Gracilioethers A�K and plakilactones A�F are a family of related polyketide metabolites recently isolated from the marine sponges Agelas gracilis and Plakinastrella mamillaris.1 Gracilioether B (1 ) and plakilactone C (2 ) are the only members of this family with a Michael acceptor on their lipophilic side chain and were identified as selective covalent agonists of peroxisome proliferator-activated receptor ? (PPAR?), a known pharmacological target for the treatment of type II diabetes.1b Armed with an attractive theory for the biogenesis of gracilioether 'furanylidenes' from known endoperoxide co-isolates,2 we commenced a program to develop an efficient and enantioselective synthesis of 1  and 2  . We have demonstrated an effective method for installing both stereocentres by selective allylic alkylation of an enantiopure oxazolidinone imide followed by a substrate-directed anti-'Sharpless mnemonic' asymmetric dihydroxylation3 leading to PMB ether 3  . On acidic deprotection this intermediate undergoes a facile cyclisation/dehydration cascade to yield a common synthetic progenitor of 1  and 2 . Our recent efforts have focused on achieving the final oxidation and olefination reactions, thereby completing total synthesis of both natural products.1) a) Ueoka, R.; et al. J. Org. Chem. 2009  , 74, 4203�4207; b) Festa, C.; et al. J. Med. Chem. 2012  , 55, 8303�8317; c) Festa, C.; et al. Tetrahedron 2012  , 68, 10157�10163; d) Festa, C.; et al. Mar. Drugs 2013  , 11, 2314�2327.2) Norris, M. D.; Perkins, M. V. Tetrahedron 2013  , 69, 9813�9818.3) Allen, P. R.; Brimble, M. A.; Prabaharan, H. J. Chem. Soc., Perkins Trans. 1 2001  , 379�389.

Strategy for a biomimetic total synthesis of the covalent PPAR? agonists gracilioether B and plakilactone C

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.