ENANTIOSELECTIVE (4+2) REACTIONS IN TOTAL SYNTHESIS

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This proposal has three themes, each associated with a different asymmetric method for the formation of carbon-carbon bonds in the highly functionalized environments of biologically interesting compounds. The first outlines current and anticipated developments and applications of both chiral 4-amino and chiral 3-amino furans as applied to the Diels- Alder reaction. This constitutes a continuation of the research sponsored under grant R01-GM49496. The second examines applications of newly developed vinylogous urea lactam enolates as four carbon synthons for the synthesis of amino sugars--in particular neuraminidase inhibitors. The third explored new applications of vinylogous urethane enolate methodology to the side chain sub-structures of zaragozic acid A. We intend to continue the development of Diels-Alder reactions of chiral 4-amino furans. In addition, we wish to further explore our recently developed Diels-Alder reaction that employs chiral 3-amino furans. Developments will include the formulation of methods for asymmetric carbon-carbon bond formation from chiral amino furans in either absolute topicity using the same optical antipode of the auxiliary. Further, we hope to take advantage of the oxa-bicyclo-heptane adducts obtained from these Diels-Alder reactions to develop new and novel stereochemical and chemospecific transformations directed towards efficient synthesis of the core of the hypocholesterolemic agent zaragozic acid, the antineoplastic agents ovalicin, fumagillol, fumagillin, the carbosugar analogs of NANA and p-amino-mannose, and the aglycone of the antineoplastic agent esperamicin. The reader will see in later sections of this proposal that the synthesis of compounds, such as ovalicin, are conducted using the oxa-bicyclic skeleton until the final step. This last step involves fluoride mediated ring opening of the oxa-bicyclic system to reveal the natural product. It occurred to us that the entire synthesis of the natural product could be conducted on a solid phase support using the silyl ketal as the connecting anchor. This could allow an enantio and chemo selective synthetic exercise to be carried out in such a fashion as to require no standard work-up procedures or chromatographic purification of intermediates. We feel that development of this type of technology and comparison of it to a comparable solution phase synthesis with respect to overall yield, reagent usage, and ease would be of great interest. We emphasize that solid phase syntheses of this type are not to be confused with combinatorial regimes. However, it should noted that the oxa-bicyclic- heptane ring systems derived from either a chiral 4 amino or 3 amino furan in combination with an electron deficient olefin could provide a multiply reactive molecular scaffold for combinatorial syntheses.