Multi-component hetero Diels-Alder reaction of N-arylimines: Synthesis of functionalized tetrahydroquinolines and total synthesis of the martinelline alkaloids

This thesis is a summary of research conducted from October 1998 in the laboratories of Professor Robert A. Batey at the University of Toronto. Chapter 1 describes the use of N-substituted 2-pyrrolines as electron rich dienophiles in the three-component hetero Diels-Alder reaction with in situ generated N-arylimines. Use of a lanthanide (III) catalyst results in the formation of substituted hexahydro-1 H-pyrrolo[3,2-c]quinolines as a mixture of endo and exo diastereomers. The reaction is general for a variety of substituted anilines, aldehydes and N-pyrrolines. The molecular scaffold generated via the multi-component reaction is further transformed into a highly functionalized analog of martinelline.;Chapter 2 focuses on the total synthesis of martinelline and martinellic acid, as well as their C4 epimers using a multi-component ABB ' Povarov reaction. The key 'biomimetic' transformation involves the coupling of two equivalents of N-Cbz-2-pyrroline with methyl 4-aminobenzoate in order to generate the requisite tricyclic triamine core. Protic acid catalysis, rather than Lewis acid catalysis, was necessary to achieve the desired sense of diastereocontrol. Other key steps include a Hg (II) promoted guanylation onto the hindered pyrrole nitrogen and a BOP-Cl mediated coupling to install the ester side chain. In this manner, the first total synthesis of (+/-)-martinelline was achieved in nine steps and 10% overall yield.;In Chapter 3, the ABB' Povarov reaction is further explored using cyclic enol ethers as dienophiles. Cyclic enol ethers, such as dihydrofuran, in the presence of a Dy(III) catalyst undergo a 2:1 coupling reaction with substituted anilines to yield tetrahydroquinolines. Temperature and solvent were found to affect the ratio of endo:exo diasteromers produced in the reaction.;The development of a new protocol for the synthesis of substituted guanidines is described in the last chapter. Here, an alkyl halide or tosylate is reacted with a carbamate substituted guanidine in the presence of a phase-transfer catalyst and KOH under biphasic conditions. The reaction is tolerant of a wide range of substitutents on both the alkyl halide and guanidine component. The new guanidinylation methodology, when combined with an EDCI promoted guanylation, allows for the three-component synthesis of guanidines to be realized.