The methods development approach to the synthesis of phenanthridinone analogs

Abstract

The phenanthridinone alkaloids pancratistatin, tran-dihydrolycoricidine and lycoricidine; isolated from certain plants of the Amaryllidaceae family, have all been found to be biologically active species. Analogs of these natural products, such as cis-dihydrolycoricidine, have not yet been discovered in nature but have also been found to be anti-tumor agents. For this reason, these compounds have been the target of many synthetic chemists. Herein, is presented a synthetic scheme that provides analogs of these natural products while forming the ring system through a non-traditional manor using a lewis acid to induce an alkyl shift from a hemiaminal. The double bond that is formed with the alkyl shift can be reduced in a cis manor to give analogs of these alkaloids that are not commonly targeted. Manipulations of the reaction scheme also show that unique functionalities and specific stereochemistry can be incorporated into the substrates if needed to provide a large library of derivatives. This new synthetic pathway circumvents the need for expensive catalysts typically used for late-stage reactions to close the ring system found in these compounds.