13, 3028-3031. 3) Tanning, DQ; Martin, Kansas; Fettinger, J.C.; Shaw, J.T. Proc. Natl. It happens. Sci. 2011, 108, 6781-6786. 4) Wei, J.; Shaw, J.T. Org. Lett, 2007, 9, 4077–4080. 5) Organic Chemistry Portal 6) 7) Thompson, MJ; Chen, B. J. Org. Chemistry. 2009, 74, 7084–7093.