Instant Macrocyclizations via Multicomponent Reactions

Macrocycles fascinate chemists due to both their structure
and
their applications. However, we still lack efficient and sustainable
synthetic methods, giving us straightforward access to them. Herein,
a rapid macrocyclization utilizing a two-step, one-pot approach based
on orthogonal multicomponent reaction (MCR) tactics is introduced.
This synthetic protocol, which is based on Ugi and Groebke–Blackburn–Bienaymé
reactions with isocyanides tethered to alkyl tosylates, yields medium
sized macrocycles that are otherwise difficult to achieve. Single
crystal structures reveal conformational reorganization via intramolecular
hydrogen bonding, and modeling studies profile the synthesized libraries.