Total Synthesis and Biological Evaluation of Grassypeptolide A

Herein, we describe in full our investigations into the synthesis of grassypeptolide A ( 1 ) in 17 linear steps with an overall yield of 11.3 %. In particular, this work features the late‐stage introduction of sensitive bis(thiazoline) heterocycles and 31‐membered macrocyclization conducted at the sterically congested secondary amide site in superb conversion (72 % yield). Biological evaluation indicated that grassypeptolide A significantly inhibited cancer cell proliferation in a dose‐dependent manner. It induced cancer cell apoptosis, which was associated with increased cleavage of poly(ADP‐ribose) polymerase (PARP) and decreased expression of bcl‐2 and bcl‐xL. Furthermore, grassypeptolide A also caused cell cycle redistribution by increasing cells in the G1 phase and decreasing cells in the S and G2 phases. In addition, cell cycle arrest was correlated with downregulation of cyclin D and upregulation of p27 and p21.