R.B. Leveson-Gower

Cylindrocyclophanes A and F and merocyclophanes A and D were synthesized by a chemoenzymatic approach. The synthesis features an enzymatic Friedel–Crafts alkylation, reagent-controlled lithiation–borylation chemistry, cobalt-catalyzed asymmetric hydroboration, and Ni- or Pd-catalyzed alkyl–alkyl cross-coupling.

Abstract

Incorporating enzymatic reactions into natural product synthesis can significantly improve synthetic efficiency and selectivity. In contrast to the increasing applications of biocatalytic functional-group interconversions, the use of enzymatic C−C bond formation reactions in natural product synthesis is underexplored. Herein, we report a concise and efficient approach for the synthesis of [7.7]paracyclophane natural products, a family of polyketides with diverse biological activities. By using enzymatic Friedel–Crafts alkylation, cylindrocyclophanes A and F and merocyclophanes A and D were synthesized in six to eight steps in the longest linear sequence. This study demonstrates the power of combining enzymatic reactions with contemporary synthetic methodologies and provides opportunities for the structure–activity relationship studies of [7.7]paracyclophane natural products.

Nature Chemical Biology, Published online: 28 September 2023; doi:10.1038/s41589-023-01426-y

The flavoenzyme nicotine oxidoreductase degrades nicotine in the bloodstream. Now, genetic selection in bacteria has been used to improve the catalytic performance of nicotine oxidoreductase, isolating variants with increased O2 reactivity that were more effective at degrading nicotine in the blood of rats.

The creation of enzymes containing non-biological functionalities with activation modes outside of Nature’s canon paves the way towards fully programmable biocatalysis. Here, we present a fully genetically encoded boronic acid containing designer enzyme with organocatalytic reactivity not achievable with natural or engineered biocatalysts. This boron enzyme catalyzes the kinetic resolution of hydroxyketones by oxime formation where crucial interactions with the protein scaffold assist in the catalysis. A directed evolution campaign lead to a variant with natural enzyme like enantioselectivities for a number of different substrates. The unique activation mode of the boron enzyme was studied via X-ray crystallography, high resolution mass spectrometry and 11B NMR spectroscopy and opens up the possibility for a new class of boron dependent biocatalysts.

Saturated N-heterocycles constitute a vital scaffold for pharmaceutical chemistry, but are challenging to access synthetically, particularly in asymmetric mode. Here we demonstrate how imine reductases can achieve annulation through tandem inter and intramolecular reductive amination processes. Imine reductases were used in combination with further enzymes to access un-substituted, α-substituted and α,α’-disubstituted N-heterocycles from simple starting materials, in one pot and under benign conditions. The work was exemplified in regard to product scope and a new route to the valuable natural product nicotine was demonstrated.

Nature, Published online: 20 September 2023; doi:10.1038/s41586-023-06529-z

Heterogeneous geminal-atom catalysts, which pair single-atom sites in specific coordination and spatial proximity, offer a new avenue for the sustainable manufacture of fine chemicals.

In this study, we describe a light-driven photocatalytic decarboxylation of palmitic acid and related fatty acids using Chlorella variabilis fatty acid photodecarboxylase (CvFAP). By utilizing violet LED light (50 W; 397 nm), we achieved a remarkable conversion efficiency of 99% within just 4 minutes, surpassing the previous 79% conversion achieved in 60 minutes using blue LED light (300 W; 439 nm). Importantly, the use of 50 W violet LED light also resulted with lower enzyme photoinactivation rate when compared to 300 W blue LED. Comparing the whole-cell biocatalyst with the enzymatic extract, we found that the former demonstrated superior catalytic performance and reduced susceptibility to photoinactivation. Furthermore, through fed-batch reactions using three pulses of 13 mM palmitic acid, we achieved the production of 39 mM of pentadecane within 1 hour, highlighting a promising strategy for enhanced productivity. These findings represent a significant advancement in CvFAP photodecarboxylation processes, utilizing an alternative light source, with potential implications for biofuel production.

Efficient Mn artificial transfer hydrogenases (ATHases) were developed using the biotin-streptavidin technology, which exhibits high activity and enantioselectivity for the transfer hydrogenation of a wide range of aryl ketones. The S112Y-K121 M double mutation and the appropriate chemical structure of the Mn cofactor play critical roles in the reactivity and enantioselectivity of the enzymes.

Abstract

Artificial (transfer) hydrogenases have been developed for organic synthesis, but they rely on precious metals. Native hydrogenases use Earth-abundant metals, but these cannot be applied for organic synthesis due, in part, to their substrate specificity. Herein, we report the design and development of manganese transfer hydrogenases based on the biotin-streptavidin technology. By incorporating bio-mimetic Mn(I) complexes into the binding cavity of streptavidin, and through chemo-genetic optimization, we have obtained artificial enzymes that hydrogenate ketones with nearly quantitative yield and up to 98 % enantiomeric excess (ee). These enzymes exhibit broad substrate scope and high functional-group tolerance. According to QM/MM calculations and X-ray crystallography, the S112Y mutation, combined with the appropriate chemical structure of the Mn cofactor plays a critical role in the reactivity and enantioselectivity of the artificial metalloenzyme (ArMs). Our work highlights the potential of ArMs incorporating base-meal cofactors for enantioselective organic synthesis.

