Extending Traditional Organopalladium Chemistry in the Total Synthesis of Heteroaromatic Natural Products

Abstract

This thesis describes efforts towards the total syntheses of the two natural products (+)- terreusinone (1) and schischkiniin (31). Two distinct total syntheses of (+)-terreusinone (1), a dipyrrolobenzoquinone with potent UV-A protecting capability, were accomplished. Commencing from enantioenriched propargyl alcohol (R)-66c, the first synthesis (Path A) features a copper- and amine-free double Sonogashira reaction with an electron rich dibromo dianiline 65c, and the second (Path B) involves a novel one-pot Larock indolization–Sonogashira coupling reaction with dibromonitroaniline 137. The resulting intermediates 143 and 165 from both pathways underwent a gold (I)-catalyzed Cacchi cyclisation to give pyrroloindole 161. A facile oxidation of 161 delivered (+)-terreusinone (1), confirming the gross structure and absolute configuration of the natural product. Schischkiniin (31) is a rare example of a natural product that contains the 1,1'-bisindole moiety. Our efforts towards this natural product culminated in the first synthetic procedure to access 1,1′-bisindoles (190), whereby various diallylated hydrazobenzenes (191) undergo simultaneous Mori-Ban cyclizations with minimal cleavage of the N-N bond. Using the methodology above, synthetic studies towards schischkiniin focused on constructing 44 and evaluating a pivotal [2+2]-cycloaddition that forms the basis of the proposed biosynthesis of the natural product. Two routes towards the key biomimetic precursor 44 were investigated, both commencing from dicarbaldehyde 264. The first involved construction of dipyrazinone 252 via Grignard reaction of 264 to 265 followed by reduction and demethylation; however, dipyrazinone 252 failed to undergo selective imine reduction to give key precursor 44. The second approach employed a Horner-Wadsworth-Emmons reaction between dicarbaldehyde 264 and phosphonoglycine 284 to give dehydroamino acid 285, which underwent reduction followed by amination and acid-mediated cyclisation to give the Boc-protected biomimetic cyclisation precursor 301. Surprisingly, the Boc groups present in 301 resisted all attempts at their removal and 44 could not be obtained. Despite being unable to attempt the [2+2]-cycloaddition and complete the total synthesis, several new synthetic methods were discovered, providing an excellent platform to complete the synthesis of this natural product.