A New Class of Non-Racemic Chiral Macrocycles: A Conformational and Synthetic Study

Amino alcohols have been used to introduce non‐racemic chirality into macrocycles using a modular approach that relies on a Heck macrocyclisation reaction. A wide variety of macrocycles have been synthesised, and their structures studied using X‐ray crystallography and molecular modelling. A fragmentation reaction encountered during the use of (S)‐1,1‐dimethylvalinol revealed that carboxylic acids generate acylals under reaction conditions often used for Heck reactions. A modular approach that relies on a Heck macrocyclisation reaction has been used for the synthesis of macrocycles based on amino alcohols. A systematic synthetic study of a range of Heck precursors and a computational study of the Heck products have been performed. The macrocycle illustrated here is based on (S)‐prolinol and results from three head‐to‐tail Heck couplings.