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 diastereoselectivity.  This methodology allows for the outline of different substituents at several positions around the
ring by the choice of building blocks used. This one-pot, four-component reaction, shown in Figure 2, forms up to three stereogenic centers in a single step.
NH2 R2 H
toluene (reflux) -H2O
R1 O N R4
R2 S R3
Figure 2: Lactam formation four-component reaction 
Shaw and co-workers utilize the above discussed 4CR reaction as a starting point for the synthesis of structurally diverse γ-lactams. The synthesis of N-H lactams has proven to be a general problem for multicomponent reactions (MCRs) that employ amines.  Multicomponent reactions (MCRs) are convergent reactions that involve the combination of three or more starting materials in a single operation and are among the most powerful methods for efficient generation of molecular complexity.  The general picture of Shaw’s study is shown in Figure 3, which allows for the synthesis of lactams that are currently not available through a direct MCR. Upon the formation of the N-H lactam, the substrate is then functionalized at the nitrogen, which provides the structural diversity that is unattainable through the original...