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Biocatalytic Enantioselective Synthesis of Atropisomers
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Accounts of Chemical Research

Cite this: Acc. Chem. Res. 2022, 55, 23, 3362–3375
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https://doi.org/10.1021/acs.accounts.2c00572
Published November 7, 2022

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Conspectus

Atropisomeric compounds are found extensively as natural products, as ligands for asymmetric transition-metal catalysis, and increasingly as bioactive and pharmaceutically relevant targets. Their enantioselective synthesis is therefore an important ongoing research target. While a vast majority of known atropisomeric structures are (hetero)biaryls, which display hindered rotation around a C–C single bond, our group’s long-standing interest in the control of molecular conformation has led to the identification and stereoselective preparation of a variety of other classes of “nonbiaryl” atropisomeric compounds displaying restricted rotation around C–C, C–N, C–O, and C–S single bonds.

Biocatalytic transformations are finding increasing application in both academic and industrial contexts as a result of a significant broadening of the range of biocatalytic reactions and sources of enzymes available to the synthetic chemist. In this Account, we summarize the main biocatalytic strategies currently available for the asymmetric synthesis of biaryl, heterobiaryl, and nonbiaryl atropisomers. As is the case with more traditional synthetic approaches to these compounds, most biocatalytic methodologies for the construction of enantioenriched atropisomers follow one of two distinct strategies. The first of these is the direct asymmetric construction of atropisomeric bonds. Synthetically applicable biocatalytic methodologies for this type of transformation are limited, despite the extensive research into the biosynthesis of (hetero)biaryls by oxidative homocoupling or cross-coupling of electron-rich arenes. The second of these is the asymmetric transformation of a molecule in which the bond that will form the axis already exists, and this approach represents the majority of biocatalytic strategies available to the synthetic organic chemist. This strategy encompasses a variety of stereoselective techniques including kinetic resolution (KR), desymmetrization, dynamic kinetic resolution (DKR), and dynamic kinetic asymmetric transformation (DYKAT).

Nondynamic kinetic resolution (KR) of conformationally stable biaryl derivatives has provided the earliest and most numerous examples of synthetically useful methodologies for the enantioselective preparation of atropisomeric compounds. Lipases (i.e., enzymes that mediate the formation or hydrolysis of esters) are particularly effective and have attracted broad attention. This success has led researchers to broaden the scope of lipase-mediated transformations to desymmetrization reactions, in addition to a limited number of DKR and DYKAT examples. By contrast, our group has used redox enzymes, including an engineered galactose oxidase (GOase) and commercially available ketoreductases (KREDs), to desymmetrize prochiral atropisomeric diaryl ether and biaryl derivatives. Building on this experience and our long-standing interest in dynamic conformational processes, we later harnessed intramolecular noncovalent interactions to facilitate bond rotation at ambient temperatures, which allowed the development of the efficient DKR of heterobiaryl aldehydes using KREDs. With this Account we provide an overview of the current and prospective biocatalytic strategies available to the synthetic organic chemist for the enantioselective preparation of atropisomeric molecules.

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Published as part of the Accounts of Chemical Research special issue “Atropisomers: Synthesis, Analysis, and Applications”.

Key References

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  • Yuan, B.; Page, A.; Worrall, C. P.; Escalettes, F.; Willies, S. C.; McDouall, J. J. W.; Turner, N. J.; Clayden, J. Biocatalytic Desymmetrization of an Atropisomer with Both an Enantioselective Oxidase and Ketoreductases. Angew. Chem., Int. Ed. 2010, 49(39), 7010–701310.1002/anie.201002580. (1)Enantiomerically enriched atropisomeric diaryl ethers are synthesized by desymmetrization, either by the enzymatic atroposelective oxidation of a benzylic hydroxy group or by the enzymatic atroposelective reduction of an aldehyde.

  • Staniland, S.; Adams, R. W.; McDouall, J. J. W.; Maffucci, I.; Contini, A.; Grainger, D. M.; Turner, N. J.; Clayden, J. Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N-Oxide Lewis Base Catalysts. Angew. Chem., Int. Ed. 2016, 55(36), 10755–1075910.1002/anie.201605486. (2)Dynamic kinetic resolution of rapidly racemizing biarylpyridine and isoquinoline N-oxide derivatives affords enantiomerically enriched conformationally stable products via KRED-mediated stereoselective reduction.

1. Introduction

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Atropisomerism is a temperature-dependent molecular property that arises from restricted rotation around a single bond, leading to the emergence of separable conformers. As a consequence of this phenomenon, chirality arises in certain classes of molecules even in the absence of a stereogenic center. Atropisomeric moieties frequently constitute crucial structural elements in bioactive compounds, (3,4) chiral ligands and organocatalysts, (5,6) and molecular machines (7) as well as many natural products such as the antibiotic vancomycin (Figure 1). (8) This has prompted efforts to develop methods for the enantioselective synthesis of atropisomeric compounds, (9) including work from our own group on the synthesis and conformational analysis of atropisomers. Our work has explored both (hetero)biaryl compounds displaying hindered rotation around a C–C single bond, as well as rarer types of non-biaryl atropisomeric compounds such as benzamides (C–C atropisomers), (10) anilides, urea and diarylamine derivatives (C–N atropisomers), (11−14) diaryl ethers (C–O), (15) and diaryl sulfones (C–S). (16,17)

Figure 1

Figure 1. Examples of important atropisomeric molecules. Atropisomeric bonds are highlighted in red.

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The most common, but also most challenging, synthetic strategy for the preparation of enantioenriched atropisomeric compounds is the direct asymmetric construction of the stereogenic axis by aromatic ring formation or the coupling of unsymmetrical partners (homo- or heterocoupling). However, several strategies for atropisomer synthesis exist in which asymmetric induction occurs after the formation of the atropisomeric bond. These include kinetic resolution (KR), desymmetrization, dynamic kinetic resolution (DKR), and dynamic kinetic asymmetric transformation (DYKAT). (9,18,19) In addition, our group has reported the development of various methods for synthesizing atropisomeric compounds using dynamic thermodynamic resolution (10,20) assisted by various chiral auxiliaries as well as the desymmetrization of prochiral molecules.
More recently, we have developed the use of enzymes in the atroposelective synthesis of biaryl compounds, exploiting the high enantioselectivities, mild conditions, and high turnover rates associated with biological catalysts. (21,22) In this Account, we will review the use of biocatalysis in the synthesis of enantioenriched atropisomeric compounds. Despite the wide variety of enzymatic transformations employed in primary and secondary metabolism and especially in the biosynthesis of natural products, biological catalysts have been applied only to a limited repertoire of transformations in synthetic organic chemistry. Among these, the subset of enzymes that have been employed in the synthesis of atropisomeric compounds is even more restricted. We shall describe reported biocatalytic methods for the synthesis of atropisomers, including the use of oxidoreductase and hydrolase enzymes across a range of synthetic strategies comprising oxidative coupling, KR, desymmetrization, DKR, and DYKAT. We conclude by discussing future prospects for the application of biocatalysts to the enantioselective synthesis of atropisomers.

2. Oxidative Coupling

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The direct asymmetric coupling of two unsymmetrical partners seems to be an appealing strategy when devising the synthesis of an enantioenriched atropisomeric product. However, such reactions are often subject to high kinetic barriers, especially in the synthesis of sterically demanding tetra-ortho-substituted biaryls. Such direct coupling reactions require the use of high temperatures, often at the expense of already nontrivial control of the stereochemical outcome. (9,19) Additionally, most cross-coupling methods require appropriate functionalization of at least one of the coupling partners to ensure control of the regioselectivity.
The synthetically appealing coupling of two unfunctionalized partners (i.e., the coupling of two C–H bonds to form a new C–C bond) is a strategy commonly employed by nature for the construction of atropisomeric natural products. (23,24) Existing nonenzymatic methodologies for such direct oxidative couplings are limited by substrate selectivity (dimerization vs cross-coupling) as well as chemoselectivity, stereoselectivity, and regioselectivity (i.e., the ability to distinguish between a number of C–H bonds of similar reactivity). (25) Enzymes, on the other hand, benefit from the complex 3D structure of their active site to ensure efficient templating of the two substrates to achieve high levels of selectivity. (26)
Many enzymes, including laccases, peroxidases, or cytochrome P450 monooxygenases, catalyze the oxidative coupling of electron-rich arenes (usually phenol derivatives) to deliver atropisomeric products with high chemo- and regioselectivity as well as stereoselectivity. (24) Interestingly, the intervention of additional enzymes and/or so-called dirigent proteins (27) (i.e., proteins that are catalytically inactive but exert control over the regioselectivity and stereochemical outcome of bimolecular oxidative couplings) is sometimes required to achieve the high selectivities observed in the atroposelective biosynthesis of some secondary metabolites. While many biosyntheses of atropisomerically enriched natural products by oxidative coupling have been uncovered, few examples of the application of the enzymes responsible for this crucial step in broader synthetic chemistry have been reported to date. (26)
Narayan and co-workers reported the use of cytochrome P450 enzyme KtnC expressed in Pichia pastoris for the homocoupling of native substrate 5 and its cross-coupling with a range of phenol derivatives to achieve non-natural biaryl products 6–10 (Scheme 1). (28) While the substrate scope is relatively extensive, the stereochemical outcome was reported only in a handful of cases. Remarkably, KtnC shows consistent regioselectivity in these couplings, achieving only the 8,8′-connected products. In a few cases, however, the 6,6′-connected product is obtained (even preferentially in the case of 10), albeit with lower levels of stereocontrol. In addition to this work with the wild-type P450 enzyme, the authors developed a strategy for its directed evolution, leading to greatly improved conversion and regioselectivity on an originally poorly responsive substrate. Further rounds of engineering led to increased stereoselectivity for the same transformation, though at the expense of yield.

