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

Abstract

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.

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

“…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. [11][12][13] 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 observedf or other monosubstituted [13]-macrodilactones.B ecause compound 3 was racemic, we furthera nticipated that two complementary enantiomers would be found in the unit cell of 7;e ach configuration of the stereogenicc arbon (R or S) would dictate the planarc hirality (pR or pS)o ft he macrocycle. The X-ray structure of 7 we obtained, therefore, allowed us to comparei twith our previously studied ring systems.…”

“…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.…”

“…These atoms are the alkyl carbon, the ester oxygen, the carbonyl carbon,a nd the a-carbon( e.g.,a toms 4-7 in Figure 1). Four atoms are also rigidified by the alkene (atoms [8][9][10][11][12].T welve of the thirteena toms in the macrocycle, therefore, are present in planar units. The connections between the planar units are of two varieties.…”

“…C2, C4, C7, C12;s ee Figure 1a, b) along the backboneo f the macrocycle, the absolutes tereochemistry of which will dictate the planar chirality of the macrocycle when there is only one substituent on the ring. [11,13] The commonality between these key centers is that they are at the terminus of ap lanar unit. Consider, for example, C4 and C7;t hese two atoms are at either endo fo ne of the ester units in the [13]-macrodilactones.T he interplay between ap oint of asymmetry and a plane or axis of asymmetry is an important way to dictate the handedness of macrocyclesa nd it has implications for the designo fd esired shapes for ap articular application.…”

Photocontrol over Molecular Shape: Synthesis and Photochemical Evaluation of Glycoazobenzene Macrocycles

“…We envisioned the design of carbohydrate‐based macrocycles that can be reversibly switched between two defined structural shapes by external stimuli. As the shape of a functional molecule can be correlated with its properties, switching the molecular shape of a carbohydrate‐based macrocycle is expected to induce a change of its physicochemical properties, chirality, supramolecular features, and of the spatial arrangement of attached functionalities. To achieve such shape switching we planned to incorporate a photoresponsive hinge into the cycle, like an azobenzene derivative (Figure ).…”