School of Chemical Science, School of Biological Sciences, Maurice Wilkins Centre for Biodiscovery, The University of Auckland, Auckland, 1021, New Zealand.
Org Biomol Chem. 2023 May 17;21(19):4052-4060. doi: 10.1039/d3ob00360d.
Depsipeptides are an important class of bioactive natural products, where a growing number of genome-mined structures that display anti-microbial activity are macrocyclic depsipeptides. Chemically, peptide ester (depsipeptide) bond formation often displays low yields, and thereby hampers efforts to access these structures for structure-activity studies. Herein, we present a systematic study of the variables that influence depsipeptide bond formation on-resin, using simplified sequences derived from antibiotic peptides, daptomycin and brevicidine, prepared Fmoc-based solid-phase synthesis. Our study highlights reaction solvent as the key determinant, where switching the solvent from DMF to DCM in almost all cases increased the amount of depsipeptide product. Limiting the number of amino-acids N-terminal to the reactive alcohol was also noted to significantly improve the acylation efficiency. The impact of different N-terminal and side-chain protecting groups, as well as stereochemistry, was also investigated. Additives to the reaction, such as inclusion of surfactants for esterification of long hydrophobic sequences, did not improve conversion. 6-ClHOBt, often added to improve acylation efficiency, notably decreased the amount of depsipeptide observed. Lastly, no significant difference between polystyrene and Tentagel® (PEG-decorated) resins were found for these sequences.
去甲肽是一类重要的生物活性天然产物，越来越多具有抗微生物活性的基因组挖掘结构是大环去甲肽。从化学上讲，肽酯（去甲肽）键的形成通常产率较低，从而阻碍了为结构活性研究获得这些结构的努力。在此，我们使用源自抗生素肽（达托霉素和布雷维菌素）的简化序列，通过 Fmoc 固相合成，对影响树脂上的去甲肽键形成的变量进行了系统研究。我们的研究强调了反应溶剂是关键决定因素，几乎在所有情况下，将溶剂从 DMF 切换到 DCM 都会增加去甲肽产物的量。还注意到将 N 末端的氨基酸数量限制在反应性醇的数量可以显著提高酰化效率。还研究了不同的 N 末端和侧链保护基以及立体化学的影响。向反应中添加添加剂（例如添加表面活性剂以酯化长疏水序列）并不能提高转化率。6-ClHOBt 通常用于提高酰化效率，但明显减少了观察到的去甲肽量。最后，对于这些序列，聚苯乙烯和 Tentagel®（PEG 修饰）树脂之间没有发现明显差异。
