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Access to both enantiomers of orphenadrine and model of the origins of stereoselectivity. a Formal syntheses of (R)- and (S)-orphenadrine using the one-pot, chemoenzymatic methodology. Conditions (Coupling: step 1): substrate (1.0 equiv), boronate (3.0 equiv), Ni(cod)2 (15 mol%), SIPr (30 mol%), K3PO4 (2.0 equiv), and H2O (0.5 M), heated at 60 °C for 24 h, followed by quenching with 1 M HCl. Conditions (Reduction: step 2): KRED (10 mg/mL), Recycle Mix P (18.2 mg/mL), i-PrOH (52 equiv), and H2O (0.025 M), heated at 35 °C and stirred for 24 h at 350 mbar; Na2NADP(+)•3H2O (0.044 equiv), heated at 35 °C and stirred for an additional 24 h at 350 mbar. Reactions were performed on 0.1 mmol scale and the yields reported reflect the average of two isolation experiments. Enantiomeric excesses (ee) were determined via chiral SFC. b Analysis of binding pocket and origins of stereoselectivities for the wild-type KRED, KRED P1-B12, and KRED 404 (ketone 14 is docked). Protein coordinates taken from “PDB ID 1ZK4, 1.0 Å resolution” and then used in modeling studies. The ketoreductases are shown in gray and NADPH is shown in yellow. Key residues in the binding pocket are shown in aqua green for P1-B12 and in purple for 404 (nitrogen shown in red, oxygen in blue)
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One-pot reactions that combine non-enzymatic and biocatalytic transformations represent an emerging strategy in chemical synthesis. Some of the most powerful chemoenzymatic methodologies, although uncommon, are those that form a carbon-carbon (C-C) bond and a stereocenter at one of the reacting carbons, thereby streamlining traditional retrosynthet...
Citations
... The archetypal example for this approach, a chemoenzymatic cascade for enantioselective synthesis of biaryl alcohols was developed by Gröger and coworkers (Fig. 1b) 24 . Although uncommon, enzymatic generation of a stereocenter at one of the chemically reacting carbons offers a new strategy for synthetic pathway design [25][26][27][28] . For example, Zhao et al. developed a chemoenzymatic cascade for formal asymmetric C-C bond formation by combining metal-catalyzed construction of C=C bond and enzymatic reduction of the newly formed C=C bond 28 . ...
Chemoenzymatic cascade catalysis has emerged as a revolutionary tool for streamlining traditional retrosynthetic disconnections, creating new possibilities for the asymmetric synthesis of valuable chiral compounds. Here we construct a one-pot concurrent chemoenzymatic cascade by integrating organobismuth-catalyzed aldol condensation with ene-reductase (ER)-catalyzed enantioselective reduction, enabling the formal asymmetric α-benzylation of cyclic ketones. To achieve this, we develop a pair of enantiocomplementary ERs capable of reducing α-arylidene cyclic ketones, lactams, and lactones. Our engineered mutants exhibit significantly higher activity, up to 37-fold, and broader substrate specificity compared to the parent enzyme. The key to success is due to the well-tuned hydride attack distance/angle and, more importantly, to the synergistic proton-delivery triade of Tyr28-Tyr69-Tyr169. Molecular docking and density functional theory (DFT) studies provide important insights into the bioreduction mechanisms. Furthermore, we demonstrate the synthetic utility of the best mutants in the asymmetric synthesis of several key chiral synthons.
... The cascade of biological and chemical catalysts, including enzymes and metal catalysts (Pd, 153,154 Ni,155 and Cu 156 ), has been extensively employed in the industry. However, when these catalysts are utilized in a one-pot reaction, a typical challenge occurs: the mutual inactivation between enzymes and metal catalysts. ...
