Study On Enantioselective Synthesis Of (-) - Hornamides

Clausenamide is a racemic pyrrolinone natural product isolated from the aqueous extract of the leaves of Clausen alassium skeels, and exhibited hepatoprotective activity. The enantiomer, (-)-Clausenamide, was later found to possess profoundly nootropic effect, and is now under clinical trial as a drug candidate for Alzheimer’s disease. Reported herein is a newly developed enantioselective synthesis of (-)-Clausenamide.The lactone 29 was synthesized from the known compound (-)-23 through acetylation, Ireland-Claisen rearrangement and bromolactonization. Subsequent aminolysis delivered the key epoxide intermediate 30, which was converted to (-)-3-deoxy-Clausenamide 20 via intramolecular SN2 reaction. Finally, the oxidation of 20 was proceeded to finish the enantioselective synthesis of Clausenamide.The Claisen-lreland rearrangement reaction was also revisited in this dissertation. Yield lowering C-silylation was found to be inevitable in all six tested examples of stoichiometric LDA/TMSCI promoted Claisen-lreland rearrangement of secondary allyl acetates. In order to circumvent this problem, a higher yielding protocol was devised after the isolated by-products were found to be excellent substrates for further rearrangement. Thus, excessive LDA/TMSCl was applied to achieve complete 3,3’-sigmatropic shift of the substrates, and the resulting mixtures of normal and α-silylated y,6-unsaturated carboxylic acids was then desilylated by one-pot application of TBAF.