SCHEME 3. Hydroxylactonization vs Iodolactonizationa Dai et al. a Reagents and conditions: (a) DIBAL-H (1.0 M in toluene, 1.1 equiv), CH2Cl2, -78 °C, 20 min; (b) NaClO2 (6.0 equiv), NaH2PO4-H2O (6.0 equiv), 2-methyl-2-butene (2.0 M in THF, 8.0 equiv), t-BuOH, rt, 5 h; (c) NaHCO3 (3.0 equiv), KI (1.3 equiv), I2 (1.3 equiv), THF, rt, overnight, 76% over three steps; (d) mCPBA (1.2 equiv), CH2Cl2, 0 °C to rt, 30% for 15a; 0% for 15b; (e) AIBN (1.0 equiv), Bu3SnH (3.0 equiv), dry air, toluene, 60 °C, 2 days; then NaBH4 (2.0 equiv), EtOH, 0 °C, 2 h, 75-78%. SCHEME 4. Synthesis of Dienophile 20a a Reagents and conditions: (a) PMB trichloroacetimidate (1.2 equiv), CSA (0.1 equiv), CH2Cl2, rt, overnight, 95%; (b) TBAF (1.0 M in THF, 2.0 equiv), THF, rt, overnight, 87%; (c) PPh3 (1.2 equiv), PhCOOH (1.2 equiv), DIAD (1.2 equiv), toluene, rt, 3 h; (d) K2CO3 (1.0 equiv), MeOH, rt, 7 h, 98%; (e) TBSOTf (2.0 equiv), 2,6-lutidine (20 equiv), CH2Cl2, 0 °C to rt, overnight, 95%; (f) LDA (1.2 equiv), THF, -78 °C, 30 min; then CH2O (gas), 0 °C, 5 min; then rt, overnight, 19: 65%, 20: 28%; (g) MsCl (2.0 equiv), TEA (4.0 equiv), CH2Cl2, 0 °C to rt, 4 h; then, DBU (3.0 equiv), CH2Cl2, 3 h, rt, 95%. proved problematic: all of our efforts to effect an Ireland- Claisen21 rearrangement of 11 were fruitless. Attempts to employ the Still22 and Inanaga protocols23 to introduce the methylene group directly were also unproductive. Fortunately, we were able to achieve rearrangement through the use of the Johnson-Claisen protocol.24 Surprisingly, at the time, the quaternary carbon center was elaborated with a complete lack of diastereoselectivity (12a:12b ) 1:1). In an attempt to achieve some level of diastereoselectivity, we replaced the silyl protect- ing group on the secondary alcohol with more electron-deﬁcient functionalities, such as acetate. The hope was that this type of functionality might exhibit some electronic interaction with the electron-rich ketene acetal moiety. However, under all conditions examined, the rearrangement gave 1:1 mixtures of rearranged products. The diastereomeric mixture of 12a and 12b was transformed to carboxylic acids 13a/13b through a two-step protocol involving DIBAL-H reduction and Pinnick oxidation (Scheme 3).25 Subsequent iodolactonization afforded a separable mixture of iodides 14a and 14b in 76% yield over three steps.26 The relative stereochemistry of 14b was conﬁrmed by X-ray (21) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897. (22) Still, W. C.; Schneider, M. J. J. Am. Chem. Soc. 1977, 99, 948. (23) Hanamoto, T.; Baba, Y.; Inanaga, J. J. Org. Chem. 1993, 58, 299. (24) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T. T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92, 741. (25) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888. (b) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825. (c) Bal, B. S.; Childers, W. E.; Pinnick, H. W., Jr. Tetrahedron 1981, 37, 2091. (26) Corey, E. J.; Guzman-Perez, A.; Lazerwith, S. E. J. Am. Chem. Soc. 1997, 119, 11769. 9578 J. Org. Chem. Vol. 73, No. 24, 2008 crystallography. Aerobic tin hydride-mediated radical reactions27 served to convert the iodolactones (14a and 14b) to hydroxy- lactones (15a and 15b, respectively). Interestingly, we also found that when the 1:1 mixture of 13a and 13b was treated with m-CPBA in CH2Cl2, only 15a was obtained, in 30% yield. Presumably it is the product of direct hydroxylactonization,28 without the intermediate formation of epoxide. We speculate that diastereomer 13b, which does not react under these conditions, most likely would suffer from prohibitive steric interactions in positioning the large -TBS-protected hydroxyl group in the concave face in the transition state (see 15b-TS). In fact, the observed result supports the notion of a direct hydroxylactonization pathway. A hypothetical intermediate epoxide would have been expected to emerge on the face opposite the resident TBS ether group. Subsequent epoxide ring opening by the intramolecularly appended carboxylate would produce 15b, rather than the observed product 15a. To gain access to sufﬁcient quantities of dienophile 20 to explore the key Diels-Alder reaction, lactones 15a and 15b were separately advanced to the same intermediate, 16b. As outlined in Scheme 4, the free alcohols of 15a and 15b were protected as the PMB ethers.29 Epimer 16a was then converted to intermediate 16b through a Mitsunobu reaction,30 which served to invert the stereocenter at the carbon bearing the (27) Nakamura, E.; Inubushi, T.; Aoki, S.; Machii, D. J. Am. Chem. Soc. 1991, 113, 8980. (28) Corey, E. J.; Brennan, T. M.; Carney, R. L. J. Am. Chem. Soc. 1971, 93, 7316. (29) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett. 1988, 29, 4139. (30) Mitsunobu, O. Synthesis 1981, 1.