A Continuous-Flow Process for Natural Product Synthesis

Significance

A continuous-flow reactor system was designed and used for the synthesis of a neolignan natural product, grossamide (8). The polymer-supported HOBt packed in the column (Reagent 4) was activated by flowing the DMF solution of ferulic acid (1), PyBrOP (2), and DIPEA. After washing the unreacted materials out, the THF solution of amine 3 was flowed into the first column. The output was then directed through the second column containing a sulfonic acid resin (Reagent 5) as a scavenger to afford amide 6 in 90% conversion. Amide 6 was diluted with a solution of hydrogen peroxide urea complex and sodium dihydrogen phosphate buffer in acetone-water. The combined flow was then passed through the third column packed with an immobilized peroxidase on silica (Reagent 7) to give grossamide.