Building bridges among different types of catalysts to construct cascades is a highly worthwhile pursuit, such as chemo-, bio-, and chemo–bio cascade reactions. Cascade reactions can improve the reaction efficiency and selectivity while reducing steps of separation and purification, thereby promoting the development of “green chemistry”. However, compatibility issues in cascade reactions pose significant constraints on the development of this field, particularly concerning the compatibility of diverse catalyst types, reaction conditions, and reaction rates. Metal–organic framework micro/nano reactors (MOF-MNRs) are porous crystalline materials formed by the self-assembly coordination of metal sites and organic ligands, possessing a periodic network structure. Due to the uniform pore size with the capability of controlling selective transfer of substances as well as protecting active substances and the organic–inorganic parts providing reactive microenvironment, MOF-MNRs have attracted significant attention in cascade reactions in recent years. In this Perspective, we first discuss how to address compatibility issues in cascade reactions using MOF-MNRs, including structural design and synthetic strategies. Then we summarize the research progress on MOF-MNRs in various cascade reactions. Finally, we analyze the challenges facing MOF-MNRs and potential breakthrough directions and opportunities for the future.
... The tolerance of biocatalysts to high titer substrate is a main bioreaction factor for the efficient application of biocatalysts (Dander et al., 2019). As displayed in Fig. 4, the substrate VAN tolerance of 30CA cells was examined in the existence of different titer VAN in buffer bioreaction medium. ...
Lignin is a critical biopolymer for creating a large number of highly valuable biobased compounds. Vanillin, one of lignin-derived aromatics, can be used to synthesize vanillylamine that is a key fine chemical and pharmaceutical intermediate. To produce vanillylamine, a productive whole-cell-catalyzed biotransformation of vanillin was developed in deep eutectic solvent - surfactant - H2O media. One newly created recombinant E. coli 30CA cells expressing ω-transaminase and L-alanine dehydrogenase was employed to transform 50 mM and 60 mM vanillin into vanillylamine in the yield of 82.1% and 8.5% under 40 °C, respectively. The biotransamination efficiency was enhanced by introducing surfactant PEG-2000 (40 mM) and deep eutectic solvent ChCl:LA (5.0 wt%, pH 8.0), and the highest vanillylamine yield reached 90.0% from 60 mM vanillin. Building an effective bioprocess was utilized for transamination of lignin-derived vanillin to vanillylamine with newly created bacteria in an eco-friendly medium, which had potential application for valorization of lignin to value-added compounds.
... The tolerance of enzymes to high substrate concentrations is a major process parameter in synthetic biology for the development of efficient biocatalysts [38]. Hence, the substrate tolerance of recombinant E. coli AT was investigated under seven different dose of 5-HMF in B:Gly-water (Figure 7b). ...
... Chemoenzymatic cascade catalysis, which combines the unique advantages of both non-enzymatic and bio-catalytic reactions, namely the reactivity of chemical catalysts and the high selectivity of enzymes, has become an emerging strategy of interest [38,39]. As illustrated in Figure 8, a combination of chemo-catalysis, using SG(SiO2) solid acid, and bio-catalysis, using E. coli AT, was used to tandemly convert D-fructose into 5-HMFA. ...
... Chemoenzymatic cascade catalysis, which combines the unique advantages of both non-enzymatic and bio-catalytic reactions, namely the reactivity of chemical catalysts and the high selectivity of enzymes, has become an emerging strategy of interest [38,39]. As illustrated in Figure 8, a combination of chemo-catalysis, using SG(SiO 2 ) solid acid, and bio-catalysis, using E. coli AT, was used to tandemly convert D-fructose Chemo-catalysis and bio-catalysis approaches have been used in the synthesis of 5-HMFA [5,40]. ...
