Hitting the right target: Differentiation between two keto moieties was accomplished by a regio‐ and enantioselective bioamination employing ω‐transaminases. Using 1,5‐diketones as substrates gave ...access to the optically pure 2,6‐disubstituted piperidine scaffold. The approach allowed the shortest synthesis of the alkaloid dihydropinidine, as well as its enantiomer, by choosing an appropriate ω‐transaminase.
The cleavage of aryl methyl ethers is a common reaction in chemistry requiring rather harsh conditions; consequently, it is prone to undesired reactions and lacks regioselectivity. Nevertheless, ...O-demethylation of aryl methyl ethers is a tool to valorize natural and pharmaceutical compounds by deprotecting reactive hydroxyl moieties. Various oxidative enzymes are known to catalyze this reaction at the expense of molecular oxygen, which may lead in the case of phenols/catechols to undesired side reactions (e.g., oxidation, polymerization). Here an oxygen-independent demethylation via methyl transfer is presented employing a cobalamin-dependent veratrol-O-demethylase (vdmB). The biocatalytic demethylation transforms a variety of aryl methyl ethers with two functional methoxy moieties either in 1,2-position or in 1,3-position. Biocatalytic reactions enabled, for instance, the regioselective monodemethylation of substituted 3,4-dimethoxy phenol as well as the monodemethylation of 1,3,5-trimethoxybenzene. The methyltransferase vdmB was also successfully applied for the regioselective demethylation of natural compounds such as papaverine and rac-yatein. The approach presented here represents an alternative to chemical and enzymatic demethylation concepts and allows performing regioselective demethylation in the absence of oxygen under mild conditions, representing a valuable extension of the synthetic repertoire to modify pharmaceuticals and diversify natural products.
C−C bond‐forming reactions are key transformations for setting up the carbon frameworks of organic compounds. In this context, Friedel–Crafts acylation is commonly used for the synthesis of aryl ...ketones, which are common motifs in many fine chemicals and natural products. A bacterial multicomponent acyltransferase from Pseudomonas protegens (PpATase) catalyzes such Friedel–Crafts C‐acylation of phenolic substrates in aqueous solution, reaching up to >99 % conversion without the need for CoA‐activated reagents. We determined X‐ray crystal structures of the native and ligand‐bound complexes. This multimeric enzyme consists of three subunits: PhlA, PhlB, and PhlC, arranged in a Phl(A2C2)2B4 composition. The structure of a reaction intermediate obtained from crystals soaked with the natural substrate 1‐(2,4,6‐trihydroxyphenyl)ethanone together with site‐directed mutagenesis studies revealed that only residues from the PhlC subunits are involved in the acyl transfer reaction, with Cys88 very likely playing a significant role during catalysis. These structural and mechanistic insights form the basis of further enzyme engineering efforts directed towards enhancing the substrate scope of this enzyme.
Crystal structures of a dodecameric enzyme: This multimeric enzyme consists of three subunits: PhlA, PhlB, and PhlC, arranged in a Phl(A2C2)2B4 composition. The PhlC subunit catalyzes the Friedel–Crafts C‐acylation of phenolic substrates in aqueous solution without the need for CoA‐activated reagents.
Black and white are opposites as are oxidation and reduction. Performing an oxidation, for example, of a sec-alcohol and a reduction of the corresponding ketone in the same vessel without separation ...of the reagents seems to be an impossible task. Here we show that oxidative cofactor recycling of NADP+ and reductive regeneration of NADH can be performed simultaneously in the same compartment without significant interference. Regeneration cycles can be run in opposing directions beside each other enabling one-pot transformation of racemic alcohols to one enantiomer via concurrent enantioselective oxidation and asymmetric reduction employing defined alcohol dehydrogenases with opposite stereo- and cofactor-preference. Thus, by careful selection of appropriate enzymes, NADH recycling can be performed in the presence of NADP+ recycling to achieve overall, for example, deracemisation of sec-alcohols or stereoinversion representing a possible concept for a “green” equivalent to the chemical-intensive Mitsunobu inversion.
