Asymmetric total synthesis of pyranicin

ORGN 666

Danielle L. Jacobs, djacobs@rider.edu, Department of Chemistry, Biochemistry & Physics, Rider University, 2083 Lawrenceville Rd, Lawrenceville, NJ 08628 and Michael T. Crimmins, Department of Chemistry, Caudill and Kenan Laboratories, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290.
Through significant advances in organic methodology, total synthesis remains one of the most significant ways to bring anti-cancer agents from the outside into our medicine cabinets. Pyrancin, a structurally-unique member of the annonaceous acetogenin family of natural products, demonstrates selective cytotoxicity against both human pancreatic and promyelocytic cells, and its unique mode of action makes it an attractive candidate as a multi-drug resistant cancer therapy. Its total synthesis has been reported. The butenolide ring was constructed via an asymmetric alkylation/ring-closing metathesis strategy. The four stereocenters of the left-hand tetrahydropyran ring were installed by efficient chiral auxiliary-mediated aldol reactions. Convergent closure of the tetrahydropyran and fusion of the alkyl backbone were affected via sequential ring-closing metathesis/dimerization/cross metathesis reactions.