5-Hydroxymethyl-2-furfurylamine (5-HMFA) as an important 5-HMF derivative has been widely utilized in the manufacture of diuretics, antihypertensive drugs, preservatives and curing agents. In this work, an efficient chemoenzymatic route was constructed for producing 5-(hydroxymethyl)furfurylamine (5-HMFA) from biobased D-fructose in deep eutectic solvent Betaine:Glycerol–water. The introduction of Betaine:Glycerol could greatly promote the dehydration of D-fructose to 5-HMF and inhibit the secondary decomposition reactions of 5-HMF, compared with a single aqueous phase. D-Fructose (200 mM) could be catalyzed to 5-HMF (183.4 mM) at 91.7% yield by SG(SiO2) (3 wt%) after 90 min in Betaine:Glycerol (20 wt%), and at 150 °C. E. coli AT exhibited excellent bio-transamination activity to aminate 5-HMF into 5-HMFA at 35 °C and pH 7.5. After 24 h, D-fructose-derived 5-HMF (165.4 mM) was converted to 5-HMFA (155.7 mM) in 94.1% yield with D-Ala (D-Ala-to-5-HMF molar ratio 15:1) in Betaine:Glycerol (20 wt%) without removal of SG(SiO2), achieving a productivity of 0.61 g 5-HMFA/(g substrate D-fructose). Chemoenzymatic valorization of D-fructose with SG(SiO2) and E. coli AT was established for sustainable production of 5-HMFA, which has potential application.
... Garg's group reported the integrated synthesis of various chiral diaryl methanols (11) ( Figure 2B) [21]. The construction of ketones via nickel-catalysed C-C bond formation was merged with biocatalytic reduction using KREDs. ...
The combination of chemo- and biocatalysis in one pot (integrated catalysis) is a powerful approach to develop new routes towards important products under mild and environmentally benign reaction conditions. Integrated catalysis can improve overall synthetic efficiency and, due to the complementary nature of chemo- and biocatalysts, transformations can be performed, which would be otherwise challenging using a single catalyst. In this review, we highlight recent trends for the combination of enzymes with chemocatalysts. Transition-metal catalysis, organocatalysis, and photoredox catalysis have been combined with different biocatalysts and are discussed accordingly. We highlight further how integrated catalysis not only delivers benign substitutes for known transformations but moreover enables transformations that would be otherwise impossible.
... However, mutual inactivation and different operating conditions of chemoand biocatalysts present a major challenge for the development of integrated processes 17 . Despite this, the merger of transition metals (TM) and biocatalysts has led to some notable cascadetype processes, including the combination of stereoselective bioreduction with Pd or Ni catalysts 18,19 . The merger of halogenase enzymes with Pd catalysed cross-coupling has also been deployed for the construction of C−C bonds via a net C−H bond functionalisation process 20,21 . ...
... Preparative scale integrated reactions were also carried out to explore the nitrile substrate scope. Various functionalised aromatic nitriles with electron-donating or -withdrawing groups in the para- (17)(18)(19)(20)(21) or meta-position (22)(23)(24) were well tolerated affording amides in good to excellent yields using the CGA009 NHase (Fig. 3). The sterically demanding tert-butyl ester provided the desired product 24 in 66% yield. ...
Amides are one of the most fundamental chemical bonds in nature. In addition to proteins and other metabolites, many valuable synthetic products comprise amide bonds. Despite this, there is a need for more sustainable amide synthesis. Herein, we report an integrated next generation multi-catalytic system, merging nitrile hydratase enzymes with a Cu-catalysed N-arylation reaction in a single reaction vessel, for the construction of ubiquitous amide bonds. This synergistic one-pot combination of chemo-and biocatalysis provides an amide bond disconnection to precursors, that are orthogonal to those in classical amide synthesis, obviating the need for protecting groups and delivering amides in a manner unachievable using existing catalytic regimes. Our integrated approach also affords broad scope, very high (molar) substrate loading, and has excellent functional group tolerance, telescoping routes to natural product derivatives, drug molecules, and challenging chiral amides under environmentally friendly conditions at scale.
... Garg and co-workers [25] developed a sequential cascade linking a nickel-catalyzed Suzuki coupling of amides and a ketoreductase (KRED)promoted reduction of diaryl ketone intermediates for the synthesis of enantioenriched diarylmethanol derivatives (Table 1, Entry 6). This cascade also suffered from incompatible reaction conditions: the Suzuki reaction was carried out in alkaline water solution at 60 • C, whereas the bioreduction proceeded at 35 • C and neutral pH. ...