Scheme 1

Scheme 1. Cytochrome P450 Enzyme-Mediated Atroposelective Oxidative Homocoupling and Cross-Coupling of Its Native Substrate 5 with Phenol Derivatives
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3. Kinetic Resolution

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A majority of enzymatic atroposelective syntheses reported have employed lipases, commensurate with their routine use in organic synthesis. Their widespread use owes its origin to their wide substrate range, high tolerance of organic solvents, and the enantioselectivity they display during acylation, deacylation, and acyl transfer reactions under mild conditions. (29) An early example of biocatalytic KR of atropisomers was reported by Ikekawa and co-workers in 1985, who obtained samples of 2,2′-dihydroxy-1,1′-binaphthyl (BINOL) (11) in enantiomeric excess of up to 96% by the deacylation of various diester derivatives using microorganism extracts. (30) Miyano and co-workers later showed that commercially available lipases such as porcine pancreatic lipase (PPL) were also suitable for this purpose (Scheme 2), (31) leading to the routine use of lipases to atroposelectively esterify dihydroxy-binaphthyl and dicarboxylic acid binaphthyl derivatives (32−37) as well as to hydrolyze aza-BINOL derivatives of binaphthyl compounds. (38,39)

Scheme 2

Scheme 2. Early Example of Biocatalytic Atroposelective Ester Hydrolysis Reported by Miyano and Co-workers, in Which Valeric Diester rac-12 Was Selectively Hydrolyzed to Afford (Sa)-BINOL 11
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BINOL-based substrates were also among the first to be subjected to atroposelective lipase-catalyzed acylation. In 1989, Oda and co-workers reported the use of the atroposelective lipase-catalyzed acylation of BINOL and the deacylation of its esters in a solely organic solvent system (Scheme 3), catalyzed by Pseudomonas cepacia lipase (PCL). This demonstrated the ability of lipases to catalyze the transesterification of alcohols from a suitable acyl donor in the absence of water, the presence of which generally also induces competitive hydrolysis to occur. (40)

Scheme 3

Scheme 3. Early Example of Biocatalytic KR of rac-BINOL 11via Acylation by a Variety of Vinyl Ester Acyl Donors to Form Monoesters 13
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Oda’s acylation employed a range of vinyl esters whose use as acyl donors in lipase-catalyzed transesterification reactions arises from their ability to push reaction equilibria toward the desired ester formation, as the enol byproducts irreversibly tautomerize to the corresponding aldehyde. A more recent example of lipase-mediated atroposelective acylation reported by Akai and co-workers was accelerated by the addition of Na2CO3. (41) Acyl transfer is not restricted to vinyl esters, as a wide variety of compounds can behave as acyl donors. Sun and co-workers showed that biaryl esters themselves can also act as acyl donors during a lipase-catalyzed transesterification between biaryl-derived ester 14 and indanol 15 in the presence of PPL enzyme, affording esterified indanol derivative 16 in 99% ee and 45% conversion (Scheme 4). (42)

Scheme 4

Scheme 4. PPL-Catalyzed Stereoselective Transesterification of Butyl Ester 14 and Indanol 15
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The scope of atroposelective biocatalytic KR was later widened to encompass biphenyls, with Sanfilippo and co-workers reporting highly enantioselective enzymatic acylations of dihydroxylated biphenyl 17 and bipyridinyl N-oxide substrate 19 in the presence of PCL and Mucor miehei lipase (MML) enzymes (Scheme 5a,b). (43,44) Several examples of KRs of dihydroxylbiphenyl ester derivatives via lipase-catalyzed hydrolysis have also since been reported, such as the enantioselective hydrolysis of a hexamethylbiphenol ester derivative by PPL (45) and the enzymatic kinetic resolution of atropisomeric intermediate 22 during the asymmetric synthesis of JNJ-4355, an inhibitor of a protein associated with myeloid leukemia (Scheme 5c). (46)

Scheme 5

Scheme 5. (a) Early Example of a Biocatalytic KR of a Biphenyl Diol rac-17 by PCL-Mediated Acylation, (b) KR of Bipyridinyl N-Oxide Atropisomers by MML-Mediated Acylation, and (c) Further Enantioenrichment of Synthetic Intermediate (Sa)-22 during the Asymmetric Synthesis of JNJ-4355 by Biocatalytic Acylation
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While most work on the lipase-catalyzed KR of atropisomers has focused on the acylation of alcohols and diacylation of esters, there are limited examples of atroposelective transformations of other functional groups. Examples of biocatalytic amidation are less common than esterification as the higher nucleophilicity of amines compared to alcohols can lead to background nonstereoselective N-acylation, necessitating the careful selection of acylating agents for these reactions. An example of atroposelective amidation was reported by Aoyagi and co-workers in 2002 (Scheme 6), in which various 1,1-binaphthylamines were derivatized to the respective amides in the presence of immobilized Pseudomonas aeruginosa lipase (PAL). (47) The reactivity of these substrates to acylation is highly dependent on the length of the alkyl chain between the aromatic ring and the amine reactive site. Out of the substrates investigated, amine 24, in which the binaphthyl core and amine were separated by an ethylene linker, was most amenable to N-acylation to corresponding amide 25 (Scheme 6a). A similar effect was observed in the transamidation of binaphthyl-based esters: phenyl and benzylic carboxylate esters were reluctant substrates for transamidation, but the desired amide 27 could be formed biocatalytically from 26 in 48% yield and 84% ee (Scheme 6b). (48)

Scheme 6

Scheme 6. (a) Lipase-Catalyzed Atroposelective Amidation Reactions of Binaphthyl-Based Amines and (b) Biocatalytic Enantioselective Transamidation of Binaphthyl-Based Carboxylate Esters
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Aoyagi and co-workers also investigated the enantioselective lipase-catalyzed acylation and hydrolysis of binaphthyl oxime derivatives 28, (E)-29, and (Z)-29 (Scheme 7). (49) While 28 was amenable to KR by either the lipase-mediated acylation of aldoxime 28 or the deacylation of acetylated derivative 30, ketoxime 29 was unsuitable for biocatalytic acylation. Interestingly, however, the reactivity of 31 toward lipase-catalyzed hydrolysis was highly dependent on the geometry of the ketoxime: hydrolysis of (E)-31 by CHIRAZYME L-2 afforded the (Sa)-enantiomer of (E)-29 in 85% ee, while the hydrolysis of (Z)-31 afforded (Ra)-(Z)-29 in 50% ee after a much longer reaction time (264 vs 4 h).

Scheme 7

Scheme 7. (a) Kinetic Resolutions of Acetylated Binaphthyl Oxime Derivatives by Atroposelective Enzymatic Hydrolysis and (b) Enantiopreference of the CHIRAZYME-L2-Mediated Hydrolysis of 31 Based on the E and Z Configurations of the Ketoxime Double Bond
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An example of atroposelective thioester hydrolysis was reported by Helmchen and co-workers, in which (1,1′-binaphthalene)-2,2′-dithiol derivative 32 was hydrolyzed to the corresponding thiol 33 in the presence of bovine pancreas acetone powder as a source of cholesterol esterase (CHE) (Scheme 8a). (50) The enzymatic hydrolysis of biphenyls carrying thioester substituents also occurs in the presence of PCL, but attempts at KR of the equivalent thiol 34 by enzymatic S-acylation proved unsuccessful, resulting in thioacetal 35 instead (Scheme 8b). (51) The lack of reactivity displayed by 34 toward acylation was attributed to the softness of thiol nucleophiles in comparison to alcohols and amines. Observed product 35 was proposed to result from the addition of thiol 34 to the acetaldehyde liberated by the lipase-catalyzed deacylation of vinyl acetate.

Scheme 8

Scheme 8. (a) Atroposelective Hydrolytic KR of Thioester 32 in the Presence of Cholesterol Esterase and (b) Enantioseparation of Thiol 34 by Lipase-Catalyzed DKR of Hemithioacetal Groups and Subsequent Hydrolysis
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Examples of other biocatalytic transformations in KRs of atropisomers remain limited. In an early example of enzymatic atroposelective reduction from Miyano and co-workers in 1988, the reduction of axially chiral binaphthyl-based aldehyde 37 proceeded to the corresponding benzylic alcohol 38 in the presence of baker’s yeast, sucrose, and ethanol (Scheme 9). (52) In this work, yeast was used as a whole-cell biocatalytic system, exploiting the cell’s native alcohol dehydrogenases (ADHs), (53) but later examples of biocatalytic atroposelective reductions would be performed with isolated ADHs/ketoreductases (KREDs). (1,2,54)

Scheme 9

Scheme 9. Early Example of the Enantioselective Biocatalytic Reduction of Binaphthyl Aldehydes in the Presence of Baker’s Yeast
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4. Desymmetrization

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While KR methods for the synthesis of enantiopure atropisomers have a maximum theoretical yield of 50%, desymmetrization, or the synthesis of a chiral product from a prochiral starting material, allows the synthesis of atropisomers in up to 100% yield and 100% ee. As with KRs, a majority of biocatalytic atroposelective desymmetrizations have been performed using lipase enzymes, with the first example being reported by Matsumoto and co-workers in 2002 as part of an atroposelective desymmetrization of tri-ortho-substituted biphenyl diacetates including 39 (Scheme 10a), with the authors later extending the scope of the methodology to include symmetrical tetra-ortho-substituted substrates such as 41 (Scheme 10b). (55,56) The same group also applied this method in the enantioselective total syntheses of (−)-euxanmodin B 45 and dermocanarin 2 48 to form the desired intermediates in >99% ee using PPL (Scheme 10d,e). (57,58)

Scheme 10

Scheme 10. (a–c) Selected Reported Examples of Atroposelective Lipase-Catalyzed Desymmetrization Reactions of Prochiral Biaryl Compounds, Including Highly Hindered Tetra-ortho-Substituted Substrates 41 and 43 and (d, e) Examples of Enantioselective Total Syntheses of Atropisomeric Natural Products Employing a Biocatalytic Desymmetrization Step
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The same group later reported that C(3′)-substituents, despite being remote from the biaryl axis, provide sufficient enantiotopic discrimination in biphenyl-2,6-diol diacetate derivatives such as 43 to induce excellent atroposelectivity when subjected to enzymatic hydrolysis (Scheme 10c). (59) Desymmetrization of similar prochiral biaryl substrates via deacylation and phenol acylation has also been reported by Akai and co-workers, the latter of which was performed using their previously developed base-promoted lipase-catalyzed acylation conditions (Section 3). (60)
Methods for the desymmetrization of pro-atropisomeric compounds mediated by biocatalytic redox enzymes have been developed by members of our group, and we have investigated the use of NAD(P)H-dependent KRED enzymes as enantioselective reducing agents (Scheme 11). (1,54) In contrast to the work by Miyano and co-workers (Section 3), which employed yeast as a whole cell biocatalyst, (52) these reductions employed isolated KRED enzymes. This necessitated the incorporation of an NAD(P)H recycling system into the reaction conditions, using glucose as a sacrificial reductant. The activity of KRED enzymes can also be reversed to catalyze alcohol oxidation when this recycling system is adapted to drive the regeneration of NAD(P) rather than NAD(P)H. (61) Despite the ability of KREDs to function as oxidation catalysts, the oxidative desymmetrization reactions we developed instead employed a mutant galactose oxidase GOase M3–5, specifically engineered to accept secondary alcohol substrates (Scheme 12). (62) This GOase belongs to a different class of oxidases from KREDs, relying on O2 as the ultimate sacrificial oxidizing agent.

