Total synthesis of tosyl‐samroiyotmycin A and its biological profiling

Abstract

AbstractA total synthesis of the enantiopure syn,syn‐tosyl‐samroiyotmycin A, a C2‐symmetric 20‐membered antimalarial macrodiolide with syn,syn‐configuration of the 8,24‐dihydroxy‐9,25‐dimethyl units and it's enantiopure anti,anti‐derivative is described. The synthesis was accomplished utilizing a linear approach in 7 steps and 3 % overall yield via a sequence of diastereoselective methylation of SuperQuat oxazolidinone auxiliary, cross metathesis and Yamaguchi macrolactonization of fully functionalized seco‐acids. By a similar approach we gained access to several samroiyotmycin analogues and precursors. Antimalarial activity was tested on multi‐resistant (K1) and sensitive (Nf54) P. falciparum strains providing insight into structure activity relationships. Both tosyl‐oxazol unit as well as the syn‐configuration of the two contiguous stereogenic centers turned out to be beneficial for antiplasmodial activity. For instance, syn,syn‐tosyl‐samroiyotmycin A showed 3.4 times higher activities than the “tosyl‐free” natural product.