Automated Process Research. An Example of Accelerated Optimization of the Friedel−Crafts Acylation Reaction, a Key Step for the Synthesis of Anti-HIV (+)-Calanolide A

An automated process research approach to reaction optimization was developed. Chemical process research can be greatly accelerated by coupling automated synthesis equipment with statistical design of experiments (DoE). With the use of an automated process approach, multiple experiments can be performed in parallel on an automated platform, and multiple parameters that may influence process performance can be examined within one set of experiments generated from statistical design. We have successfully applied an automated process research approach to optimize the Friedel−Crafts acylation reaction that was used in our total synthesis of (+)-calanolide A, a potential anti-HIV agent currently in clinical trials. The in situ yield for a coumarin product was successfully optimized, increasing from 70% to 97% by HPLC analysis.