AbstractThe three‐component reaction of indole, isobutyraldehyde, and methyl acetoacetate affords methyl 2‐(acetyl)‐3‐(1H‐indol‐3‐yl)‐4‐methylpentanoate as a single diastereomer. To investigate the origin of the observed diastereoselectivity, the thermodynamics and kinetics of interconversion of diastereomers 1 and 2 in solution were studied by a combination of 1H nuclear magnetic resonance (NMR) spectroscopy, high‐performance liquid chromatography (HPLC), mass spectrometry, and deuteration experiments. The results indicate that interconversion is both acid‐ and base‐catalyzed, and that the alpha carbon is the only stereolabile center in the molecule. The evidence points to an enolization mechanism for the interconversion process. The selective precipitation of 1 in the presence of the equilibrium 1⇆2 eventually results in the exclusive formation of 1 (crystallization‐induced asymmetric transformation). Chirality 27:779–783, 2015. © 2015 Wiley Periodicals, Inc.