National Basic Research Program (973 Program) of China [2010CB833200]; Natural Science Foundation of China (NSFC) [21332007]; Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) of Ministry of Education, China ; We demonstrated, for the first time, that on the basis of chemistry principles, the hexacyclic peptidyl alkaloid (-)-chaetominine (1) can be synthesized in a straightforward manner from L-Trp. The approach features the efficient generation of molecular complexity via a tandem C3/C14 syn-selective epoxidation (dr = 3 : 2)-annulative ring-opening reaction and a regioselective epimerization at C14. The successful production of (-)-chaetominine (1) from L-Trp could be helpful for revealing how the configuration of L-tryptophan becomes inverted in the biosynthetic pathway of (-)-chaetominine (1).