Discovering new molecular scaffolds and synthetic reactions is very important for drug discovery. Georges Dewynter at Université Montpellier, France, and colleagues have discovered an unprecedented ring contraction reaction that they used to access new lactam-constrained dipeptide mimetics. Professor Dewynter explains more about his work in the short interview below. 

1. Please explain, for a non-specialist, the significance of your article. 

The manuscript shows an unprecedented reaction allowing an efficient, mild and exceptional stereocontrolled synthesis of dissymmetric pyrrolidine-2,4-diones starting from activated diketopiperazines (DKP), that could be seen as the smallest cyclic dipeptides. This reaction could allow the synthesis of highly substituted aminotetramates leading to the preparation of valuable and original scaffolds. We describe the stereocontrolled synthesis of different series of pyrrolidine-2,4-diones and we suggest a mechanism for this transannular rearrangement of activated lactams (TRAL) and its alkylated variation. We insist on the scoop of this reaction allowing in one step the access to various functionalised heterocyclic bio-molecules with a remarkable stereospecificity. Taking advantage of the exceptional stereocontrolled TRAL linked to an unprecedented ring-closing metathesis (RCM) reaction, we then described the access to new valuable heterocyclic scaffolds that could be received as lactam-constrained pseudodipeptides. The manuscript develops a suitable method to access to over-constrained compounds. The [5+6] spiro- or bicyclic derivatives could be prepared, via a challenging ring closing metathesis on pyrrolidine-2,4-diones, starting from suitable N-Boc activated 2,5-diketopiperazines. We finally display a pertinent strategy involving a TRAL/O-allylation/Claisen-like rearrangement/RCM sequence. The originality of our strategies, leading to new chemical entities, lies in the fact that all the reaction involved in this paper occurred in a highly stereocontrolled manner. 

2. What has motivated you to conduct this work? 

In our initial strategy, we envisioned the derivatisation of DKP in bis-N-tert-butoxycarbonyl DKPs in order to perform ionic condensations at positions 3 and 6 by enolate induction, and also to enhance the electrophile character of such substituted lactams. Unexpectedly, in some basic conditions, we were the first to observe that the two Boc moieties, instead of displaying a conventional protecting group character, reacted as electron-withdrawing activators on the heterocyclic nitrogen atoms, allowing the unusual transformation of bis-Boc-DKPs into the corresponding 3-aminopyrrolidine-2,4-diones. This serendipitous discovery was the starting point of our work. 

3. Where do you see this work developing in the future? 

We believe the findings described in this paper will be of broad interest for organic or medicinal chemists. The TRAL could be considered as a ring contraction reaction, renowned as one of the basic tools for structure-activity relationship. In daily medicinal chemistry practice, ring-chain transformation is now a universal analogical approach to reach biologically more potent ligands, structurally close to the original active lead compound. A direct access to designed ring-contracted scaffolds, to the required structural variations is critical to convert the lead compound to a new library of derivatives. Our works are now devoted to expand the scope of the TRAL to other heterocycles and to o access to new biologically potent scaffolds. 

4. Are there any particular challenges facing future research in this area? 

Especially, we wish now to oligomerise some of our constrained structures in order to access to pseudoproteins or new functionalised foldamers.