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Tandem Oxidative Cyclization With Rhenium(VII) Oxides: Synthesis of Annonaceous Acetogenins

S.C. Sinha, E. Keinan, P. Neogi, H. Avedissian, S.C. Sinha, A. Yazbak

The tandem oxidative polycyclization reaction with rhenium(VII) reagents, first reported in 1995, is a powerful method for converting polyene alcohols into poly-tetrahydrofuran (poly-THF) products in a single step. A set of rules has been deduced that can be used to predict the stereochemistry of the THF rings on the basis of the behavior of 4 possible isomeric dienol substrates: The stereochemistry of the first THF ring is always trans, whereas that of subsequent ones depends on the stereochemistry of the 2 vicinal oxygen functions formed in the first cyclization. When these vicinal oxygen functions have a threo relationship, the next cyclization will produce a cis THF ring; when they have an erythro relationship, the next cyclization will produce a trans THF ring. These rules are valid for polycyclization with trifluoroacetylperrhenate of polyenols in a single step producing a single isolatable compound.

Annonaceous acetogenins, particularly those with adjacent bis-THF rings, have remarkable cytotoxic, antitumor, antimalarial, immunosuppressive, pesticidal, and antifeedant activities. Many of these fatty acid derivatives have similar carbon skeletons; their striking diversity originates mainly from the relative and absolute configuration of their various stereogenic oxygen functions. More than 300 different acetogenins have been isolated, and the naturally occurring repertoire of these compounds is probably on the order of thousands.

Total synthesis of many naturally occurring and nonnatural analogs of acetogenins has been accomplished by using our "naked carbon skeleton" strategy. With this strategy, enantioselective olefin oxidation methods are combined with ligand-assisted chirality transfer techniques based on the previously described chemistry of rhenium(VII) oxides. The acetogenins synthesized include mono-THF structures, such as solamin and reticulatacin; bis-THF compounds, such as asimicin, bullatacin, trilobacin, trilobin, uvaricin, squamotacin, and rolliniastatin; and even rarer, tris-THF molecules, such as goniocin and its isomers (Fig. 1).

PUBLICATIONS

Neogi, P., Doundoulakis, T., Yazbak, A., Sinha, S.C., Sinha, S.C., Keinan, E. Total synthesis of mucocin. J. Am. Chem. Soc., in press.

Sinha, S.C., Keinan, E., Sinha, S.C. Rules of stereoselectivity in the tandem oxidative cyclization reaction with rhenium(VII) oxides. J. Am. Chem. Soc. 120:9076, 1998.

Sinha, S.C., Sinha, A., Sinha, S.C., Keinan, E. Tandem oxidative cyclization with rhenium oxide: Total synthesis of 17,18-bisepi-goniocin. J. Am. Chem. Soc. 119:12014, 1997.

Sinha, S.C., Sinha, A., Sinha, S.C., Keinan, E. Total synthesis of goniocin and cyclogoniodenin T: Unique biosynthetic implications. J. Am. Chem. Soc. 120:4017, 1998.

Yazbak, A., Sinha, S.C., Keinan, E. Total synthesis of uvaricin. J. Org. Chem. 63:5863, 1998.