Total Synthesis of Spirotenuipesines A and B SCHEME 11. Completion of the Total Synthesis of Spirotenuipesine A and Ba a Reagents and conditions: (a) OsO4 (0.05 M in toluene, 1.1 equiv), pyridine, rt, 1.5 h; (b) NaIO4, THF/H2O (1:1), 0 °C to rt, 2 h, 90%; (c) CH3M (see Table 1 above, 10 equiv), THF, -78 °C, then 0 °C, 3 h; (d) DDQ (2.0 equiv), CH2Cl2/buffer solution pH ) 7.00 (18:1), rt, 5 h, 80%; (e) Oxone (12.5 equiv), CH2Cl2/MeOH/phosphate buffer (pH 9.2)/acetone (1:4:2:0.3), 0 °C, 6 h, 91%. ether located on the concave face of dienophile 20 would be expected to reinforce the sense of diastereoselectivity. Not surprisingly, the desired cycloadduct 30 was obtained upon heating diene 6a and dienophile 20 in toluene, with methylene blue as stabilizer (Scheme 8). The cycloadduct 30 formed as a mixture of stereoisomers. Without further puriﬁcation, both components were hydrolyzed by acidic Amberlite I-120 to afford a separable mixture of enones (dr 8:1), from which the desired epimer, 31, was isolated in 80% yield. We hoped next to convert the C9 ketone function to a terminal oleﬁn group and to install the requisite C3-C15 transannular acetal functionality. Thus, enone 31 was advanced to 32 through Wittig methenylation followed by removal of the -TBS protect- ing group. Subsequent lactone reduction afforded hemiacetal 33 as a 2:1 mixture of isomers. Somewhat surprisingly, 33 is apparently quite stable, and only trace amounts of material cyclized spontaneously after 2 days at room temperature. Upon exposure to catalytic amounts of camphorsulfonic acid and molecular sieves for 1 h, transannular acetal 34 was obtained in 90% yield. The ﬁnal challenge to be faced was that of installing the tertiary alcohol at C9 with the required stereochemistry. We ﬁrst considered a straightforward strategy involving oxidation of the exo-methylene group of 34. However, all efforts to epoxidize the exo-methylene group were unsuccessful, and chemoselective dihydroxylation using OsO4 in pyridine afforded a 2:1 mixture of diastereomers (35b and 35a, Scheme 9). Upon mesylation, followed by superhydride reduction and removal of the PMB ether, we learned that the major epimer (35b) was the undesired one, leading to formation of 9-epi-spirotenuipesine. It would seem that the tert-butyl-like large group (RL) at C5 locks the conformation of the cyclohex- enyl ring, forcing C15 (RS) into a pseudo-axial position. Thus, OsO4 approaches the exomethylene group from its outside axial face, presumably in order to avoid torsional strain. The major product is 35b (Scheme 10). It seemed that, by reversing the sequence of introduction of the methyl and hydroxyl groups, we would be able to establish the stereochemistry at C9 in the desired sense. As depicted in Scheme 10, path b, a generic methyl nucleophile (MeM) would be expected to deliver the methyl group through axial attack of ketone 37, giving the desired 36a as the major product. To test this hypothesis, we converted 34 to 37 through dihydroxylation followed by oxidative cleavage (Scheme 11).39 Diastereoselective nucleophilic methylation was accomplished through the action of methyllithium and ceric chloride,40 thereby affording 36a in 82% yield with 6:1 stereoselection in the desired sense. Higher ratios of diastereoselection could be achieved (16:1), though in reduced yield, with methylmagnesium bromide (73%) (Table 1 in Scheme 11). As hoped, it was found that stereoselection does indeed favor attack of the nucleophile from the axial face, wherein the sp3 spiro center serves as an equatorially based conformational lock. The total synthesis of spirotenuipesine A (1a) was now completed upon removal of the PMB group, as shown. In addition to the congruencies of the spectral properties with those of natural product, our assignments are secured by a crystallographic determination of fully synthetic 1a. Parenthetically, we note that we could convert 1a to 1b following a reported protocol.13 Asymmetric Synthesis of Spirotenuipesines A and B. Upon completion of the syntheses of racemic spirotenuipesine A (1a) and B (1b), we devised a second-generation asymmetric route. In examining our ﬁrst-generation synthesis, we focused on reaching dienyl alcohol 10 or cyclopentenyl alcohol 11 in optically active form. With the absolute stereochemistry of the secondary alcohol established at an early stage of the synthesis, we could be conﬁdent that our ﬁrst-generation diastereoselective route would enable the installation of the subsequent stereo- centers in the desired sense. Two possible strategies for the synthesis of enantioenriched or enantiopure 11 presented themselves (Scheme 12). Both routes would begin with readily available optically active (R)-epichlorohydrin (38). The ﬁrst (path a) envisions sequential openings of 38, ﬁrst with isopro- penyl cuprate 39 and then with functionalized isopropenyl cuprate 40, as shown, to ultimately give rise to an intermediate of the type 41. The unspeciﬁed “X” group would be transformed into a hydroxyl group to afford substrate 10, which is the precursor for the previously discussed RCM reaction. In an alternate route (path b), sequential opening of 38 with isopro- penyl cuprate 39 and acetylide 42 would eventually afford an intermediate of the type 43. Ring-closing enyne metathesis (39) Garlaschelli, L.; de Tullio, P.; Vidari, G. Tetrahedron 1991, 47, 6769. (40) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392. J. Org. Chem. Vol. 73, No. 24, 2008 9581