Carboxylation of Hydroxyaromatic Compounds with HCO3− by Enzyme Catalysis: Recent Advances Open the Perspective for Valorization of Lignin-Derived Aromatics

Abstract

This review focuses on recent advances in the field of enzymatic carboxylation reactions of hydroxyaromatic compounds using HCO3− (as a CO2 source) to produce hydroxybenzoic and other phenolic acids in mild conditions with high selectivity and moderate to excellent yield. Nature offers an extensive portfolio of enzymes catalysing reversible decarboxylation of hydroxyaromatic acids, whose equilibrium can be pushed towards the side of the carboxylated products. Extensive structural and mutagenesis studies have allowed recent advances in the understanding of the reaction mechanism of decarboxylase enzymes, ultimately enabling an improved yield and expansion of the scope of the reaction. The topic is of particular relevance today as the scope of the carboxylation reactions can be extended to include lignin-related compounds in view of developing lignin biorefinery technology.

Non‐Oxidative Enzymatic (De)Carboxylation of (Hetero)Aromatics and Acrylic Acid Derivatives

“…The phenolic OH group seems to be mandatory, since NH 2 (aniline) and SH variants (thiophenol) are not accepted due to inaccurate electronic (lower or significantly higher p K a of the SH or NH protons, respectively) and/or structural (atomic diameter) properties. Carboxylation is inevitably associated to a free ortho ‐position . Regarding the substitution pattern, the meta ‐position ( m 2 , Figure ) opposite to the carboxylation site is most flexible tolerating weakly e − ‐withdrawing (halogens) and in particular e − ‐donating groups (alkyl, alkoxy, hydroxy, and amino functionalities), which can be even extended to (conjugated) aromatic systems to encompass remarkably large polyphenols, such as resveratrol .…”

“…In order to drive the equilibrium towards the energetically disfavored carboxylation direction, an excess of bicarbonate (usually 2–3 M) is most commonly applied as CO 2 source, alternatively pressurized (∼30 bar) or sub‐/supercritical carbon dioxide is used to a minor extent.…”

“…The stability and broad substrate tolerance of o ‐BDCs (such as 2,3‐dihydroxybenzoic acid decarboxylases from Aspergillus and Fusarium species, salicylic acid decarboxylase from Trichosporon moniliiforme , and 2,6‐dihydroxybenzoic acid/γ‐resorcylate decarboxylases from Agrobacterium , Rhizobium , Pandoraea , Rhodococcus and Polaromonas species) recommended them as excellent biocatalysts for the regioselective ortho ‐carboxylation of phenols also on a preparative scale. This also applies for 5‐carboxyvanillate decarboxylases (LigWs, from Sphingomonas and Novosphingobium species), although they exhibit a more restricted substrate tolerance . The minimal structural requirements (shown in Figure ) are characterized by a phenolic motif, in which the aromatic system supports the resonance stabilization of the carbanion intermediate.…”

“…The overall robustness and substrate tolerance of PADs is more limited compared to those of o ‐BDCs . The introduction of functionalization is mainly restricted to the ortho ‐positions ( o 1 and/or o 2 ) tolerating e − ‐donating (alkyl, alkoxy) and ‐withdrawing groups (halogens), whereas meta ‐substitution ( m 1 , m 2 ) led to unstable products.…”

“…The latter are applicable to the decarboxylation of acrylic acid derivatives as well as the para ‐carboxylation of phenols. Furthermore, a general overview is given for the ortho ‐ and side‐chain (de)carboxylation of phenol‐ and hydroxystyrene‐type substrates by metal‐dependent and cofactor‐independent decarboxylases, both summarized in a recent comprehensive review by I. C. Tommasi …”