Scheme 11

Scheme 11. KRED-Mediated Enantioselective Desymmetrization of Pro-atropisomeric Compounds by Aldehyde Reduction
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Scheme 12

Scheme 12. GOase-Mediated Enantioselective Desymmetrization of Pro-atropisomeric Bisbenzylic Alcohol Compounds 56 by Oxidation, Which Can Be Followed by a Second Enantioselective Oxidation to the Corresponding Dialdehyde 58
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Both KRED- and GOase-mediated atroposelective desymmetrizations were first reported by members of our group, working with Prof. Nicholas Turner, during the synthesis of atropisomeric diaryl ether derivative 49. (1) The diaryl ether linkage is a common motif in natural products such as vancomycin and teicoplanin, (63) but there were no general asymmetric routes to this class of unusual atropisomer. Subsequent work in the group extended the scope of both the reduction and oxidation methodologies to access a range of monoaldehyde biaryl substrates 50–55 in high enantioselectivity (Schemes 11 and 12, respectively). For several substrates, the enantiomer of monoaldehyde obtained depended on the choice of KRED enzyme (Scheme 11).
The GOase-mediated oxidation of pro-atropisomeric compounds carrying two benzylic alcohol groups (generalized as 56 in Scheme 12) also proceeds in high conversion and excellent stereoselectivity. Docking studies revealed insights into the origins of the enantioselectivities of the GOase-mediated oxidations. As is common in desymmetrization reactions, the enantiomeric excesses of the desymmetrization products 57 obtained by GOase oxidation increased over time, as the enantioenrichment of 57 is the result of two stereoselective processes: a desymmetrization and a subsequent KR process. Following enantioselective oxidation of 56 to form monoaldehyde (maj)-57, further GOase oxidation is also highly stereoselective, resulting in preferential conversion of the minor atropisomer (min)-57 to dialdehyde 58. This results in further enantioenrichment of 57 over time, albeit at the expense of yield. (64)

5. Dynamic Kinetic Resolution and Dynamic Kinetic Asymmetric Transformation

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In the earliest example of the use of dynamic kinetic resolution for the asymmetric synthesis of atropisomers, Sanfilippo and co-workers used the DKR of rapidly interconverting hemithioacetal stereocenters to create a pair of atropodiastereomers which were separated chromatographically (Section 3, Scheme 8b). (65) This work is unique in its use of the DKR of stereocenters remote from the chiral axis to resolve the atropisomers, whereas most atroposelective dynamic resolutions exploit the rotational lability of the (pro)chiral axis. Conformationally labile compounds may undergo transformations that increase their rotational energy barrier sufficiently to lock the axial conformation and create stable atropisomers. Such transformations may be used in DKRs if they proceed stereoselectively and if they are coupled to fast rates of rotation around the prochiral axis in the starting material.
Biaryl lactones in which two groups ortho to the connecting aryl–aryl bond are linked by an ester bridge usually have a relatively low barrier to Ar–Ar rotation, despite being often tri- or tetra-ortho-substituted. (9) The reduced barrier to rotation is due to the planarization enforced by the bridge which minimizes steric interactions between the ortho substituents in the transition state for rotation. The fast interconversion of the enantiomeric lactone conformers allows for the atroposelective cleavage of the lactone bridge by the addition of nucleophiles under dynamic kinetic resolution. Building on the extensive research dedicated to lipase-mediated atroposelective transformation, Deska and co-workers attempted the DKR of lactone 59 by ring opening using various lipases. (66) This transformation proved sluggish, and only up to 11% conversion to open ester 60 was observed in 0% ee in the presence of Candida antarctica type B lipase after 7 days at 40 °C, while a pig liver esterase (PLE) delivered the product with 13% ee and only 6% conversion under the same conditions (Scheme 13).

Scheme 13

Scheme 13. Ring Opening of Lactone 59 Using PLE
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Other examples of conformationally labile compounds are 2-formyl-1-benzamide derivatives such as 61 due to the small size and planar nature of their aldehyde substituent as well as an intramolecular noncovalent n → π* interaction between the amide nitrogen lone pair and aldehyde substituent. The barrier to rotation of 61 and derivatives can be dramatically increased by the transformation of the aldehyde into a bulkier, tetrahedral substituent in which the intramolecular interaction no longer exists (Figure 2). (67) We exploited this property to achieve the dynamic resolution of these compounds under thermodynamic control. (68)

Figure 2

Figure 2. Experimentally determined barriers to rotation and half-lives of racemization at 20 °C of selected 1-naphthamide derivatives. The dashed red line indicates a barrier-lowering n → π* interaction.

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Based on this experience, we reasoned that the same type of intramolecular interaction would be present in 2-arylisoquinoline oxide derivative 65, enabling its preparation by dynamic kinetic resolution. Our investigations started with aldehyde 66, but this compound quickly proved unsuitable for a dynamic kinetic resolution. In fact, its barrier to rotation was so high that decomposition occurred faster than bond rotation at elevated temperatures. Taking advantage of this conformational stability, 66 was used as a model to determine the ability of commercially available ketoreductases (KREDs) to mediate the stereoselective reduction of the aldehyde function under nondynamic kinetic resolution (Scheme 14).

Scheme 14

Scheme 14. Kinetic Resolution of Biaryl rac-66 by KRED-Catalyzed Stereoselective Aldehyde Reduction
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Absolute configurations of enantioenriched 65 and 66 are unknown.
While the best results were obtained with KRED 113, affording unreacted 66 with 46% yield and >99% ee, other KREDs gave high selectivities, indicating that the enzymes’ active sites were able to accommodate the presence of the atropisomeric biaryl N-oxides and distinguish their enantiomers.
With the results from this KR in hand, the development of analogous DKR methodology necessitated the study of aldehyde compounds with much lower barriers to enantiomerization. Heterobiaryl N-oxides 67 and 68 were prepared, and their rotational barriers were experimentally determined to be 68 and 66 kJ/mol, respectively (i.e., they possess half-lives of racemization shorter than 100 ms at 25 °C). By contrast, their alcohol counterparts 69 and 70 were shown to have much higher barriers to rotation and to be conformationally stable for at least several months at room temperature (Figure 3). When compounds 67 and 68 were screened against a range of KREDs, dynamic kinetic resolution took place with excellent yields and stereoselectivities (Scheme 15).

Figure 3

Figure 3. Experimentally determined barriers to rotation and half-lives of racemization at 20 °C of selected biaryl aldehydes and alcohols. The dashed red line indicates a barrier-lowering n → π* interaction.

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Scheme 15

Scheme 15. Dynamic Kinetic Resolution of Biaryls 67 and 68 by KRED-Catalyzed Stereoselective Aldehyde Reduction
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Catalysis using KRED 130 gave the (Ra) enantiomer of 69 and the (Sa) enantiomer of 70 quantitatively and with excellent stereocontrol. The other enantiomers of both 69 and 70 could be obtained with similarly high efficiencies using KRED 112 and 124, respectively. Computational modeling of compounds 67 and 68 at the B3LYP/6-31+G(d,p) level of theory suggested significant distortion of the aldehyde carbon toward a tetrahedral geometry, implying that an intramolecular n → π* interaction between the N-oxide and aldehyde may result in the lower barriers to rotation observed in these compounds. (69) The enantioenriched atropisomeric biaryl N-oxide products performed well as Lewis base organocatalysts for the asymmetric allylation of aldehydes.
Shortly after the submission of this Account, Lewis and co-workers reported the DKR of 3-aryl-4(3H)-quinazolinone derivatives via atroposelective C–H bromination using an engineered flavin-dependent halogenase. (70) High levels of regioselectivity and stereoselectivity were obtained for a range of compounds, and atropostable starting substrates underwent nondynamic KR. This represents the first example of the use of both a halogenase in atroposelective synthesis and the biocatalytic enantioselective preparation of C–N atropisomers.
Akai and co-workers have reported the two-step deracemization of a range of 2,2′-binaphthol (BINOL) derivatives 71 (Scheme 15). (71) These 2,2′-BINOL derivatives are conformationally stable but may undergo enantiomerization through the use of a Ru(II) racemization catalyst. The Ru(II) catalyst is proposed to mediate an oxidative SET of the BINOL substrate, generating a free radical on the carbon center at the biaryl axis, which induces conformational lability even at low temperature. Combining this racemization step with a concurrent lipase-catalyzed acylation using isopropenyl acetate 72 gave a range of monoacetates (Ra)-73 atroposelectively. It is worth noting that although this sequence was characterized as a DKR by the authors, the overall transformation rather falls into the definition of a dynamic kinetic asymmetric transformation (DYKAT), as the starting substrates are conformationally stable and undergo catalyst-mediated rapid interconversion. (18,72) Monoacetates (Ra)-73 were subsequently subjected to deacylation by an inorganic base to afford the deracemized diols (Ra)-71 with high overall yields and enantioselectivities.

Scheme 16

Scheme 16. (a) DYKAT of BINOL Derivatives rac-71 by Concurrent Ru(II)-Catalyzed Racemization and Lipase-Mediated Acylation and (b) Proposed Mechanism of the Ru(II)-Catalyzed Racemization
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6. Conclusions and Prospects

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The use of biocatalysts for the enantioselective synthesis of atropisomeric compounds is a promising field of research. Although oxidative couplings are common in biosynthetic pathways, the synthetic potential of these enzymes as biocatalysts is yet to be realized in routine applications. The majority of currently reported strategies rely on the KR of racemic mixtures of conformationally stable compounds or the desymmetrization of prochiral molecules. We have shown that enantioenriched biaryl and nonbiaryl atropisomers, such as arylisoquinoline-N-oxides and diaryl ethers, can be accessed by desymmetrization using oxidoreductases. Although ideally suited to the asymmetric synthesis of atropisomers, owing to the the inherent rotational lability of single bonds, biocatalytic dynamic resolution methods remain comparatively underexploited. We have demonstrated that intramolecular noncovalent interactions contributing to low barriers to rotation in heterobiaryls allow biocatalysis to achieve dynamic kinetic resolution, transforming them into products in which these intramolecular interactions are suppressed.
While we and others have reported the biocatalytic enantioselective preparation of axially chiral biaryls, heterobiaryls, and diarylethers, several increasingly important classes of molecules known to exhibit atropisomerism around C–C and C–Het bonds (Het = N, S, B) have not yet been prepared by such means (Figure 4).

Figure 4

Figure 4. Important classes of atropisomeric compounds that have or have not yet been made enantioselectively by biocatalytic methods (green and red boxes, respectively).

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It is also interesting that several biocatalytic deracemization strategies, including stereoinversion, linear or cyclic deracemization, and enantioconvergent processes, have been described previously but are yet to be applied to the enantioselective preparation of atropisomers. (73) Additionally, artificial metalloenzymes (i.e., the artificial combination of a non-native catalytically active metal catalyst within a protein scaffold), (74) which combine the diverse reactivity of homogeneous metal catalysts with the substrate selectivity and well-defined 3D structures of enzyme active sites, represent a promising approach to the synthesis of enantioenriched atropisomers. For instance, an interesting example of a biocatalytic atroposelective cross-coupling reaction using an artificially evolved “Suzukiase” has been reported, (75) demonstrating that this field, though still in its infancy, could lead to numerous future applications.
In light of important advances in enzyme discovery and engineering as well as computational design, biocatalysis is increasingly becoming an essential part of the synthetic organic chemist’s toolbox. It is likely that new strategies incorporating biocatalysts will be developed for the stereoselective preparation of atropisomers and more broadly for the control of molecular conformation.

Author Information

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  • Corresponding Author
  • Authors
    • Olivia F. B. Watts - School of Chemistry, University of Bristol, Bristol BS8 1TS, U.K.
    • Jordan Berreur - School of Chemistry, University of Bristol, Bristol BS8 1TS, U.K.
    • Beatrice S. L. Collins - School of Chemistry, University of Bristol, Bristol BS8 1TS, U.K.;  Orcidhttps://orcid.org/0000-0002-2545-3458
  • Author Contributions

    O.F.B.W. and J.B. contributed equally. The manuscript was written through the contributions of all authors.

  • Funding

    We acknowledge the support of the Leverhulme Trust, the EPSRC (through the Bristol CDT for Technology-Enhanced Chemical Synthesis), the Royal Society, and the European Research Council.

