Challenging Resolution using Diastereomeric Crystallization

Abstract

The application of modern crystallographic methods to the classical topic of chiral resolution through diastereomeric salts formation is investigated. In particular the concept of “challenging resolutions” in which shape similarity of enantiomeric ions leads to disorder of the ion site(s) in a single crystalline solid phase is explored. Over 100 crystalline phases have been examined by single crystal X-ray diffraction with careful analysis of possible disorder. Examples from a continuum of resolution outcomes are presented along with development of a family of aryltartramide spiroborate anions that show promise for engineering of %ee. Aryl spiroborate esters derived from benzillic or hydroxynaphthoic acids with B- centred chirality are isolated and resolved. These are enantio-stable in aprotic media. Finally the use of metal salts and complexes of mandelic acid for resolution is investigated. The challenging case of sec-butylamine is successfully tackled with single step crystallization of [S-NH₃CHMeEt][Cu(R-Man)₂] with 70%ee starting from racemic amine and polymeric [Cu(R-ManH)₂]. A rich coordination chemistry is uncovered with anionic, neutral or cationic mononuclear or polynuclear complexes of chiral copper and aluminium mandelates that offer further opportunity for resolution of even the most “challenging” cases.

Date of Award	2025
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Ian Duncan WILLIAMS (Supervisor)