FEATURED ARTICLE pubs.acs.org/joc
Total Synthesis of Iejimalide B† Qingshou Chen,‡,§ Dirk Schweitzer,‡ John Kane,‡ V. Jo Davisson,*,§ and Paul Helquist*,‡ ‡
Department of Chemistry and Biochemistry and Harper Cancer Research Center, University of Notre Dame, Notre Dame, Indiana 46556, United States § Department of Medicinal Chemistry & Molecular Pharmacology, Laboratory for Chemical Biology & Drug Development, Bindley Bioscience Center at Purdue Discovery Park, West Lafayette, Indiana 47907-2057, United States
bS Supporting Information ABSTRACT: Iejimalide B, a structurally unique 24-membered polyene macrolide having a previously underutilized mode of anticancer activity, was synthesized according to a strategy employing JuliaKocienski olefinations, a palladiumcatalyzed Heck reaction, a palladium-catalyzed Marshall propargylation, a Kecktype esterification, and a palladium-catalyzed macrolide-forming, intramolecular Stille coupling of a highly complex cyclization substrate. The overall synthesis is efficient (19.5% overall yield for 15 linear steps) and allows for more practical scaled-up synthesis than previously reported strategies that differed in the order of assembly of key subunits and in the method of macrocyclization. The present synthesis paves the way for efficient preparation of analogues for drug development efforts.
’ INTRODUCTION Natural products have long served as invaluable resources in the search for structurally novel compounds as leads for the development of drugs having many therapeutic applications, including antibiotics and anticancer agents. More than two decades ago, a bioassay-guided screen of marine organism metabolites led to the discovery of the iejimalides,1 a class of natural macrolides originally isolated from the tunicate species Eudistoma cf. rigida native to the coral reefs of Ie Island (Iejima) near Okinawa, Japan. As disclosed by Kobayashi and coworkers,1a,b the unique structural architecture of the iejimalides consists of a novel 24-membered polyene macrolide core structure containing five chiral centers and four dienes. Of these dienes, three have the E,E-configuration, one has the E,Z-configuration, and one is a skipped triene. Three of the dienes reside in the macrocyclic ring, whereas the fourth is seen in an interesting side chain terminated in an N-formyl L-serine residue (Figure 1).1c This structural assignment resulted from a correction of previous studies.1a,b Bioassays2 showed that the iejimalides possess potent growth inhibitory activity against a wide range of human tumor cell lines, with iejimalide B being especially potent. Recently reported data from the NCI,3 obtained for samples provided by our laboratories, showed that iejimalide B is cytostatic (GI50) at
