Regio- and Stereoselective Synthesis of Benzoquinolizidines

An enantioselective domino Michael addition-cyclization-dehydration sequence was performed in the reaction of a 3,4-dihydroisoquinolin-1(2H)-ylideneethanenitrile derivative and alpha,beta-unsaturated aldehydes using cinchona- and diphenylprolinol-type organocatalyts. The D2PM-TMS organocatalyst was found to show the best performance up to 95 % enantiomeric excess. The resultant 6,7-dihydro-2H-pyrido[2,1-a]isoquinolines was reduced by catalytic hydrogenation to produce benzo[c]quinolizidines diastereoselectively with three chirality centers, the skeleton of which is a comman structural motif in alkaloids. The stereochemistry of products was studied by single crystal X-ray diffraction and solution TDDFT-ECD and DFT-VCD approaches. With the aid of VCD and ECD calculations, characteristic VCD and ECD transitions were identified, which reported the absolute configuration of the tricyclic skeleton by simple comparison regardless the different C-2 substituents.