Solid-Phase Synthesis of Peptide Thioureas and Thiazole-Containing Macrocycles through Ru-Catalyzed Ring-Closing Metathesis

Abstract

N-Terminally modified α-thiourea peptides can selectively be synthesized on solid support under mild reaction conditions using N,N'-di-Boc-thiourea and Mukaiyama's reagent (2-chloro-1-methyl-pyridinium iodide). This N-terminal modification applies to the 20 proteinogenic amino acid residues on three commonly used resins for solid-phase synthesis. Complementary methods for the synthesis of α-guanidino peptides have also been developed. The thiourea products underwent quantitative reactions with α-halo ketones to form thiazoles in excellent purities and yields. When strategically installed between two alkene moieties, said thiazole core was conveniently embedded in peptide macrocycles via Ru-catalyzed ring-closing metathesis reactions. Various 15-17 membered macrocycles were easily accessible in all diastereomeric forms using this methodology. The developed "build/couple/pair" strategy is well suited for the generation of larger and stereochemically complete screening libraries of thiazole-containing peptide macrocycles.

Synthesis of Cyclic Peptides and Peptidomimetics by Metathesis Reactions

“…Further increasing the conversion could be accomplished by repeating the RCM reaction on the solid support once. Gratifyingly, this RCM protocol afforded access to 15-, 16-, and 17-membered macrocycles with up to three stereocenters in the ring, which all underwent cyclization, in excellent product yields and purity [171].…”

“…Herein, these examples focus on a large structural variation of the peptide derivatives, and special attention is paid to the reaction conditions of the RCM or CM protocols and to approaches to optimize the metathesis reaction. The first example describes the solid-phase synthesis of peptide thioureas and thiazole-containing macrocycles (represented by 128) obtained by Ru-catalyzed ring-closing metathesis [171], as shown in Scheme 28. This class of functionalized peptides is frequently encountered in biologically active derivatives, with antibacterial, antifungal, and antiviral properties.…”

“…As a typical example, solid-phase-bound Scheme 28 Synthesis of thiazole-functionalized peptide macrocycles [171] D.T.S. Rijkers tripeptide H-Phe-Alg-Gly 125 was treated with N,N 0 -di-Boc-thiourea in the presence of Mukaiyama's reagent (2-chloro-1-methyl-pyridinium-iodide) and Et 3 N as base in CH 2 Cl 2 as the solvent, to afford the corresponding N-terminal α-thiourea intermediate in a yield >95%, after optimization of the addition/preactivation procedure.…”

Organische Chemie 2014

“…Das Methodenrepertoire für die organische Synthese an fester Phase (SPOS) erweiterten Bugarin et al mit einer Dötz‐Anellierung zur Herstellung von Naphthochinonen (38) (Abbildung 14) 42. Nielsen et al synthetisierten an der festen Phase eine komplette Matrix von Diastereomeren der 15‐ bis 17‐gliedrigen Makrocyclen (39) , bei denen der Hoveyda‐Grubbs‐Katalysator der zweiten Generation die kritische Ringschlussmethathese (RCM) in sehr guten Ausbeuten vermittelte 43. Waldmann et al stellten die polymerunterstützte Synthese einer stereochemisch divergenten naturstoffinspirierten Oxepanbibliothek (40) vor.…”

Metathesis Reactions on Solid-Phase: Towards New Synthesis Challenges

“…In this case the Petasis olefination and a RCM reaction was utilized as key steps. A convenient sequential on-resin RCM approach has also be used for the synthesis of a carbocyclic lantibiotic peptide [35], the synthesis of a new peptidomimetic alkene-structure (a dipeptidosulfonamide isostere) described by Liskamp and co-authors [36] on solid phase via a olefin CM reaction, the RCM reaction for the synthesis of b3-peptides [37], synthesis of analogues to Dynorphin A-peptides [38], and preparation of histone deacetylase inhibitors [39], cyclic peptoids [40], cyclic pseudopeptides [41], cyclic 11-and 10-mer peptide derivatives [42], glycopeptoids [43], lipophilic tetrapeptides [44], and peptide thioureas and triazole-containing macrocycles [45]. The CM reaction has nevertheless also been used for the preparation of many simple organic molecules and heterocycles (Fig.…”