見過ごされていた共役イミンの環化反応：合成的展開と生体機能制御の可能性

Abstract

Imines are among the most ubiquitous species in organic and bioorganic chemistry; however, the reactivities of N-alkyl unsaturated imines have not been thoroughly explored due to their instability profiles. We describe the novel reactivity of the N-alkyl-unsaturated imines derived from substituted aldehydes, aminoalcohol or diamine, and paraformaldehyde to produce 2,6,9-triazabicyclo [3.3.1] nonanes, 1,5-diazacyclooctanes, hexahydropyrimidines and 1,3,5-triazacyclooctanes through a formal [4+4], [4+2] and [4+2+2] cycloaddition reaction. When using the chiral aminoalcohol, the iminocycloaddition reaction proceeded in a stereocontrolled manner. The reaction products were successfully transformed via simple functional group manipulations to the variously substituted chiral 1,3-diamines, which could not be simply accessed by the other methods. Furthermore, we synthetically demonstrated that eight-membered heterocycles, namely, 2,6,9-triazabicyclo [3.3.1] nonanes and 1,5-diazacyclooctanes, are the exclusive products of the reaction of acrolein with biologically relevant amines, e.g., polyaimes. These compounds are produced in much higher amounts and efficiencies than the acrolein biomarker in current use. Our results not only indicate that eight-membered heterocycles may potentially be used as new biomarkers, but also strongly suggest the involvement of these heterocycles in various important biological phenomena, e.g., an acrolein-mediated mechanism underlying oxidative stress or inhibitory effects of amyloid peptide fibrillization.