Synthesis of a library of "lead-like" γ-lactams by a one pot, four-component reaction

Abstract

The synthesis of a pilot scale library of 116 structurally diverse γ-lactams is reported. The library core structure emanates from a γ-lactam forming one-pot, four-component reaction of ammonium acetate, p-methoxythiophenol, p-methoxybenzaldehyde, and maleic anhydride. Structural diversity then arises from amide coupling, thioaryl cleavage, N-functionalization, and heterocycle forming reactions on this core structure. Computational analysis reveals that the library contains molecular properties and shape diversity suitable for drug lead and biological probe discovery.

Figure 1

γ-Lactam natural products and lead compounds in drug discovery.

Figure 2

Summary of Library Strategy Based on the One-Pot, Four-Component Reaction (4CR).

Figure 3

Diversity reagents for schemes 2–6.

Figure 4

Molecular properties of library

Figure 5

Scatter plot with principle moments of inertia (PMI) ratios plotted to compare molecular shape diversity of γ-lactam library. Ratios were calculated for all conformers ≤3 kcal/mol from the minimum energy conformer. Bioactive γ-lactams 1–3 are in red and library members are in black.

Scheme 1

Assembly of (A)N-substituted and (B) N-H γ-lactams using a 4CR.

Scheme 2

(A) Optimization of amide coupling conditions with 26{1}(B) crystal structure of 18{1}, and (C) synthesis of 18{2–14}.

Scheme 3

(A)N-arylation of N-H amides 18{1–4} and (B) crystal structure of 19{3,3}.

Scheme 4

(A)N-acylation of N-H amides 18{1–5} and (B) crystal structure of 20{3,6}.

Scheme 5

Desulfurization reactions

Scheme 6

(A) Synthesis of 1,2,4-oxadiazoles 23 and (B)N-functionalization of 23{1}.