Total Synthesis of Spirotenuipesines A and B Mingji Dai,† Isaac J. Krauss,‡ and Samuel J. Danishefsky*,†,‡ Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, New York, New York 10027, and Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York AVenue, New York, New York 10065 s_danishefsky@mskcc.org ReceiVed July 30, 2008 Spirotenuipesines A and B, isolated from the entomopathogenic fungus Paecilomyces tenuipes by Oshima and co-workers, have been synthesized. The synthesis features the highly stereoselective construction of two vicinal all-carbon quaternary centers (C5 and C6) via an intramolecular cyclopropanation/radical initiated fragmentation sequence and a diastereoselective intermolecular Diels-Alder reaction between R-methylenelactone dienophile 20 and synergistic diene 6a. Installation of the C9 tertiary alcohol occurred via nucleophilic methylation. An RCM reaction to produce a tetrasubstituted double bond in the presence of free allylic alcohol and homoallylic oxygenated functional group is also described. This route shortened the synthesis of 11 from 9 steps to 3 steps. We have further developed a strategy to gain access to optically active spirotenuipesines A and B through the synthesis of enantioenriched 10 from commercially available R-(-)-epichlorohydrin. Introduction Our laboratory has been exploring the therapeutic potential of small molecule, nonpeptidyl, neurotrophically active agents. It is well-known that naturally occurring, polypeptidyl neu- rotrophic factors (such as NGF, BDNF, and GDNF) play a central role in maintaining critical neurological functions.1 These neurotrophic factors are responsible for mediating neuronal survival, differentiation, outgrowth, and apoptosis. Diminished neurotrophic support has been linked to the progression of a range of neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Given their centrality in maintaining proper neurological function, it is not surprising that neurotrophic factors have been the focus of a great amount of interdisciplinary research. Most efforts to date have centered on exposing neurologically compromised subjects to naturally † Columbia University. ‡ Sloan-Kettering Institute for Cancer Research. (1) (a) Lodish, H.; Berk, A.; Zipursky, S. L.; Matsudaria, P.; Baltimore, D.; Darnell, J. Molecular Cell Biology, 4th ed.; W. H. Freeman & Co.: New York, 1999; Section 23.8. (b) Kaneko, M.; Saito, Y.; Saito, H.; Matsumoto, T.; Matsuda, Y.; Vaught, J. L.; Dionne, C. A.; Angeles, T. S.; Glicksman, M. A.; Neff, N. T.; Rotella, D. P.; Kauer, J. C.; Mallamo, J. P.; Hudkins, R. L.; Murakata, C. J. Med. Chem. 1997, 40, 1863. (c) Levi-Montalcini, R.; Hamburger, V. J. Exp. Zool. 1951, 116, 321. (d) Bennett, M. R.; Gibson, W. G.; Lemon, G. Auton. Neurosci. 2002, 95, 1. (e) Dawbarn, D.; Allen, S. J. Neuropathol. Appl. Neurobiol. 2003, 29, 211. 9576 J. Org. Chem. 2008, 73, 9576–9583 occurring peptidyl neurotrophic factors, in the hopes of promot- ing neurite outgrowth and survival.2 However, this approach suffers from some serious drawbacks. Most notably, these polypeptidic agents generally exhibit unfavorable pharmacoki- netic properties and require inconvenient drug-delivery tech- niques, such as direct microinjection to the brain. An alternative approach would be one in which the patient is treated with a small molecule, nonpeptidyl agent that stimulates the production of endogenous neurotrophic factors. Presumably, an appropri- ately selected small molecule nonpeptidyl agent would be better disposed to cross the blood-brain barrier. Toward this end, we have taken note of a number of small molecule natural products with demonstrated ability to enhance neurite outgrowth, presumably through the induction of key neurotrophic factors.3 To date, we have synthesized and evaluated a range of these neurologically active small molecules, including tricycloillicinone,4 merrilactone A,5 scabronine G (2) Kirik, D.; Georgievska, B.; Bjorklund, A. Nat. Neurosci. 2004, 7, 105. (3) (a) Wilson, R. M.; Danishefsky, S. J. Acc. Chem. Res. 2006, 39, 539. (b) Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329. (4) Pettus, T. R. R.; Chen, X.-T.; Danishefsky, S. J. J. Am. Chem. Soc. 1998, 120, 12684. (5) (a) Birman, V.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 2080. (b) Meng, Z. Y.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2005, 44, 1511. 10.1021/jo8016814 CCC: $40.75  2008 American Chemical Society Published on Web 10/31/2008