RMMR SPPS of Cyclodepsipeptides Destruxin B and [2S,3S-Hmp]-Aureobasidin L

Abstract

Cyclodepsipeptides represent a distinctive family of natural cyclic peptides endowed with diverse and potent biological activities, making them promising scaffolds for drug development and agrochemical applications. Incorporation of N-methylated amino acids further enhances their metabolic stability and oral bioavailability by resisting proteolytic degradation. However, the synthesis of such cyclodepsipeptides, especially those containing multiple sterically hindered N-methylated residues, remains a significant challenge for conventional solid-phase peptide synthesis (SPPS) due to inefficient on-resin acylation, sluggish coupling kinetics, and conformational constraints. Herein, we report the first successful application of a novel solid-phase peptide synthesis (SPPS) strategy based on immobilized ribosome-mimicking molecular reactors (RMMRs) for the efficient synthesis of two representative bioactive cyclodepsipeptides: destruxin B (a hexadepsipeptide with two consecutive N-methylated amino acids) and [2S,3S-Hmp]-aureobasidin L (a nonapeptide featuring four N-methylated amino acids). A crucial approach is the use of pre-assembled depsidipeptide building blocks, which mitigate side reactions associated with on-resin esterification, combined with the RMMR platform that accelerates the coupling of sterically hindered residues via an artificial pseudo-intramolecular acyl-transfer mechanism. The linear precursors were efficiently assembled on Oxyma-C RMMR-HMPA resin with high/moderate crude purities (90% for destruxin B, 45% for [2S,3S-Hmp]-aureobasidin L) and much reduced synthesis times (≈15 h and ≈60 h, respectively). Subsequent solution-phase macrocyclization using HATU/DIPEA yielded the target compounds in satisfactory yields (75% for destruxin B, 50% for [2S,3S-Hmp]-aureobasidin L). This robust and time-economic methodology overcomes key limitations of conventional methods, providing a broadly applicable platform for the synthesis of complex cyclodepsipeptides and facilitating future medicinal chemistry exploration of this valuable class of bioactive molecules.

Keywords

Solid-phase peptide synthesis / Ribosome-mimicking molecular reactor / Cyclodepsipeptide / Destruxin B / [2S,3S-Hmp]-AbL / Depsidipeptide building block / N-Methylated hindered peptide / Time economy

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2025 SIOC, CAS, Shanghai, & WILEY-VCH GmbH