  • Notes
    The authors declare no competing financial interest.

Biographies

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Olivia F. B. Watts obtained her M.Chem. from the University of Manchester in 2020, during which she completed a final year project with Prof. David Leigh. She then joined the groups of Dr. Beatrice S. L. Collins and Prof. Jonathan Clayden as a Ph.D. student at the University of Bristol, investigating the development of chemically fueled molecular motors.

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Jordan Berreur obtained his Ph.D. from the University of Strasbourg in 2020 with Dr. Frédéric Leroux and Dr. Armen Panossian. He then joined the groups of Dr. Beatrice S. L. Collins and Prof. Jonathan Clayden at the University of Bristol, working on the development of a biocatalytically driven molecular motor.

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Beatrice S. L. Collins completed a Ph.D. in 2014 with Professor Matthew Gaunt at the University of Cambridge. She then undertook periods of postdoctoral research with Professor Ben Feringa at the University of Groningen and Professor Varinder Aggarwal at the University of Bristol. In 2018, she was awarded a university research fellowship from the Royal Society and started her independent research career at the University of Bristol. Her research is focused on the control of motion at the molecular level and the development of functional molecular systems.

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Jonathan Clayden completed a Ph.D. in 1992 at the University of Cambridge with Dr. Stuart Warren. After postdoctoral work with Prof. Marc Julia at the École Normale Supérieure in Paris, he began his independent research career in 1994 at the University of Manchester before moving to Bristol in 2015. His research interests lie broadly in the areas of dynamic molecular shape and function.

Acknowledgments

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Our work on atroposelective biocatalysis was initiated through a collaboration with the group of Professor Nicholas Turner at the University of Manchester, and we acknowledge the invaluable contributions of Nick and his group to the development of this area.

References

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This article references 75 other publications.

