Highly Stereoselective Peptide Modifications through Pd‐Catalyzed Allylic Alkylations of Chelated Peptide Enolates

Abstract

Deprotonation of peptides in the presence of zinc chloride gives rise to highly reactive nucleophiles that can be subjected to palladium-catalyzed allylic alkylation reactions. Excellent diastereoselectivities are obtained that are nearly independent of the allylic substrate used. By using this protocol, highly functionalized side chains can also be incorporated in excellent yields and selectivities. The stereochemical outcome of the reaction is exclusively controlled by the peptide chain as long as terminal pi-allyl-palladium complexes are involved. Probably, there is a threefold coordination, at least, of the deprotonated peptide chain to the chelating zinc ion. In such metal peptide complexes, one face of the generated enolate is shielded by the side chain of the adjacent amino acid, thus directing the electrophilic attack onto the opposite face. This behavior explains why an S amino acid always generates an R amino acid (and the other way round).

A versatile synthetic approach to grandisol monoterpene pheromone

“…Alkylation of commercially available methyl benzenesulfonylacetate 4 with 4-bromo-1-butene 6 and coupling of the resulting methyl hexanoate 5 with known allyl carbonate 7 (Deska and Kazmaier, 2007) in the presence of Grubbs' 2 nd generation catalyst 8 (Scholl et al, 1999) afforded 3.…”

Domino Process Achieves Site-Selective Peptide Modification with High Optical Purity. Applications to Chain Diversification and Peptide Ligation

“…This strategy has allowed the modification of both peptides and proteins . A variation involves the use of customizable units, where the core of the starting amino acid is transformed into a quite different one (e.g., by cleavage of the lateral chain and replacement by new ones). − …”

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Total Synthesis of Trapoxin A, a Fungal HDAC Inhibitor from Helicoma ambiens

“…This is mainly caused by an unknown conformation of the polydeprotonated peptide formed under the basic reaction conditions. We could solve this problem by adding multivalent metal salts, probably resulting in the formation of a metal–peptide enolate complex, in which one face of the peptide enolate is shielded by the side chain of the adjacent amino acid. Generally, an ( S )-amino acid generates an ( R )-amino acid and the other way round.…”