Total Synthesis of Verlamelin A and (5R)‑Verlamelin A with Antifungal Activity

Verlamelin A is a naturally occurring macrocyclic depsipeptide exhibiting high and broad-spectrum antifungal activity. The first unified total synthesis of verlamelin A and its (5R)-verlamelin A (C5-epimer) is reported. This strategy involved homogeneous solution-phase synthesis of Fmoc-l-Val-O-(5S/5R)-tetradecanoic acid, solid-phase peptide synthesis of pentapeptide NH2–d-allo-Thr–d-Ala–l-Pro–l-Gln–d-Tyr–OH, on-resin coupling of these two fragments to form a linear precursor 17, and off-resin cyclization followed by global deprotection to generate the final verlamelin A and (5R)-verlamelin A in 6.8 and 7.8% overall yields, respectively. 1H/13C{1H} NMR, HRMS, and analytic HPLC were performed to confirm our successful total synthesis of verlamelin A. Antimicrobial evaluation revealed that both compounds exhibited potent antifungal activity against Alternaria alternate, Alternaria solani, and Rhizoctonia solani with MIC values ranging from 4 to 16 μg/mL. (5R)-verlamelin A showed superior efficacy against A. alternate (MIC = 4 μg/mL) compared with verlamelin A (MIC = 8 μg/mL), suggesting its potential as a lead antifungal candidate for further development against this pathogen.