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    In common with other hindered structures contg. two arom. rings linked by a short tether, diarylamines may exhibit atropisomerism (chirality due to restricted rotation). Previous examples have principally been tertiary amines, esp. those with cyclic scaffolds. Little is known of the structural requirement for atropisomerism in structurally simpler secondary and acyclic diarylamines. In this paper we describe a systematic study of a series of acyclic secondary diarylamines, and we quantify the degree of steric hindrance in the ortho positions that is required for atropisomerism to result. Through a detailed exptl. and computational anal., the role of each ortho-substituent on the mechanism and rate of conformational interconversion is rationalized. We also present a simple predictive model for the design of configurationally stable secondary diarylamines.
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    Clayden, J.; Worrall, C. P.; Moran, W. J.; Helliwell, M. Enantioselective Synthesis of an Atropisomeric Diaryl Ether. Angew. Chem., Int. Ed. 2008, 47 (17), 3234– 3237,  DOI: 10.1002/anie.200705660
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    Enantioselective synthesis of an atropisomeric diaryl ether
    Clayden, Jonathan; Worrall, Christopher P.; Moran, Wesley J.; Helliwell, Madeleine
    Angewandte Chemie, International Edition (2008), 47 (17), 3234-3237CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Introduction of a bulky alkylsulfinyl substituent ortho to the C-O axis of a diaryl ether imposes a powerful conformational preference. The preference persists upon oxidn. of the sulfoxide to a sulfone, leading to dynamic thermodn. resoln. of the atropisomeric ether. This is the first enantioselective synthesis of an atropisomeric diaryl ether not forming part of a macrocyclic ring.
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  16. 16
    Clayden, J.; Senior, J.; Helliwell, M. Atropisomerism at C-S Bonds: Asymmetric Synthesis of Diaryl Sulfones by Dynamic Resolution Under Thermodynamic. Control. Angew. Chem. Int. Ed. 2009, 48 (34), 6270– 6273,  DOI: 10.1002/anie.200901718
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    Clayden, J.; Fletcher, S. P.; Senior, J.; Worrall, C. P. Hindered Diarylether and Diarylsulfone Bisphosphine Ligands: Atropisomerism and Palladium Complexes. Tetrahedron: Asymmetry 2010, 21 (11), 1355– 1360,  DOI: 10.1016/j.tetasy.2010.06.017
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    Hindered diarylether and diarylsulfone bisphosphine ligands: atropisomerism and palladium complexes
    Clayden, Jonathan; Fletcher, Stephen P.; Senior, James; Worrall, Christopher P.
    Tetrahedron: Asymmetry (2010), 21 (11-12), 1355-1360CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
    Phosphines and bisphosphines derived from hindered ortho-substituted diaryl ethers and diarylsulfones by lithiation are, with appropriate substitution patterns, resolvable atropisomeric ligands which form cryst. complexes with Pd dichloride. The racemization kinetics of o-diphenylphosphinophenyl 2-diphenylphosphino-6-methoxymethylphenyl ether and the crystal structures of palladium complexes with Me substituted bis(o-diphenylphosphinophenyl) ethers are reported.
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  18. 18
    Steinreiber, J.; Faber, K.; Griengl, H. De-Racemization of Enantiomers versus De-Epimerization of Diastereomers─Classification of Dynamic Kinetic Asymmetric Transformations (DYKAT). Chem.─Eur. J. 2008, 14 (27), 8060– 8072,  DOI: 10.1002/chem.200701643
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    De-racemization of enantiomers versus de-epimerization of diastereomers - classification of dynamic kinetic asymmetric transformations (DYKAT)
    Steinreiber, Johannes; Faber, Kurt; Griengl, Herfried
    Chemistry - A European Journal (2008), 14 (27), 8060-8072CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The isolation of single stereoisomers from a racemic (or diastereomeric) mixt. by enzymic or chem. resoln. techniques goes in hand with the disposal of 50% (racemate) or more (diastereomeric mixts.) of the "undesired" substrate isomer(s). In order to circumvent this drawback, dynamic systems have been developed for the de-racemization of enantiomers and the de-epimerizations of diastereomers. Key strategies within this area are discussed and are classified according to their underlying kinetics, i.e., dynamic kinetic resoln. (DKR), dynamic kinetic asym. transformations (DYKAT), and hybrids between both of them. Finally, two novel types of DYKAT are defined.
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    Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F. Recent Advances and New Concepts for the Synthesis of Axially Stereoenriched Biaryls. Chem. Soc. Rev. 2015, 44, 3418– 3430,  DOI: 10.1039/C5CS00012B
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    Recent advances and new concepts for the synthesis of axially stereoenriched biaryls
    Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F.
    Chemical Society Reviews (2015), 44 (11), 3418-3430CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Axial chirality was a key feature of many important org. mols., such as biol. active compds., stereogenic ligands and optically pure materials. Significant efforts in the field of the atropisomeric synthesis of biaryls was hence undertaken over the past decade. Several major improvements of the already known methods to build up such chiral backbones (e.g. oxidative couplings and stereoselective Suzuki-Miyaura arylations) were achieved and, in parallel, novel concepts were emerged enabling unprecedented synthetic routes toward mols. of this kind. These outstanding steps further unlocked the door to the prepn. of previously difficult-to-access precursors of privileged ligands like BINOL, BINAM, QUINAP and many other mols. of interest.
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    Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel, D. J.; Weisenburger, G. A. Dynamic Thermodynamic Resolution: Control of Enantioselectivity through Diastereomeric Equilibration. Acc. Chem. Res. 2000, 33 (10), 715– 727,  DOI: 10.1021/ar000077s
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    Dynamic Thermodynamic Resolution: Control of Enantioselectivity through Diastereomeric Equilibration
    Beak, Peter; Anderson, David R.; Curtis, Michael D.; Laumer, Jason M.; Pippel, Daniel J.; Weisenburger, Gerald A.
    Accounts of Chemical Research (2000), 33 (10), 715-727CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A theor. foundation, tools for recognition and control, and recent examples of a class of asym. transformation termed dynamic thermodn. resoln. are presented. Enantioselective reaction pathways that involve an induced diastereomeric equilibration to intermediates, which are configurationally stable on the time scale of a subsequent reaction, are illustrated. Dynamic thermodn. resoln. differs from the classic, well-documented pathways of kinetic resoln. and dynamic kinetic resoln. in that equilibration and resoln. can be operative on one system in sep. controllable steps. This approach offers a high level of flexibility and provides multiple opportunities for optimization of enantioselectivity; 38 refs.
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  21. 21
    Bell, E. L.; Finnigan, W.; France, S. P.; Green, A. P.; Hayes, M. A.; Hepworth, L. J.; Lovelock, S. L.; Niikura, H.; Osuna, S.; Romero, E.; Ryan, K. S.; Turner, N. J.; Flitsch, S. L. Biocatalysis. Nat. Rev. Methods Primers 2021, 1 (1), 1– 21,  DOI: 10.1038/s43586-021-00044-z
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    Hall, M. Enzymatic Strategies for Asymmetric Synthesis. RSC Chem. Biol. 2021, 2 (4), 958– 989,  DOI: 10.1039/D1CB00080B
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    Enzymatic strategies for asymmetric synthesis
    Hall, Melanie
    RSC Chemical Biology (2021), 2 (4), 958-989CODEN: RCBSBP; ISSN:2633-0679. (Royal Society of Chemistry)
    Enzymes, at the turn of the 21st century, are gaining a momentum. Esp. in the field of synthetic org. chem., a broad variety of biocatalysts are being applied in an increasing no. of processes running at up to industrial scale. In addn. to the advantages of employing enzymes under environmentally friendly reaction conditions, synthetic chemists are recognizing the value of enzymes connected to the exquisite selectivity of these natural (or engineered) catalysts. The use of hydrolases in enantioselective protocols paved the way to the application of enzymes in asym. synthesis, in particular in the context of biocatalytic (dynamic) kinetic resolns. After two decades of impressive development, the field is now mature to propose a panel of catalytically diverse enzymes for (i) stereoselective reactions with prochiral compds., such as double bond redn. and bond forming reactions, (ii) formal enantioselective replacement of one of two enantiotopic groups of prochiral substrates, as well as (iii) atroposelective reactions with noncentrally chiral compds. In this review, the major enzymic strategies broadly applicable in the asym. synthesis of optically pure chiral compds. are presented, with a focus on the reactions developed within the past decade.
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    Zetzsche, L. E.; Narayan, A. R. H. Broadening the Scope of Biocatalytic C–C Bond Formation. Nat. Rev. Chem. 2020, 4 (7), 334– 346,  DOI: 10.1038/s41570-020-0191-2
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    23
    Broadening the scope of biocatalytic C-C bond formation
    Zetzsche, Lara E.; Narayan, Alison R. H.
    Nature Reviews Chemistry (2020), 4 (7), 334-346CODEN: NRCAF7; ISSN:2397-3358. (Nature Research)
    Abstr.: Enzymes exercise impeccable control over chemoselectivity, site selectivity and stereoselectivity in reactions they mediate, such that we have witnessed a surge in the development of new biocatalytic methods. Although carbon-carbon (C-C) bonds are the central framework of org. mols., biocatalytic methods for their formation have largely been limited to a select few lyase enzymes. Thus, despite several decades of research, there are not many biocatalytic C-C-bond-forming transformations at our disposal. This Review describes the suite of enzymes available for highly selective, biocatalytic C-C bond formation. We discuss each class of enzyme in terms of native activity, alteration of this activity through protein or substrate engineering, and its utility in abiotic synthesis. [graphic not available: see fulltext].
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    Hüttel, W.; Müller, M. Regio- and Stereoselective Intermolecular Phenol Coupling Enzymes in Secondary Metabolite Biosynthesis. Nat. Prod. Rep. 2021, 38 (5), 1011– 1043,  DOI: 10.1039/D0NP00010H
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    Regio- and stereoselective intermolecular phenol coupling enzymes in secondary metabolite biosynthesis
    Huettel, Wolfgang; Mueller, Michael
    Natural Product Reports (2021), 38 (5), 1011-1043CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
    Covering: 2005 to 2020Phenol coupling is a key reaction in the biosynthesis of important biopolymers such as lignin and melanin and of a plethora of biarylic secondary metabolites. The reaction usually leads to several different regioisomeric products due to the delocalization of a radical in the reaction intermediates. If axial chirality is involved, stereoisomeric products are obtained provided no external factor influences the selectivity. Hence, in non-enzymic org. synthesis it is notoriously difficult to control the selectivity of the reaction, in particular if the coupling is intermol. From biosynthesis, it is known that esp. fungi, plants, and bacteria produce biarylic compds. regio- and stereoselectively. Nonetheless, the involved enzymes long evaded discovery. First progress was made in the late 1990s; however, the breakthrough came only with the genomic era and, in particular, in the last few years the no. of relevant publications has dramatically increased. The discoveries reviewed in this article reveal a remarkable diversity of enzymes that catalyze oxidative intermol. phenol coupling, including various classes of laccases, cytochrome P 450 enzymes, and heme peroxidases. Particularly in the case of laccases, the catalytic systems are often complex and addnl. proteins, substrates, or reaction conditions have a strong influence on activity and regio- and atroposelectivity. Although the field of (selective) enzymic phenol coupling is still in its infancy, the diversity of enzymes identified recently could make it easier to select suitable candidates for biotechnol. development and to approach this challenging reaction through biocatalysis.
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    Wu, J.; Kozlowski, M. C. Catalytic Oxidative Coupling of Phenols and Related Compounds. ACS Catal. 2022, 12 (11), 6532– 6549,  DOI: 10.1021/acscatal.2c00318
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    Catalytic Oxidative Coupling of Phenols and Related Compounds
