![]() 1), such as FST B 12, pyrazolofluostatins A‒C 16, and FST R 17 have been proposed to derive from the corresponding epoxide precursors however, given the activity of FlsH it is not entirely clear how the epoxide would be cleaved and what enzymes if any would be responsible. Naturally isolated FSTs (Supplementary Fig. The α/β-hydrolase FlsH from the FST pathway in the South China Sea-derived Micromonospora rosaria SCSIO N160 has been shown to catalyze deacylation of acyl FSTs 18 however, it is unable to catalyze hydrolysis of the epoxide in FSTs despite its homology to Alp1U 18. Alp1U has also been shown to hydrolyze the epoxide of FST C ( 1) to afford the two stereoisomeric FSTs C1 ( 2) and C2 ( 3) (Fig. The α/β hydroxylases Alp1U and Lom6 were recently reported to catalyze stereoselective epoxide hydrolysis reactions during the biosynthesis of kinamycins and lomaiviticin 23. The atypical angucyclines are often characterized by a highly oxygenated A-ring that can undergo further modifications such as acylation, epoxidation, glycosylation, and dimerization leading to significant structural diversity 18, 21, 27, 31, 32. The benzofluorene core of the kinamycins and lomaiviticins is further decorated with a diazo group endowing these compounds with potent antitumor activities that has attracted considerable attention 29, 30. 1) 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, kinamycins 23, lomaiviticins 24, 25, and nenestatins 26, 27, 28 constitute a family of atypical angucyclines with a benzofluorene core (Supplementary Fig. In particular, the fluostatins (FSTs, e.g. Our findings extend the repertoire of known flavin chemistry that may provide new and useful tools for organic synthesis.Įpoxides are also an important structural element found in a wide variety of natural products and reactive intermediates in biosynthetic pathways 1. Similar reactions also take place in both natural products and other organic compounds harboring an epoxide adjacent to a carbonyl group that is conjugated to an aromatic moiety. These reactions lead to multiple products with different redox states that possess a single hydroxyl group at C-2, a 2,3-vicinal diol, a contracted five-membered A-ring, or an expanded seven-membered A-ring. The 2,3-epoxide ring in FST C is shown to open reductively via a putative enol intermediate, or oxidatively via a peroxylated intermediate with molecular oxygen as the oxidant. Here we report that fluostatins (FSTs), a family of atypical angucyclines with a benzofluorene core, can undergo nonenzyme-catalyzed epoxide ring opening reactions in the presence of flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NADH). Recall that alkyl substituents can donate electron density through hyper conjugation and stabilize a positive charge on a carbon.Epoxide ring opening reactions are common and important in both biological processes and synthetic applications and can be catalyzed in a non-redox manner by epoxide hydrolases or reductively by oxidoreductases. Then the carbon-oxygen bond begins to break (step 2) and positive charge begins to build up on the more substituted carbon. First, the oxygen is protonated, creating a good leaving group (step 1 below). The best way to depict the acid-catalyzed epoxide ring-opening reaction is as a hybrid, or cross, between an S N2 and S N1 mechanism. In a regioselective reaction, two (or more) different constitutional isomers are possible as products, but one is formed preferentially (or sometimes exclusively).Īcid-Catalyzed Epoxide Ring-Opening by Alcoholysis These are both good examples of regioselective reactions. When an asymmetric epoxide undergoes alcoholysis in basic methanol, ring-opening occurs by an S N2 mechanism, and the less substituted carbon is the site of nucleophilic attack, leading to what we will refer to as product B:Ĭonversely, when solvolysis occurs in acidic methanol, the reaction occurs by a mechanism with substantial S N1 character, and the more substituted carbon is the site of attack. If the epoxide is asymmetric, the structure of the product will vary according to which mechanism dominates. ![]() Ring-opening reactions can proceed by either S N2 or S N1 mechanisms, depending on the nature of the epoxide and on the reaction conditions. ![]() The ring-opening reactions of epoxides provide a nice overview of many of the concepts discussed in earlier chapters of this book. Additional Stereochemical Considerations of Ring-Opening.Epoxide Ring-Opening by Other Basic Nucleophiles.Acid-Catalyzed Epoxide Ring-Opening by Alcoholysis.Basic Epoxide Ring-Opening by Alcoholysis.
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