I. Rapid access to [4.3.1]propellanes via Fischer carbene complexes. II. Protein kinase C-betaII binding by modified phorbol esters with functionalized lipophilic regions

In Chapter 1, the library of Fischer carbene-mediated cyclizations is expanded to include tricyclic propellane frameworks. Treatment of molybdenum Fischer carbene complexes with 6-methylene-7-octen-1-yne derivatives at 40°C generated substituted tricyclo[4.3.1.01,6]deca-2,4-dienes in good yield. Pentacarbonyl(butyl-methoxycarbene)molybdenum(0) afforded the highest yield of propellane (54%) while the analogous chromium carbene complex gave no reaction. The range of dienyne substrates that participate in this reaction is explored and its mechanism is analyzed and discussed.; Chapter 2 presents the synthesis and protein kinase C-recruiting ability of seventeen novel phorbol esters. These derivatives, designed to be non-activating PKC ligands, were semisynthesized by EDCI condensation of the 12 and/or 13 phorbol alcohols with functionalized carboxylic acids. The analogs contain various polar functional groups to inhibit membrane-insertion of the PKC-phorbol ester complex. Diterpene starting materials phorbol 20-trityl and phorbol 13-acetate-20-trityl were obtained from croton oil, the seed oil of Croton tiglium L. Overall yields were generally good (57% average yield) despite the sensitivity of phorbol esters to heat, air, light, acids, and bases.; The capacity of these analogues to membrane recruit PKC-βII was determined using a modified PKC binding assay. Phorbol 12-octanoate-13-acetate derivatives translocated PKC-βII to different degrees depending on their lipophilicity; decreasing polarity always increased PKC recruitment. Likewise, the degree of translocation by several carboxylic acid-containing phorbol esters was dependent upon the length and composition of the hydrocarbon tether at C12. At the C12 position, long-chain analogs were better at PKC translocation than short-chain analogs and saturated analogs were more potent than their unsaturated counterparts. Phorbol analogs with short carboxylic acids on their C12 and C13 acyl chains were completely inactive. Phorbol esters with polar functional groups at the C13 position were less potent than their C12 constitutional isomers. All of the phorbol ester analogs prepared in this study were as or less efficient than phorbol 12-myristate-13-acetate at recruiting PKC-βII to the lipid bilayer.