Natural Product Synthesis DOI: 10.1002/anie.200703886 Differentiation of Nonconventional “Carbanions”—The Total Synthesis of Nemorosone and Clusianone** Chihiro Tsukano, Dionicio R. Siegel, and Samuel J. Danishefsky* Recently, our research group described the total synthesis of the ChAT inhibitor garsubellin A (3) as its racemate. [1,2] The attainment of that goal required the crafting of novel methodology to accommodate the introduction of the three prenyl-like moieties. In garsubellin A, one of these “prenyl equivalents” appears in an oxidatively cyclized form. Also incorporated in the original synthesis of 3 was an isobutyryl group in the context of a non-enolizable b,b’-tricarbonyl setting. More recently, we noted with interest the appearance of a structurally related compound, nemoro- sone (1), which was isolated from the flowers of Clusia rosea. [3] In contrast to garsubellin A, nemorosone had been reputed to have significant cytotoxic activ- ity, possibly associated with telomerase inhibition as well as inhibition of ERK-1/2. A previously isolated compound from the family of acylphloroglucinols was the com- pound clusianone (2 ; Scheme 1). Isolated originally from Clusia congestiflora, its structure was initially determined by McClandish et al. by X-ray crystallogra- phy. [4a] Subsequently, extensive 2D NMR analysis on the family of clusianones was described by Rastrelli and co-workers. [4b] Again, this structure belongs to a broad family, wherein polyprenyloids project from a carbobicyclo[3.3.1] framework. From a biological perspective, the anti-HIV properties claimed on behalf of clusianone were of interest as were the antitumor properties of nemorosone. Given the subtle but important differences in the struc- tures found in this class of natural products, and the range of theirprofilesofbiologicalactivity,itseemedthataprogramin total synthesis would be desirable to secure access to relevant probe structures which might help revise structure–activity relationship (SAR) patterns. In particular, we focused on nemorosone (1) and clusianone (2). Herein we describe the concise total syntheses of these targets. [5] Influenced by the apparent similarity of these targets to garsubellin A, we started with the assumption that the hard- won lessons learned in our total synthesis of the latter would provide a clear-cut route to our new targets. The thought was to reach both targets from a common intermediate, 4, which wouldbederivedthroughextendedteachingsfromourearlier garsubellin work. As matters transpired, nemorosone and clusianone emerged as much more difficult targets than garsubellin A. In retrospect, the existence of the fused tetrahydrofuran ring in garsubellin A, wherein one of the prenyl groups is uniquely presented at a higher oxidation level, served as a stabilizing device, which was used to good advantage in that total synthesis. Moreover, the chemical Scheme 1. Nemorosone (1) and clusianone (2). [*] Prof. Dr. S. J. Danishefsky Laboratory of Bioorganic Chemistry Memorial Sloan-Kettering Cancer Center 1275 York Avenue, Box 106 New York, NY 10021 (USA) Fax: (+ 1)212-772-8691 E-mail: danishes@mskcc.org and Department of Chemistry Columbia University 3000 Broadway New York, NY 10027 (USA) Dr. C. Tsukano, Dr. D.R. Siegel Laboratory of Bioorganic Chemistry Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10021 (USA) [**] This work was supported by the National Institutes of Health (grant CA103823). A fellowship for C.T. from the Japan Society for the Promotion of Science is gratefully acknowledged. D.R.S. is grateful for a fellowship from the CDMRP Department of Defense Prostate Cancer Research Program (W81XWH-05-1-0609). Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Communications 8840 # 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2007, 46, 8840 –8844 &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Take advantage of blue reference links &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&