Stereodivergent Synthesis of Hetero-Fused Isoquinolines by Acyliminium and Metallation Methods

Abstract

Diastereodivergent syntheses of 1,10b-cis- and 1,10b-trans-thiazolo[4,3-a]isoquinoline systems are reported. The key transformations are based on the intramolecular cyclization of aryllithiums and N-acyliminium ions. With 5-substituted N-phenethylthiazolidinediones as substrates, hydride reduction or the organolithium addition−N-acyliminium cyclization sequence stereoselectively afforded the 1,10b-cis derivatives. Alternatively, the tandem Parham cyclization−hydroxyl reduction using the corresponding iodinated thiazolidinediones occurred with complete control of stereoselectivity, producing the 1,10b-trans diastereomers. Although it was not possible to synthesise imidazo[4,3-a]isoquinolinones by N-acyliminium cyclizations, application of the Parham cyclization−reduction sequence to N-phenethylhydantoins constituted an efficient alternative for the synthesis of these hetero-fused isoquinolines with 1,10b-trans stereochemistry. Ready access to 1-phenethylisoquinolines is also described.