Solid-phase synthesis represents the methodological showcase for technological advances such as split-and-pool combinatorial chemistry and the automated synthesis of peptides, nucleic acids and polysaccharides. These strategies involve iterative coupling cycles that do not generate functional diversity besides that incorporated by the amino acids, nucleosides and monosaccharide building blocks. In sharp contrast, multicomponent reactions (MCRs) are traditionally used to generate both skeletal and appendage diversity in short, batchwise procedures. On-resin MCRs have traditionally been employed for the construction of heterocycle and peptidomimetic libraries, but that scenario has changed recently, and today the focus is more on the solid-phase derivatization of peptides and oligonucleotides. This review presents relevant experimental details and addresses the synthetic scope of such on-resin multicomponent protocols employed to accomplish specific biopolymer covalent modifications that are practically inviable by traditional solution-phase methodologies. Recommendations are provided to facilitate the implementation of solid-supported protocols and avoid possible pitfalls associated with the selection of the polymeric resin, the solvent and the order and amount of the reagents employed. We describe procedures comprising the multicomponent lipidation, biotinylation and labeling of both termini and the side chains, as well as the use of MCRs in the traceless on-resin synthesis of ligated and cyclic peptides. Solid-phase protocols for the assembly of α-helical and parallel β-sheet peptides as well as hybrid peptide–peptoid and peptide–peptide nucleic acid architectures are described. Finally, the solid-supported multicomponent derivatization of DNA oligonucleotides is illustrated as part of the DNA-encoded library technology relying on MCR-derived heterocyclic compounds.

固相合成代表了技术进步的方法学展示，例如分裂和合并组合化学以及肽、核酸和多糖的自动合成。这些策略涉及迭代偶联循环，除了氨基酸、核苷和单糖构建块所包含的功能多样性外，它们不会产生功能多样性。与之形成鲜明对比的是，多组分反应 (MCR) 传统上用于在简短的分批程序中生成骨骼和附属物的多样性。传统上，树脂上 MCR 用于构建杂环和拟肽文库，但这种情况最近发生了变化，今天的重点更多地放在肽和寡核苷酸的固相衍生化上。这篇综述介绍了相关的实验细节，并解决了此类树脂上多组分方案的合成范围，这些方案用于完成传统溶液相方法实际上无法实现的特定生物聚合物共价修饰。提供建议以促进固体支持方案的实施，并避免与聚合物树脂、溶剂的选择以及所用试剂的顺序和数量相关的可能的陷阱。我们描述了包括末端和侧链的多组分脂化、生物素化和标记的程序，以及 MCR 在连接肽和环肽的无痕树脂合成中的使用。描述了用于组装 α-螺旋和平行 β-折叠肽以及混合肽-类肽和肽-肽核酸结构的固相方案。最后，DNA 寡核苷酸的固体支持多组分衍生化作为依赖于 MCR 衍生杂环化合物的 DNA 编码库技术的一部分进行了说明。