A divergent strategy for synthesis of the tetrahydroisoquinoline alkaloids renieramycin G and a lemonomycin analog

A divergent synthesis to the tetrahydroisoquinoline alkaloids (±)-renieramycin G and (±)-lemonomycinone amide is reported. A strategy was developed that allowed access to both the diazabicyclo[3.3.1]nonane and diazabicyclo[3.2.1]octane ring systems of the respective targets from a common advanced intermediate. The high diastereoselectivity observed throughout the synthesis is controlled by the first stereocenter formed from alkylation of an unactivated isoquinoline. Key findings include the synthesis of isoquinolines under palladium-free Larock conditions, diastereoselective ionic hydrogenation conditions to set the 1,3-cis-tetrahydroisoquinoline architecture, a highly diastereoselective reprotonation, and a thiophilic Lewis acid-catalyzed 5-endo-trig N-acyl iminium ion silyl enol ether cyclization. This divergent approach to the tetrahydroisoquinoline alkaloids offers an alternative strategy to further structural diversity in this family of natural products.