SignificanceBioinformatics and virus-induced gene silencing (VIGS)-guided gene discovery combined with biochemical enzyme assays show that tabersonine 3-oxygenase (T3O) and tabersonine 3-reductase (T3R) are required to form 3-hydroxy-16-methoxy-2,3-dihydrotabersonine, an intermediate in the formation of anticancer drug precursor vindoline from tabersonine. In the absence of T3R, tabersonine is converted by T3O to a series of byproducts that can no longer be used by T3R, suggesting a concerted reaction mechanism. Engineering the seven-gene pathway in yeast demonstrated a prototype platform of high potential for industrial production of the anticancer drug precursor vindoline.

This update covers the syntheses of Amaryllidaceae alkaloids since the publication of the last major review in 2008. A short summary of past syntheses and their step count is provided for the major constituents; pancratistatin, 7-deoxypancratistatin, narciclasine, lycoricidine, lycorine, and for other natural constituents, as well as for unnatural derivatives. Discussion of biological activities is provided for unnatural derivatives. Future prospects and further developments in this area are covered at the end of the review. The literature is covered to the end of August 2015.

Discovering bioactive metabolites within a metabolome is challenging because there is generally little foreknowledge of metabolite molecular and cell-targeting activities. Here, single-cell response profiles and primary human tissue comprise a response platform used to discover novel microbial metabolites with cell-type-selective effector properties in untargeted metabolomic inventories. Metabolites display diverse effector mechanisms, including targeting protein synthesis, cell cycle status, DNA damage repair, necrosis, apoptosis, or phosphoprotein signaling. Arrayed metabolites are tested against acute myeloid leukemia patient bone marrow and molecules that specifically targeted blast cells or nonleukemic immune cell subsets within the same tissue biopsy are revealed. Cell-targeting polyketides are identified in extracts from biosynthetically prolific bacteria, including a previously unreported leukemia blast-targeting anthracycline and a polyene macrolactam that alternates between targeting blasts or nonmalignant cells by way of light-triggered photochemical isomerization. High-resolution cell profiling with mass cytometry confirms response mechanisms and is used to validate initial observations.

A new periodate-based reactive assay system enables the rapid evaluation of the cis-dihydroxylation activity of Rieske dioxygenase enzymes.

Scheme 1. Asymmetric dihydroxylation of aromatic substrates catalyzed by Rieske dioxygenases (RDOs), and examples of the synthetic utility of the resultant cis-diol metabolites.

The hydroxylated cyclohexenone carboxylic acid moiety of xylosmin was synthesized in eight steps from benzoic acid. The key steps in the synthesis involved the enzymatic dihydroxylation of benzoic acid by the whole cell fermentation with Ralstonia eutrophus B9, and Henbest epoxidation. Early attempts led to the synthesis of a C6 epimer of the methyl ester of the hydroxylated cyclohexenone carboxylic acid moiety. The absolute stereochemistry of an advanced intermediate was confirmed by X-ray crystallography. Complete characterization of the previously reported but not fully characterized hydroxylated cyclohexenone carboxylic acid is provided.

As part of our research exploring the influence of molecular variations of Calone 1951® on marine fragrance performance, we report the synthesis, crystal structures, and olfactory analysis of the first saturated benzodioxepinone analogues. By substitution of the aromatic moiety of the benzodioxepinone fragrance molecule with a saturated ring counterpart, we endeavoured to discover the molecular interactions of the aromatic and aliphatic rings with fragrance receptor sites, and also to shed light on any potential chiral interactions occurring within the receptor. Our results showed that an aromatic ring system is necessary for binding to the marine odour receptor(s), and that the addition of an alkene or methyl substituent has little effect on the low receptor affinity. However, a weak marine odour character was found for the 6‐methyl saturated derivatives, which could possibly be explained by superposition analysis of the respective structures, which were derived from X‐ray coordinates.

Advanced intermediates for the syntheses of tetrodotoxin reported by the groups of Fukuyama, Alonso, and Sato were prepared. Key steps include the toluene dioxygenase mediated dihydroxylation of either iodobenzene or benzyl acetate. The resulting diene diols were transformed into Fukuyama's intermediate in six steps, into Alonso's intermediate in nine steps, and into Sato's intermediate in ten steps.