An improved Pictet-Spengler method for the construction of a modified β-carboline moiety from an α,β-unsaturated aldehyde is described. The Pictet-Spengler reactions between ircinal A (1) and tryptamine derivatives under milder conditions have resulted in shorter reaction times and higher product yields (70 to 89%) with control of stereochemistry. The Pictet-Spengler products (9 and 11) are two new manzamine alkaloids, which display strong activities against Mycobacterium intracellulare with IC50 values of 0.2 and 0.06 μg/mL, respectively. © 2007 The Japan Institute of Heterocyclic Chemistry.