    Wu, Jingze; Kozlowski, Marisa C.
    ACS Catalysis (2022), 12 (11), 6532-6549CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    A review. Phenols and their derivs. are the elementary building blocks for several classes of complex mols. that play essential roles in biol. systems. Nature has devised methods to selectively couple phenolic compds., and many efforts have been undertaken by chemists to mimic such coupling processes. A range of mechanisms can be involved with well-studied catalysts, and the reaction outcomes in phenol-phenol oxidative coupling reactions can be predicted with a good level of fidelity. However, reactions with catalysts that have not been studied or that do not behave similarly to known catalysts can be hard to predict and control. This perspective provides an overview of catalytic methods for the oxidative coupling of phenols, focusing on the last 10 years, and summarizes current challenges.
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    Zetzsche, L. E.; Chakrabarty, S.; Narayan, A. R. H. The Transformative Power of Biocatalysis in Convergent Synthesis. J. Am. Chem. Soc. 2022, 144 (12), 5214– 5225,  DOI: 10.1021/jacs.2c00224
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    The Transformative Power of Biocatalysis in Convergent Synthesis
    Zetzsche, Lara E.; Chakrabarty, Suman; Narayan, Alison R. H.
    Journal of the American Chemical Society (2022), 144 (12), 5214-5225CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A review. Achieving convergent synthetic strategies has long been a gold std. in constructing complex mol. skeletons, allowing for the rapid generation of complexity in comparatively streamlined synthetic routes. Traditionally, biocatalysis has not played a prominent role in convergent lab. synthesis, with the application of biocatalysts in convergent strategies primarily limited to the synthesis of chiral fragments. Although the use of enzymes to enable convergent synthetic approaches is relatively new and emerging, combining the efficiency of convergent transformations with the selectivity achievable through biocatalysis creates new opportunities for efficient synthetic strategies. This Perspective provides an overview of recent developments in biocatalytic strategies for convergent transformations and offers insights into the advantages of these methods compared to their small mol.-based counterparts.
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  27. 27
    Paniagua, C.; Bilkova, A.; Jackson, P.; Dabravolski, S.; Riber, W.; Didi, V.; Houser, J.; Gigli-Bisceglia, N.; Wimmerova, M.; Budínská, E.; Hamann, T.; Hejatko, J. Dirigent Proteins in Plants: Modulating Cell Wall Metabolism during Abiotic and Biotic Stress Exposure. J. Exp. Bot. 2017, 68 (13), 3287– 3301,  DOI: 10.1093/jxb/erx141
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    Dirigent proteins in plants: modulating cell wall metabolism during abiotic and biotic stress exposure
    Paniagua, Candelas; Bilkova, Anna; Jackson, Phil; Dabravolski, Siarhei; Riber, Willi; Didi, Vojtech; Houser, Josef; Gigli-Bisceglia, Nora; Wimmerova, Michaela; Budinska, Eva; Hamann, Thorsten; Hejatko, Jan
    Journal of Experimental Botany (2017), 68 (13), 3287-3301CODEN: JEBOA6; ISSN:1460-2431. (Oxford University Press)
    Dirigent (DIR) proteins were found to mediate regio- and stereoselectivity of bimol. phenoxy radical coupling during lignan biosynthesis. Here we summarize the current knowledge of the importance of DIR proteins in lignan and lignin biosynthesis and highlight their possible importance in plant development. We focus on the still rather enigmatic Arabidopsis DIR gene family, discussing the few members with known functional importance. We comment on recent discoveries describing the detailed structure of two DIR proteins with implications in the mechanism of DIR-mediated catalysis. Further, we summarize the ample evidence for stress-induced dirigent gene expression, suggesting the role of DIRs in adaptive responses. In the second part of our work, we present a preliminary bioinformatics-based characterization of the AtDIR family. The phylogenetic anal. of AtDIRs complemented by comparison with DIR proteins of mostly known function from other species allowed us to suggest possible roles for several members of this family and identify interesting AtDIR targets for further study. Finally, based on the available metadata and our in silico anal. of AtDIR promoters, we hypothesize about the existence of specific transcriptional controls for individual AtDIR genes and implicate them in various stress responses, hormonal regulations, and developmental processes.
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  28. 28
    Zetzsche, L. E.; Yazarians, J. A.; Chakrabarty, S.; Hinze, M. E.; Murray, L. A. M.; Lukowski, A. L.; Joyce, L. A.; Narayan, A. R. H. Biocatalytic Oxidative Cross-Coupling Reactions for Biaryl Bond Formation. Nature 2022, 603 (7899), 79– 85,  DOI: 10.1038/s41586-021-04365-7
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    Biocatalytic oxidative cross-coupling reactions for biaryl bond formation
    Zetzsche, Lara E.; Yazarians, Jessica A.; Chakrabarty, Suman; Hinze, Meagan E.; Murray, Lauren A. M.; Lukowski, April L.; Joyce, Leo A.; Narayan, Alison R. H.
    Nature (London, United Kingdom) (2022), 603 (7899), 79-85CODEN: NATUAS; ISSN:1476-4687. (Nature Portfolio)
    Biaryl compds., with two connected arom. rings, are found across medicine, materials science and asym. catalysis1,2. The necessity of joining arene building blocks to access these valuable compds. has inspired several approaches for biaryl bond formation and challenged chemists to develop increasingly concise and robust methods for this task3. Oxidative coupling of two C-H bonds offers an efficient strategy for the formation of a biaryl C-C bond; however, fundamental challenges remain in controlling the reactivity and selectivity for uniting a given pair of substrates4,5. Biocatalytic oxidative cross-coupling reactions have the potential to overcome limitations inherent to numerous small-mol.-mediated methods by providing a paradigm with catalyst-controlled selectivity6. Here we disclose a strategy for biocatalytic cross-coupling through oxidative C-C bond formation using cytochrome P 450 enzymes. We demonstrate the ability to catalyze cross-coupling reactions on a panel of phenolic substrates using natural P 450 catalysts. Moreover, we engineer a P 450 to possess the desired reactivity, site selectivity and atroposelectivity by transforming a low-yielding, unselective reaction into a highly efficient and selective process. This streamlined method for constructing sterically hindered biaryl bonds provides a programmable platform for assembling mols. with catalyst-controlled reactivity and selectivity.
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    Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis: Regio- and Stereoselective Biotransformations; Wiley, 2006.
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    Fujimoto, Y.; Iwadate, H.; Ikekawa, N. Preparation of Optically Active 2,2′-Dihydroxy-l,1 ′mbinaphthyl via Microbial Resolution of the Corresponding Racemic Diester. J. Chem. Soc. Chem. Commun. 1985, 19, 1333– 1334,  DOI: 10.1039/C39850001333
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    Miyano, S.; Kawahara, K.; Inoue, Y.; Hashimoto, H. A Convenient Preparation of Optically Active 1,1′-Binaphthyl-2,2′-Diol via Enzymatic Hydrolysis of the Racemic Diester. Chem. Lett. 1987, 16 (2), 355– 356,  DOI: 10.1246/cl.1987.355
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    Kazlauskas, R. J. Resolution of Binaphthols and Spirobiindanols Using Cholesterol Esterase. J. Am. Chem. Soc. 1989, 111 (13), 4953– 4959,  DOI: 10.1021/ja00195a059
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    Resolution of binaphthols and spirobiindanols using cholesterol esterase
    Kazlauskas, Romas J.
    Journal of the American Chemical Society (1989), 111 (13), 4953-9CODEN: JACSAT; ISSN:0002-7863.
    Simple, synthetic-scale procedures (200 g) procedures are detailed for the resoln. of [1,1'-binaphthalene]-2,2'-diol (I) and 2,2',3,3'-tetrahydro-2,2',3,3'-tetramethyl-1,1'spirobi[1H-indene]-6,6'-diol (II) using cholesterol esterase-catalyzed hydrolysis of their diesters. Resoln. of I involved hydrolysis of the dipentanoate ester catalyzed by crude , inexpensive enzyme (bovine pancreas acetone powder) and yielded each enantiomer in >60% of theor. yield with ≥99% enantiomeric purity.n. Similar resoln. of II by hydrolysis of the dihexanoate ester yielded each enantioimer in >50% of theor. yield with >95% enantiomeric purity. These resolns. involve 2 enzymic reactions: hydrolysis of the diester to the monoester followed by the hydrolysis of the monoester the diol. A theor. anal. of such 2-step resolns. suggests that 2-step resolns. can yield products with higher enantiomeric purity than 1-step resolns.
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    Kazlauskas, R. J. (S)-(−)- and (R)-(+)-1,1′-Bi-2-Naphthol. Org. Synth. 1992, 70, 60,  DOI: 10.15227/orgsyn.070.0060
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    (S)-(-)- and (R)-(+)-1,1'-Bi-2-naphthol
    Kazlauskas, Romas J.
    Organic Syntheses (1992), 70 (), 60-7CODEN: ORSYAT; ISSN:0078-6209.
    Esterification of racemic 1,1'-bi-2-naphthol with pentanoyl chloride gave racemic binaphthol dipentanoate, which when treated with cholesterol esterase (as bovine pancreas acetone powder) gave 64-67% highly pure (S)-(-)-1,1'-bi-2-naphthol by fractional crystn. Concn. of the filtrate gave (R)-binaphthol dipentanoate, which was sapond. with NaOMe in MeOH to give enantiomerically pure (R)-(+)-1,1'-bi-2-naphthol.
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    Furutani, T.; Hatsuda, M.; Imashiro, R.; Seki, M. Facile Synthesis of Enantiopure 1,1′-Binaphthyl-2,2′-Dicarboxylic Acid via Lipase-Catalyzed Kinetic Resolution. Tetrahedron: Asymmetry 1999, 10 (24), 4763– 4768,  DOI: 10.1016/S0957-4166(99)00555-8
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    Facile synthesis of enantiopure 1,1'-binaphthyl-2,2'-dicarboxylic acid via lipase-catalyzed kinetic resolution
    Furutani, Toshiyuki; Hatsuda, Masanori; Imashiro, Ritsuo; Seki, Masahiko
    Tetrahedron: Asymmetry (1999), 10 (24), 4763-4768CODEN: TASYE3; ISSN:0957-4166. (Elsevier Science Ltd.)
    Enantiopure (R)- and (S)-1,1'-binaphthyl-2,2'-dicarboxylic acid have been synthesized through the lipase-catalyzed kinetic resoln. of racemic 2,2-bis(hydroxymethyl)-1,1'-binaphthyl and subsequent oxidn. of the hydroxymethyl groups.
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    Seki, M.; Furutani, T.; Hatsuda, M.; Imashiro, R. Facile Synthesis of C2-Symmetric Chiral Binaphthyl Ketone Catalysts. Tetrahedron Lett. 2000, 41 (13), 2149– 2152,  DOI: 10.1016/S0040-4039(00)00120-9
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    Facile synthesis of C2-symmetric chiral binaphthyl ketone catalysts
    Seki, Masahiko; Furutani, Toshiyuki; Hatsuda, Masanori; Imashiro, Ritsuo
    Tetrahedron Letters (2000), 41 (13), 2149-2152CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
    C2-sym. chiral binaphthyl ketones I (R = H, Cl), efficient catalysts for asym. epoxidn., were synthesized through an intramol. Ullmann reaction and/or a lipase-catalyzed enantioselective hydrolysis of the resp. 11-membered cyclic binaphthyl acetate.
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    Juárez-Hernandez, M.; Johnson, D. V.; Holland, H. L.; McNulty, J.; Capretta, A. Lipase-Catalyzed Stereoselective Resolution and Desymmetrization of Binaphthols. Tetrahedron: Asymmetry 2003, 14 (3), 289– 291,  DOI: 10.1016/S0957-4166(02)00792-9
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    Lipase-catalyzed stereoselective resolution and desymmetrization of binaphthols
    Juarez-Hernandez, Marcela; Johnson, Dean V.; Holland, Herbert L.; McNulty, James; Capretta, Alfredo
    Tetrahedron: Asymmetry (2003), 14 (3), 289-291CODEN: TASYE3; ISSN:0957-4166. (Elsevier Science Ltd.)
    We have investigated the use of lipoprotein lipase enzymes from Pseudomonas sp. and Pseudomonas fluorescens for the enantioselective resoln. and desymmetrization of racemic binaphthols I (R = H, Br, OMe). The reactions were carried out using a non-aq. environment (iPr2O/acetone/vinyl acetate), and yielded mono-acetate ester products of the parent unsubstituted substrate, the 6,6'-dibromo-substrate, and the 6,6'-dimethoxy-substrate with high enantiomeric selectivity.
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    Tanaka, K.; Furuta, T.; Fuji, K.; Miwa, Y.; Taga, T. Preparation and Absolute Configuration of Hexahydroxyter- and Octahydroxyquaternaphthalene Derivatives. Tetrahedron: Asymmetry 1996, 7 (8), 2199– 2202,  DOI: 10.1016/0957-4166(96)00270-4
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    Preparation of absolute configuration of hexahydroxyternaphthalene and octahydroxyquaternaphthalene derivatives
    Tanaka, Kiyoshi; Furuta, Takumi; Fuji, Kaoru; Miwa, Yoshihisa; Taga, Tooru
    Tetrahedron: Asymmetry (1996), 7 (8), 2199-2202CODEN: TASYE3; ISSN:0957-4166. (Elsevier)
