This research proposal reflects our general interest in the development of new reagents and their use in the asymmetric synthesis of complex organic molecules that may have relevance in the treatment of human cancers. The long term objectives are the eventual achievement of the asymmetric synthesis of representative members of an emerging class of ansabridge macrocyclic lactams possessing a wide range of antitumor and antibiotic activity. Certain members, macbecin-I and herbimycin A have been shown to function as selective inhibitors of tyrosine protein kinase. In this regard we intend to: Demonstrate the utility of diasteromerically and enatimerically pure functionalized (E)-crotylsilane reagents 1, in chiral allylsilane-base bond construction methodology for the asymmetric synthesis of complex organic molecule. Specifically, diasteroface selective addition reactions with achiral aryl an aliphatic acetal will be investigated for the construction of functionalized homoallylic ethers. These homoallylic ethers will be used as key intermediates for the construction of advanced synthons in asymmetric synthesis of ansamycin natural products. The total synthesis of the ansamycin antitumor antibiotic (+)- macbecin I (2a), the total synthesis of structurally related herbimycin A (2b). These natural products and structurally related molecules (synthetic intermediates) will be evaluated as selective inhibitors of tyrosine protein kinases. The approach is based on the diasteroface selective addition of (2R,3R)-1d to aryl acetal. The asymmetric synthesis of trienomycin-A 3a and (+)-mycotirenin I (3b). The approach is based on the development of new methodology for the asymmetric synthesis syn-and anti-1,3-diols and is based on two sequential stereoselective reactions: enantioselective addition of the anti(E)-crotylsilane (2S,3R)-1a to an acetal followed by a suprafacial allelic ester transposition. This protocol will be used for the assembly of the C11, C12 & C13 sterocenters of trienomycin A and (+)-mycotirenin-I. We will begin studies directed at chemical synthesis of the cytotoxic macrolides, ulapualide A & B, other wise known as the halichondramides 4a,b. Utilizing our developing chiral crotylsilane based bond construction methodology for key asymmetric C-C bond forming reactions to be employed in the synthesis of anti- homoallylic alcohol and anti-1,3-diol synthons which are characteristic subunits of the ulapualides.
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