Total Synthesis of Verlamelin A and (5<i>R</i>)-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 (5<i>R</i>)-verlamelin A (C5-epimer) is reported. This strategy involved homogeneous solution-phase synthesis of Fmoc-l-Val-O-(5<i>S</i>/5<i>R</i>)-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 <b>17</b>, and off-resin cyclization followed by global deprotection to generate the final verlamelin A and (5<i>R</i>)-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 <i>Alternaria alternate</i>, <i>Alternaria solani</i>, and <i>Rhizoctonia solani</i> with MIC values ranging from 4 to 16 μg/mL. (5<i>R</i>)-verlamelin A showed superior efficacy against <i>A. alternate</i> (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.