text: Cyclic molecules often exist in much more rigid conformations than their linear counterparts. Even very large macrocycles like erythromycin exist in defined geometries despite having many degrees of freedom. Because of these properties, it is often easier to achieve asymmetric induction with macrocyclic substrates rather than linear ones. Early experiments performed by W. Clark Still and colleagues showed that medium- and large-ring organic molecules can provide striking levels of stereo induction as substrates in reactions such as kinetic enolate alkylation, dimethylcuprate addition, and catalytic hydrogenation. Even a single methyl group is often sufficient to bias the diastereomeric outcome of the reaction. These studies, among others, helped challenge the widely-held scientific belief that large rings are too floppy to provide any kind of stereochemical control. 
  A number of total syntheses have made use of macrocyclic stereocontrol to achieve desired reaction products. In the synthesis of (−)-cladiella-6,11-dien-3-ol, a strained trisubstituted olefin was dihydroxylated diasetereoselectively with N-methylmorpholine N-oxide (NMO) and osmium tetroxide, in the presence of an unstrained olefin. En route to (±)-periplanone B, chemists achieved a facial selective epoxidation of an enone intermediate using tert-butyl hydroperoxide in the presence of two other alkenes. Sodium borohydride reduction of a 10-membered ring enone intermediate en route to the sesquiterpene eucannabinolide proceeded as predicted by molecular modelling calculations that accounted for the lowest energy macrocycle conformation. Substrate-controlled synthetic schemes have many advantages, since they do not require the use of complex asymmetric reagents to achieve selective transformations.