Multi-step one-pot chemoenzymatic cascade reactions (mo-CECRs) bridging chemo- and bio-catalysis can not only accomplish chemical transformations with minimized purification steps, low cost and improved stereochemical control, but also enhance reactivity and outcomes through the cooperative effect of multiple catalysts. Despite the attractiveness of the concept which meets the principles of green and sustainable chemistry, the establishment of such catalytic networks faces important challenges due to the incompatibilities between different catalytic disciplines. The purpose of this review is to chart progress on mo-CECRs, including temporal compartmentalization, spatial compartmentalization and chemo-bio nanoreactors, with an emphasis on platform methods and technologies involved. The perspectives on future challenges and strategies in this burgeoning research are declared. This review may provide guidance for the design of new and robust mo-CECRs.
... Ultimately, a one-pot chemoenzymatic synthesis of enantioenriched alcohols was achieved through the combined use of nickel and biocatalysis in collaboration with Codexis. 92 For example, enantioenriched diarylmethanol 54 was accessed in 72% yield and 97% enantiomeric excess (ee) utilizing the methodology, which combined a Suzuki−Miyaura cross-coupling and ketoreductase (KRED)-mediated reduction in a one-pot, sequential process. These studies validated the utility of amide C−N bond activation in stereocomplexitygenerating transformations. ...
... The use of water as solvent, although traditionally neglected because of the low solubility and stability of many organic compounds in this medium, has challenged chemists to develop new methodology for adapting useful synthetic transformations to occur "on water" or under mild aqueous conditions. 106,107 In addition to enzymatic reactions, which are compatible with aqueous media and sustainable catalyst production, 108 transition metal catalysis employing earth-abundant base metals offers similar environmental and economic advantages. 109 Although nickel, iron, and cobalt catalysts have historically seen fewer pharmaceutical industry applications as compared to their precious metal counterparts, there has been recent progress in the development of first row metals for use in large-scale catalytic processes. ...
The SARS-CoV-2 pandemic has prompted scientists from many disciplines to work collaboratively toward an effective response. As academic synthetic chemists, we examine how best to contribute to this ongoing effort. The current pandemic draws comparisons to past global health crises where synthetic chemists have made significant translational contributions through fundamental research. In the context of manufacturing compounds like remdesivir, several research areas are outlined herein which require further development and creativity from chemists in order to drive advances in antiviral research during this time of need. As a community, driving future innovations in synthetic chemistry will be imperative if we are to tackle global health threats such as COVID-19.
... In a recent example, Gröger and coworkers demonstrated a sequence of rhodium-catalyzed hydroformylation and enzymatic aldoxime dehydration for the HCN-free synthesis of bulk chemical nitriles starting from readily available alkenes (Figure 1b) [10]. Other prominent examples include tandem combinations of rutheniumcatalyzed metathesis with enzymatic ester hydrolysis [11] or laccase/TEMPO-catalyzed aromatization [12], ruthenium-catalyzed nitrile hydration [13] or nickelcatalyzed SuzukieMiyaura coupling of amides [14] with asymmetric ketone bioreduction, rhodiumcatalyzed diazocoupling with 'ene'-reductase-mediated reduction [15], rhodium-catalyzed addition/condensation with cyclohexylamine oxidase-catalyzed deracemization [16], palladium-catalyzed cross-couplings with enzymatic transamination [17,18] or ketone reduction [19], palladium-catalyzed Wacker-Tsuji oxidation with biotransamination [20], and TiO 2 -supported goldpalladium nanoparticles catalyzed in situ generation of H 2 O 2 with evolved unspecific heme-thiolate peroxygenase PaDa-I catalyzed CeH bond hydroxylation [21]. These examples have greatly expanded the repertoire of integrated chemo-and enzyme catalysis. ...
The integration of biocatalysis with chemocatalysis combines the excellent selectivity of the former with the robust reactivity of the latter and offers many advantages, such as lower cost, higher yield, enhanced selectivity, as well as less waste generation. In spite of the challenge of incompatibilities between different classes of catalysts, recent advances in synthetic chemistry and biology provide ample opportunities for multistep cascade transformations that combine biocatalysis and chemocatalysis. Herein, we review recent progress in merging biocatalysis with chemocatalysis, highlighting selected examples of photo-/electricity-driven biotransformations and recently developed strategies for addressing the catalyst incompatibility issue.
