PIFA-Mediated Coupling of Vindoline with β-Ketoesters and Related Model Velbanamine Precursors.

A study of PIFA-mediated arylations of advanced model β-ketoesters and related substrates with vindoline for the total synthesis of vinblastine and related analogues are reported. The studies demonstrate the viability of the reaction in establishing the central C16'-C15 bond linking the upper velbanamine and lower vindoline subunits as well as define factors influencing formation of the natural C16' stereochemistry. Central to the potential of such an approach is the subsequent use of the β-ketoester-derived ketone for the divergent installation of a series of heterocycles, including the velbanamine indole required for vinblastine itself, from a common late-stage synthetic intermediate. Notably, such an approach represents the first that does not rely on a biomimetic coupling reaction, which necessarily requires an embedded indole in the velbanamine subunit precursor precluding indole replacements in the target structure.