    Oxidative coupling reactions of the stereochem. defined tetrahydroxybinaphthalene derivs. gave a separable mixt. of two diastereomers of (S,S,S)-quaternaphthalenes and (S,R.S)-quaternaphthalenes, whose structures were confirmed by an alternative chem. transformation through the ternaphthalenes as well as the X-ray structure anal. The CD spectra of the corresponding diastereomers were indicative of the stereochem. across the axis.
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    Banerjee, S.; Riggs, B. E.; Zakharov, L. N.; Blakemore, P. R. Synthesis, Properties, and Enantiomerization Behavior of Axially Chiral Phenolic Derivatives of 8-(Naphth-1-Yl)Quinoline and Comparison to 7,7′-Dihydroxy-8,8′-Biquinolyl and 1,1′-Bi-2-Naphthol. Synthesis 2015, 47 (24), 4008– 4016,  DOI: 10.1055/s-0035-1560640
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    Synthesis, Properties, and Enantiomerization Behavior of Axially Chiral Phenolic Derivatives of 8-(Naphth-1-yl)quinoline and Comparison to 7,7'-Dihydroxy-8,8'-biquinolyl and 1,1'-Bi-2-naphthol
    Banerjee, Somdev; Riggs, Brian E.; Zakharov, Lev N.; Blakemore, Paul R.
    Synthesis (2015), 47 (24), 4008-4016CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)
    An aza-analog of 1,1'-bi-2-naphthol (BINOL, III), 7-hydroxy-8-(2-hydroxynaphth-1-yl)quinoline (8-azaBINOL, II), was prepd. in 3 steps and 49% yield from N,N-di-Et O-(7-hydroxy-8-iodoquinolyl)carbamate via Suzuki coupling with 1-naphthylboronic acid followed by Sanford oxidn. and sapon. II was resolved into (-)-(aS) and (+)-(aR) atropisomers via enzymic hydrolysis of its racemic divalerate deriv. with bovine pancreas acetone powder. The configurational stability of diol II was found to be intermediate to that of 7,7'-dihydroxy-8,8'-biquinolyl (least stable) and BINOL (most stable). Eyring plot anal. of the enantiomerization kinetics of I, II, and III, in DMSO soln. revealed activation parameters of ΔH⧺ = +27.4, +19.9, +23.2 kcal mol-1, and ΔS⧺ = +3.8, -27.9, -25.3 cal mol-1 K-1, resp. The unique character of ΔH⧺ and ΔS⧺ values for biquinolyl I suggests that the enantiomerization mechanism for I is distinct to that for naphthalenes II and III. Monohydroxy analogs of II, 7-hydroxy-8-(naphth-1-yl)quinoline (IV) and 8-(2-hydroxynaphth-1-yl)quinoline (V), were similarly prepd. and their racemization half-lives at room temp. were detd.; τ1/2(rac) was strongly dependent on solvent for naphthol V [τ1/2(rac) at 24°: in CHCl3 = 2.7 h, in MeOH = 89 h] but not for the quinol IV [τ1/2(rac) at 24°: in CHCl3 = 106 h, in MeOH = 120 h].
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    Blakemore, P. R.; Milicevic, S. D.; Zakharov, L. N. Enzymatic Resolution of 7,7′-Dihydroxy-8,8′- Biquinolyl Dipentanoate and Its Conversion to 2,2′-Di-Tert-Butyl-7,7′-Dihydroxy-8,8′-Biquinolyl. J. Org. Chem. 2007, 72 (24), 9368– 9371,  DOI: 10.1021/jo701611u
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    Enzymatic resolution of 7,7'-dihydroxy-8,8'-biquinolyl dipentanoate and its conversion to 2,2'-Di-tert-butyl-7,7'-dihydroxy-8,8'-biquinolyl
    Blakemore, Paul R.; Milicevic, Selena D.; Zakharov, Lev N.
    Journal of Organic Chemistry (2007), 72 (24), 9368-9371CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Incubation of (±)-7,7'-di(pentanoyloxy)-8,8'-biquinolyl (I) with a crude cholesterol esterase prepn. (from bovine pancreas) yielded highly enantioenriched unreacted dextrorotatory material, (+)-(aR)-I (46%, ≥99% ee), accompanied by the expected diol product, (-)-(aS)-7,7'-dihydroxy-8,8'-biquinolyl, in modest enantiomeric excess (≥37%, ≥77% ee). Treatment of scalemic diester I with t-BuLi, followed by sapon. in the presence of air, gave 2,2'-di-tert-butyl-7,7'-dihydroxy-8,8'-biquinolyl (II) in enantio enriched form. Biquinolyl II is less configurationally stable than I, racemizing rapidly in CHCl3 (t1/2(rac) = 1.9 h, rt), and with a moderate rate in MeOH (t1/2(rac) = 30.5 h, rt).
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    Inagaki, M.; Hiratake, J.; Nishioka, T.; Jun’ichi, O. Lipase-Catalyzed Stereoselective Acylation of [1,1′-Binaphthyl]-2,2′-Diol and Deacylation of Its Esters in an Organic Solvent. Agric. Biol. Chem. 1989, 53 (7), 1879– 1884,  DOI: 10.1080/00021369.1989.10869551
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    Lipase-catalyzed stereoselective acylation of [1,1'-binaphthyl]-2,2'-diol and deacylation of its esters in an organic solvent
    Inagaki, Minoru; Hiratake, Jun; Nishioka, Takaaki; Oda, Junichi
    Agricultural and Biological Chemistry (1989), 53 (7), 1879-84CODEN: ABCHA6; ISSN:0002-1369.
    A kinetic resoln. of [1,1'-binaphthyl]-2,2'-diol (binaphthol) [(±)-I) and its esters was first accomplished by lipase-catalyzed transesterification in an org. solvent. Acylation of binaphthol with enol esters in diisopropyl ether-acetone (9:1) gave solely (R)-2-acyloxy-2'-hydroxy-1,1'-binaphthyl (binaphthyl monoesters) having 90 ∼ 95% optical purities. The unreacted binaphthol, which was also recovered in high chem. yields, was the S enantiomer with 69 ∼ 89% (enantiomeric excess). On the other hand, the lipase-catalyzed deacylation or alcoholysis of racemic binaphthyl monoesters gave (S)-monoesters and (R)-I in high chem. and optical yields (>90% enantiomeric excess). In deacylation, the reaction period was much shortened by introducing the more electroneg. Cl atom into the acetyl group of the substrate.
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    Moustafa, G. A. I.; Kasama, K.; Higashio, K.; Akai, S. Base-Promoted Lipase-Catalyzed Kinetic Resolution of Atropisomeric 1,1′-Biaryl-2,2′-Diols. RSC Adv. 2019, 9 (3), 1165– 1175,  DOI: 10.1039/C8RA09070J
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    Base-promoted lipase-catalyzed kinetic resolution of atropisomeric 1,1'-biaryl-2,2'-diols
    Moustafa, Gamal A. I.; Kasama, Kengo; Higashio, Koichi; Akai, Shuji
    RSC Advances (2019), 9 (3), 1165-1175CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    A dramatic acceleration of the lipase-catalyzed kinetic resoln. of atropisomeric 1,1'-biaryl-2,2'-diols sym. R-R (R = 7-bromo-2-hydroxynaphthalen-1-yl, 2-hydroxy-6-methylphenyl, 3-bromo-2-hydroxynaphthalen-1-yl, etc.) and non sym. R1-R2 (R1 = 6-[ethoxy(carbonyl)]-2-hydroxynaphthalen-1-yl, 3-bromo-2-hydroxynaphthalen-1-yl, 2,5-dichloro-6-hydroxy-3-methoxyphenyl, etc.; R2 = 2-hydroxynaphthalen-1-yl, 6-bromo-2-hydroxynaphthalen-1-yl) by the addn. of sodium carbonate has been reported. This result likely originates from the increased nucleophilicity of the phenolic hydroxyl group toward the acyl-enzyme intermediate. Under these conditions, various substituted C2-sym. and non-C2-sym. binaphthols and biphenols were efficiently resolved with ∼50% conversion in only 13-30 h with excellent enantioselectivity.
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    Lin, G.; Chen, S.-J.; Sun, H.-L. Multiple Enantioselection by an Enzyme-Catalyzed Transacylation Reaction. J. Chin. Chem. Soc. 1994, 41 (4), 459– 465,  DOI: 10.1002/jccs.199400060
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    Multiple enantioselection by an enzyme-catalyzed transacylation reaction
    Lin, Gialih; Chen, Show-Jane; Sun, Hwey-Lin
    Journal of the Chinese Chemical Society (Taipei, Taiwan) (1994), 41 (4), 459-65CODEN: JCCTAC; ISSN:0009-4536.
    Multiply enantioselective enzyme-catalyzed transacylation reactions are described. Two instances of triply enantioselective enzyme-catalyzed transacylations are (1) the reaction of rac-1-indanol (rac-1) with rac-1,1'-bi-2-naphthyl-2,2'-dibutyrate to afford (S)-1, (R)-1-indanyl butyrate (R-3), (S)-1,1'-bi-2-naphthyl-2,2'-diol, and (R)-1,1'-bi-2-naphthyl-2,2'-dibutyrate and (2) the reaction of rac-1 with rac-2,2'-bis(butyroxymethyl)biphenyl to afford (S)-1, (R)-3, (S)-2,2'-biphenyldimethanol, and (R)-2,2'-bis(butyroxymethyl)biphenyl. Doubly enantioselective enzyme-catalyzed transacylations are described according to two instances: (1) the reaction of rac-1 with rac-1,1'-bi-2-naphthyl-2-ol-2'-butyrate afforded (S)-1, (R)-3, (S)-1,1'-bi-2-naphthyl-2,2'-diol, and (R)-1,1'-bi-2-naphthyl-2-ol-2'-butyrate, and (2) the reaction of rac-1 with 1,3,5-O-methylidyne-2,4,6-tri-O-butyrate-myo-inositol to afford (S)-1, (R)-3, and 1,3,5-O-methylidyne-2,6-di-O-butyrate-myo-inositol. Multiply enantioselective enzyme-catalyzed reactions have a merit of the enhancement of enantiomeric excess over singly enantioselective ones.
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    Sanfilippo, C.; Nicolosi, G.; Delogu, G.; Fabbri, D.; Dettori, M. A. Access to Optically Active 2,2′-Dihydroxy-6,6′-Dimethoxy-1,1′-Biphenyl by a Simple Biocatalytic Procedure. Tetrahedron: Asymmetry 2003, 14 (21), 3267– 3270,  DOI: 10.1016/j.tetasy.2003.08.002
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    Access to optically active 2,2'-dihydroxy-6,6'-dimethoxy-1,1'-biphenyl by a simple biocatalytic procedure
    Sanfilippo, Claudia; Nicolosi, Giovanni; Delogu, Giovanna; Fabbri, Davide; Dettori, Maria Antonietta
    Tetrahedron: Asymmetry (2003), 14 (21), 3267-3270CODEN: TASYE3; ISSN:0957-4166. (Elsevier Science B.V.)
    Lipase from Pseudomonas cepacia was found to catalyze acetylation in tert-Bu Me ether of the title alc. The action of four different P. cepacia prepns. was compared, all possessing high steric recognition, that results in an efficient kinetic resoln. of this atropisomeric biphenyl.
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    Sanfilippo, C.; D’Antona, N.; Nicolosi, G. Lipase-Catalysed Resolution by an Esterification Reaction in Organic Solvent of Axially Chiral (±)-3,3′-Bis(Hydroxymethyl)-2,2′-Bipyridine N,N-Dioxide. Tetrahedron: Asymmetry 2006, 17 (1), 12– 14,  DOI: 10.1016/j.tetasy.2005.11.028
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    Lipase-catalysed resolution by an esterification reaction in organic solvent of axially chiral (±)-3,3'-bis(hydroxymethyl)-2,2'-bipyridine N,N-dioxide
    Sanfilippo, Claudia; D'Antona, Nicola; Nicolosi, Giovanni
    Tetrahedron: Asymmetry (2006), 17 (1), 12-14CODEN: TASYE3; ISSN:0957-4166. (Elsevier B.V.)
    The enzymic kinetic resoln. of atropisomeric (±)-3,3'-bis(hydroxymethyl)-2,2'-bipyridine N,N-dioxide (±)-3 was investigated via enantioselective esterification in the unusual medium of alc./vinyl acetate (20:80). Lipase from Mucor miehei (immobilized lipase prepn., Lipozyme) was found to give good enantioselectivity with an (aS)-enantiopreference in the axial recognition, and allowed to efficiently perform the prepn. of both enantioforms with ee >98%. Lipase from Pseudomonas cepacia (immobilized lipase prepn., PS-D) also catalyzed the reaction although with low enantioselectivity and showing opposite stereopreference.
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    Takemura, T.; Emoto, G.; Satoh, J.; Kobayashi, Y.; Yaginuma, C.; Takahashi, Y.; Utsukihara, T.; Horiuchi, C. A. Optical Resolution of Hexamethylbiphenol by Cholesterol Esterase and Porcine Pancreas Lipase. J. Mol. Catal. B Enzym. 2008, 55 (3–4), 104– 109,  DOI: 10.1016/j.molcatb.2008.02.007
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    Optical resolution of hexamethylbiphenol by cholesterol esterase and porcine pancreas lipase
    Takemura, Tetsuo; Emoto, Go; Satoh, Jun; Kobayashi, Yoshitaka; Yaginuma, Chihiro; Takahashi, Yuta; Utsukihara, Takamitsu; Horiuchi, C. Akira
    Journal of Molecular Catalysis B: Enzymatic (2008), 55 (3-4), 104-109CODEN: JMCEF8; ISSN:1381-1177. (Elsevier B.V.)
    Both enantiomers of 2,2'-dihydroxy-4,4',5,5',6,6'-hexamethybiphenyl (2), a potentially useful chiral synthon, were obtained with >99% ee in high enantioselectivity by cholesterol esterase or porcine pancreas lipase (PPL)-mediated hydrolysis of the corresponding (±)-dipentanoate or (±)-dihexanoate, resp. Abs. configuration of (S)-3-bromo-2,6'-dimethoxy-4,5,6,2',3',4'-hexamethyl-biphenyl (2h) was detd. by X-ray anal.
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    Jouffroy, M.; Neufeld, K. Synthesis of Atropisomeric Biaryls via Chiral Suzuki–Miyaura/Enzymatic Kinetic Resolution. ACS Catal. 2022, 12 (14), 8380– 8385,  DOI: 10.1021/acscatal.2c02090
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    Synthesis of Atropisomeric Biaryls via Chiral Suzuki-Miyaura/Enzymatic Kinetic Resolution
    Jouffroy, Matthieu; Neufeld, Katharina
    ACS Catalysis (2022), 12 (14), 8380-8385CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    An unprecedented chiral Suzuki-Miyaura/enzymic kinetic resoln. sequence for the synthesis of JNJ-4355 (I) and other atropisomeric biaryls yielding the targets in high enantiopurity without chiral sepn. was reported.
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    Aoyagi, N.; Izumi, T. Kinetic Resolution of 1,1′-Binaphthylamines via Lipase-Catalyzed Amidation. Tetrahedron Lett. 2002, 43 (32), 5529– 5531,  DOI: 10.1016/S0040-4039(02)01162-0
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    Kinetic resolution of 1,1'-binaphthylamines via lipase-catalyzed amidation
    Aoyagi, Naoto; Izumi, Taeko
    Tetrahedron Letters (2002), 43 (32), 5529-5531CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
