Tetrahydrofurans, Tetrahydropyrans and 2H-Furanones

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DESCRIPTION (provided by applicant): The long term objective of this project is the application of allylic hydroxy phosphonates and their derivatives as chiral, nonracemic building blocks for the synthesis of biologically active molecules. The immediate goal is the efficient stereoselective synthesis of tetrahydrofurans, pyrans, and 2H-furanones via the palladium (0)-catalyzed addition of oxygen and carbon nucleophiles to phosphono allylic carbonates. Tetrahydro furans and pyrans are common structural features in a number of important classes of natural product. Preliminary results have demonstrated that oxygen nucleophiles undergo both inter and intra-molecular palladium catalyzed addition to phosphono allylic carbonates with complete chirality transfer. Since the palladium catalyzed cyclization is stereospecific, the stereochemistry of the phosphono allylic carbonates dictates the stereochemistry of new furan ring for a fixed alcohol stereochemistry. Thus, cross metathesis and cyclization with either the R or S phosphonate will yield the cis or trans tetrahydrofurans from a common intermediate. The synthesis of two stereoisomeric lipid furans from a common intermediate will serve as demonstration of the flexibility of the proposed method. A further demonstration of the method will be the synthesis of a series of functionalized thf building which can be used for the synthesis of a wide range of thf containing natural products. In the second aim it is proposed to synthesize the thf containing potent (nanomolar) cytotoxic marine natural product amphidinolide C and confirm structure and the reported biological activity. A convergent synthesis is proposed which will also allow the preparation of side chain derivatives to determine important structural features required for high for activity. The third aim involves the synthesis of selected members of cyclipostin family and some phosphonate analogs. As inhibitors of HSL, the cyclipostins are lead compounds for the treatment of type II diabetes. The planned method of synthesis is flexible will allow variation in the chain and the absolute stereochemistry at C3a. Furthermore, a series of simple acyclic analogs are easily prepared from commercially available acyl butyrolactone. The synthesized compounds will be used to probe the mode of action of the cyclipostins with rat HSL.