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

Abstract

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.

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

“…Compared with standard batch chemistry methods, continuous flow reactions have many significant advantages, such as better control and reproducibility, improved safety, cost efficiency, increased product quality and yield, etc. Through the efficient continuous flow multistep strategy, many natural and unnatural cyclic depsipeptides and peptidomimetics have been successfully synthesized, providing more possibilities for the discovery of new drugs …”

Flow Technology for Organometallic-Mediated Synthesis

“…In another work by Kappe, linear peptoids containing terminal azido and acetylenic functionalities were efficiently synthesized by a continuous multistep protocol by using an Ugi fourcomponent reaction [56].…”

Selective Mono-Ozonolysis of a Cyclic 1,5,9-Cyclododecatrien

“…A solution of (4Z,8Z)-12,12-dimethoxydodeca-4,8-dien-1-yl 4-methylbenzenesulfonate (0.5 gm, 1.26 mmol) in tetrahydrofuran (5 mL) was added dropwise to a suspension solution of Lithium Aluminium hydride (0.3 gm, 7.9 mmol) in tetrahydrofuran (10 mL) at 0 °C [10,15,18]. The reaction mixture was stirred 16 hours and was worked up as above to give (4Z,8Z)-1,1-dimethoxydodeca-4,8-diene (0.25 gm, 89%) (Fig.…”