Samarium diiodide-mediated tandem radical-ionic reactions: Model studies towards the total synthesis of penitrem D.

摘要

This thesis describes model studies directed towards the synthesis of rings A-F of penitrem D. The BCD ring system of penitrem D was rapidly constructed using a novel strategy for the synthesis of fused cyclobutane ring systems based on a 6-exo cyclization of a phenyl radical to a cyclobutene ring. Ketal-, silyl ether-, and methylene-bearing cyclobutene cyclization precursors were synthesized and studied. Ketal bearing cyclobutene cyclization precursors were shown to be the most efficient based on the cyclization rate constant and isolated yields of the SmI₂-mediated tandem 6- exo cyclizations with acetone and t-butanol quenching. Alternative reagents were screened for their ability to mediate the 6- exo cyclization. Both the palladium- and tributyltin hydride-mediated 6-exo cyclizations of the cyclobutene models proceeded in high yields.; The synthesis of the DEF ring system of penitrem D was studied in the context of finding a N-sulfonamide protecting group that was reduced slower than aryl bromides by samarium diiodide. Several 5- exo cyclization precursors with different N-sulfonamides were synthesized by Mitsunobu coupling of 4-phenoxy cyclopent-2-enol with the appropriate N-(2-bromophenyl)-4-sulfonamides. After comparing the efficiency of the SmI₂-mediated cyclizations of the precursors, it was found that the N-methanesulfonamide protecting group was the most stable to the SmI₂-HMPA reaction conditions and provided optimal yields for both the Mitsunobu coupling and the 5-exo-cyclization.; An efficient synthetic route has been developed for the preparation of the aromatic core fragment with differentiated halogens, using a Liedholm formylation as the key step, in 11 steps and 15% overall yield. This represents a significant step forward in the pursuit of the synthesis of penitrem D model.; The last part of the thesis describes the progress made in the synthesis of two different key cyclization precursors. Extensive experimentation to couple the cyclobutene moiety to the aromatic core, applying the methodology used for the synthesis of the cyclobutene cyclization precursors, failed to provide the desired product. However, several promising alternative alkylation strategies were identified that will allow for the cyclobutene moiety and the aromatic core to be coupled. Finally, progress has been made towards the synthesis of Amos Smith's “western hemisphere” fragment of Penitrem D applying the methodology used for the synthesis of the cyclobutene cyclization precursors.