Fast and versatile microwave‐assisted intramolecular Heck reaction in peptide macrocyclization using microwave energy

Abstract

We have revisited the intramolecular Heck reaction and investigated the microwave-assisted macrocyclization on preformed peptides using a model series of ring-varying peptides acryloyl-Gly-[Gly](n)-Phe(4-I)NHR; n = 0-4. The method was applied to both solution and solid supported cyclizations. We demonstrate that the intramolecular Heck reaction can be performed in peptides both in solution and solid support using a modified domestic microwave within 1 to 30 minutes in DMF under reflux with moderate yields ranging from 15 to 25% for a scale between 2-45 mg of linear precursors. The approach was applied to the synthesis of a constrained biologically relevant peptidomimetic bearing an Arg-Gly-Asp (RGD) sequence. These results make the microwave-assisted Heck reaction an attractive renovated approach for peptidomimetics.

Mizoroki–Heck Reactions: Modern Solvent Systems and Reaction Techniques

“…The intermolecular Mizoroki-Heck reaction in macrocyclization of peptides was demonstrated by Byk et al [207]. The reactions were done out in milligram scale with 15-25% yield.…”

Synthesis and Evaluation of a Dimeric RGD Peptide as a Preliminary Study for Radiotheranostics with Radiohalogens

“…U-87 MG glioblastoma cells were purchased from DS Pharma Biomedical (Osaka, Japan). Fmoc-4-iodo-D-phenylalanine [Fmoc-D-Phe(4-I)] was synthesized according to a previous report [21]. N,N-Diisopropylethylamine (DIPEA) was purchased from Nacalai Tesque (Kyoto, Japan).…”

The Synthesis of Macrocycles for Drug Discovery

“…312 Indeed, it is one of the few approaches that provides efficient access to such ring sizes. For example, the class of cyclic dopamine antagonists exemplified by the 10-membered ring azecine LE300 (207) can be synthesized using reductive opening of a quaternized multicyclic quinolizine precursor (Figure 11.16, site and reagents for bond breakage shown, broken bond dashed). 313 Similar procedures have been applied to generate a wide range of potent dopamine antagonists.…”

“…206 Microwave heating has been reported to be useful in accelerating both solution and solid phase Heck reactions to form peptidomimetic macrocycles. 207 This procedure was also used to facilitate an intramolecular Heck reaction that was the key step in the exploration of macrocyclic inhibitors (100) of anaplastic lymphoma kinase (ALK). 208 The coupling proceeded equally well regardless of the ring location of the reacting vinyl and halide functionalities (indicated in the Figure by the alternative reaction sites).…”