Part I, The total synthesis of (±)-securinine and (±)-allosecurinine and synthetic strategies for a second generation synthesis of the securinega alkaloids and Part II, The use of (+)-K252a in the semi-synthesis of indolocarbazole natural products and novel analogs thereof

Abstract

In part I, the total syntheses of (±)-securinine ((±)-1.001) and (±)-allosecurinine ((±)-1.003) are described. The syntheses feature the use of a Rh-initiated O—H insertion/Claisen rearrangement/1,2-allyl migration, which would allow for an enantioselective synthesis when an enantioenriched allylic alcohol (ie: (+)-1.137) is used. Three more steps generates the common intermediate imine 1.144, which upon reduction gives a pair of diastereomers. Protection of the free amine and a second reduction gives 1.146a and 1.146b, which were advanced to (±)-1.003 and (±)-1.001 respectively. Additional investigations into improving the endgame and devising a more streamlined synthesis were conducted. This focused on reducing the number of oxidation state changes at C13. Part II of this dissertation details efforts to employ (+)-K252a (2.016) as a starting material for the synthesis of potential Hox-A14 inhibitors based on the indolocarbazole scaffold. It also covers the development of a novel method of selectively protecting the amide of 1.016 with a DMB group. This protected analog was employed as the starting material for a potential synthesis of the recently isolated indolocarbazoles Streptocarbazole A (2.019) and B (2.020). The proposed route to these compounds is via C—N bond migration on ketone 2.138 or dimethylketal 2.158. Substrates 2.138 and 2.158 have been synthesized. Preliminary investigations into conditions for the desired rearrangement have been conducted.