Symmetry-modified conformational mapping and classification of the medium rings from crystallographic data. III. <i>endo</i>-unsaturated seven-membered rings

Allen, Frank H.; Garner, Stephanie E.; Howard, Judith A. K.; Pitchford, N. A.

doi:10.1107/s010876819400090x

Cited by 10 publications

(10 citation statements)

References 16 publications

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“…They typically adopt only one or two basic conformations and, depending on the substitution pattern, their mirror image counterparts. Allen et al performed systematic analyses of exocyclic 97 and endocyclic 98 unsaturated cycloheptane derivatives. Their formal approach of symmetry-modified conformational mapping and clustering has led to a set of preferred conformers for cycloheptene, cyclohepta-1,3-diene, cyclohepta-1,4-diene, and cyclohepta-1,3,5-triene.…”

Section: Seven-membered Ringsmentioning

confidence: 99%

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Brameld

Kuhn

Reuter

et al. 2008

J. Chem. Inf. Model.

327

332

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Based on torsion angle distributions of frequently occurring substructures, conformation preferences of druglike molecules are presented, accompanied by a review of the relevant literature. First, the relevance of the Cambridge Structural Database (CSD) for drug design is demonstrated by comparing substructures present in compounds entering clinical trials with those found in the CSD and protein-bound ligands in the Protein Data Bank (PDB). Next, we briefly highlight preferred conformations of elementary acyclic systems, followed by a discussion of sulfonamide conformations. Due to their central role in medicinal chemistry, we discuss properties of aryl ring substituents in depth, including biaryl systems and systems of two aryl rings connected by two acyclic bonds. For a subset of torsion motifs, we also compare torsion angle histograms derived from CSD structures with those derived from ligands in the PDB. Furthermore, selected properties of some six-and seven-membered ring systems are discussed. The article closes with a section on attractive sulfuroxygen contacts.

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Section: Seven-membered Ringsmentioning

confidence: 99%

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Brameld

Kuhn

Reuter

et al. 2008

J. Chem. Inf. Model.

327

332

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“…In this conformation each pair of benzylic hydrogens directs its axial CH bond parallel to the SS (or S δ+ S δ- ) bond, while the other proton resides in a pseudoequatorial orientation. From a more general perspective, simple cycloheptenes are known to adopt a chair conformation stabilized by 0.6−3.5 kcal/mol over the twist and boat conformations. , At the same time, replacement of the CC double bond with a benzene ring to give benzocycloheptenes has been suggested to preferentially stabilize the chair form relative to the twist conformer as a consequence of α-hydrogen C sp2 /H eclipsing of the type observed in toluene. , The stability supposition has been subsequently confirmed for the all-carbon 7-rings by analysis of X-ray structures found in the Cambridge Crystallographic database …”

Section: Resultsmentioning

confidence: 98%

Crossover Point between Dialkoxy Disulfides (ROSSOR) and Thionosulfites ((RO)₂SS): Prediction, Synthesis, and Structure

et al. 2005

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Isomeric preference between cyclic dialkoxy disulfides and thionosulfites is governed by the ring size of the heterocycle. Rings smaller than seven atoms prefer the thionosulfite connectivity, whereas larger rings or acyclic analogues favor the unbranched dialkoxy disulfide structure. Density functional calculations were employed to predict the crossover point at which both constitutional isomers are of comparable stability. Follow-up synthesis provides the previously unknown eight-membered ring dialkoxy disulfide 14 and seven-membered ring thionosulfite 15 from the same reaction. X-ray crystallography for all but one of the reaction products and complementary NMR analysis furnishes insights into both solid-state and solution conformations. A long-standing issue regarding the concerted vs catalyzed isomerization pathway between XSSX and X(2)S=S has been addressed for X = RO and shown to be acid dependent.

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“…We have so far presented the gas-phase puckering preference, using in vacuo GFN2 energy evaluations. To gain insights into the puckering preference in solid state, we compared our results with previous empirical studies on crystal structures from the Cambridge Structural Database − and the 63814 experimentally determined X-ray crystal structures from COD. These empirical studies focused on medium-sized rings, in particular, 7- and 8-membered rings, and showed similar puckering preferences and pseudo-rotations of the dominant canonical conformations.…”

Section: Resultsmentioning

confidence: 99%

Understanding Ring Puckering in Small Molecules and Cyclic Peptides

Chan

Hutchison

Morris

2021

J. Chem. Inf. Model.

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The geometry of a molecule plays a significant role in determining its physical and chemical properties. Despite its importance, there are relatively few studies on ring puckering and conformations, often focused on small cycloalkanes, 5- and 6-membered carbohydrate rings, and specific macrocycle families. We lack a general understanding of the puckering preferences of medium-sized rings and macrocycles. To address this, we provide an extensive conformational analysis of a diverse set of rings. We used Cremer–Pople puckering coordinates to study the trends of the ring conformation across a set of 140 000 diverse small molecules, including small rings, macrocycles, and cyclic peptides. By standardizing using key atoms, we show that the ring conformations can be classified into relatively few conformational clusters, based on their canonical forms. The number of such canonical clusters increases slowly with ring size. Ring puckering motions, especially pseudo-rotations, are generally restricted and differ between clusters. More importantly, we propose models to map puckering preferences to torsion space, which allows us to understand the inter-related changes in torsion angles during pseudo-rotation and other puckering motions. Beyond ring puckers, our models also explain the change in substituent orientation upon puckering. We also present a novel knowledge-based sampling method using the puckering preferences and coupled substituent motion to generate ring conformations efficiently. In summary, this work provides an improved understanding of general ring puckering preferences, which will in turn accelerate the identification of low-energy ring conformations for applications from polymeric materials to drug binding.

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Symmetry-modified conformational mapping and classification of the medium rings from crystallographic data. III. endo-unsaturated seven-membered rings

Cited by 10 publications

References 16 publications

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Crossover Point between Dialkoxy Disulfides (ROSSOR) and Thionosulfites ((RO)₂SS): Prediction, Synthesis, and Structure

Understanding Ring Puckering in Small Molecules and Cyclic Peptides

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Symmetry-modified conformational mapping and classification of the medium rings from crystallographic data. III. endo-unsaturated seven-membered rings

Cited by 10 publications

References 16 publications

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Crossover Point between Dialkoxy Disulfides (ROSSOR) and Thionosulfites ((RO)2SS): Prediction, Synthesis, and Structure

Understanding Ring Puckering in Small Molecules and Cyclic Peptides

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Crossover Point between Dialkoxy Disulfides (ROSSOR) and Thionosulfites ((RO)₂SS): Prediction, Synthesis, and Structure