Total Synthesis of Spirotenuipesines A and B SCHEME 5. Intramolecular Cyclopropanation and Ring-Opening Fragmentation SCHEME 6. Synthesis of Dienophile 20 via Cyclopropanation and Fragmentationa a Reagents and conditions: Key: (a) Ac2O, DMAP, TEA, CH2Cl2, rt; TBAF, THF, rt, 84% over two steps; (b) glyoxylic acid chloride tosylhydrazone, N,N-dimethylaniline; TEA, CH2Cl2, 0 °C to rt, 88%; (c) bis(N-tert-butylsalicylaldiminato)copper(II), tol., reﬂux, (slow addition of starting material), 91%; (d) Li/NH3, THF, -78 °C to reﬂux, 1 h, 0-30%; (e) K2CO3, MeOH, rt; (f) KHMDS; CS2; MeI, THF, rt; (g) n-Bu3SnH, AIBN, tol., 110 °C, 5 h, 60% over three steps; (h) KOH, MeOH, 60 °C; HCl, then NaHCO3, KI, I2, THF, rt; (i) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 77% over three steps. secondary alcohol. Mindful of the sterically hindered environ- ment adjacent to the R-carbon of lactone 16b, we elected to employ Grieco’s protocol31 to elaborate 16b to the R-methylene lactone 20. The expected hydroxymethyl lactone 19 was obtained in 65% yield, along with 28% of R-methylene lactone 20. Compound 19 was then fully converted to 20 in 95% yield through standard mesylation followed by base induced -elim- ination. It is worth mentioning in passing that the hindered R-methylene could not be installed through the use of Eschen- moser’s salt32 or Bredereck’s reagent.33 Intramolecular Cyclopropanation and Radical-Initiated Fragmentation. Although we could, in practice, reincorporate each of the Claisen adducts (12a and 12b) into our synthesis through a multistep process (Scheme 4), this strategy would force us to compromise in terms of both synthetic efﬁciency and aesthetic standards. Upon reﬂection, we began to consider an alternative means by which we might stereoselectively gain access to our target γ,δ-unsaturated esters. As outlined in Scheme 5, we envisioned that bicyclo compound 21 could be obtained from [3.2.1]bicyclolactone 22 due to the cis-relation- ship between the highlighted carboxylate and secondary alcohol moieties. Presumably, 22 could be accessed through a reductive or radical-based ring opening of the cyclopropane ring in compound 23, operating through cleavage of the Walsh bond.34 The latter, in turn, would be assembled through an intramo- lecularly tethered cyclopropanation of 24 (itself derived from 11). Through such an intramolecular cyclopropanation, we hoped to secure the critical cis-relationship between the 2-carbon carboxylate and the secondary hydroxyl group. It was this deﬁned stereochemical relationship which had eluded us under the original Claisen paradigm. (31) (a) Grieco, P. A. Synthesis 1975, 67. (b) Crimmins, M. T.; DeLoach, J. A. J. Am. Chem. Soc. 1986, 108, 800. (32) (a) Danishefsky, S.; Schuda, P. F.; Kitahara, T.; Etheredge, S. J. J. Am. Chem. Soc. 1977, 99, 6066. (b) La Clair, J. J.; Lansbury, P. T.; Zhi, B. X.; Hoogsteen, K. J. Org. Chem. 1995, 60, 4822. (33) Marcos, I.; Redero, E.; Bermejo, F. Tetrahedron Lett. 2000, 41, 8451. (34) Walsh, A. D. Nature 1947, 159, 165 and 712. The modiﬁed route (see Scheme 6) commenced with the previously synthesized compound 11. The latter was advanced to 25 through a straightfoward sequence consisting of protection of the primary alcohol, removal of the TBS protecting group, and installation of the diazoacetic ester through the Corey-Myers modiﬁed House’s procedure.35 Upon thermal decomposition in the presence of catalytic bis(N-tert-butylsalicylaldiminato)cop- per(II) in toluene, diazoester 25 smoothly underwent intramo- lecular cyclopropanation to provide the activated cyclopropane 26 in excellent yield.36 We note that no dimerization or C-H insertion products were observed when copper(II) was used as catalyst, though we did ﬁnd slow introduction of diazoester 25 into the reaction to be critical. In screening various reaction conditions for reductive ring-opening fragmentation, it seemed to us that Li/NH3 was the most efﬁcient reducing system, though affording only a 30% yield of 29. Furthermore, the reaction suffered from poor reproducibility. Accordingly, we sought an alternate fragmentation protocol. Upon further investigation, we identiﬁed a reliable route from 26 to 29. Thus, selective K2CO3- mediated deprotection of the acetate in the presence of the strained lactone afforded primary alcohol 27, which was then readily transformed to xanthate 28. Finally, Barton-McCombie deoxygenation37 triggered the tandem radical process, giving rise to [3.2.1]bicyclolactone 29 in over 60% yield for three steps. Hydrolysis of 29 followed by iodolactonization38 and TBS protection afforded intermediate 14b, which could be trans- formed to dienophile 20 using the chemistry described above (Schemes 3 and 4). It is instructive to reﬂect on the implications of the interplay between the Claisen and cyclopropanation routes. Consider substrate 11; under the Claisen protocol, this starting material (35) (a) House, H. O.; Blankley, C. J. J. Org. Chem. 1968, 33, 53. (b) Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559. (36) Danishefsky, S. J. Acc. Chem. Res. 1979, 12, 66. (37) Barton, D. H.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574. (38) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675. J. Org. Chem. Vol. 73, No. 24, 2008 9579