Chain Assembly Tactics for Efficient Syntheses of Callyspongiolide and Portimine
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Chain Assembly Tactics for Efficient Syntheses of Callyspongiolide and Portimine


Marine natural products are a rich source of small molecules with novel structures and potentially valuable biological activities. We have studied two new molecules of this type. Callyspongiolide is a sponge-derived macrolide harboring an arylated dien-yne appendage. Portimine is a macrobicyclic ketal scaffolded by a spirobicyclic imine isolated from a dinoflagellate. Both compounds strongly inhibit the growth of multiple human cancer cell lines at nanomolar concentrations, yet they appear to function very differently at the level of apoptotic signaling. The activity of callyspongiolide is caspase-independent and does not involve canonical apoptosis. In contrast, portimine is a selective potentiator of apoptosis that does not cause cellular damage or necrosis even at much higher doses. Its activity parallels the effects of pro-apoptotic biologics such as TNF alpha and TRAIL. As a steps towards understanding their biology, this thesis describes experiments to synthesize the highly functionalized backbones of each of these natural products in acyclic form, and subsequently convert those species into the natural products. It also outlines our collaborative discovery that callyspongiolide’s cellular target is the vacuolar H+ ATPase. Chapter one describes an asymmetric total synthesis of callyspongiolide, wherein the macrolactone core is built unconventionally from a saccharide and a monoterpene without the intermediacy of a seco-acid. Two main fragments were joined using Krische’s iridium-catalyzed asymmetric redox allylation. Fe(II)-promoted fragmentation of a perhemiketal and immediate Cu(II)-mediated β-hydride elimination selectively afforded a homoallylic alcohol, from which the macrolactone was synthesized via a carbonylative macrocyclization. The Z-acrylate was established by photolysis of the corresponding E-acrylate. Further homologation and Sonogashira coupling provided the natural product in an efficient manner. Chapter two discusses the discovery that callyspongiolide is a potent vacuolar ATPase inhibitor (IC50 = 10 nM) and the first V-ATPase inhibitor known to be expelled by Pdr5p. Chapter three discusses the re-assignment of the relative stereochemistry previously ascribed to product diastereomers resulting from imidazolidinone-catalyzed vinylogous Mukaiyama-Michael reaction of 2-trimethylsiloxyfuran and trans-crotonaldehyde. A modified procedure that uses a diphenylprolinol catalyst was subsequently developed to selectively provide the ‘syn’ diastereomeric product in high enantiomeric excess on decagram scales. Chapter four details the efforts towards the synthesis of portimine. Intramolecular Diels-Alder reaction was proposed for the construction of the macrocyclic carbon framework. A deoxygenated model system of portimine was designed and synthesized in 3 steps from the butenolide described in the previous chapter. It contains all the carbons present in portimine and allows the exploration of key transformations. En route to the natural product, the contiguous oxygenated stereocenters were established via aldol reaction followed by Narasaka-Prasad reduction. Substrates for Diels-Alder reaction were synthesized in 9 or 10 steps from the butenolide, with only one protecting group installed in the longest linear sequence. Diels-Alder cycloaddition of a dendralene substrate afforded an isomeric spiroimine framework.

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