Synthesis of Cyclic Peptides by Ring-Closing Metathesis

Abstract

The synthesis of a series of "amide to amide" cyclized peptides by ring-closing metathesis (RCM) as well as a convenient synthesis for the linear precursors is described. In addition, the influence of the length of the alkene substituents and the influence of the peptide sequence is investigated, leading to a set of general rules to obtain "amide to amide" cyclized peptides by RCM.

Synthesis of Cyclic Peptides and Peptidomimetics by Metathesis Reactions

“…This failure against ring closure originates from the formation of inappropriate secondary structures that prevents the peptides from macrocyclization by RCM. As shown by Reichwein and Liskamp [28,29], incorporation of N-alkenyl amino acids or proline residues will foster the efficiency of the cyclization reaction. Alternatively, reversible backbone protection by, among others, amide protection by either a 2,4-dimethoxybenzyl functionality [80] or tert-butyloxycarbonyl group [81] or by incorporation of pseudoprolines [82] is a versatile approach to overcome these difficulties during RCM-mediated cyclization reactions [79].…”

“…type I (22) type IIa (23) n = 0, 1 type IIb (24) type IIc (25) type IVa (29) type IVb (30) type IIIa (26) type IIIb (27) type IIIc (28) tripeptide motif amide" cyclized peptides in order to define a set of rules for RCM (in the presence of Ru-catalyst G1) as function of the length of the alkene substituent versus the length/nature of the peptide sequence [29]. From their studies the following "rules" for cyclization of bis-N-alkenylated peptides by G1-mediated RCM could be inferred: cyclic dipeptides -involving two amide bonds -could be obtained starting from bis-N-allyl (or longer alkene) substituents.…”

“…While cyclic tetra-, penta-, and hexapeptides -involving four, five, or six amide bonds, respectively -could be obtained starting from N-homoallyl (or longer alkene) substituents. In addition to this, the introduction of either proline or a single D-amino acid in the peptide sequence increased the overall yield of the cyclization reaction [29,30]. These insights were used to develop the so-called rolling loop scan to probe the bioactive conformation of cyclic peptides [31].…”

“…However, the hexamer as well as the octamer underwent macrocyclization (to give a 20-and 23-membered macrocycle, respectively) only in the presence of HG2 under microwave irradiation (300 W, 2 min) in 1,2-dichlorobenzene albeit in very low yield (10-20%). Since it is known that RCM efficiency strongly depends on the length of the olefinic amine [29,182], heptamer 145 was synthesized containing 3-buten-1-amine moieties. This heptamer reacted with G1, G2, and HG2 (2 mol%) under microwave irradiation (300 W, 2 min) in 1,2-dichlorobenzene, and after cleavage from the resin, the 25-membered macrocycle 146 was isolated in 10, 20, and 80% yield, respectively.…”

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

“…The Grubbs metathesis between two olefins tethered on the peptide chain catalyzed with ruthenium complexes has displaced the Heck reaction as it proceeds much faster and efficiently. [12][13][14][15] On the other hand, during the last four years, a large number of organic reactions were shown to proceed much faster with high yields using microwave as the energy source. [16][17][18][19] A large number of novel organic procedures emerged demonstrating that microwave energy will take a central place in the near future in organic chemistry laboratories.…”