Studies on Nazarov/ene tandem cyclizations and their application in the total synthesis of (-)-illisimonin A

Abstract

In the first part of this thesis, the mechanistic insights behind the key step of this total synthesis, the diastereoselective Nazarov/ene tandem cyclization, are unravelled. First, the introduction of an additional methylene in the side chain served the purpose of understanding the connection between the flexibility of the side chain and the feasibility of the desired cyclization. Second, the cyclization in presence of a (Z)-substituent at the terminal olefin afforded only products whose double bond occupied the position of the former (E)-methyl group, suggesting selective migration of an hydrogen atom from the (E)-position. Third, the synthesis of a perdeuterated precursor, bearing a CD3-substituent in lieu of the (E)-methyl group, confirmed the aforementioned migration hypothesis. Finally, crossover experiments outruled the existence of an intermolecular proton/deuterium transfer, confirming a concerted, intramolecular ene-like mechanism. In the second part, the acquired chemical background for the stereoselective construction of spirocompounds via Nazarov/ene cyclizations was transferred to the total synthesis of (−)-illisimonin A, a caged sesquiterpenoid isolated by Ma et al. from the fruits of Illicium simonsii, commonly known as star anise. The construction of its unprecedented tricyclo[5.2.1.01,6]decane skeleton was attempted with an early-stage functionalization strategy and a late-stage parallel approach, in which C-11 functionalization followed one-carbon homologation. While the early-stage plan stranded at an advanced intermediate, the functionalization of the previously homologated spirocycle proved to be successful. A Ti(III)-mediated reductive cyclization of an epoxy-enone, a type III semipinacol rearrangement and a selective deprotection successfully led to a formal synthetic intermediate. In the third and final act, an enantioenriched cross-conjugated precursor for the key Nazarov/ene cyclization diastereoselectively built the desired stereotriad in the aforementioned spirocompound. In turn, this spiroketone followed the steps of its racemic congener, fruitfully reproducing the optimized synthesis until a second, more advanced, formal intermediate. A carboxylic acid-mediated White-Chen C−H activation gave access to (−)-illisimonin A and concluded this thesis.