The utilization of CO2 as a carbon source for organic synthesis meets the urgent demand for more sustainability in the production of chemicals. Herein, we report on the enzyme‐catalyzed para‐carboxylation of catechols, employing 3,4‐dihydroxybenzoic acid decarboxylases (AroY) that belong to the UbiD enzyme family. Crystal structures and accompanying solution data confirmed that AroY utilizes the recently discovered prenylated FMN (prFMN) cofactor, and requires oxidative maturation to form the catalytically competent prFMNiminium species. This study reports on the in vitro reconstitution and activation of a prFMN‐dependent enzyme that is capable of directly carboxylating aromatic catechol substrates under ambient conditions. A reaction mechanism for the reversible decarboxylation involving an intermediate with a single covalent bond between a quinoid adduct and cofactor is proposed, which is distinct from the mechanism of prFMN‐associated 1,3‐dipolar cycloadditions in related enzymes.

The utilization of carbon dioxide as a C 1 ‐building block for the production of valuable chemicals has recently attracted much interest. Whereas chemical CO 2 fixation is dominated by C−O and C−N bond forming reactions, the development of novel concepts for the carboxylation of C‐nucleophiles, which leads to the formation of carboxylic acids, is highly desired. Beside transition metal catalysis, biocatalysis has emerged as an attractive method for the highly regioselective (de)carboxylation of electron‐rich (hetero)aromatics, which has been recently further expanded to include conjugated α,β‐unsaturated (acrylic) acid derivatives. Depending on the type of substrate, different classes of enzymes have been explored for (i) the ortho ‐carboxylation of phenols catalyzed by metal‐dependent ortho ‐benzoic acid decarboxylases and (ii) the side‐chain carboxylation of para ‐hydroxystyrenes mediated by metal‐independent phenolic acid decarboxylases. Just recently, the portfolio of bio‐carboxylation reactions was complemented by (iii) the para ‐carboxylation of phenols and the decarboxylation of electron‐rich heterocyclic and acrylic acid derivatives mediated by prenylated FMN‐dependent decarboxylases, which is the main focus of this review. Bio(de)carboxylation processes proceed under physiological reaction conditions employing bicarbonate or (pressurized) CO 2 when running in the energetically uphill carboxylation direction. Aiming to facilitate the application of these enzymes in preparative‐scale biotransformations, their catalytic mechanism and substrate scope are analyzed in this review.

The C-C bond cleavage catalyzed by metal-dependent iso-orotate decarboxylase (IDCase) from the thymidine salvage pathway is of interest for the elucidation of a (hypothetical) DNA demethylation pathway. IDCase appears also as a promising candidate for the synthetic regioselective carboxylation of N-heteroaromatics. Herein, we report a joint experimental-theoretical study to gain insights into the metal identity, reaction mechanism, and substrate specificity of IDCase. In contrast to previous assumptions, the enzyme is demonstrated by ICPMS/MS measurements to contain a catalytically relevant Mn2+ rather than Zn2+. Quantum chemical calculations revealed that decarboxylation of the natural substrate (5-carboxyuracil) proceeds via a (reverse) electrophilic aromatic substitution with formation of CO2. The occurrence of previously proposed tetrahedral carboxylate intermediates with concomitant formation of HCO3- could be ruled out on the basis of prohibitively high energy barriers. In contrast to related o-benzoic acid decarboxylases, such as γ-resorcylate decarboxylase and 5-carboxyvanillate decarboxylase, which exhibit a relaxed substrate tolerance for phenolic acids, IDCase shows high substrate fidelity. Structural and energy comparisons suggest that this is caused by a unique hydrogen bonding of the heterocyclic natural substrate (5-carboxyuracil) to the surrounding residues. Analysis of calculated energies also shows that the reverse carboxylation of uracil is impeded by a strongly disfavored uphill reaction.

