Azaspiracid (1) DOI: 10.1002/ange.200701515 Total Synthesis of (+)-Azaspiracid-1. Part I: Synthesis of the Fully Elaborated ABCDAldehyde** David A. Evans,* Lisbet Kværnø, Jason A. Mulder, Brian Raymer, Travis B. Dunn, AndrØ Beauchemin, Edward J. Olhava, Martin Juhl, and Katsuji Kagechika Dedicated to Professor Dieter Seebach on the occasion of his 70th birthday (À)-Azaspiracid-1 (2, Figure 1) is a structurally complex marine neurotoxin that is implicated in seafood poisoning. Outbreaks of azaspiracid poisoning were first reported in 1995 [1] and in 1998 the causative toxin was isolated in minute amounts from blue mussels (Mytilus edulis). Extensive NMR spectroscopic studies resulted in the proposed structural assignment 1,inwhichtherelativeconfigurationsbetweenthe ABCDE and FGHI domains, as well as the absolute config- uration, remained uncertain. [2] The intriguing chemical struc- ture of azaspiracid-1, in combination with its scarcity in nature,hasspurredconsiderableinterestamongthechemical community. [3] These efforts resulted in a synthesis of the proposed structure 1 in 2003 by the research group of Nicolaou with the finding that this structure did not match that of the natural product. [4] Subsequent efforts in the research group of Nicolaou involving numerous degradation studiesandthesynthesisofmultiplediastereomersresultedin asignificantstructuralrevisionthatallowedtheunambiguous structural assignment of (À)-azaspiracid-1 (2) in 2004. [5] Based on these impressive studies, an improved total syn- thesisofazaspiracid-1in39linearstepswasrecentlyreported by Nicolaou and co-workers. [6] Herein and in the following Communication, [7] we de- scribe our efforts, which culminated in a synthesis of (+)- azaspiracid-1 (ent-2, Scheme 1). This target requires only minimal changes in our original synthesis plan that targeted the originally proposed structure 1 of (À)-azaspiracid-1, namely the design of a new AB ring fragment and the synthesisoftheenantiomeroftheEringfragment.Hereinwe Figure 1. Originally proposed structure (1) [2] and correct structure of (À)-azaspiracid-1 (2). [5] Scheme 1. Retrosynthetic analysis of the ABCD aldehyde 3 of (+)- azaspiracid-1 (ent-2). See Ref.[9] for abbreviations. [*] Prof. D. A. Evans, Dr. L. Kværnø, Dr. J. A. Mulder, B. Raymer, T. B. Dunn, Dr. A. Beauchemin, E. J. Olhava, M. Juhl, Dr. K. Kagechika Department of Chemistry & Chemical Biology Harvard University Cambridge, MA 02138 (USA) Fax: (+ 1) 617-495-1460 E-mail: evans@chemistry.harvard.edu [**] Financial support has been provided by the National Institutes of Health (GM-33328-20), the Merck Research Laboratories, Amgen, and Eli Lilly. Fellowships were provided to L.K. by the Villum Kann Rasmussen and the Carlsberg Foundations (Denmark), to J.A.M. by the National Institutes of Health, to T.B.D. by the National Science Foundation, to A.B. by the NSERC (Canada), and to M.J. by the Technical University of Denmark. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie 4777 Angew. Chem. 2007, 119, 4777 –4781 # 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim