Organocatalytic Asymmetric Alkylation of Isoquinolines: Organocatalysis meets acylating agents

Isoquinoline derivatives have a leading role in medicinal and natural products chemistry. However, only a few examples of catalytic asymmetric synthesis of these compounds by the attack of carbon nucleophiles to activated isoquinolinium intermediates are reported. Organocatalytic methodologies to access enantioenriched dihydroisoquinolines were also described, but were not general, and of limited use. Herein, we present an effective, simple enantioselective organocatalytic alkylation of isoquinoline with aldehydes, combining simple enamine catalysis with the formation of N-acyl isoquinolynium ions. We have discovered a practical, efficient, and general methodology that allows the use of chiral secondary amine-based organocatalysts in the presence of acylating agents such as Boc2O and CbzCl. With this methodology a straightforward access to stable 1,2-dihydro- and 1,2,3,4-tetrahydroisoquinoline building blocks in high enantiomeric excesses (ee up to 99%) was established. In addition, we have found a simple and efficient procedure for the synthesis of enantioenriched isoquinoline derivatives.