Efficient syntheses of macrocycles ranging from 22–28 atoms through spontaneous dimerization to yield bis-hydrazones

Sharma, Vishal; Mehmood, Arshad; Janesko, Benjamin G.; Simanek, Eric E.

doi:10.1039/c9ra08056b

Cited by 8 publications

(15 citation statements)

References 20 publications

(18 reference statements)

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“…A folded structure for a derivative of G−G is observed using single-crystal X-ray diffraction. 25 Consistent with the prediction of a compact structure, the solid-state structure is found to be symmetric and shows extensive π−π stacking of the triazine ring upon the hydrazone. NMR obtained in CD 3 CN (Figure 2).…”

Section: ■ Results and Discussionsupporting

confidence: 76%

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Well-Tempered Metadynamics Simulations Predict the Structural and Dynamic Properties of a Chiral 24-Atom Macrocycle in Solution

et al. 2022

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Inspired by therapeutic potential, the molecular engineering of macrocycles is garnering increased interest. Exercising control with design, however, is challenging due to the dynamic behavior that these molecules must demonstrate in order to be bioactive. Herein, the value of metadynamics simulations is demonstrated: the free-energy surfaces calculated reveal folded and flattened accessible conformations of a 24-atom macrocycle separated by barriers of ∼6 kT under experimentally relevant conditions. Simulations reveal that the dominant conformer is folded—an observation consistent with a solid-state structure determined by X-ray crystallography and a network of rOes established by 1 H NMR. Simulations suggest that the macrocycle exists as a rapidly interconverting pair of enantiomeric, folded structures. Experimentally, 1 H NMR shows a single species at room temperature. However, at lower temperature, the interconversion rate between these enantiomers becomes markedly slower, resulting in the decoalescence of enantiotopic methylene protons into diastereotopic, distinguishable resonances due to the persistence of conformational chirality. The emergence of conformational chirality provides critical experimental support for the simulations, revealing the dynamic nature of the scaffold—a trait deemed critical for oral bioactivity.

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Section: ■ Results and Discussionsupporting

confidence: 76%

“…The predictions from WT-MetaD simulations, both in terms of the structure and dynamic behavior of G–G , are supported by the experiments. A folded structure for a derivative of G–G is observed using single-crystal X-ray diffraction …”

Section: Resultsmentioning

confidence: 99%

Well-Tempered Metadynamics Simulations Predict the Structural and Dynamic Properties of a Chiral 24-Atom Macrocycle in Solution

et al. 2022

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“…29 Initial efforts produced macrocycles ranging from 22 to 28 atoms�each a different Murcko framework�displaying different molecular shapes ranging from ones that were compact and folded to those that were extended and flat. 27,28 During the course of these studies, however, two isomeric 24atom macrocycles were prepared�one with glycine and a three carbon acetal (−NHCH 2 CONHCH 2 CH 2 C�N−) and the other with β-alanine and a two-carbon acetal (−NHCH 2 CH 2 CONHCH 2 C�N−). 27 Both showed markedly similar, folded structures in the solid state.…”

Section: ■ Introductionmentioning

confidence: 99%

“…27,28 During the course of these studies, however, two isomeric 24atom macrocycles were prepared�one with glycine and a three carbon acetal (−NHCH 2 CONHCH 2 CH 2 C�N−) and the other with β-alanine and a two-carbon acetal (−NHCH 2 CH 2 CONHCH 2 C�N−). 27 Both showed markedly similar, folded structures in the solid state. To better define the conformational landscape associated with this framework, we chose to prepare additional 24-atom macrocycles that varied in the choice of amino acid.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Our longstanding interest in triazine chemistry and recent studies of hydrazine-substituted triazines , led us to explore macrocycles incorporating triazinyl hydrazones as molecular frameworks. , The ease of synthesis and the numerous sites available to explore functional variation make triazine-based macrocycles a versatile platform for pursuing structure–property relationships. Zerkowski and coworkers showed earlier that static, covalent chemistry could yield similar triazine targets …”

Section: Introductionmentioning

confidence: 99%

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A Model for the Rapid Assessment of Solution Structures for 24-Atom Macrocycles: The Impact of β-Branched Amino Acids on Conformation

et al. 2023

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Experiment and computation are used to develop a model to rapidly predict solution structures of macrocycles sharing the same Murcko framework. These 24-atom triazine macrocycles result from the quantitative dimerization of identical monomers presenting a hydrazine group and an acetal tethered to an amino acid linker. Monomers comprising glycine and the β-branched amino acids threonine, valine, and isoleucine yield macrocycles G-G, T-T, V-V, and I-I, respectively. Elements common to all members of the framework include the efficiency of macrocyclization (quantitative), the solution- and solid-state structures (folded), the site of protonation (opposite the auxiliary dimethylamine group), the geometry of the hydrazone (E), the C2 symmetry of the subunits (conserved), and the rotamer state adopted. In aggregate, the data reveal metrics predictive of the three-dimensional solution structure that derive from the fingerprint region of the 1D 1H spectrum and a network of rOes from a single resonance. The metrics also afford delineation of more nuanced structural features that allow subpopulations to be identified among the members of the framework. Well-tempered metadynamics provides free energy surfaces and population distributions of these macrocycles. The areas of the free energy surface decrease with increasing steric bulk (G-G > V-V ∼ T-T > I-I). In addition, the surfaces are increasingly isoenergetic with decreasing steric bulk (G-G > V-V ∼ T-T > I-I).

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Controlling Swing Rates in Macrocyclic Molecular Mortise Hinges

Menke,

Mellberg,

Pan

et al. 2023

Chemistry A European J

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Hinge motion is observed in macrocyclic, mortise‐type molecular hinges using variable temperature NMR spectroscopy. The data is consistent with dynamic hinging from a folded‐to‐extended‐to‐folded enantiomeric state. Crystallographic and solution structures of the folded states are reported. Chemical shift predictions derived from crystallographic data corroborate fully revolute hinge motion. The rate of hinging is affected by steric congestion at the hinge axis. A macrocycle containing glycine, 1, hinges faster than one comprising aminoisobutyric acid, 2. The free energies of activation, ΔG≠, for 1 and 2 were determined to be 13.3±0.3 kcal/mol and 16.3±0.3 kcal/mol, respectively. This barrier is largely independent of solvent across those surveyed (CD3OD, CD3CN, DMSO‐d6, pyridine‐d5, D2O). Experiment and computation predict energy barriers that are consistent with disruption of an intramolecular network of hydrogen bonds. DFT calculations reveal a pathway for hinge motion.

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Efficient syntheses of macrocycles ranging from 22–28 atoms through spontaneous dimerization to yield bis-hydrazones

Abstract: Acid treatment of a triazine displaying both a tethered acetal and BOC-protected hydrazine group leads to spontaneous condensation to yield macrocyclic dimers in excellent yields and purity.

Cited by 8 publications

References 20 publications

Well-Tempered Metadynamics Simulations Predict the Structural and Dynamic Properties of a Chiral 24-Atom Macrocycle in Solution

Well-Tempered Metadynamics Simulations Predict the Structural and Dynamic Properties of a Chiral 24-Atom Macrocycle in Solution

A Model for the Rapid Assessment of Solution Structures for 24-Atom Macrocycles: The Impact of β-Branched Amino Acids on Conformation

Controlling Swing Rates in Macrocyclic Molecular Mortise Hinges

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