Synthesis of Ribosomally Synthesized and Post-Translationally Modified Peptides Containing C-C Cross-Links

Abstract

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are known for their macrocyclic structures, which impart unique biological activity. One rapidly emerging subclass of RiPP natural products contains macrocyclic C-C cross-links between two amino acid side chains. These linkages, often biosynthetically formed by a single rSAM or P450 enzyme, introduce significant structural and synthetic complexity to the molecules. While nature utilizes elegant mechanisms to produce C-C cross-linked RiPPs, synthetic tools are only able to access a portion of these biologically relevant natural products. This review provides an overview of the structures in this subclass as well as a discussion on their chemical syntheses.

Figure 1.

Structures of RiPPs containing tryptophan C–C linkages. Light blue shading indicates atoms are behind the plane, and bold indicates atoms are projected forward.

Figure 2.

Potential anticancer RiPP natural product celogentin C.

Figure 3.

Macrocyclic RiPP natural product streptide.

Figure 4.

Trimacrocyclic RiPP natural product tryptorubin A. Light blue shading indicates atoms are behind the plane, and bold indicates atoms are projected forward.

Figure 5.

Tryglysins A and B, which contain a novel double C–C cross-link of a single tryptophan residue.

Figure 6.

Structure of xenorceptide, a RiPP natural product with three separate C–C cross-links.

Figure 7.

Darobactin and its interactions with the β1-strand of BamA.

Figure 8.

RiPPs with C–C cross-links that incorporate tyrosine.

Figure 9.

PQQ contains a peptide C–C cross-link that is disguised by multiple additional oxidations.

Figure 10.

Cittilins A and B are bimacrocyclic RiPPs that inhibit CsrA, a critical virulence factor of opportunistic bacteria.

Figure 11.

The ryptide subclass of natural products has not been fully characterized but is distinguished by the inclusion of the Arg–Tyr cross-link.

Figure 12.

The four types of cross-linking motifs found in class III lanthipeptides.

Figure 13.

Class III lanthipeptides containing only labionin macrocyclic cross-linkages and the labionin motif. The residues that form the labionin residue in each peptide are highlighted in orange, and the C–C cross-link is encircled in blue. Some RiPPs in this category also contain disulfide bridges, and the Cys residues that form these bridges are highlighted in blue.

Figure 14.

Class III lanthipeptides containing both labionin (orange) and lanthionin (pink) motifs. The structures for erythreapeptin and stackepeptins C and D have both been elucidated and are indicated by solid lines. The structures of avermipeptin and griseopeptin are not fully elucidated, and the uncertainty of lanthionin/labionin composition is indicated by dashed lines.

Figure 15.

Avionin-containing RiPPs. The avionin connection is an unsaturated form of the labionin linkage. The residues that make the avionin connection are highlighted in orange.

Figure 16.

Pantocin A is a RiPP natural product with antibiotic activity against fire blight pathogen, containing a C(sp³)–C(sp³) cross-link in its cyclic architecture that is disguised by subsequent decarboxylation.

Scheme 1.

Moody and Co-workers’ Synthesis of the Central Tryptophan–Leucine Subunit of Celogentin C

Scheme 2.

Campagne and Co-workers’ Synthesis of the Central Tryptophan–Leucine Subunit of Celogentin C

Scheme 3.

Castle and Co-workers’ Synthesis of Celogentin C

Scheme 4.

Jia and Co-workers’ Synthesis of Celogentin C

Scheme 5.

Chen and Co-workers’ Synthesis of Celogentin C

Scheme 6.

Wang and Co-workers’ Synthesis of the A Ring of Celogentin C

Scheme 7.

Key C–C Bond-Forming Steps of Boger and Co-workers’ Synthesis of Streptide

Scheme 8.

Chen’s General Strategy for the Installation of Aryl–Alkyl Linkages in Cyclophane-Braced Peptide Macrocycles

Scheme 9.. Baran’s Total Synthesis of Tryptorubin A^a

^aLight blue shading indicates atoms are behind the plane, and bold indicates atoms are projected forward.

Scheme 10.

Synthesis of the C–C Linkage between Phenylalanine and Asparagine in Xenorceptide

Scheme 11.. Synthesis of Darobactin A by Sarlah and Co-workers^a

^aLight blue shading indicates atoms are behind the plane, and bold indicates atoms are projected forward.

Scheme 12.. Synthesis of Darobactin A by Baran and Co-workers^a

^aLight blue shading indicates atoms are behind the plane, and bold indicates atoms are projected forward.

Scheme 13.

First Chemical Syntheses of PQQ: (A) the Weinreb Synthesis; (B) the Corey Synthesis

Scheme 14.

Syntheses of PQQ from the Hendrickson and Büchi Groups

Scheme 15.

Synthesis of the C–C Cross-Link between Two Tyrosine Residues in the Western Macrocycle of Cittilin A

Scheme 16.

Zhu and Co-workers’ Synthesis of an Unnatural Cittilin A Atropisomer

Scheme 17.

Boger and Co-workers’ Synthesis of the Cittilin A Western Macrocycle

Scheme 18.. An Abbreviated Biosynthetic Mechanism for the Synthesis of Lanthionin, Labionin/Methyl-labionin, and Avionin Linkages^a

^aThe C–C cross-links contained within each moiety are encircled in blue.

Scheme 19.

Chemical Syntheses of the Labionin Motif: (A) Süssmuth Semisynthesis of Protected Labionin; (B) Sani Synthesis of Orthogonally Protected Labionin

Scheme 20.. Two Potential Biosynthetic Pathways for Pantocin A^a

^aPaaA catalyzes either enolate or amide addition to a Glu side chain. Dehydration and decarboxylation follow to yield pantocin A (138).