A Scalable High‐Yielding and Selective Oxidative Heck Cross‐Coupling – A Key Step for the Synthesis of trans‐Stilbenes

Abstract

A selective oxidative Heck cross‐coupling method was developed and optimized as a pivotal step for a synthetic route leading to the trans‐stilbene framework. The developed method and synthesis were needed in a SAR study in progress that concerned design and development of an inhibitor for the human cell xCT antiporter system. The developed oxidative Heck cross‐coupling method was examined with a variety of substrates and reagents to produce a library of different substituted trans‐stilbenes, which revealed the method to hold a very good tolerance for an assortment of functional groups. The final synthetic route was successfully scaled‐up (from mg scale) and performed in a 150 g (>1000×up‐scaled) batch run to obtain an overall yield of 73 % (over three steps), which corresponds to a mean step yield of 90 %. The inhibitor candidate DC10 [(E)‐5‐(2‐([1,1′‐biphenyl]‐4‐yl)vinyl)‐2‐hydroxy‐benzoic acid] was produced in multi‐gram quantities (≈33 g) that subsequently was forwarded for animal efficacy and toxicology studies. The scaled‐up process constitutes the first example of an oxidative Heck cross‐coupling on >100‐gram scale.