Many of the acetogenins isolated from the Annonaceae plants1 have shown remarkable cytotoxic, antitumor, antimalarial, immunosuppressive, pesticidal, and antifeedant activities.2 Classification of these fatty acid derivatives into three subgroups is based on the number and relative positioning of the tetrahydrofuran moieties within the molecule: the mono-THF, the adjacent bis-THF, and the nonadjacent bis-THF acetogenins.1 We have recently shown that many acetogenins of the first and second subgroups, including solamin, reticulatacin, asimicin, bullatacin, trilobacin, and trilobin, can be efficiently synthesized3 either by a convergent approach or via the “naked” carbon skeleton strategy,4,5 combining the Sharpless asymmetric dihydroxylation (AD) reaction6 with the Kennedy oxidative cyclization reaction.7 Goniocin, which has been recently isolated from Goniothalamus giganteus,8 possesses three adjacent THF rings and, therefore, represents the first example of a new subclass of Annonaceous acetogenins. Structure 1 was proposed for goniocin on the basis of its MS and 1H and 13C NMR data.8 Clearly, construction of the tris-trans-THF fragment I with the appropriate configuration of the seven stereogenic carbinol centers represents the main challenge in the synthesis of 1. Our retrosynthetic analysis (Scheme 1) was based on previous findings that two consecutive oxidative cyclizations with 4,8dienols can be carried out in a single step to produce bis-THF derivatives.9 We reasoned that I could be synthesized from a 4,8,12-trienol substrate using the tandem oxidative cyclization methodology. Coupling of I with the butenolide fragment II could lead to an efficient total synthesis of 1. Here, we report that all trans-4,8,12-trienol substrates indeed undergo a highly stereospecific triple oxidative cyclization reaction in the presence of a rhenium(VII) reagent to produce a single stereoisomer of a tris-THF product. Surprisingly, however, the product’s stereochemistry is not trans-threo-transthreo-trans-threo as expected, but trans-threo-cis-threo-cisthreo. Consequently, we have synthesized 17,18-bisepigoniocin (2) rather than 1. The key intermediate in our synthesis (Scheme 2) is the “naked” carbon skeleton (6) which is easily prepared from (E,E)ethyl heneicosa-4,8-dienoate3a (see the Supporting Information). Asymmetric epoxidation10 of 3 using Ti(OPr)4 and (-)-DIPT produces epoxy alcohol 4 in more than 95% ee. Reductive cleavage of the epoxide ring using Red-Al affords the 1,3-diol 5,11 which is then monoprotected at the primary position to give the silyl ether 6. We planned to use the single stereogenic center in 6 as the only source of chirality at the tris-THF fragment and achieve the other six stereogenic carbinol centers by a tandem oxidative cyclization reaction using a Re(VII) reagent. We found that both reagents originally used by Kennedy, i.e. Re2O7/lutidine and Re2O7/H5IO6 in dichloromethane, are useful for monocyclization with simple substrates possessing one double bond. However, for double cyclization with substrates containing two double bonds, the more reactive mixture, Re2O7/H5IO6, was † The Scripps Research Institute. ‡ Technion. (1) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J. L. Nat. Prod. Rep. 1996, 275. (2) Gu, Z.-M.; Zhao, G.-X.; Oberlies, N. H.; Zeng, L.; McLaughlin, J. L. In Recent AdVances in Phytochemistry; Arnason, J. T., Mata, R., Romeo, J. T., Eds.; Plenum Press: New York, 1995; Vol. 29, pp 249-310. (3) (a) Sinha, S. C; Keinan, E. J. Am. Chem. Soc. 1993, 115, 4891. (b) Sinha, S. C.; Sinha-Bagchi, A.; Yazbak, A.; Keinan, E. Tetrahedron Lett. 1995, 36, 9257. (c) Sinha, S. C.; Sinha, A.; Yazbak, A.; Keinan, E. J. Org. Chem. 1996, 61, 7640. (d) Sinha, A.; Sinha, S. C.; Keinan, E. Submitted. (4) Keinan, E.; Sinha, A.; Yazbak, A.; Sinha, S. C.; Sinha, S. C. Pure Appl. Chem. 1997, 69, 423. (5) (a) Sinha, S. C; Keinan, E. J. Org. Chem. 1994, 59, 949. (b) Sinha, S. C; Keinan, E. J. Org. Chem. 1997, 62, 377. (c) Sinha, S. C; SinhaBagchi, A.; Keinan, E. J. Org. Chem. 1993, 58, 7789. (6) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483. (7) (a) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 3729. (b) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5299. (c) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5303. (d) Boyce, R. S.; Kennedy, R. M. Tetrahedron Lett. 1994, 35, 5133. (8) Gu, Z.-M.; Fang, X.-P.; Zeng, L.; McLaughlin, J. L. Tetrahedron Lett. 1994, 35, 5367. (9) Sinha, S. C; Sinha-Bagchi, A.; Keinan, E. J. Am. Chem. Soc. 1995, 117, 1447. (10) (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers Inc.: New York, 1993; p 103. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. (11) (a) Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719. (b) Viti, S. M. Tetrahedron Lett. 1982, 23, 4541. Scheme 1
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