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.

Diastereoselective Base-Catalyzed Formal [4 + 2] Cycloadditions of N-Sulfonyl Imines and Cyclic Anhydrides

“… , As part of a longstanding interest in accessing such lactam cores, our group has developed new methods for the formal [4 + 2] cycloaddition of imines and cyclic, enolizable anhydrides based on the foundational work of Castagnoli , and Cushman . To this end, our group has previously contributed to advances in mechanistic understanding of the Castagnoli–Cushman reaction, , which we now call the anhydride Mannich reaction (AMR), developed a novel four-component reaction − (4CR), and reported the first base-promoted AMR variant using N -sulfonyl imines in the synthesis of bisavenanthramide B-6 . While the AMR has proven a powerful means of synthesizing complex lactams in diversity-oriented and natural product syntheses, most reports of such reactions employ N -alkylimines, which react readily with many anhydrides in the absence of catalyst .…”

The first solvent-free synthesis of privileged γ- and δ-lactams via the Castagnoli–Cushman reaction

“…3 The latter are exceptionally useful, privileged 4 motifs in drug design considering the plethora of pharmacological effects reported for small molecules containing these heterocyclic cores. 5 In addition, the possibility of independently varying the reaction components offered by this reaction (and multicomponent reactions in general), allows pre-meditating further reactions within the product of the multicomponent step and thus quickly building up skeletal complexity. 6 One of the prominent features of this formally three-component process is its outstanding atom-economy: 7 indeed, all atoms originating from the aldehyde, primary amine and cyclic anhydride components 8 become incorporated into the product structure, except for the condensation water formed during the formation of the Schiff base (Scheme 1).…”

“…Employment of glutaric anhydride (3) as well as its 3,3disubstituted variant (4)(5) in the solvent-free CCR followed by the environmentally friendly basic/acidic aqueous isolation protocol described above, resulted in signicantly improved product yields and purities while additional crystallization from aqueous ethanol was required in only one case, 7g (Table 3). Such a satisfactory result was likely due to lower likelihood of the reaction proceeding along the non-productive path as the formation of an 8-membered analog of postulated cyclic adduct 12 would be much less favored (however, contamination with glutaric monoanilide akin to 10 was still quite noticeable for 7g which mandated additional crystallization).…”

Transition Metal Acetate Promoted Syntheses of Some New N‐Heterocycles by Multicomponent Reactions

“…The double bicyclic framework of 3 was constructed via nine‐component cyclization from four N ‐tosyl‐ethylenediamine and three glyoxal molecules together with two methanol molecules. The targeted molecules produced from three or four simple components in one operation are often seen in documents. However, the multicomponent reactions with more components in one operation are rare.…”