All for one: A combination of three biocatalysts (ω‐transaminase, alanine dehydrogenase, and an enzyme such as formate dehydrogenase for cofactor recycling) catalyze a cascade to achieve the ...asymmetric transformation of a ketone into a primary α‐chiral unprotected amine through a formal stereoselective reductive amination (see scheme). Only ammonia and the reducing agent (formate) are consumed during this reaction.
Stereoselective methods for the synthesis of tetrahydro‐ß‐carbolines are of significant interest due to the broad spectrum of biological activity of the target molecules. In the plant kingdom, ...strictosidine synthases catalyze the C−C coupling through a Pictet–Spengler reaction of tryptamine and secologanin to exclusively form the (S)‐configured tetrahydro‐ß‐carboline (S)‐strictosidine. Investigating the biocatalytic Pictet–Spengler reaction of tryptamine with small‐molecular‐weight aliphatic aldehydes revealed that the strictosidine synthases give unexpectedly access to the (R)‐configured product. Developing an efficient expression method for the enzyme allowed the preparative transformation of various aldehydes, giving the products with up to >98 % ee. With this tool in hand, a chemoenzymatic two‐step synthesis of (R)‐harmicine was achieved, giving (R)‐harmicine in 67 % overall yield in optically pure form.
The unexpected: Strictosidine synthases possess a much broader aldehyde substrate tolerance than hitherto assumed. It was shown that strictosidine synthases catalyze the Pictet–Spengler reaction of tryptamine with low‐molecular‐weight aldehydes to give unexpected access to the (R)‐configured products in high yields with up to 98 % ee, in contrast to the natural (S)‐configured product. This allowed the synthesis of (R)‐harmicine in two steps in optically pure form.
Breaking the mirror: A purified alcohol dehydrogenase (ADH) for stereoselective reduction and whole cells of a microorganism for enantioselective oxidation operated concurrently to effect the ...stereoinversion of one enantiomer of a racemic secondary alcohol and provide the optically pure alcohol in >99 % yield (see scheme). R,R′=alkyl.
Organofluorine compounds have become important building blocks for a broad range of advanced materials, polymers, agrochemicals, and increasingly for pharmaceuticals. Despite tremendous progress ...within the area of fluorination chemistry, methods for the direct introduction of fluoroalkyl-groups into organic molecules without prefunctionalization are still highly desired. Here we present a concept for the introduction of the trifluoromethyl group into unprotected phenols by employing a biocatalyst (laccase), tBuOOH, and either the Langlois' reagent or Baran's zinc sulfinate. The method relies on the recombination of two radical species, namely, the phenol radical cation generated directly by the laccase and the CF
-radical. Various functional groups such as ketone, ester, aldehyde, ether and nitrile are tolerated. This laccase-catalysed trifluoromethylation proceeds under mild conditions and allows accessing trifluoromethyl-substituted phenols that were not available by classical methods.
One-pot combinations of sequential catalytic reactions can offer practical and ecological advantages over classical multi-step synthesis schemes. In this context, the integration of enzymatic and ...chemo-catalytic transformations holds particular potential for efficient and selective reaction sequences that would not be possible using either method alone. Here, we report the one-pot combination of alcohol dehydrogenase-catalysed asymmetric reduction of 2-azido ketones and Pd nanoparticle-catalysed hydrogenation of the resulting azido alcohols, which gives access to both enantiomers of aromatic 1,2-amino alcohols in high yields and excellent optical purity (ee >99%). Furthermore, we demonstrate the incorporation of an upstream azidolysis and a downstream acylation step into the one-pot system, thus establishing a highly integrated synthesis of the antiviral natural product (S)-tembamide in 73% yield (ee >99%) over 4 steps. Avoiding the purification and isolation of intermediates in this synthetic sequence leads to an unprecedentedly low ecological footprint, as quantified by the E-factor and solvent demand.
Tomato source: 12‐Oxophytodienoate reductase isoenzymes OPR1 and OPR3 from tomato possess a broad substrate spectrum for the asymmetric bioreduction of α,β‐unsaturated enals, enones, dicarboxylic ...acids, and N‐substituted maleimides (see scheme). Stereocomplementary behavior of both isoenzymes was observed in the reduction of a nitroalkene that led to the formation of opposite stereoisomers in high enantiomeric excess.
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