Intramolecular N-Acyliminium Cascade (INAIC) Reactions in Cyclization of Peptide-Like Molecules

Abstract

The present review describes the implementation of N-acyliminium ion chemistry of peptide aldehydes in the context of solid phase peptide synthesis. The INAIC reaction is a cascade reaction in which an aldehyde, located within a peptide, initially reacts with proximate and weakly nucleophilic amide nitrogen to form a hydroxylactam. Under acidic conditions the hydroxylactam eliminates water and produces highly reactive N-acyliminium ions. These in turn reacts with high stereospecificity with any nucleophile nearby in the peptide, including C-nucleophiles or even a second amide nitrogen to form two new heterocyclic rings which can both be 5 membered or they can be 5,6; 6,5; 6,6; or 5,7 membered. In this manner simple peptides can be transformed into interesting heterocycles with structures that may interact with 7TM receptors and are valuable in drug screening programs. In addition to amides, carbamoyl nitrogens can also act as the primary nucleophile in the analogous INCIC reaction, thus expanding the scope of these reactions significantly. Due to the high reactivity of the N-acyl-iminium ions deactivated C-nucleophiles such as dichlorobenzene rings may be employed in addition to the reactive C-nucleophiles, e.g., indoles commonly used in the related Pictet-Spengler reaction. In this manner complex annulated tetrahydro β-carbolines and tetrahydroisoquinoline can be synthesized within the peptide framework. The scope of the INAIC and INCIC reactions is significant with more than 40 different heterocyclic scaffolds currently synthesized and even more new scaffolds possible.