Cis ‐Diastereoselectivity in Pictet–Spengler Reactions of L ‐Tryptophan and Electronic Circular Dichroism Studies

The diastereoselective synthesis of optically active 1,3‐disubstituted tetrahydro‐β‐carbolines using polar protic Pictet–Spengler cyclization of ( S )‐tryptophan methyl ester with five aldehydes RCHO (R═CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , and C 6 H 5 ) was studied. As an alternate route, the cyclization of ( S )‐tryptophan with the same aldehydes and subsequent methylation of the resulting tetrahydro‐β‐carboline carboxylic acids were also performed for comparison. 13 C NMR and electronic circular dichroism (ECD) studies and time‐dependent density functional theory ECD calculations data established the relative 1,3 cis / trans and the absolute configuration (1 S ,3 S / 1 R ,3 S ) of the synthesized compounds. The solid‐state and solution ECD study of the prepared compounds, supported by ECD calculation and X‐ray data, afforded a reliable ECD method for the configurational assignment of 1,3‐disubstituted tetrahydro‐β‐carbolines and revealed the stereochemical factors that determine the characteristic ECD data. Chirality 24:789–795, 2012 . © 2012 Wiley Periodicals, Inc.