FR 252921

FR252921, FR252922, and FR256523 are a family of potent macrocyclic polyene immunosuppressive agents with a novel mode of action. However, the lack of an efficient and flexible synthesis has hindered further biological studies, mostly due to the fact that the natural products appear to be kinetic isomers regarding the triene moiety. Herein, we report the development and application of an unprecedented, unique domino Suzuki-Miyaura/4π-electrocyclic ring-opening macrocyclization, resulting in a concise, unified, and stereoselective synthetic route to these complex targets in only 10 steps. This in turn enables ready access to a range of unnatural analogues, among which several compounds showed inhibition of T-lymphocyte proliferation at levels equal or superior to those of the natural products themselves.

Concise and highly convergent syntheses of the immunosuppressive agent FR252921 and the related antimicrobial natural product pseudotrienic acid B were achieved from a common intermediate by using optically active titanium complexes to control the configuration of the stereogenic centers, a highly stereo- and regioselective cross-metathesis to generate the triene moieties, and a Stille cross-coupling to install the dienic units.

A formal synthesis of FR252921, a potent macrocyclic immunosuppressive agent, and a six-step synthesis of vitamin A have been demonstrated. The application of a ruthenium-catalyzed step-economic and environmentally benign strategy for the highly stereo- and chemoselective construction of valuable polyene motifs of FR252921 and vitamin A highlights the syntheses. The key features for the synthesis FR252921 include preparation of the triene moiety followed by two consecutive peptide couplings of the three fragments.