Rapid generation of macrocycles with natural-product-like side chains by multiple multicomponent macrocyclizations (MiBs)

• Published in: Organic & biomolecular chemistry 2008-01, Vol.6 (10), p.1787-1795
• Main Authors: Rivera, Daniel G, Vercillo, Otilie E, Wessjohann, Ludger A
• Format: Article
• Language: English
• Subjects: Biological Products - chemical synthesis; Biological Products - chemistry; Cyclization; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Molecular Structure; Time Factors
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/b715393g

A small parallel library of peptoid macrocycles with natural-product-derived side chains of biological importance was produced by Ugi-type multiple multicomponent macrocyclizations including bifunctional building blocks (Ugi-MiBs). Diverse exocyclic elements of high relevance in natural recognition processes, i.e., all functional amino acid residues (e.g., Cys, Arg, His, Trp) and even sugar moieties, can be introduced in a one-pot process into different types of peptoid-containing macrocyclic skeletons. This is exemplified by the use of a diamine/diisocyanide combination of Ugi-MiBs and N-protected alpha-amino acids or carboxy-functionalized carbohydrates as source for the natural-product-like exocyclic elements. Employed as the acid components of the multiple Ugi reactions, they appear as N-amide substituents on the macrocyclic cores. The use of different diamines and diisocyanides allows an easy variation of the N- to C-directionality and therefore of the position of the exocyclic elements.