Over the past several decades, macrocyclic
compounds have emerged
as increasingly significant therapeutic candidates in drug discovery.
Their pharmacological activity hinges on their rotationally restricted
three-dimensional orientation, resulting in a unique conformational
preorganization and a high enthalpic gain as a consequence of high-affinity
macrocycle–protein binding interactions. Synthetic access to
macrocyclic drug candidates is therefore crucial. From a synthetic
point of view, the efficiency of macrocyclization events commonly
suffers from entropic penalties as well as undesired intermolecular
couplings (oligomerization). Although over the past several decades
ring-closing metathesis, macrolactonization, or macrolactamization
have become strategies of choice, the toolbox of organic synthesis
provides a great number of versatile transformations beyond the aforementioned.
This Outlook focuses on a selection of examples employing what we
term
unconventional macrocyclizations
toward the
synthesis of natural products or analogues.