Building Block Approaches to the Synthesis of Lasso Peptides and Polycyclic Saturated N-Heterocycles

The first part of this dissertation describes the synthesis of peptide-based [1]rotaxanes (lasso peptides). Lasso peptides are bacterially produced natural products with unique interlocked structure that endows them exceptional proteolytic stability. Therefore, lasso peptides have been employed as scaffolds to enhance the proteolytic stability of linear peptides. This approach – so-called molecular grafting– has been achieved by biosynthetic methods; however, there had been no example accomplished by the chemical synthesis. To achieve the synthesis of peptide-based [1]rotaxanes, we took a two-stage approach: the first is formation of [2]rotaxanes whose components are prefunctionalized with hydroxylamine and thioester for the subsequent steps; the second is two consecutive amide-forming ligation reactions, namely alpha-ketoacid-hydroxylamine ligation (KAHA ligation) and native chemical ligation (NCL) to attach linear peptide epitopes to the [2]rotaxane scaffold, ultimately providing peptide-based [1]rotaxanes. In this way, the incorporation of linear peptide epitopes with different lengths and amino acid residues onto a common rotaxane scaffold was achieved. The threaded structure in the synthesized molecules was confirmed by NMR, HPLC, and analysis of partial enzymatic degradation products. The synthetic lasso peptide mimetics were thermally stable and importantly, linear peptide epitopes gained significant proteolytic stability upon grafting onto the [1]rotaxane scaffold, as demonstrated by proteolytic stability assays using three different types of proteases. The stability of peptide-based [1]rotaxanes were comparable to the head-to-tail cyclic peptide bearing the same sequence. The second part of this dissertation deals with iterative, programmable synthesis of polycyclic saturated N-heterocycles with defined three-dimensional shapes. Shape is an important property of organic molecules and closely related to their properties and functions. This relationship is clearly observed in biomolecules such as proteins that adopt unique three-dimensional structures by folding. However, both de novo design of proteins and the synthesis of organic molecules with predictable shapes remain to be challenging. By executing iterative cyclizations with carefully designed SnAP reagents, we achieved the synthesis of polycyclic saturated N-heterocycles. The rigid backbones based on spirocyclic and/or fused bicyclic structures enabled reliable computational prediction of molecular shapes. A considerable number of X-ray crystal structures of dimers and trimers supported shape predictability of polycyclic molecules. The terminal ketone was further elaborated by the synthesis of fused N-heteroaromatics, amines, and carboxylic acids, demonstrating potential applications of the polycyclic compounds for catalysis, molecular recognition, and drug development