Multicomponent Diels-Alder Sequences of 1-Aminodendralenes

Abstract

This thesis explores the use of in situ generated acyclic 1-aminodendralenes in multicomponent diene-transmissive Diels-Alder (DTDA) reaction sequences. Dendralenes have previously been shown to generate polycyclic frameworks in a step-economic manner. The 1-amino substituent is shown to promote very high levels of site selectivity in these processes. Chapter 1 reviews the Diels-Alder reactions of 1-amino-1,3-butadienes and is divided into three sections. The first two sections cover the Diels-Alder reactions of 1-amino-1,3-butadienes and 1-amino-3-siloxy-1,3-butadienes (Rawal’s dienes) generated with a stoichiometric amount of amine. The third section covers enantioselective Diels-Alder reactions involving 1-amino-1,3-butadienes generated in situ with a catalytic amount of a chiral amine. While there have been many reports of Diels-Alder reactions of 1-amino-1,3-butadienes and 1-amino-3-siloxy-1,3-butadienes, there has been only one involving a semi-cyclic 1-amino[3]dendralene. There have been few examples which combine these Diels-Alder reactions with other transformations in multicomponent reactions to generate polycyclic frameworks. Chapter 2 describes the use of acyclic 1-amino[3]dendralenes in multicomponent reactions to generate a diverse range of heterocyclic structures. The condensation/Diels- Alder reaction sequence was tolerant of a variety of amines as well as carbon and hereoatom-based dienophiles. The Diels-Alder reactions of 1-amino[3]dendralenes were highly site-selective, taking place exclusively at the amine substituted 1,3-butadiene unit. The sequence was extended to a one-pot four-component reaction by including an additional dienophile for a Diels-Alder reaction to take place at the newly generated semi-cyclic diene. These condensation/Diels-Alder/Diels-Alder cycloadducts were generated with high diastereoselectivity, the origins of which were investigated and explained with the use of density functional theory calculations (carried out by Prof Paddon-Row). By reversing the order of events, that is performing a Diels-Alder reaction on the skipped dienal precursor before the condensation/Diels-Alder reaction sequence, constitutional isomers were accessed. The second Diels-Alder reaction could be performed intramolecularly when an amine bearing an alkenyl substituent was used. This condensation/Diels-Alder/intramolecular Diels-Alder reaction sequence furnished a variety of tricyclic and tetracyclic heterocycles. Chapter 3 describes the use of acyclic 1-aminodendralenes bearing chiral amines in organocatalytic, enantioselective Diels-Alder reactions to deliver enantioenriched cycloadducts. The enantioselective Diels-Alder reaction between 1-amino[3]dendralenes, the condensation product of skipped dienals and chiral amines, and various dienophiles followed by elimination of the amine generated trienal cycloadducts in good yield and high enantioselectivity. The reaction tolerates substitution on the skipped dienal as well as dienophiles possessing an aldehyde substituent at the α position. Extension of this methodology by performing Wittig and Diels-Alder reactions on the trienal cycloadducts enabled access to enantioenriched polycyclic products. By using a diene-dialdehyde as the starting precursor, it is anticipated that the Horeau principle would operate in the twofold condensation/Diels-Alder/elimination reaction sequence would furnish the cycloadduct in high enantioselectivity. A preliminary attempt successfully generated the desired cycloadduct as the major product.