Total Synthesis and Biomimetic Studies of Nine-Membered Enediynes Martin J. Lear*, Keiichiro Hirai, Kei Yamada, Ryo Takahashi, Masahiro Hirama* Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578 [email protected] The kedarcidin and C1027 chromophores are formidable targets of total synthesis. During our 20-year study of these nine-membered enediyne chromophores, several powerful, yet chemoselective methods have been developed: stereoselective epoxyalkyne formation, atropselective Pd/Cu-Sonogashira coupling, 2-deoxy-α-glycosylation, CeX3-mediated enediyne cyclisation, and SmI2-based reductive olefination. Besides their total syntheses, application of these methods to the biomimetic study of the putative enediyne-precursors of the cyanosporasides, sporolides, and fijiolides will be presented. In particular, we disclose biomimetic evidence of a p-benzyne diradical species reacting in either a radical mode (hydrogen abstraction) or ionic mode (chloride attack) at the same sterically exposed site, leading to either monochlorinated cyanosporaside A/F or cyanosporaside B–E, respectively. The ionic monochlorination of the cycloaromatized p-benzyne of the C1027 enediyne core to generate the fijiolide aglycon framework will also be presented. Cl OH OH 3 O N OH O OH O "H", "Cl" incorporation 6 OH O Cl NHR Fijiolide A: R = COCH3 Fijiolide B: R = H N OH O Biomimetic Studies and Total Synthesis of Natural Enediynes O O OH O OH O O Cl MasamuneBergman cyclization NHR Pre-fijiolide (C1027-like) i-PrO [Sugar] OH 1 O R CN HO "H", "Cl" incorporation OH O [Sugar] O MeO O OOH / Ac OMe Cl N NH O O O O NMe2 OH O CN R2 Cyanosporaside A/F: R1= Cl, R2= H Cyanosporaside B-E: R1= H, R2= Cl OH Pre-cyanosporaside (proposed) HO HO O O O Kedarcidin chromophore *Dedicated to the lasting contributions of Professor Emeritus Masahiro Hirama to Total Synthesis CV of Attendant: Martin J. LEAR (マ ー テ ィ ン ・ リ ア ー ). Picture of Speaker Education: University of Glasgow, Scotland, UK (B.Sc., 1991; Ph.D., 1996). (35 mm × 45 mm) Professional career: Since Jan 2013, he has been a Lecturer and then Associate Professor at Tohoku University (Sendai, Japan). During 2005 to 2012, he was as a Lecturer and core-member of the Medicinal Chemistry Group at the National University of Singapore (NUS). During 2000 to 2004, he was an Assistant Professor at Tohoku University with Masahiro Hirama (Sendai, Japan). Awards / other information: Postdoctoral fellowships include Parke-Davis (Cambridge, UK, 1996), ICSN-CNRS (Gif-sur-Yvette, France, 1997) and Tohoku University (JSPS and CREST, 1997-2000). Dr. Lear is also a Co-founder and Director of www.BioLynxTech.com (Singapore, since March 2011).
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