title: Total synthesis of zoanthamine alkaloids.
abstract: Zoanthamine alkaloids, isolated from organisms in the Zoanthus genus, constitute a distinctive family of marine metabolites. These molecules exhibit a broad spectrum of unique biological properties. For example, norzoanthamine inhibits interleukin-6, the key mediator of bone resorption in osteoporosis, providing a promising drug candidate for a disease that affects more than 10 million people over age 50 in the United States. In addition, these natural products are characterized by a densely functionalized heptacyclic framework, as exemplified by the structures of zoanthamine, norzoanthamine, and zoanthenol, which makes them extremely attractive targets for chemical synthesis. Prior to our first total synthesis of norzoanthamine in 2004, the densely functionalized and complex stereostructures of the zoanthamine alkaloids had impeded synthetic studies of these molecules. In this Account, we describe our synthetic approach toward the total synthesis of zoanthamine alkaloids, focusing on how we overcame various synthetic challenges.  At the beginning of our synthetic studies, we aimed to develop an efficient route that was flexible enough to provide access to several members of the family while allowing the synthesis of various analogues for biological testing. Our first project was the total synthesis of norzoanthamine, and we established an efficient synthetic route based on a novel strategy involving the following key features. First, we used a sequential three-component coupling reactions and subsequent photosensitized oxidation of a furan moiety to synthesize the precursor for the key intramolecular Diels-Alder reaction. Second, the key intramolecular Diels-Alder reaction constructed the ABC-ring carbon framework bearing two adjacent quaternary asymmetric carbon atoms at the C12 and C22 positions in a single stereoselective step. Third, we installed the third quaternary asymmetric carbon center at the C9 position by an intramolecular acylation of a keto alcohol followed by successive O-methylation and C-methylation reactions with complete stereoselectivity. Through the exploitation of a deuterium kinetic isoptope effect, we then efficiently synthesized the alkyne segment. Next, a coupling reaction between the alkyne segment and the amino alcohol segment and several subsequent synthetic transformations afforded the bis-aminoacetalization precursor. Finally, bis-aminoacetalization reactions carried out in one-pot constructed the DEFG-ring system and culminated in the total synthesis of norzoanthamine. Our synthetic route to norzoanthamine also allowed access to other zoanthamine alkaloids from a common synthetic intermediate, by way of stereoselective introduction of the C19 methyl group for zoanthamine, and isoaromatization for construction of the aromatic A-ring in zoanthenol. The chemistry described here not only allowed us to overcome formidable synthetic challenges but also opened a completely chemical avenue to naturally occurring zoanthamine alkaloids and their synthetic derivatives.
authors.affiliation: Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yoshimura
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanino
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyashita
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry*; D003903:Deuterium / Q000737:chemistry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry*; D006572:Heterocyclic Compounds, Bridged-Ring / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D001381:Azepines; D006576:Heterocyclic Compounds, 4 or More Rings; D006572:Heterocyclic Compounds, Bridged-Ring; D011804:Quinolines; C542309:zoanthamine; C457061:zoanthenol; C400280:norzoanthamine; D003903:Deuterium