A Sequential Ugi Multicomponent/Cu-Catalyzed Azide–Alkyne Cycloaddition Approach for the Continuous Flow Generation of Cyclic Peptoids

The development of
a continuous flow multistep strategy for the
synthesis of linear peptoids and their subsequent macrocyclization
via Click chemistry is described. The central transformation of this
process is an Ugi four-component reaction generating the peptidomimetic
core structure. In order to avoid exposure to the often toxic and
malodorous isocyanide building blocks, the continuous approach was
telescoped by the dehydration of the corresponding formamide. In a
concurrent operation, the highly energetic azide moiety required for
the subsequent intramolecular copper-catalyzed azide–alkyne
cycloaddition (Click reaction) was installed by nucleophilic substitution
from a bromide precursor. All steps yielding to the linear core structures
can be conveniently coupled without the need for purification steps
resulting in a single process generating the desired peptidomimetics
in good to excellent yields within a 25 min reaction time. The following
macrocyclization was realized in a coil reactor made of copper without
any additional additive. A careful process intensification study demonstrated
that this transformation occurs quantitatively within 25 min at 140
°C. Depending on the resulting ring strain, either a dimeric
or a monomeric form of the cyclic product was obtained.