Observations on the Influence of Precursor Conformations on Macrocyclization Reactions

Abstract

Macrocycles hold great promise in drug discovery as an underutilized class of lead compounds. The low abundance of these molecules can in part be explained by the inherent difficulties in the synthesis of macrocycles and the lack of general methods for their rapid assembly. We have undertaken a research program aimed at developing methods for facile synthesis of macrocycles from simple precursors. The synthesis of two new cyclization precursors is described and the results of their reaction with thionyl chloride are presented and discussed. Where one acyclic diol, smoothly underwent macrocyclization to afford a mixture of diastereomeric sulfites, subjection of the other precursor to identical reaction conditions resulted in the isolation of the linear dichloride. We hypothesize that there is a difference in the ability of the two molecules to adopt a conformation germane to macrocyclization, a proposition that is supported by conformational analyses using molecular mechanics.

Orientation Control of Molecularly Functionalized Surfaces Applied to the Simultaneous Alignment and Sorting of Carbon Nanotubes

“…Probing the interaction of our functionalized surface with SWNTs would offer a convenient handle to probe the alignment of molecules on the surface while at the same time providing an exciting application for this technique. Iptycenes have excellent affinity for binding to SWNTs in solution through π–π interactions . Compound 1 should possess the aptitude to interact with SWNTs given that it contains two full triptycene cores.…”

“…Tubes with diameters smaller than 1.25 nm are substantially reduced in our samples, whereas tubes with diameters around 1.59 nm become the most prevalent. We hypothesize that this selectivity arises from the varying interactions between SWNTs with different diameters and the triptycene units with a fixed size and shape in 1 . Future improvements in this technique will focus on varying the size, shape, and electronic properties of the small molecule bound to the surface to tune the interactions with SWNTs and improve selectivity for different types of SWNTs.…”

Towards the Synthesis of Highly Hindered Pyrrolidines by Intramolecular AAC Click Reactions: What Can Be Learned from DFT Calculations?**

“…However, the number of successful conformationally controlled syntheses of macrocycles is rather scarce [39,42] . This may be due, at least in part, to the associated difficulties in predicting the conformational preferences of flexible systems, for which computational chemistry is an invaluable aid [43–46] . To the best of our knowledge, however, no systematic computational study has been performed to investigate the conformational dependence in intramolecular AAC reactions.…”