Can an n_(O) → π* Interaction Provide Thermodynamic Stability to Naturally Occurring Cephalosporolides?

Abstract

The stereocontrolled synthesis of naturally occurring products containing a 5,5-spiroketal molecular structure represents a major synthetic problem. Moreover, in a previous work, the stereocontrolled synthesis of cephalosporolide E (ceph E), which presumably was obtained from its epimer congener (ceph F) through an acid-mediated equilibration process, was reported. Consequently, we performed a theoretical investigation to provide relevant information regarding the title question, and it was found that the higher thermodynamic stability of ceph E, relative to ceph F, is caused by an n → π* interaction between a lone electron pair of the oxygen atom of the spiroketal ring (nO) and the antibonding orbital of the carbonyl group (π*C=O). Although similar stereoelectronic interactions have been disclosed in other molecular structures, its presence in ceph E, and very likely in other related naturally occurring products, represents a novel nonanomeric stabilizing effect that should be introduced into the chemical literature.

Isolation and structural characterization of stable carbamic–carbonic anhydrides: an experimental and computational study

“…Orbital interactions (as n → π* and n → σ*) have attracted growing interest in recent years, as they are widely present in biomolecules, materials, drugs, and can affect their geometry and stability. [33][34][35] These interactions are composed of the delocalization of an oxygen's lone pair (n) over the antibonding π*/ σ* of a nearby carbonyl C-O bond. Natural bond orbital (NBO) analysis was then performed at the ωB97XD/6-31+G(d,p) level for the cis species (Fig.…”

Effect of the nO → π*C═O Interaction on the Conformational Preference of 1,3-Diketones: A Case Study of Riolozatrione Derivatives

“…In 1998, Allen and co-workers found from a sample of 9049 single-crystal X-ray data that 15% of them had contacts between two carbonyl groups with an interacting distance less than 3.6 Å. These contacts are a structural motif found in proteins that produce stabilizing conformations and have motivated interesting studies on chemical reactivity. , For instance, these interactions have found relevance in organic chemistry in asymmetric synthesis, as an additional element to conformational effects such as the anomeric effect. , …”

“…9,10 For instance, these interactions have found relevance in organic chemistry in asymmetric synthesis, as an additional element to conformational effects such as the anomeric effect. 11,12 Several models have been proposed to explain the stabilizing nature of heteroatom X-carbonyl group interaction; some of them are the n X → π* CO interaction, Coulombic effect, dipolar moment, and charge transfer. 13 It is clear then that the observed conformation is not a product from one type of interaction but rather from the balance between different interactions.…”

A Search for X-ray Crystallographic Evidence of n → π* Interactions in a Series of Substituted 2-(Dimethylamino)biphenyl-2′-carboxaldehydes

“…An n → π* interaction is possible when a suitably positioned electron-rich heteroatomic lone pair (e.g., from an O, N, S atom) transfers electron density to a sufficiently electrophilic π* receptor (e.g., CO, CS). , This aptly named stabilizing interaction has recently gained wider recognition and appreciation for exerting its effect on the conformation and crystal structures of small molecules, − metal complexes, polymers, − and proteins. − The interaction has been experimentally observed spectroscopically − as well as via X-ray crystallography. ,,,,,,, Although fairly weak in nature, the effects are often still significant, especially when multiple such interactions combine to work in an additive manner. ,, There have been reported several examples of how this interaction can be “tuned” by altering the nature of the donor atom (or group) or the π* receptor or with substituent groups. ,,,− A thorough understanding of how n → π* interactions are affected by these changes could allow for predictable engineering of the crystal structures of compounds in which these interactions occur.…”