Efficient Strategies for Chemical Synthesis

Abstract

Chapter one describes how synthetic strategy has enabled an investigation of the reactivities of new structural archetypes of tetravinylethylene (TVE) and tetraethynylethylene (TEE), which are two structurally similar compounds that exhibit stark differences in reactivity. The synthesis of five hybrid compounds, representing all possible combinations of vinyl and ethynyl groups arranged around a central ethylene core, was achieved using dibromoolefin lynchpins which were engaged in either, twofold or sequential stereoselective cross-coupling reactions. Design and implementation of our strategy resulted in the development of new methodology, namely, selective single cross-couplings and stereoselective second cross-couplings of ketone derived dibromoolefins, which will be broadly useful in the general synthetic context.

Chapter two outlines an extremely concise synthesis of the metacyclophane macrocyclic alkaloid lythranidine. Our five-step synthesis demonstrates how a carefully considered direct strategy can produce a vast improvement in overall synthetic efficiency. The shortest previous synthesis of lythranidine required fifteen steps to access this natural product. The key to the efficiency of our approach is the exploitation of a barely hidden C2 symmetry in the natural product. This allows us to address the construction of the carbon macrocyclic framework while, in tandem, establishing the stereochemical relationships of the 2,6-trans-piperidine and secondary alcohol functionalities in only three steps. The efficiency of our approach has enabled access to gram quantities of advanced intermediates which have facilitated for the first-time useful quantities of material for biological evaluation.

Chapter three showcases a novel strategy in divergent total synthesis, which offers a solution to the construction alkaloids whose core skeletons differ at multiple stereogenic centres. Our strategy leverages the dynamic stereochemistry of carbon-nitrogen bonds to enable, from a single precursor, the first total synthesis of the tetracyclic quinolizidine alkaloid isomatrine, along with the shortest total syntheses of its diastereomeric family members, the natural products matrine and allomatrine in a total of eleven reactions. The efficiency of this approach is facilitated by the ability to rapidly construct the core of the natural products via a twofold intramolecular hetero-Diels-Alder reaction sequence of a dendralenic precursor. Access to significant quantities of these compounds enabled preparation of a further twelve matrine type natural products through late-stage manipulations providing a platform for a systematic study of their biological activity.

Chapter four presents a proof of principle for a general strategy which employs diene transmissive intramolecular Diels-Alder (IMDA) reactions of substituted [3]dendralenes to efficiently access diversely substituted multicyclic frameworks. The strategic application of Weinreb amide functionalised building blocks allows the late-stage step-economic introduction of various internally activated tethered dienophiles. Following the introduction of the dienophile, these compounds are engaged in IMDA reactions to generate semicyclic dienes which may then be further elaborated to tetracyclic structures via intermolecular Diels-Alder reactions. The development of diastereoselective IMDA reactions using dendralenes under Lewis acid promoted conditions, and the first examples of dehydro IMDA reactions of dendralenes with alkyne dienophiles have enabled the synthesis of structurally diverse polycyclic frameworks with further synthetic utility. The power of the strategy is demonstrated through its extension to the synthesis of additional types of [3]dendralene precursors which contain two tethers that allow for twofold Lewis acid promoted diene transmissive IMDA reactions to generate tetracyclic structures in a single step from acyclic precursors.