ino acids with the biosynthesis. the biosynthesis.Figure 3. Cyclomarazines.CymA and CymB had been isolated in the Streptomyces sp. CNB-982, collectively with CymA and CymB were isolated from the Streptomyces sp. CNB-982, collectively with CymD that was missing the N-methyl group on the -hydroxyleucine . It It can be clear that CymD that was missing the N-methyl group around the -hydroxyleucine 2 . is clear that -hydroxylation by P450 leucine hydroxylase happens more IP list rapidly than N-methylation, and tryptohydroxylation by P450 leucine hydroxylase occurs more rapidly than N-methylation, and tryptophan hydroxylation isis critical for prolonging the peptide chain. If hydroxylation does phan hydroxylation important for prolonging the peptide chain. If this this hydroxylation not occur adequately, the incompletely processed dipeptide is cleaved from the NRPS NRPS doesn’t happen properly, the incompletely processed dipeptide is cleaved from the on account of ineffective processing by the by module. This reaction is a special unique in which a on account of ineffective processing nextthe subsequent module. This reaction is aexampleexample in megasynthetase can create make two different organic goods of distinctive sizes which a megasynthetase can two distinct natural goods of distinct sizes merely by triggering triggering -oxidation around the priming Trp unit. Notably, cyclomarazines usually do not simply by the level ofthe level of -oxidation on the priming Trp unit. Notably, cyclomarashow considerable biological CYP51 Molecular Weight activity. zines usually do not show important biological activity. The second main way in which cyclomarins differ from ilamycins may be the incorporaThe second major way in which cyclomarins differ from ilamycins will be the incorporation of -methoxyphenylalanine (MeOPhe) as an alternative to nitrotyrosine. This amino acid is tion of -methoxyphenylalanine (MeOPhe) as an alternative to nitrotyrosine. This amino acid is obtained from a peptide-bound Phe through a P450-catalyzed -hydroxylation followed by obtained from a peptide-bound Phe via a P450-catalyzed -hydroxylation followed by OO-methylation [35]. methylation [35]. During their soil metagenome project, Brady et al. also investigated the biosynthesis During their soil metagenome project, Brady et al. also investigated the biosynthesis of metamarin. In this cyclomarin derivative, the unsaturated amino acid is replaced by of metamarin. In this cyclomarin derivative, the unsaturated amino acid is replaced by valine (Figure 2c) [32]. A further valine is incorporated instead of alanine 3 . As a result, it is actually valine (Figure 2c) [32]. A further valine is incorporated rather than alanine . Therefore, it is not surprising that the gene cluster is comparable for the cyclomarin cluster, and only the genes responsible for ADH biosynthesis are missing.4. Total Syntheses of Marine CycloheptapeptidesMar. Drugs 2021, 19,six ofnot surprising that the gene cluster is comparable towards the cyclomarin cluster, and only the genes responsible for ADH biosynthesis are missing. four. Total Syntheses of Marine Cycloheptapeptides The fascinating biological properties and unusual building blocks of marine cycloheptapeptides sparked the interest of synthetic chemists, and also the syntheses of numerous different amino acids and fragments have been reported within a current assessment [37]. For that reason, they may not be discussed in detail here, along with the focus might be on the total syntheses in the natural products. four.1. Total Synthesis of Ilamycins/Rufomycins To date, only 1 synthetic route has been described for ilamycins E1 and F b