SCHEME 12. Synthetic Plan for the Asymmetric Synthesis of Spirotenuipesines A and B Dai et al. SCHEME 13. Asymmetric Synthesis of 10a a Reagents and conditions: (a) CuI cat., 2-propenylmagnesium bromide, Et2O -78 to -30 °C, 15 min; then R-(-)-epichlorohydrin, -30 to -20 °C; (b) NaOH, CH2Cl2, 24 h, 58% for two steps; (c) Mg (0), 1,2- dibromoethane, 1-bromo-1-trimethylsilylmethylethene, reﬂux, THF; epoxide 45, CuI, THF, -60 °C, 2 h, 98%; (d) TBSCl, imidazole, DMF, 0 °C to rt, 24 h, 93%; (e) PhSeCl, SnCl2 cat., CH2Cl2, -78 to 0 °C, 23 min; then 30% (wt) H2O2, pyridine, CH2Cl2, 20 min, 73%. would then give rise to 44, which, following suitable degradation of the terminal oleﬁn, would provide 11. As shown in Scheme 13, the viability of path a was investigated. Following treatment with isopropenyl cuprate, R-(-)-epichlorohydrin underwent the desired epoxide ring opening/ring closure sequence to afford 45. Our preliminary efforts to attack the newly generated epoxide of 45 with cuprate reagents derived from 2-bromoprop-2-en-1-ol41 or its ethers (cf. 47) were unsuccessful, presumably due to low reactivity or to 1,2-elimination of the cuprate, which would lead to unproductive formation of allene.42,43 An alternate cuprate reagent, derived from 1-bromo-1-trimethylsilylmethylethene,44 was chosen to avoid the problem of 1,2-elimination. The expectation was that the TMS group could be subsequently transformed into the requisite hydroxyl group.45 As shown in Scheme 13, under these conditions compound 48 was formed in excellent yield from 45 through a two-step sequence of cuprate addition and (41) Cousseau, J. Synthesis 1980, 805. (42) (a) Corey, E. J.; Widiger, G. N. J. Org. Chem. 1975, 40, 2975. (b) Corey, E. J.; Cane, D. E.; Libit, L. J. Am. Chem. Soc. 1971, 93, 7016. (43) We also made enyne intermediate A by the following sequential epoxide ring openings with following deprotection and protection procedures. However, enyne metathesis of A gave diene B as a minor product as well as triene C as major product. The difﬁculties encountered by selective oxidative cleavage of B and C discouraged us from further pursuing this route. (44) (a) O’Brien, M.; Taylor, N. H.; Thomas, E. R. Tetrahedron Lett. 2002, 43, 5491. (b) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12058. (45) Nishiyama, H.; Itagaki, K.; Sakuta, K.; Itoh, K. Tetrahedron Lett. 1981, 22, 5285. 9582 J. Org. Chem. Vol. 73, No. 24, 2008 protection of the resultant secondary alcohol. Upon exposure to PhSeCl and subsequent H2O2 oxidation, the optically active alcohol 10 was generated. We noted that this two-step sequence provided a general solution to the problem of 1,2-elimination of metallo-reagents bearing oxygenated leaving groups. With an efﬁcient route to enantioenriched 10 in hand, we are conﬁdent that we now have means by which to gain entry into the optically active series of spirotenuipesines A and B. Conclusion In summary, the syntheses of spirotenuipesines A (1a) and B (1b) have been accomplished. Key features of the synthesis include (1) the development of an improved RCM route to the tetrasubstituted cyclopentenyl system, 11, (2) the diastereose- lective synthesis of the key bicyclic lactone 21 through recourse to a tethered cyclopropanation strategy, and (3) the stereose- lective assembly of the spirocyclic system through Diels-Alder reaction between R-methylenelactone dienophile 20 and syn- ergistic diene 6a.46 We have further developed a strategy by which to access optically active spirotenuipesines A and B through the synthesis of enantioenriched 10. At a biological level, the concise stereocontrolled total syntheses have allowed us access to sufﬁcient quantities of material to begin to study the biological activity of these compounds. Biological studies are underway and will be reported in due course. Experimental Section (R)-2-(2-Methylallyl)oxirane (45). To a suspension of CuI (1.73 g, 9.08 mmol) in Et2O (90 mL) was added 2-propenylmagnesium bromide (0.5 M in THF, 100 mL, 50 mmol) at -78 °C. The resulting mixture was placed in a -30 °C bath for 15 min, and then R-(-)-epichlorohydrin (3.56 mL, 45.4 mmol) was added dropwise. The mixture was stirred for 30 min at -30 to -20 °C, by which time the initial yellow-orange color had turned to black. The reaction was quenched with saturated aqueous NH4Cl and washed with 4 × 20 mL of H2O to give 6.2 g chlorohydrin as a colorless oil, which by 1H NMR contained a small amount of THF but was otherwise pure. 1H NMR (500 MHz, CDCl3): 4.91 (s, 1H), 4.83 (s, 1H), 3.98 (m, 1H), 3.63 (dd, J ) 11.1, 3.8 Hz, 1H), 3.53 (dd, J ) 11.1, 6.4 Hz, 1H), 2.30 (m, 2H), 2.18 (d, J ) 3.9 Hz, 1H), 1.78 (s, 3H). The above crude chlorohydrin (6.2 g, ∼45 mmol) was dissolved in 50 mL of CH2Cl2, crushed NaOH pellets (3.6 g, 90 mmol) were added, and the resulting suspension was stirred at room temperature for 24 h (reaction was monitored by 1H NMR of aliquots). MgSO4 was then added, and the reaction mixture was ﬁltered and (46) For earlier precedents: (a) Schlessinger, R. H.; Nugent, R. A. J. Am. Chem. Soc. 1982, 104, 1116. (b) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1998, 120, 7411.