Total Synthesis of Spirotenuipesines A and B SCHEME 1. and B Synthetic Strategy toward Spirotenuipesines A SCHEME 2. Nonstereoselective Claisen Rearrangementa methyl ester,6 NGA0187,7 jiadifenin,8 11-O-debenzoyltashiro- nin,9 garsubellin A,10 and paecilomycine A.11 Our involvement in this ﬁeld also led us to pursue the total synthesis of the structurally complex small molecule neurotrophins, spiro- tenuipesines A and B.12 Spirotenuipesines A (1a) and B (1b) were isolated from the entomopathogenic fungus, Paecilomyces tenuipes by Oshima and co-workers in 2004.13 The researchers found that, upon introduction to 1321N1 human astrocytoma cells, both natural products appeared to facilitate the expression and release of key neurotrophic factors, as evidenced by the ability of the cells to then promote the neuronal differentiation of rat pheochromocy- toma cells (PC-12). We recently launched an investigation toward the total synthesis of spirotenuipesines A and B, in the hopes of identifying lead candidates for further biological investigations against neurodegenerative disorders. Structurally, spirotenuipesines A (1a) and B (1b), are uniquely cyclized trichothecanes14 containing spirocyclic, tricyclo ring systems. The ﬁrst-generation total syntheses of spirotenuipesines A and B were completed in 2007.12 We describe herein the details of the total syntheses of these challenging natural products, and the way in which each stereocenter was installed in an efﬁcient and selective manner. We further disclose an asymmetric strategy by which to gain access to optically active natural product. Results A First-Generation Strategy for the Synthesis of Spiro- tenuipesines A and B. Our general strategy toward spiro- tenuipesines A (1a) and B (1b) is outlined in Scheme 1. A key feature of the synthesis would be a Diels-Alder reaction between an R-methylenelactonic dienophile (see 5) and a synergistic diene15 (i.e., 6). Cycloaddition would presumably occur from the convex face of the bicyclic system. Following (6) Waters, S.; Tian, Y.; Li, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 13514. (7) Hua, Z.; Carcache, D. A.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Org. Chem. 2005, 70, 9849. (8) (a) Cho, Y. S.; Carcache, D. A.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 14358. (b) Carcache, D. A.; Cho, Y. S.; Hua, Z. H.; Tian, Y.; Li, Y. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1016. (9) Cook, S. P.; Polara, A.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 16440. (10) Siegel, D. R.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1048. (11) Min, S. J.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 2199. (12) Dai, M. J.; Danishefsky, S. J. J. Am. Chem. Soc. 2007, 129, 3498. (13) Kikuchi, H.; Miyagawa, Y.; Sahashi, Y.; Inatomi, S.; Haganuma, A.; Nakahata, N.; Oshima, Y. J. Org. Chem. 2004, 69, 352. (14) Reference for trichothecanes: (a) Grove, J. F. Nat. Prod. Rep. 1988, 187. (b) Grove, J. F. Prog. Chem. Org. Nat. Prod. 1996, 69, 1. (c) Fraga, B. M. Nat. Prod. Rep. 2004, 21, 669. (15) Danishefsky, S. J. Acc. Chem. Res. 1981, 14, 400. a Reagents and conditions: (a) TBSCl (1.0 M in THF, 1.2 equiv), imid. (1.2 equiv), DMF, rt, overnight, 95%; (b) 5% SeO2 on silica gel (0.05 equiv), t-BuOOH (5-6 M in nonane, 2.5 equiv), CH2Cl2, rt, 2 days, 40-50%; (c) Grubbs second-generation catalyst (0.05 equiv), benzene, reﬂux, 3-4 h, 82%; (d) propionic acid (0.06 equiv), triethyl orthoacetate (7.0 equiv), 180 °C, 2 days, 87%, 1:1 dr. unraveling of the primary adduct, enone 7 would be produced. This intermediate would be advanced to spirotenuipesine A (1a) through a sequence which includes functionalization of C9, reduction of the C15 lactonic carbonyl group, followed by acetal formation between the C3 hydroxyl group and C15, disposed on the concave face of the molecule. In contemplating the synthesis of the potential Diels-Alder dienophile, 5, we anticipated that the lactone functionality (4) could be installed through an as- yet unspeciﬁed oxidative lactonization protocol (3 f 4). From the outset, it was presumed that precursor 3 might be generated through a Claisen-like rearrangement of an allylic alcohol of the type 2. It was further supposed, with what was ultimately revealed to be unwarranted optimism, that the sigmatropic rearrangement would occur with high stereoselectively anti to the resident protected alcohol. Operating under the Claisen rearrangement paradigm, the need for an eventual inversion of conﬁguration at C3 (i.e., 2 f 4) was anticipated. Studies Directed toward a Stereoselective Claisen Rear- rangement. Our synthesis of the pre-Claisen rearrangement substrate (11) commenced with the known dienol 8,16 which was protected as the -TBS ether to provide 9 (Scheme 2). Catalytic oxidation with selenium dioxide on silica gel (5%)17 mediated by tert-butylhydrogen peroxide as a co-oxidant afforded the desired allylic alcohol 10. In an effort to achieve maximum efﬁciency, we evaluated the feasibility of executing the ring-closing metathesis directly with the unprotected allylic alcohol 10. We were pleased to ﬁnd that when diene 10 was heated in benzene under reﬂux, with slow addition of the Grubbs second-generation catalyst,18 the cycopentenyl adduct 11, incorporating a tetrasubstituted oleﬁn, was isolated in 82% yield. It should be noted that the RCM route described here constitutes a major simpliﬁcation to the preparation of 11. Under this protocol, adduct 11 was accessed in 35% overall yield in three steps, while the previously reported literature procedure requires nine steps for the synthesis of this key intermediate.19 This protocol also represents one of only a few instances in which RCM has been employed to generate a tetrasubstituted oleﬁn.20 With 11 in hand, we now turned our attention to the key Claisen rearrangement. To our surprise, the key rearrangement (16) Breit, B.; Breuninger, D. J. Am. Chem. Soc. 2004, 126, 10244. (17) (a) Singh, J.; Sabharwal, A.; Sayal, P. K.; Chhabra, B. R. Chem. Ind. 1989, 533. (b) Chhabra, B. R.; Hayano, K.; Ohtsuka, T.; Shirahama, H.; Matsumoto, T. Chem. Lett. 1981, 1703. (18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. (19) Ziegler, F. E.; Metcalf III, C. A.; Nangia, A.; Schulte, G. J. Am. Chem. Soc. 1993, 115, 2581. (20) (a) Berlin, J. M.; Campbell, K.; Ritter, T.; Funk, T. W.; Chlenov, A.; Grubbs, R. H. Org. Lett. 2007, 9, 1339. (b) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589. J. Org. Chem. Vol. 73, No. 24, 2008 9577