The incorporation of the recently discovered reciprocal n → π∗ interactions in 2,5-diketopiperazines (DKPs) is reported to design a novel N,N′-di(acylamino)-2,5-diketopiperazine (daa-DKP) scaffold. The design, synthesis, and structural features of daa-DKPs and the effect of reciprocal n → π∗ interactions in their structural rigidity is discussed. Copyright © 2018 American Chemical Society.

Rahim A.

Sahariah B.

Sarma B.K.

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Shiv Nadar University

Organic Letters

We report the solid-phase synthesis of N,N′-di(acylamino)-2,5-diketopiperazine, an acylhydrazide-based conformationally rigid 2,5-DKP scaffold having exocyclic N-N bonds. We also show that different combinations of acylhydrazides, carbazates, semicarbazides, amino acids, and primary amines can be used to synthesize a highly diverse collection of hybrid DKP molecules via the solid-phase submonomer synthesis route. Finally, we show incorporation of a methyl substituent in one of the carbon atoms of the DKP ring to generate chiral daa- and hybrid-DKPs without compromising the synthetic efficiency. Copyright © 2020 American Chemical Society.

Journal of Organic Chemistry

Solid-Phase Synthesis of Hybrid 2,5-Diketopiperazines Using Acylhydrazide, Carbazate, Semicarbazide, Amino Acid, and Primary Amine Submonomers

Carbonyl-carbonyl (CO⋯CO) interactions are emerging noncovalent interactions found in many small molecules, polyesters, peptides and proteins. However, little is known about the effect of the relative orientation of the two carbonyl groups on the nature of these interactions. Herein, we first show that simple homodimers of acetone and formaldehyde can serve as models to understand the effect of relative orientations of the two carbonyl groups on the nature of CO⋯CO interactions. Further, from a comprehensive statistical analysis of molecules having inter- or intramolecular CO⋯CO interactions, we show that the molecules can be broadly categorized into six different structural motifs (I-VI). The analysis of pyramidality of the acceptor carbon atoms in these motifs and natural bond orbital (NBO) analysis suggest that the relative orientation of the two interacting carbonyl groups determines whether the orbital interaction between the two carbonyl groups would be n → π∗ or π → π∗ or a combination of both. © 2019 The Royal Society of Chemistry.

Fulltext

Chemical Science

Relative orientation of the carbonyl groups determines the nature of orbital interactions in carbonyl-carbonyl short contacts

Carbonyl-carbonyl n→πinteractions where a lone pair (n) of the oxygen atom of a carbonyl group is delocalized over the πorbital of a nearby carbonyl group have attracted a lot of attention in recent years due to their ability to affect the 3D structure of small molecules, polyesters, peptides, and proteins. In this paper, we report the discovery of a "reciprocal" carbonyl-carbonyl interaction with substantial back and forth n→πand π→πelectron delocalization between neighboring carbonyl groups. We have carried out experimental studies, analyses of crystallographic databases and theoretical calculations to show the presence of this interaction in both small molecules and proteins. In proteins, these interactions are primarily found in polyproline II (PPII) helices. As PPII are the most abundant secondary structures in unfolded proteins, we propose that these local interactions may have implications in protein folding. © 2017 The Author(s).

Nature Communications

Reciprocal carbonyl-carbonyl interactions in small molecules and proteins

Macromolecules

Cis-Cisoid Helical Structures of Poly(3,5-disubstituted phenylacetylene)s Stabilized by Intramolecular n → π* Interactions

Accounts of Chemical Research

The n→π* Interaction

The Journal of Organic Chemistry

Comparative Study of the Synthesis and Structural and Physicochemical Properties of Diketopiperazines vs Aza-diketopiperazines

A General Approach to the Aza-Diketomorpholine Scaffold

N, N′-Di(acylamino)-2,5-diketopiperazines: Strategic Incorporation of Reciprocal n → π∗ Interactions in a Druglike Scaffold