Development of cross-coupling routes to macrocyclic polyenes: the first total synthesis of phacelocarpus 2-pyrone A

This thesis describes the development of a synthetic approach to an unusual pyrone-containing macrocyclic natural product isolated from the marine alga Phacelocarpus labillardieri. This comprises the synthesis of a simplified model system followed by the completion of the first total synthesis of the natural product and its suggested stereochemical reassignment, as well as studies on related palladium catalysis methodology. An overview of macrocyclic 2-pyrone natural products is given initially, along with a discussion of 2-pyrone reactivity and general macrocyclisation strategies in natural product synthesis (Chapter 1). The synthetic route was originally developed for the synthesis of the aromatic analogue, and various attempts and strategies towards this compound are described, culminating in its completion (Chapter 2). An account of the application of this strategy to the successful synthesis of the natural product is then given, the accomplishment of which allows a reassignment of the stereochemistry around the enol ether double bond from the previously assigned E to Z in the natural compound (Chapter 3). The remainder of the thesis focuses on two studies carried out on succinimide-based palladium complexes. The first concerns an investigation into the effect of air on the efficiency of Stille cross-coupling reactions catalysed by an established catalyst (Chapter 4), and the second an examination of two novel complexes including their synthesis, characterisation and catalytic activity (Chapter 5)

Unexpected Nickel Complex Speciation Unlocks Alternative Pathways for the Reactions of Alkyl Halides with dppf-Nickel(0)

The mechanism of the reactions between dppf-Ni0 complexes and alkyl halides has been investigated using kinetic and mechanistic experiments and DFT calculations. The active species is [Ni(κ2-dppf)(κ1-dppf)], which undergoes a halide abstraction reaction with alkyl halides and rapidly captures the alkyl radical that is formed. The rates of the reactions of [Ni(COD)(dppf)] with alkyl halides and the yields of prototypical nickel-catalyzed Kumada cross-coupling reactions of alkyl halides are shown to be significantly improved by the addition of free dppf ligand

Inhibition of (dppf)nickel-catalysed Suzuki-Miyaura cross-coupling reactions by α-halo-N-heterocycles

A nickel/dppf catalyst system was found to successfully achieve the Suzuki-Miyaura cross-coupling reactions of 3- and 4-chloropyridine and of 6-chloroquinoline but not of 2-chloropyridine or of other α-halo-N-heterocycles. Further investigations revealed that chloropyridines undergo rapid oxidative addition to [Ni(COD)(dppf)] but that α-halo-N-heterocycles lead to the formation of stable dimeric nickel species that are catalytically inactive in Suzuki-Miyaura cross-coupling reactions. However, the corresponding Kumada-Tamao-Corriu reactions all proceed readily, which is attributed to more rapid transmetalation of Grignard reagents

Synthetic approaches to pallimamine and analogues using direct imine acylation

The use of Direct Imine Acylation (DIA) methodology for the total synthesis of pallimamine is described, with three different synthetic routes examined. The construction of three advanced δ-lactam precursors, all utilising DIA, is described, along with attempts to progress these compounds further, using three distinct desymmetrisation strategies, two involving alcohol-aryl coupling, and a third involving an unusual diastereoselective lactonisation

The Effect of Added Ligands on the Reactions of [Ni(COD)(dppf)] with Alkyl Halides: Halide Abstraction can be Reversible

The reactions of dppf-nickel(0) with alkyl halides proceed via three-coordinate nickel(0) intermediates of the form [Ni(dppf)(L)]. The effect of the identity of the added ligand (L) on catalyst speciation and the rates of reactions of [Ni(COD)(dppf)] with alkyl halides has been investigated using kinetic experiments and DFT calculations. A series of monodentate ligands have been investigated in attempts to identify trends in reactivity. Sterically bulky and electron donating ligands are found to decrease the reaction rate. It was found that (i) the halide abstraction step is not always irreversible, and the subsequent recombination of a nickel(I) complex with an alkyl halide can have a significant effect on the overall rate of the reaction; and (ii) some ligands lead to very stable[Ni(dppf)(L) 2 ] species. The yields of prototypical (dppf)nickel-catalysed Kumada cross-coupling reactions of alkyl halides are significantly improved by the addition of free ligand, which provides another important variable to consider when optimizing nickel-catalysed reactions of alkyl halides

The effect of added ligands on the reactions of [Ni(COD)(dppf)] with alkyl halides : halide abstraction may be reversible

The reactions of dppf-nickel(0) with alkyl halides proceed via three-coordinate nickel(0) intermediates of the form [Ni(dppf)(L)]. The effects of the identity of the added ligand (L) on catalyst speciation and the rates of reactions of [Ni(COD)(dppf)] with alkyl halides have been investigated using kinetic experiments and density functional theory calculations. A series of monodentate ligands have been investigated in attempts to identify trends in reactivity. Sterically bulky and electron-donating ligands are found to decrease the reaction rate. It was found that (i) the halide abstraction step is not always irreversible and the subsequent recombination of a nickel(I) complex with an alkyl halide can have a significant effect on the overall rate of the reaction and (ii) some ligands lead to very stable [Ni(dppf)(L) 2] species. The yields of prototypical (dppf)nickel-catalyzed Kumada cross-coupling reactions of alkyl halides are significantly improved by the addition of free ligands, which provides another important variable to consider when optimizing nickel-catalyzed reactions of alkyl halides

Unexpected Nickel Complex Speciation Unlocks Alternative Pathways for the Reactions of Alkyl Halides with dppf-Nickel(0)

The mechanism of the reactions between dppf-Ni0 complexes and alkyl halides has been investigated using kinetic and mechanistic experiments and DFT calculations. The active species is [Ni(dppf)2], which undergoes a halide abstraction reaction with alkyl halides and rapidly captures the alkyl radical that is formed. The yields in prototypical nickel-catalysed Kumada cross-coupling reactions are shown to be improved by the addition of free phosphine ligands<br /

4-Hydroxy-6-alkyl-2-pyrones as nucleophilic coupling partners in Mitsunobu reactions and oxa-Michael additions

Two mild and efficient strategies have been developed for the O-functionalisation of 4-hydroxy-6-alkyl-2-pyrones, by using them as nucleophilic partners in oxa-Michael additions and the Mitsunobu reaction. The reactions proceed in moderate to excellent yields on a range of substrates containing useful functionality. The reactions serve as practical and valuable synthetic methods to construct complex 2-pyronyl ethers, which are found embedded in a number of natural products

Total synthesis and stereochemical revision of phacelocarpus 2-pyrone A

The first total synthesis of phacelocarpus 2-pyrone A is reported. The original natural compound was tentatively assigned (by NMR spectroscopy) as containing two cis-alkenes and a trans-vinyl ether connected to a 2-pyrone ring motif. Our computational predictions indicated that a cis-vinyl ether motif was equally feasible. Attempts to prepare the trans-vinyl ether were met with no success. The all cis-target compound was synthesised in nine steps, employing key regio- and stereoselective reactions including AuI-catalysed vinyl etherification, Wittig alkenylation and end-game Stille macrocyclisation. Analysis of the NMR data enabled identification and confirmation of the correct structure of phacelocarpus 2-pyrone A, containing a cis-vinyl ether. Our studies pave the way for future development of methodologies to these structurally distinct pyrone skipped-polyenyne natural products