Chiral pool approaches to lycopodium alkaloids, orchidaceae alkaloids and photoswitchable ceramides

The following dissertation presents a series of chiral pool approaches to amine-containing natural products and photoactive lipid analogues. The first chapter summarizes the asymmetric total synthesis of lycopalhine A – a compact and stereochemically dense Lycopodium alkaloid – using L-glutamic acid as a starting point. The route features a diastereoselective Pauson–Khand reaction and an L-proline promoted 5-endo-trig Mannich cyclization. The successful synthesis allowed the characterization of a second co-eluting alkaloid, epi-lycopalhine A, and confirmed its interconversion with lycopalhine A through a retro-aldol/aldol equilibrium. A tentative path to palhinine D involving a reductive piperidine cyclization is afterwards presented. An azomethine ylide [3 + 2]-cycloaddition strategy towards the bioactive Orchidaceae alkaloid (+)-dendrobine is described in the second chapter. A cyclization precursor was generated in seven steps from (R)-carvone through a convergent esterification and an unconventional high-pressure Ireland–Claisen rearrangement. The resulting aldehyde was employed in a decarboxylative azomethine ylide cycloaddition following condensation with N-methylglycine to yield 5-deoxymubironine C, which differs from the natural product mubironine C by the absence of a single hydroxyl group. Thwarted attempts to incorporate this final functional group include an α-chlorination/lactonization sequence and an unplanned enal–ene reaction. The final chapter describes the synthesis of two photoswitchable sphingoid bases (aSph-1 and -2) from L-serine, and their coupling with alkyne-bearing fatty acids to generate clickable azobenzene-containing ceramide analogues (caCer-3 and caCer-4). Together with fatty acid azobenzene (FAAzo)-based caCer-1 and caCer-2 developed by postdoctoral researcher Henry Toombs-Ruane, these molecules were evaluated as optically active substrates for sphingomyelin synthase (SMS2). CaCers were successful incorporated into supported lipid bilayers (SLBs) and could alter the ordered/disorded domain ratio upon light irradiation. CaCer-1, -2 and -3 were competent substrates for SMS2 and conversion to their sphingomyelin analogues could be controlled in a light-dependent manner in both yeast membranes and HeLa cells