text: Stereocontrol for cyclohexane rings is well established in organic chemistry, in large part due to the axial/equatorial preferential positioning of substituents on the ring. Macrocyclic stereocontrol models the substitution and reactions of medium and large rings in organic chemistry, with remote stereogenic elements providing enough conformational influence to direct the outcome of a reaction.
  Early assumptions towards macrocycles in synthetic chemistry considered them far too floppy to provide any degree of stereochemical or regiochemical control in a reaction. The experiments of W. Clark Still in the late 1970s and 1980s challenged this assumption, while several others found crystallographic data  and NMR data  that suggested macrocyclic rings were not the floppy, conformationally ill-defined species many assumed.
  The degree to which a macrocyclic ring is either rigid or floppy depends significantly on the substitution of the ring and the overall size.  Significantly, even small conformational preferences, such as those envisioned in floppy macrocycles, can profoundly influence the ground state of a given reaction, providing stereocontrol such as in the synthesis of miyakolide.  Computational modeling can predict conformations of medium rings with reasonable accuracy, as Still used molecular mechanics modeling computations to predict ring conformations to determine potential reactivity and stereochemical outcomes.
  Reaction classes used in synthesis of natural products under the macrocyclic stereocontrol model for obtaining a desired stereochemistry include: hydrogenations such as in neopeltolide  and  (±)-methynolide, epoxidations such as in (±)-periplanone B and lonomycin A, hydroborations such as in 9-dihydroerythronolide B, enolate alkylations such as in (±)-3-deoxyrosaranolide, dihydroxylations such as in cladiell-11-ene-3,6,7-triol, and reductions such as in eucannabinolide.