Development of a Second Generation Palladium-Catalyzed Cycloalkenylation and its Application to Bioactive Natural Product Synthesis

Abstract

A novel palladium-catalyzed intramolecular oxidative alkylation of unactivated olefins is described. This protocol was devised to solve one of the drawbacks of the original palladium-catalyzed cycloalkenylation that we developed. We call this new procedure the 'second generation palladium-catalyzed cycloalkenylation'. This protocol has been applied to the total syntheses of cis-195A, trans-195A, boonein, scholareins A, C, D, and α-skytanthine.

Methods Utilizing First-Row Transition Metals in Natural Product Total Synthesis

“…Broadly speaking, first-row transition metal analogues of classical Pd-catalyzed reactions have been less frequently employed in natural product synthesis. − , In Hu and co-workers’ total synthesis of the fungal macrolide recifeiolide ( 24 - 6 ), a nickel-catalyzed Suzuki–Miyaura coupling was used to synthesize esterification precursor 24 - 5 (Scheme ). The researchers began by performing a hydroboration of alkyne 24 - 1 .…”

“…The metals that deviate positively from the linear correlation are suspected to be overutilized in total synthesis relative to other fields, while those that deviate from linearity in a negative fashion are thought to be underutilized. It is unsurprising that Ru, − Os, Rh, − Ir, − and Pd − have a disproportionate occurrence with “total synthesis” given the dramatic impact that these metals have had on organic synthesis. , The remarkable occurrence of Pd in articles on total synthesis contrasts sharply with the abundance and deviation from linearity seen with Fe, and to a lesser extent the other first-row transition metals, with Cu being an exception.…”