Oceanic cyanobacteria are the most abundant oxygen-generating phototrophs on our planet, and therefore, important to life. These organisms are infected by viruses called cyanophages, recently shown to encode metabolic genes that modulate host photosynthesis, phosphorus cycling and nucleotide metabolism. Herein, we report the characterisation of a wild type flavin-dependent viral halogenase (VirX1) from a cyanophage. Notably, halogenases have been previously associated 2 with secondary metabolism, tailoring natural products. Exploration of this viral halogenase reveals it capable of regioselective halogenation of a diverse range of substrates, with a preference for forming aryl iodide species; this has potential implications for the metabolism of the infected host. Until recently, a flavin-dependent halogenase (FDH) capable of iodination in vitro had not been reported. VirX1 is interesting from a biocatalytic perspective showing strikingly broad substrate flexibility, and a clear preference for iodination, as illustrated by kinetic analysis. These factors together render it an attractive tool for synthesis. The selective formation of carbon-halogen (C-X) bonds is of great importance to the pharmaceutical and agrochemical industries 1,2. The introduction of a halogen (X) into a molecule can be used to modulate bioactivity, bioavailability and metabolic stability 1-3. Traditional chemical methodologies of halogenating aromatic substrates generally employ highly reactive reagents and generate harmful waste. As traditional reagents lack components that enable the tuning of product selectivity, they oftentimes generate products in which either only the most nucleophilic position is halogenated or mixtures of products are produced. Conversely, biosynthetic (enzymatic) halogenation is mild, highly selective and utilises simple salts such as NaCl or NH 4 Br as the source of halide while oxygen serves as the oxidant 1-3. Consequently, the discovery and structural characterisation of flavin-dependent halogenases (FDHs) capable of selectively forming C-Cl and C-Br bonds 4,5 and the discovery of a S-adenosylmethionine (SAM)-dependent fluorinase 6 , able to mediate nucleophilic C-F bond formation, attracted considerable attention. Until recently, a FDH capable of generating C-I bonds remained to be discovered and characterised 7 .

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This contribution describes a synthetic approach to alkaloid GB 13, previously isolated from the North Australian and Papua New Guinean rain forest tree Galbulimima belgraveana. A Birch reductive alkylation of 2,5-dimethoxybenzoic acid by 3-methoxybenzyl bromide, followed by an acid-catalyzed cyclization was used to synthesize the [3.3.1]bicyclononane 8. A ring contraction performed on the diazo derivative 9 of the [3.3.1]bicyclononane led to [3.2.1]bicyclooctane 10. This [3.2.1]bicyclooctane was converted into a dienophile and subjected to a Diels-Alder reaction to generate a pentacyclic intermediate 13 with a carbon skeleton closely resembling the target alkaloid. The surplus substituent, required for activation and regioselectivity in the Diels-Alder reaction, was removed using Birch reductive conditions to effect a decyanation. It was discovered that a Birch reduction of the aromatic ring also present in the molecule could be performed at the same time to give the enone 15, which was cleaved by means of an Eschenmoser fragmentation. The piperidine ring found in the natural product was formed by reductive cyclization of the bis-oxime 18 derived from the alkynyl ketone 17 and the resulting material further elaborated to GB 13 (1) via ketone 20.