Stereogenic α-carbons determine the shape and topology of [13]-macrodilactones

Magpusao, Anniefer N.; Rutledge, Kelli; Mercado, Brandon Q.; Peczuh, Mark W.

doi:10.1039/c5ob00402k

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…Taken together, it is reasonable that, whereas ribbon 6 is 4 kcal mol −1 more stable that ribbon 7 , there is a relatively low barrier associated with interconversion between ribbon and heart conformers for both of them. The fact that the heart conformer of 6 is not observed in the crystal structure of related α‐substituted [13]‐macrodilactones may simply be related to crystal packing forces.…”

Section: Resultsmentioning

confidence: 99%

“…When α‐substituted [13]‐macrodilactone 6 was the substrate, two diastereomeric epoxides, 9 and 10 (Figure ), were obtained in a ratio of approximately 1:3. This result initially seemed inconsistent with results obtained for epoxidation on related α‐phenyl substituted [13]‐macrodilactone 8 . When the reaction was revisited, however, we found that 8 does, in fact, provide two diastereomeric epoxide products in a ratio of approximately 1:3 ( 11 : 12 ).…”

Section: Resultsmentioning

confidence: 99%

“…The structure obtained from X‐ray diffraction data for the unsubstituted [13]‐macrodilactone is shown in Figure c . Data from the solid state has been valuable to our understanding of how the functional groups and their connections translate into conformations in this family of macrocycles.…”

Section: Introductionmentioning

confidence: 99%

“…The interplay between a point of asymmetry and a plane or axis of asymmetry is an important way to dictate the handedness of macrocycles and it has implications for the design of desired shapes for a particular application. The principle seems to be relatively general, with instances in both natural products and de novo compounds . Studies of other macrocycle motifs have shown that substitution at the allylic position could either have an effect on the overall conformation or have no effect at all, as in (−)‐exiguolide and dictyostatin .…”

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: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…[13]-Macrodilactones 2-6 are comprised of three four-atom planar units, a sp 3hybridized hinge atom, and asymmetric centers. It was observed that the interplay between these components gave rise to planar chirality in [13]-macrodilactones, and the handedness of the twist was determined by the absolute configuration of only one asymmetric center, at either C2 (2-5) or C7 (6), present in the macrocycles [16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and structure of a carbohydrate-fused [15]-macrodilactone

Peczuh

2016

Carbohydrate Research

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The design, synthesis and structural characterization of a new α-d-glucose fused [15]-macrodilactone is reported. The macrolide was synthesized by a route involving sequential acylations of glucose at the C4' and C6' hydroxyl groups followed by an intramolecular Stille reaction previously established for other [15]-macrodilactones. Analysis of the X-ray crystallographic structure of the macrolide revealed a unique conformation of this macrocycle that differs from earlier models for [13]- and [15]-macrodilactones. Organizing the three planar units and the pyranose moiety into a macrocyclic ring resulted in a cup-shaped structure with planar chirality. Further, the gt conformation of the exocyclic hydroxymethyl group in the glucose unit was found to be crucial for controlling the planar chirality and, hence, governing the molecular shape and overall topology of the compound.

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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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Stereogenic α-carbons determine the shape and topology of [13]-macrodilactones

Cited by 9 publications

References 34 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

Synthesis and structure of a carbohydrate-fused [15]-macrodilactone

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

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