Sulfur trioxide acts as a strong oxidizer towards halides as well as pseudohalides. Therefore, reactions of sulfur trioxide with cyanide anions do usually not lead to the formation of cyanido-sulfates anion but to oxidation of the cyanide ion. This problem can be avoided if a sulfur trioxide-pyridine complex is used instead of neat sulfur trioxide. In this way, the oxidation power is sufficiently reduced, and the pyridine molecule can be replaced by the cyanide anion under formation of the cyanido-sulfate anion, SO₃CN⁻. Thus sulfur trioxide gets rid of the badly smelling pyridine molecule, however, at the expense of gaining the toxic cyanide anion. More information can be found in the Research Article by M. S. Wickleder and co-workers (DOI: 10.1002/chem.202301761).

Generating artificial metalloenzymes (ArMs) by incorporating a non-natural metallocofactor within a protein host is an attractive strategy to complement homogeneous catalysts and enzymes. In an effort to achieve Co(TAML) catalyzed asymmetric radical-type oxygen atom transfer catalysis, we anchored a biotinylated Co(TAML) cofactor into streptavidin. In the presence of iodosylbenzene and α-methylstyrene, the Co(TAML) based ArM led to the corresponding enantioenriched oxirane, thereby expanding the scope of ArMs that facilitate radical-type transformations. Screening of the Sav library—that included (double) mutations at positions S112 and K121—enabled improvement of both the activity and the selectivity of the Co-TAML-catalyzed epoxidation reaction. Evaluation of the secondary coordination sphere around the Co(TAML) cofactor by analysis of the X-ray structures of two different ArMs: Co(TAML) · Sav WT and Co(TAML) · Sav S112Y, suggested how mutations may affect the catalytic properties.

Proceedings of the National Academy of Sciences, Volume 120, Issue 37, September 2023.

Nature Catalysis, Published online: 14 September 2023; doi:10.1038/s41929-023-01024-0

Non-natural photobiocatalysis is attractive but usually involves UV light activation or the formation of electron donor–acceptor complexes. Now direct visible-light excitation of flavin-dependent ene-reductases allows stereocontrolled intermolecular radical hydroarylation of alkenes initiated by single-electron oxidation.

Taste perception plays a pivotal role in guiding nutrient intake and aiding in the avoidance of potentially harmful substances through five basic tastes - sweet, bitter, umami, salty, and sour. Taste perception originates from molecular interactions in the oral cavity between taste receptors and chemical tastants. Hence, the recognition of taste receptors and the subsequent perception of taste heavily rely on the physicochemical properties of food ingredients. In recent years, several advances have been made towards the development of machine learning-based algorithms to classify chemical compounds' tastes using their molecular structures. Despite the great efforts, there remains significant room for improvement by developing multi-class models to predict the entire spectrum of basic tastes. Here, we present a multi-class predictor aimed at distinguishing three different tastes, i.e., bitter, sweet, and umami, from other taste sensations. The developed model has been integrated into a publicly accessible web platform. This work lays the groundwork for a comprehensive understanding of the molecular features that drive the perception of tastes, paving the way towards new methodologies in the rational design of foods, such as the pre-determination of specific tastes, the engineering of complementary diets to traditional pharmacological treatments, and many others.

Communications Chemistry, Published online: 11 September 2023; doi:10.1038/s42004-023-00998-z

Microbial enzymes are capable of degrading certain synthetic polymers, with most polyethylene terephthalate (PET) degrading enzymes known to derive from bacteria or fungi. Here, the authors describe an archaeal originating feruloyl-esterase PET46 enzyme with a flexible lid domain and PET degradation capability.

Biocatalytic group transfer reactions can efficiently generate highly complex molecules under mild and environmentally friendly conditions. This Minireview highlights inspiring examples of the development of non-natural donor reagents to power such enzymatic transformations, while discussing the design aspects behind the choice of reagent.

Abstract

Biocatalysis has become a major driver in the innovation of preparative chemistry. Enzyme discovery, engineering and computational design have matured to reliable strategies in the development of biocatalytic processes. By comparison, substrate engineering has received much less attention. In this Minireview, we highlight the idea that the design of synthetic reagents may be an equally fruitful and complementary approach to develop novel enzyme-catalysed group transfer chemistry. This Minireview discusses key examples from the literature that illustrate how synthetic substrates can be devised to improve the efficiency, scalability and sustainability, as well as the scope of such reactions. We also provide an opinion as to how this concept might be further developed in the future, aspiring to replicate the evolutionary success story of natural group transfer reagents, such as adenosine triphosphate (ATP) and S-adenosyl methionine (SAM).

Nature Chemistry, Published online: 11 September 2023; doi:10.1038/s41557-023-01333-8

Merging carbonyls to form an alkene by removing their oxygens is rare, yet synthetically useful, and the selective combination of two different carbonyls is especially challenging. Now, two strategies for cross-metathesis of unbiased carbonyls have been developed. An Fe-catalysed carbene/ylide strategy affords Z-alkenes, while Cr-catalysed gem-di-metals yield E-alkenes.

Science, Volume 381, Issue 6660, Page 836-836, August 2023.

Science, Volume 381, Issue 6662, Page 1040-1041, September 2023.