Ring‐Expansion Approach to Medium‐Sized Lactams and Analysis of Their Medicinal Lead‐Like Properties

Abstract

Medium-sized rings are widely considered to be under-represented in biological screening libraries for lead identification in medicinal chemistry. To help address this, a library of medium-sized lactams has been generated by using a simple, scalable and versatile ring-expansion protocol. Analysis of the library by using open-access computational tool LLAMA suggested that these lactams and their derivatives have highly promising physicochemical and 3D spatial properties and thus have much potential in drug discovery.

Synthesis of Cyclic Peptide Mimetics by the Successive Ring Expansion of Lactams

“…A key design feature of this method is that that the β‐keto ester group (highlighted) needed to promote the rearrangement is regenerated upon ring expansion, meaning that controlled successive ring expansion (SuRE) can be achieved by repeating the same acylation/deprotection sequence on the product 8 . This proof‐of‐concept study highlighted the potential of SuRE‐type methods, although its reliance on a relatively reactive β‐keto ester motif is a drawback, because this limits the utility of the products; for example, for medicinal applications, additional synthetic steps are needed to remove the metabolically labile β‐keto ester . Average yields of approximately 50–60 % and the fact that this method only works consistently well with β‐amino acid derivatives were also identified as areas in need of improvement.…”

“…Cyclic peptides and their mimics are of significant medicinal interest, hence, we were keen to demonstrate that α‐amino acid derivatives could also be used in this method. α‐Amino acid derivatives proved to be much more challenging than their β‐homologues in our published β‐keto ester SuRE reactions (which only work consistently well with glycine derivatives), but pleasingly, the current lactam ring expansions are far more robust. Thus, N‐acylation and ring expansion can be achieved with a range of α‐amino acid chlorides, including examples with hydrocarbon side chains, tryptophan, methionine, and proline derivatives ( 11 l – u , Scheme C) .…”

Smart Design of Small‐Molecule Libraries: When Organic Synthesis Meets Cheminformatics

“…The same approach was also exploited by Unsworth and coworkers to validate if 8-to 12-membered ring lactams, generated through ar ing-expansion synthetic strategy,c ould possess sufficient lead-likenessp roperties for biological screening campaigns. [25] Although medium-sized and macrocyclic ring systemsc an display better bioavailability and greater metabolic stabilityt han that of five-and six-membered ring systems, [26] the issue related to their synthesis [27] has limited their applica-tion in medicinal chemistry. [28] In this context, the ring-expansion synthetic approacha ble to generate 8-to 12-membered ring products 12 starting from b-keto ester 11 represents a major improvement (Scheme 2).…”

Traceless Solid‐Phase Synthesis of Fused Chiral Macrocycles via Conformational Constraint‐Assisted Cyclic Iminium Formation

“…[3,5,54,55] From the calculation side, the anilinic-nitrogen (the nucleophile for the 7-membered ring) has al ow electrostatic potential and is planar comparedt ot he sulfonamide nitrogen. Formation of larger rings via ar ing expansion have been reported.…”