Discovery And Development Of The Natural Product Derivative Spi-1865 As A Gamma Secretase Modulator For Alzheimer'S Disease

This chapter describes the scale-up synthesis of the natural product derivative SPI-1865, employing a semi-synthetic approach. The challenge of securing a good quantity of starting material was solved by preparation of two cycloartenol glycosides in multikilogram scale via extraction/isolation from biomass and a ZrCl4-catalyzed reaction. By developing a protecting group-free ether formation reaction and a significantly improved five-step/3 pot process, we achieved kilogram-scale synthesis of SPI-1865 in good overall yield.