Utilizing N-Acyl Iminium Ion Cyclizations to Efficiently Synthesize Natural Product Alkaloids

Abstract

The total synthesis of a natural product alkaloids was achieved using acyl iminium ion electrophiles to promote intramolecular cyclizations. A rapid total synthesis of seco-phenanthroindolizidine alkaloids was achieved involving a one-pot acid catalyzed deprotection condensation-electrocyclization strategy. This synthetic route provided a concise synthesis of (±)-seco-antofine and (±)-septicine in only 4 steps with an overall yield of 22% and 17%, respectively. Excellent aryl methoxy substitution pattern dependent control demonstrated an exclusive dichotomous relationship between Pictet-Spengler and aza-Nazarov type mechanisms. Lewis acidic (FeCl3) versus Bronsted acidic (PTSA·H2O) reagent control highlighted additional selectivity between the formation of rare amide N-oxides, a spirocyclic oxidatively coupled quinone and the [4+2] electrocyclization cascade. Additionally, a concise total synthesis of Cuscutamine was achieved involving a diastereoselective intramolecular acyl iminium ion mediated Pictet-Spengler reaction. This synthetic strategy provided a direct route to (11S, 13R)-Cuscutamine in only 3 steps with an overall yield of 56% and an enantiomeric ratio of 88%. The diastereoselectivity of the reaction is consistent with previous studies that proceed via more highly puckered transition states and the present results thus reveal the importance of the steric contributions to the observed diastereoselectivity. Following the Cuscutamine synthetic methodology, accessing 5-hydroxy-Cuscutamine derivatives proved challenging due to a late stage deprotection. Ultimately, the 5-OBn Cuscutamine was achieved in 6 steps with an overall yield of 48%. Overall, the mechanistic selectivity discovered, based on substrate and reagent control, allowed for selecting efficient synthetic routes using N-acyl iminium ion electrophiles to fused rings systems found in a variety of natural product alkaloid families.