Biocatalytic Aromaticity-Breaking Epoxidation of Naphthalene and Nucleophilic Ring-Opening Reactions

Abstract

Aromatic hydroxylation reactions catalyzed by heme-thiolate enzymes proceed via an epoxide intermediate. These aromatic epoxides could be valuable building blocks for organic synthesis giving access to a range of chiral trans-disubstituted cyclohexadiene synthons. Here, we show that naphthalene epoxides generated by fungal peroxygenases can be subjected to nucleophilic ring opening, yielding non-racemic trans-disubstituted cyclohexadiene derivates, which in turn can be used for further chemical transformations. This approach may represent a promising shortcut for the synthesis of natural products and APIs.

Biocatalysis making waves in organic chemistry

“…191,212 This intermediate, however, can also be trapped via nucleophilic attack yielding trans-disubstituted cyclohexadienes (Scheme 23). 213 Very recently, some new flavin-dependent monooxygenases have been discovered that catalyse the aromaticity-breaking hydroxylation of resorcinol derivates. 214 So far the enzymes TropB, SorbC and AzaH with complementary site-and stereoselectivities have been identified from biosynthetic pathways.…”

Identification and Expression of New Unspecific Peroxygenases – Recent Advances, Challenges and Opportunities

“…Of course, one must always keep in mind that the rules of directed evolution apply, i.e., "you get what you screen for" (Schmidt-Dannert and Arnold, 1999). In case of the optimized variant PaDa-I, it turned out that it also oxides thermodynamically inert compounds such as aromatics providing access to naphthalene epoxides that can be subjected to nucleophilic ring opening reactions yielding chiral trans-disubstituted cyclohexane derivatives (Zhang et al, 2021). However, background absorption of medium compounds like soybean meal, the key inducing ingredient for UPO production in various fungal species, often leads to detection interferences and thus to limitations in the applicability of spectrophotometric assays (Anh et al, 2007;Poraj-Kobielska et al, 2012).…”

“…More than 400 substrates are now known to be converted by UPOs ( Hobisch et al, 2020 ). These reactions range from aromatic oxidations ( Ramirez-Ramirez et al, 2020 ), epoxidation of aromatics ( Zhang et al, 2021 ), oxidation of alcohols ( Kiebist et al, 2017 ), dealkylation ( Püllmann and Weissenborn, 2021 ), to oxygenation of unsaturated fatty acids ( Linde et al, 2020 ) and halogenations ( Ullrich et al, 2004 ).…”

“…Of course, one must always keep in mind that the rules of directed evolution apply, i.e., “you get what you screen for” ( Schmidt-Dannert and Arnold, 1999 ). In case of the optimized variant PaDa-I, it turned out that it also oxides thermodynamically inert compounds such as aromatics providing access to naphthalene epoxides that can be subjected to nucleophilic ring opening reactions yielding chiral trans-disubstituted cyclohexane derivatives ( Zhang et al, 2021 ).…”

Immobilization of the Peroxygenase from Agrocybe aegerita. The Effect of the Immobilization pH on the Features of an Ionically Exchanged Dimeric Peroxygenase

“…More recently, a His-tagged variant has been immobilized on EziG carriers with respectable activity recoveries between 53% and 78% [98]. Peroxygenases have been used as catalysts for selective hydroxylation, [70][71][72][73][74][75][76][77][78][79][80][81][82] epox idation [83][84][85][86] and sulfoxidation reactions [87,88]. Engineered enzymes with tailored sub strate specificity have been reported [64,80,81,[89][90][91], and issues related to the oxidativ inactivation in the presence of H2O2 have been solved as various in situ H2O2 generatio systems are now available [92].…”