Progress in Lanthionine and Protected Lanthionine Synthesis

Abstract

Lanthionine (Lan), a non‐proteinogenic natural amino acid, is an essential component of peptidoglycan found in the cell wall of Fusobacterium species. Lan and β‐methyllanthionine are also key constituents in lantibiotics, a prevalent class of peptide antibiotics. The development of those new antibacterial drugs with enhanced properties is the focus of recent research. Since multiple isomers of Lan are possible, a regio‐ and diastereoselective synthesis is challenging. This comprehensive review summarizes the known chemical syntheses of lanthionine from various precursors (e.g., β‐chloroalanine, cystine, dehydroalanine, β‐iodoalanine, aziridine, serine lactone, sulfamidate) since 1941. Methods for preparation of unprotected, protected, orthogonally protected, and mutually orthogonally protected lanthionine with relevant experimental details and perspectives on their usefulness are provided. The potential of these Lan derivatives is illustrated by one recent application.

Organometallic AlaM reagents for umpolung peptide diversification

“…This strategy is complementary to the earlier synthetic studies that relied on nucleophilic substitution of β-haloalanine with free cysteine. 96 This example further demonstrates that oligopeptides can be efficiently coupled without detrimental formation of Dha that frequently competes with substitutions of βhaloalanine electrophiles. These results led us then to extend the scope of C-heteroatom cross-couplings with symmetrical D-glucose diselenide (22e) and N-sulfenylsuccinimidate donors (22f), resulting in 68% and 78%, respectively, with retention of anomeric configuration for both examples.…”

Molecular Recognition of Lipid II by Lantibiotics: Synthesis and Conformational Studies of Analogues of Nisin and Mutacin Rings A and B

“…To date, only a limited number of effective approaches have been established. 28 We have developed a powerful solid-phase peptide synthesis (SPPS) strategy for the synthesis of lanthionine-containing peptides. 29 This is based on the incorporation of orthogonally protected lanthionine building blocks into linear peptides, followed by chemoselective deprotection, on-resin cyclization, and chain extension where required, leading to lanthionine-bridged peptides with complete control of stereochemistry at the α-positions (and β-positions) and complete regioselectivity of cyclization.…”

Organometallic AlaM Reagents for Umpolung Peptide Diversification

“…This strategy is complementary to the earlier synthetic studies that relied on nucleophilic substitution of β-haloalanine with free cysteine. 90 This example further demonstrates that oligopeptides can be efficiently coupled without detrimental formation of Dha that frequently competes with substitutions of βhaloalanine electrophiles. These results led us then to extend the scope of C-heteroatom cross-couplings with symmetrical D-glucose diselenide (22e) and N-sulfenylsuccinimidate donors (22f), resulting in 68% and 78%, respectively, with retention of anomeric configuration for both examples.…”