Utilizing the pKa Concept to Address Unfavorable Equilibrium Reactions in the Total Synthesis of Palau’amine

Abstract

Herein, we introduce the pKa concept as a strategy for proceeding with unfavorable reactions in the total synthesis of palau’amine. The cascade reaction aimed at constructing palau’amine’s ABDE tetracyclic ring core initially encountered poor reproducibility due to an unfavorable equilibrium reaction. However, the addition of 1.0 equivalent of AcOH enabled the progression of the unfavorable equilibrium reaction. In the second-generation synthesis, the improved cascade reaction to construct CDE ring core also initially did not proceed due to an unfavorable equilibrium reaction, but using Ph2NLi as a base was later found to enable the reaction to proceed smoothly. The conjugate acid of Ph2NLi proved to be a suitable acid in the unfavorable equilibrium mixture. These investigations of the cascade reactions revealed that the coexistence of an appropriate acid played an important role in allowing the unfavorable equilibrium reaction to proceed. The authors propose a general equation for proceeding with an unfavorable equilibrium reaction.