Studies on the Oxidation of Aromatic Amines Catalyzed by Trametes versicolor Laccase

Abstract

The bio-oxidation of a series of aromatic amines catalyzed by T. versicolor laccase has been investigated exploiting either commercially available nitrogenous substrates [(E)-4-vinyl aniline and diphenyl amine] or ad hoc synthetized ones [(E)-4-styrylaniline, (E)-4-(prop-1-en-1-yl)aniline and (E)-4-(((4-methoxyphenyl)imino)methyl)phenol]. At variance to their phenolic equivalents, the investigated aromatic amines were not converted into the expected cyclic dimeric structures under T. versicolor catalysis. The formation of complex oligomeric/polymeric or decomposition by-products was mainly observed, with the exception of the isolation of two interesting but unexpected chemical skeletons. Specifically, the biooxidation of diphenylamine resulted in an oxygenated quinone-like product, while, to our surprise, in the presence of T. versicolor laccase (E)-4-vinyl aniline was converted into a 1,2-substited cyclobutane ring. To the best of our knowledge, this is the first example of an enzymatically triggered [2 + 2] olefin cycloaddition. Possible reaction mechanisms to explain the formation of these products are also reported.

Keywords: T. versicolor laccases; anilines; bio-oxidation; biocatalyzed [2 + 2] olefin cycloaddition; radical chemistry.

Scheme 1

Mechanistic insights on phenazines formation via radical-cationic oxidation of substituted phenoxazinones (a) and phenazines (b,c) catalyzed by CotA-laccase.

Scheme 2

Oxygenated heterocycles synthetized via T. versicolor laccase catalysis: hexahydrofuro [3,4-c]furan (a), benzodioxane (b), and 2,3-dihydrobenzofuran (c) cores.

Figure 1

T. versicolor laccase-mediated domino process to 2,3-DHBs via a formal oxidative homocoupling. Examples of preparations of bioactive compounds: (A) δ-viniferin, a natural antioxidant able to bind to human hemoglobin [34] and (B) synthetic inhibitor of Hsp90 variants potentially endowed with antiproliferative activity [31].

Scheme 3

Substrates 1–5 and their likely expected laccase-catalyzed oxidation products.

Scheme 4

Synthetic entries to substrates 1, 2 and 4.

Figure 2

Hypothesized structure of the trimeric Bandrowski’s base-like product 2a formed in traces from 2 [36].

Scheme 5

Reaction of vinyl aniline 3 to give 3a via T. versicolor laccase–catalysis.

Scheme 6

Reaction of diphenyl amine 5 to give 5a via T. versicolor laccase–catalysis.

Scheme 7

Proposed mechanism for the biooxidation of 5.

Scheme 8

Proposed mechanism for the bio-oxidation of 3: a laccase-initiated [2 + 2] cycloaddition via a radical-cation activated species [39,40,41].