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Pure Appl. Chem., 2010, Vol. 82, No. 9, pp. 1735-1748

Published online 2010-06-04

Lessons from the total synthesis of (±)‑phalarine: Insights into the mechanism of the Pictet–Spengler reaction

John D. Trzupek1, Chaomin Li2, Collin Chan2, Brendan M. Crowley1, Annekatrin C. Heimann1 and Samuel J. Danishefsky2,1*

1 Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
2 Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, NY 10027, USA

Abstract: The furanobisindole alkaloid, phalarine, possesses a unique structural framework within the alkaloid family of natural products. Our laboratory recently disclosed the racemic total synthesis of phalarine, featuring an efficient azaspiroindolenine rearrangement; this achievement is revisited in detail. Upon completion of the first-generation total synthesis, we explored some interesting mechanism-level issues with regard to the key azaspiroindolenine rearrangement. These investigations provided valuable insights into the mechanism of racemization during the azaspiroindolenine rearrangement en route to synthetic phalarine. In addition, in the course of these studies, we demonstrated the Pictet–Spengler capture reaction for C2-aryl indoles, and successfully isolated the elusive azaspiroindolenine intermediate of the Pictet–Spengler reaction. Key insights into the remarkably subtle stereoelectronics that govern this rearrangement for C2-arylated indoles are discussed.