Novel route to chaetomellic acid A and analogues: Serendipitous discovery of a more competent FTase inhibitor

Abstract A new practical route to chaetomellic acid A ( ACA ), based on the copper catalysed radical cyclization (RC) of ( Z )-3-(2,2-dichloropropanoyl)-2-pentadecylidene-1,3-thiazinane, is described. Remarkably, the process entailed: (i) a one-pot preparation of the intermediate N -α-perchloroacyl-2-( Z )-alkyliden-1,3-thiazinanes starting from N -(3-hydroxypropyl)palmitamide, (ii) a two step smooth transformation of the RC products into ACA and (iii) only one intermediate chromatographic purification step. The method offers a versatile approach to the preparation of ACA analogues, through the synthesis of an intermediate maleic anhydride with a vinylic group at the end of the aliphatic tail, a function that can be transformed through a thiol–ene coupling. Serendipitously, the disodium salt of 2-(9-(butylthio)nonyl)-3-methylmaleic acid, that we prepared as a representative sulfurated ACA analogue, was a more competent FTase inhibitor than ACA . This behaviour was analysed by a molecular docking study.