Remote induction of asymmetry in [13]-macro-dilactone topology by a single stereogenic center

Fyvie, W. Sean; Peczuh, Mark W.

doi:10.1039/b807562j

Cited by 16 publications

(33 citation statements)

References 25 publications

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“…To our delight, [13]‐macrodilactone 7 was a crystalline solid. We have previously relied on X‐ray crystallography to understand how planar units and stereogenic centers at key centers affect the solid‐state conformations of these macrocycles . We expected that the carbon with the aryl ring, at the terminus of the alkene planar unit, would guide the adoption of a ribbon conformation by the macrocyclic backbone, as we had observed for other monosubstituted [13]‐macrodilactones.…”

Section: Resultsmentioning

confidence: 99%

“…Subsequently, we have identified several key atoms (i.e. C2, C4, C7, C12; see Figure a, b) along the backbone of the macrocycle, the absolute stereochemistry of which will dictate the planar chirality of the macrocycle when there is only one substituent on the ring . The commonality between these key centers is that they are at the terminus of a planar unit.…”

Section: Introductionmentioning

confidence: 99%

“…The ability to access multiple conformationslikely assists in binding and also in tuningp hysical properties. As part of ap roject that aims to characterize the interplay between stereogenic centers at key positions in am odel [13]-macrodilactonea nd the planar chirality of the ring, we have discoveredt hat substitution at an allylic carbon modulates the dynamics of the ring between two interrelated conformers. Althoughd iscovered in the solid state, computation and solutione xperiments indicatet hat the interconversion, or "flutter", between conformationsa lso occursi ns olution.…”

Section: Introductionmentioning

confidence: 99%

“…Ap articularf amily of [13]-macrodilactones, typified by the macrocycle depicted in Figure1,h as provided am odel system for the investigation of parameters that drive to the structure and conformation of macrocycles. [11][12][13][14] Several factors contrib-ute to the rigidification of this family of macrocycles; of which the primary ones are the two ester units and the alkene. The esters, for example, organize four ring atoms each.…”

Section: Introductionmentioning

confidence: 99%

“…The structure obtained from X-ray diffraction data for the unsubstituted [ 13]-macrodilactone is shown in Figure 1c. [11b] Data from the solid state has been valuabletoo ur understanding of how the functional groups and their connections translate into conformationsi nt his family of macrocycles.…”

Section: Introductionmentioning

confidence: 99%

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Macrocycles All Aflutter: Substitution at an Allylic Center Reveals the Conformational Dynamics of [13]‐Macrodilactones

Rutledge

Hamlin

Baldisseri

et al. 2017

Chemistry An Asian Journal

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The shapes adopted by large-ring macrocyclic compounds play a role in their reactivity and their ability to be bound by biomolecules. We investigated the synthesis, conformational analysis, and properties of a specific family of [13]-macrodilactones as models of natural-product macrocycles. The features of our macrodilactones enabled us to study the relationship between stereogenic centers and planar chirality through the modular synthesis of new members of this family of macrocycles. Here we report on insights gained from a new [13]-macrodilactone that is substituted at a position adjacent to the alkene in the molecule. Analysis of the compound, in comparison to an α-substituted regioisomer, by using X-ray crystallography, NMR coupling constants, and reaction-product characterization in concert with computational chemistry, revealed that the alkene unit is dynamic. That is, the data support a model in which the alkene in our [13]-macrodilactones oscillates between two conformations. A difference in reactivity of one conformation compared to the other leads to manifestation of this dynamic behavior. The results underscore the local conformational dynamics observed in some natural-product macrocycles, which could have implications for biomolecule binding.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Macrocycles All Aflutter: Substitution at an Allylic Center Reveals the Conformational Dynamics of [13]‐Macrodilactones

Rutledge

Hamlin

Baldisseri

et al. 2017

Chemistry An Asian Journal

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Organocatalytic Stereoselective α‐Formylation of Ketones

et al. 2012

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Rules of Macrocycle Topology: A [13]‐Macrodilactone Case Study

Magpusao

Rutledge

Hamlin

et al. 2016

Chemistry A European J

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Shape is an inherent trait of a molecule that dictates how it interacts with other molecules, either in binding events or intermolecular reactions. Large-ring macrocyclic compounds in particular leverage their shape when they are selectively bound by biomolecules and also when they exhibit macrocyclic diastereoselectivity. Nonetheless, rules that link structural parameters to the conformation of a macrocycle are still rudimentary. Here we use a structural investigation of a family of [13]-macrodilactones as a case study to develop rules that can be applied generally to macrocycles of different sizes and with a variety of functionality. A characteristic "ribbon" shape is adopted by the [13]-macrodilactones in the absence of stereogenic centres, which exhibits planar chirality. When one stereogenic centre at key positions on the backbone is incorporated into the structure, the planar chirality is dictated by the configuration of the centre. In cases where two stereogenic centres are present, their relationships can either reinforce the characteristic ribbon shape or induce alternative shapes to be adopted. The rules established in the case study are then applied to the analysis of a structure of the natural product migrastatin. They lay the groundwork for the development of models to understand macrocycle-biomolecule interactions and for the preparation of macrocycles with designed properties and activities.

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Remote induction of asymmetry in [13]-macro-dilactone topology by a single stereogenic center

Abstract: Analysis of a series of unsaturated [13]-macro-dilactones showed that the configuration of a single carbon dictates the planar chirality of a macrocycle backbone and in turn remotely switches the facial display of an embedded alkene unit.

Cited by 16 publications

References 25 publications

Macrocycles All Aflutter: Substitution at an Allylic Center Reveals the Conformational Dynamics of [13]‐Macrodilactones

Macrocycles All Aflutter: Substitution at an Allylic Center Reveals the Conformational Dynamics of [13]‐Macrodilactones

Organocatalytic Stereoselective α‐Formylation of Ketones

Rules of Macrocycle Topology: A [13]‐Macrodilactone Case Study

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