| In part A, a diastereoselective anti-anti aldol reaction was developed utilizing beta-aroyloxy ketones 72a-d. The diastereoselectivities were found to be related to the electronic nature of substituents on the aroyl ring. Substrate 72a with electron-donating groups on the aromatic ring gave the highest diastereoselectivity while 72d with an electron-withdrawing group on the aromatic ring gave much lower diastereoselectivity. Employment of the anti-anti aldol product 77a as a starting material, the C1-C27 subunit of the aplyronines was synthesized featuring a Kocienski modified Julia olefination reaction as a key step in the construction of the C20-C21 trans-double bond. Notably, aldehyde 64 with the dienoate ester functionality incorporated underwent the olefination reaction without complications.; In part B, a stereoselective aza-Claisen rearrangement was utilized to construct the seven membered lactam 45 with a quaternary center. The condensation reaction between 3,4-dimethoxyaniline and aldehyde 30 followed by an intramolecular hetero-Diels-Alder reaction afforded tetracyclic compound 46 diastereoselectively. During efforts to generate the imine functionality necessary for the aminal formation in the natural product, we discovered that an iminoquinone intermediate was generated upon oxidation by CAN which underwent disproportionation on silica gel, while a small amount of imine 63 was obtained during its separation over alumina. A bromine atom was then introduced on the aromatic ring with expect to prevent aromatization. Notably, the condensations between aniline 64 and aldehydes 18, 30 and 77 afforded the cyclization products as single regioisomers with the bromine atom close to the side chain. However, the side chain still occupies the equatorial position as shown in the X-ray structure of compound 65 and NOE experiments of compound 81. Thus these efforts fail to prevent the overoxidation to quinoline. In order to avoid the tricky oxidation state modifications, a new retrosynthesis was proposed, in which a dication intermediate 84 was imagined to be a precursor for the hetero-Diels-Alder reaction. Synthetic efforts have been directed toward the syntheses of compounds 86, 95 and 96, which are reasonable precursors to the desired intermediate compound 85. |