Nitrogen heterocycles (azacycles) are common structural motifs in numerous pharmaceuticals, agrochemicals, and natural products. Many powerful methods have been developed and continue to be advanced for the selective installation and modification of nitrogen heterocycles through C–H functionalization and C–C cleavage approaches, revealing new strategies for the synthesis of targets containing these structural entities. Here, we report the first total syntheses of the lycodine-type Lycopodium alkaloids casuarinine H, lycoplatyrine B, lycoplatyrine A, and lycopladine F as well as the total synthesis of 8,15-dihydrohuperzine A through bioinspired late-stage diversification of a readily accessible common precursor, N -desmethyl-β-obscurine. Key steps in the syntheses include oxidative C–C bond cleavage of a piperidine ring in the core structure of the obscurine intermediate and site-selective C–H borylation of a pyridine nucleus to enable cross-coupling reactions.

Broad substrate tolerance and excellent regioselectivity, as well as independence from sensitive cofactors have established benzoic acid decarboxylases from microbial sources as efficient biocatalysts. Robustness under process conditions makes them particularly attractive for preparative‐scale applications. The divalent metal‐dependent enzymes are capable of catalyzing the reversible non‐oxidative (de)carboxylation of a variety of electron‐rich (hetero)aromatic substrates analogously to the chemical Kolbe‐Schmitt reaction. Elemental mass spectrometry supported by crystal structure elucidation and quantum chemical calculations verified the presence of a catalytically relevant Mg2+ complexed in the active site of 2,3‐dihydroxybenoic acid decarboxylase from Aspergillus oryzae (2,3‐DHBD_Ao). This unique example with respect to the nature of the metal is in contrast to mechanistically related decarboxylases, which generally have Zn2+ or Mn2+ as the catalytically active metal.

Transaminases (TAs) have recently been established as catalysts for the asymmetric, reductive amination of prochiral ketones. Depending on the ketone substrate and the amine donor (the cosubstrate), equilibrium constants may limit high conversions; thus, methods to overcome this limitation are required. Removal of the co‐product from the reaction equilibrium through spontaneous, intramolecular reactions has provided a successful solution to this problem; therefore, these amine donors have been named “smart cosubstrates”. Here, we present a comparison of various bifunctional amine donors including vicinal diamines as potential structural cosubstrate motifs. Upon TA‐catalyzed deamination of 1,2‐diamines, spontaneous dimerization of the resulting α‐aminoketones and oxidation gave heteroaromatic pyrazines.

Dihydropinidine is a piperidine alkaloid found in spruce needles that has shown promising antifeedant activity against the large pine weevil, a widespread and economically relevant pest of coniferous tree plantations. Chemo-enzymatic approaches have previously been shown to enable a stepeconomic access to both enantiomers of this alkaloid, but the scalability of these syntheses is limited. Herein, we report a chemo-enzymatic route to dihydropinidine that is dominated by biocatalytic steps and affords the target alkaloid in excellent stereoisomeric purity (>99% ee and de) and high yield (57% overall) on multigram scale. Our synthesis makes use of a solvent-free, Lewis acid-catalyzed Michael addition and a biocatalytic alternative to Krapcho dealkoxycarbonylation, achieved by pig liver esterase (PLE)-catalyzed ester hydrolysis and acidification, and specifically developed for this purpose, to access a key intermediate, nonane-2,6-dione. This diketone is then converted into dihydropinidine by a concurrent one-pot (cascade) biotransformation catalyzed by a transaminase, an imine reductase, and an alcohol dehydrogenase. High yields and excellent regio-and stereoselectivities of the individual transformations render chromatographic purification of intermediates unnecessary and make it possible to carry out the entire sequence with a final hydrochloride precipitation of the target alkaloid as the sole purification step.

The catalytic promiscuity of a ferulic acid decarboxylase from Enterobacter sp. (FDC_Es) and phenolic acid decarboxylases (PADs) for the asymmetric conjugate addition of water across the C=C bond of hydroxystyrenes was extended to the N‐, C‐ and S‐nucleophiles methoxyamine, cyanide and propanethiol to furnish the corresponding addition products in up to 91% ee. The products obtained from the biotransformation employing the most suitable enzyme/nucleophile pairs were isolated and characterized after optimizing the reaction conditions. Finally, a mechanistic rationale supported by quantum mechanical calculations for the highly (S)‐selective addition of cyanide is proposed.