General Synthesis and New Applications of Dendralenes

Abstract

The objectives of the research work carried out and presented in this thesis are to develop a better understanding of chemical reactivity and to devise improved synthetic methods by following the principles of the 'ideal synthesis'. Described herein are three projects based on generating molecular complexity from commercially available, structurally simple starting materials in a step-, atom-economical fashion. Dendralenes, which are acyclic, cross-conjugated hydrocarbons, provide the focus of this research. Dendralenes are important building blocks in synthetic organic chemistry as they undergo diene transmissive Diels-Alder (DTDA) reaction sequences with a range of dienophiles to generate all carbon and heteroatom-containing multi-cyclic complex frameworks. Chapter 1 provides an overall introduction to subsequent chapters of this thesis.

Chapter 2 outlines the first general synthetic route to substituted [3]dendralenes, via twofold Negishi cross-couplings of dibromomethylenes with alkenyl zinc reagents. The requisite dibromomethylenes are synthesised from the corresponding aldehydes using the Ramirez dibromomethylenation reaction. We report herein subsequently the first stereoselective synthesis of substituted dendralenes by a catalyst-controlled sequential twofold Negishi cross-coupling of dibromomethylenes with different nucleophilic coupling partners. This strategy makes it possible to synthesise both geometrical isomers of substituted [3]dendralenes. The versatility of these compounds in further chemistry is highlighted by their use in both DTDA cycloaddition sequences and domino 6pi-electrocyclisation sequences.

Chapter 3 explores the Diels-Alder reactions between substituted [3]dendralenes and in situ generated benzynes as dienophiles to generate 2-vinyl-1,4-dihydronaphthalenes. Both substituted and unsubstituted benzynes were found to react well with substituted [3]dendralenes. The products of the first Diels-Alder reaction were shown to react with different dienophiles to generate aromatic-ring-containing, multicyclic complex molecules. The DTDA reaction sequences can be performed in one pot, avoiding work up and purification of the intermediate semicyclic diene. It is also shown that this chemistry can be utilised to rapidly generate the tetracyclic framework of 7-arylangucyclines, a new "hybrid drug" structure.

Chapter 4 investigates the organocatalysed, enantioselective Diels-Alder reactions of substituted [3]dendralenes. A high level of regio-, diastereo- and enantioselectivity was observed. The substrate-controlled second Diels-Alder reaction on these enantioenriched substrates was also performed to obtain enantiopure, complex polycyclic compounds.