    Lipase-catalyzed N-acylation of binaphthyl-substituted amine I (n = 2) with aliph. esters gave optically active binaphthyls (R)-II (n = 2; R = Me, Et, Pr) with high enantiomeric excess. The analog with shorter aliph. chain, I (n = 1), was less reactive and under similar conditions gave the corresponding amides II (n = 1; R = Me, F3C, Pr) with lower enantioselectivity.
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    Aoyagi, N.; Kawauchi, S.; Izumi, T. Effect of the Alkyl Chain Length of 1,1′-Binaphthyl Esters in Lipase-Catalyzed Amidation. Tetrahedron Lett. 2003, 44 (30), 5609– 5612,  DOI: 10.1016/S0040-4039(03)01373-X
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    Effect of the alkyl chain length of 1,1'-binaphthyl esters in lipase-catalyzed amidation
    Aoyagi, Naoto; Kawauchi, Shinji; Izumi, Taeko
    Tetrahedron Letters (2003), 44 (30), 5609-5612CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science B.V.)
    Lipase-catalyzed amidation of 2-[2-(ethoxycarbonyl)ethyl]-1,1'-binaphthyl [(±)-I] yielded optically active (S)-I and (R)-2-[2-(2-cyanoethylaminocarbonyl)ethyl]-1,1'-binaphthyl with high enantiomeric excess. For these lipase-catalyzed amidations, the optimal alkyl chain length between the binaphthyl ring and the ester group was detd. to be an ethylene spacer.
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    Aoyagi, N.; Kawauchi, S.; Izumi, T. Different Recognitions of (E)- and (Z)-1,1′-Binaphthyl Ketoximes Using Lipase-Catalyzed Reactions. Tetrahedron Lett. 2004, 45 (27), 5189– 5192,  DOI: 10.1016/j.tetlet.2004.05.051
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    Different recognitions of (E)- and (Z)-1,1'-binaphthyl ketoximes using lipase-catalyzed reactions
    Aoyagi, Naoto; Kawauchi, Shinji; Izumi, Taeko
    Tetrahedron Letters (2004), 45 (27), 5189-5192CODEN: TELEAY; ISSN:0040-4039. (Elsevier)
    Lipase-catalyzed hydrolysis of (E)-2-[α-(acetoxyimino)benzyl]-1,1'-binaphthyl (I) [(E)-(±)-I] and (Z)-2-[α-(acetoxyimino)benzyl]-1,1'-binaphthyl [(Z)-(±)-I] yielded optically active (E)-2-[α-(hydroxyimino)benzyl]-1,1'-binaphthyl (II) [(E,S)-II] and (Z)-2-[α-(hydroxyimino)benzyl]-1,1'-binaphthyl [(Z,R)-II], resp., with high enantiomeric excess. Selectivity for the opposite enantiomer of the axial binaphthyl skeleton was shown by (Z)-isomer I against (E)-isomer I.
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    Kiefer, M.; Vogel, R.; Helmchen, G.; Nuber, B. Resolution of (1,1′-Binaphthalene)-2,2′-Dithiol by Enzyme Catalysed Hydrolysis of a Racemic Diacyl Derivative. Tetrahedron 1994, 50 (24), 7109– 7114,  DOI: 10.1016/S0040-4020(01)85237-6
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    Resolution of (1,1'-binaphthalene)-2,2'-dithiol by enzyme catalyzed hydrolysis of a racemic diacyl derivative
    Kiefer, Matthias; Vogel, Rainer; Helmchen, Guenter; Nuber, Bernhard
    Tetrahedron (1994), 50 (24), 7109-14CODEN: TETRAB; ISSN:0040-4020.
    Both enantiomers of (1,1'-binaphthalene)-2,2'-dithiol (1) can be obtained with 98% ee by enzymic (cholesterol esterase) resoln. of the corresponding S,S'-dipentanoate. Abs. configuration and enantiomeric purity were detd. by crystal structure and 1H NMR anal., resp., of a diastereomeric deriv. of 1.
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    Sanfilippo, C.; Nicolosi, G.; Delogu, G.; Fabbri, D.; Dettori, M. A. Synthesis and Biocatalytic Resolution of a New Atropisomeric Thiobiphenyl: (2,2′,6,6′-Tetramethoxybiphenyl-3,3′-Diyl)Dimethanethiol. Tetrahedron: Asymmetry 2005, 16 (6), 1079– 1084,  DOI: 10.1016/j.tetasy.2005.01.028
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    Synthesis and biocatalytic resolution of a new atropisomeric thiobiphenyl: (2,2',6,6'-tetramethoxybiphenyl-3,3'-diyl)dimethanethiol
    Sanfilippo, Claudia; Nicolosi, Giovanni; Delogu, Giovanna; Fabbri, Davide; Dettori, Maria Antonietta
    Tetrahedron: Asymmetry (2005), 16 (6), 1079-1084CODEN: TASYE3; ISSN:0957-4166. (Elsevier B.V.)
    Both atropisomers of racemic thiobiphenyl (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol were obtained in enantiopure form using lipase catalyzed procedures. The esterification reaction of (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol in the presence of vinyl acetate gave in a one-pot reaction (+)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol and (-)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol via a lipase assisted dynamic kinetic resoln. of epimerizing hemithioacetal intermediates. The alcoholysis of the diacetyl thioester, (±)-of ethanethioic acid S,S'-[2,2',6,6'-tetra(methoxy)[1,1'-biphenyl]-3,3'-diyl] ester is an alternative strategy for access to the enantiomers of (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol with high enantiomeric excess.
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    Staniland, S.; Yuan, B.; Giménez-Agulló, N.; Marcelli, T.; Willies, S. C.; Grainger, D. M.; Turner, N. J.; Clayden, J. Enzymatic Desymmetrising Redox Reactions for the Asymmetric Synthesis of Biaryl Atropisomers. Chem.─Eur. J. 2014, 20 (41), 13084– 13088,  DOI: 10.1002/chem.201404509
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    Enzymatic Desymmetrising Redox Reactions for the Asymmetric Synthesis of Biaryl Atropisomers
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    Matsumoto, T.; Konegawa, T.; Nakamura, T.; Suzuki, K. Facile and Highly Enantioselective Synthesis of Axially Chiral Biaryls by Enzymatic Desymmetrization. Synlett 2002, 2002 (1), 0122– 0124,  DOI: 10.1055/s-2002-19349
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    Enantioselective Total Synthesis of (-)-Euxanmodin B: An Axially Chiral Natural Product with an Anthraquinone-Xanthone Composite Structure
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    The first total synthesis of (-)-euxanmodin B (I) was achieved starting from an axially chiral, enantiomerically pure biphenyl substrate II. Further studies are in progress, including the biol. assay for nonracemic and racemic materials.
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    Yamaguchi, S.; Takahashi, N.; Yuyama, D.; Sakamoto, K.; Suzuki, K.; Matsumoto, T. First Total Synthesis of Dermocanarin 2. Synlett 2016, 27 (8), 1262– 1268,  DOI: 10.1055/s-0035-1561417
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    First Total Synthesis of Dermocanarin 2
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    Synlett (2016), 27 (8), 1262-1268CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
    The first total synthesis of dermocanarin 2 (I) is described. The synthesis features the construction of the anthraquinone and naphthoquinone frameworks through annulation reactions onto an axially chiral biphenyl intermediate, obtained by an enzyme-catalyzed enantioselective desymmetrization of a σ-sym. precursor, followed by a stereoselective aldol reaction to construct the stereogenic center in the side chain.
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    Ochiai, M.; Akisawa, Y.; Kajiyama, D.; Matsumoto, T. Desymmetrization of σ-Symmetric Biphenyl-2,6-Diyl Diacetate Derivatives by Lipase-Catalyzed Hydrolysis: Unexpected Effect of C(3′)-Substituent on the Enantiotopic Group Selectivity. Synlett 2019, 30 (5), 557– 562,  DOI: 10.1055/s-0037-1611701
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    Desymmetrization of σ-Symmetric Biphenyl-2,6-diyl Diacetate Derivatives by Lipase-Catalyzed Hydrolysis: Unexpected Effect of C(3')-Substituent on the Enantiotopic Group Selectivity
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    Synlett (2019), 30 (5), 557-562CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
    Highly enantioselective desymmetrization of σ-sym. 3'-substituted 2',6'-dimethoxybiphenyl-2,6-diyl diacetate derivs. I (R = CO2CH3, C(O)CH3, 2-furanyl, etc.) to the corresponding monoacetates II and III was effected by using Rhizopus oryzae lipase (ROL) and porcine pancreatic lipase (PPL), despite the remoteness of the C(3') substituent from the acetate groups. ROL promoted hydrolysis of the pro-S-acetates, irresp. of the type of C(3') substituent, whereas PPL promoted hydrolysis of the pro-R-acetates, and selectivity was only attainable when the C(3') substituent was a polar group.
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    Kasama, K.; Aoyama, H.; Akai, S. Enantiodivergent Synthesis of Axially Chiral Biphenyls from σ-Symmetric 1,1′-Biphenyl-2,6-Diol Derivatives by Single Lipase-Catalyzed Acylative and Hydrolytic Desymmetrization. Eur. J. Org. Chem. 2020, 2020 (6), 654– 661,  DOI: 10.1002/ejoc.201901583
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    Enantiodivergent Synthesis of Axially Chiral Biphenyls from σ-Symmetric 1,1'-Biphenyl-2,6-diol Derivatives by Single Lipase-Catalyzed Acylative and Hydrolytic Desymmetrization
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    European Journal of Organic Chemistry (2020), 2020 (6), 654-661CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The enzymic acylative desymmetrization of σ-sym. 2'-halo-1,1'-biphenyl-2,6-diols was achieved for the first time using com. available Burkholderia cepacia lipase immobilized on diatomaceous earth to give (S)-mono esters. The hydrolytic desymmetrization of the corresponding diacetates was also achieved using the same lipase to give (R)-mono esters. The authors' results, therefore, demonstrate that a single lipase can conduct the enantiodivergent synthesis of axially chiral biphenyl compds. in high chem. and optical yields.
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    Dong, J.; Fernández-Fueyo, E.; Hollmann, F.; Paul, C. E.; Pesic, M.; Schmidt, S.; Wang, Y.; Younes, S.; Zhang, W. Biocatalytic Oxidation Reactions: A Chemist’s Perspective. Angew. Chem., Int. Ed. 2018, 57 (30), 9238– 9261,  DOI: 10.1002/anie.201800343
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    Biocatalytic Oxidation Reactions: A Chemist's Perspective
    Dong, JiaJia; Fernandez-Fueyo, Elena; Hollmann, Frank; Paul, Caroline E.; Pesic, Milja; Schmidt, Sandy; Wang, Yonghua; Younes, Sabry; Zhang, Wuyuan
    Angewandte Chemie, International Edition (2018), 57 (30), 9238-9261CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Oxidn. chem. using enzymes is approaching maturity and practical applicability in org. synthesis. Oxidoreductases (enzymes catalyzing redox reactions) enable chemists to perform highly selective and efficient transformations ranging from simple alc. oxidns. to stereoselective halogenations of non-activated C-H bonds. For many of these reactions, no "classical" chem. counterpart is known. Hence oxidoreductases open up shorter synthesis routes based on a more direct access to the target products. The generally very mild reaction conditions may also reduce the environmental impact of biocatalytic reactions compared to classical counterparts. In this Review, we critically summarize the most important recent developments in the field of biocatalytic oxidn. chem. and identify the most pressing bottlenecks as well as promising solns.
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    Escalettes, F.; Turner, N. J. Directed Evolution of Galactose Oxidase: Generation of Enantioselective Secondary Alcohol Oxidases. ChemBioChem. 2008, 9 (6), 857– 860,  DOI: 10.1002/cbic.200700689
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    Directed evolution of galactose oxidase: generation of enantioselective secondary alcohol oxidases
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    A colorimetric solid phase assay which allowed to assess the activity of individual clones when grown on agar plates is described. This screening method which relies upon capture of the hydrogen peroxide byproducts produced in the oxidn. reaction, is versatile, in that different substrate can easily be introduced into the assay and also reasonably high-throughput allowing up to 100,000 clones to be readily screened per round of evolution. Libraries of M3 GOase were generated using error-prone PCR in which the av. no. of amino acids mutations per gene was about 3-4. These libraries were used to transform E. coli and the resulting colonies screened on solid phase against but-3-en-2-ol as substrate. Variants of GOase were identified that possess good activity towards a range of secondary alcs. based upon the 1-phenylethanol template and high enantioselectivity in the kinetic resoln. of (±)-3 fluoro-1-phenylethanol.
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    Nicolaou, K. C.; Boddy, C. N. C.; Bräse, S.; Winssinger, N. Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics. Angew. Chem., Int. Ed. 1999, 38 (15), 2096– 2152,  DOI: 10.1002/(SICI)1521-3773(19990802)38:15<2096::AID-ANIE2096>3.0.CO;2-F
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    Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics
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    The war against infectious bacteria is not over! Although vancomycin and glycopeptide antibiotics have provided a strong last line of defence against many drug-resistant bacteria, their overuse has given rise to more dangerous strains of bacteria. An understanding of the chemistry and biology of these highly complex glycopeptides are destined to play a crucial role in the discovery of new antibiotics.
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    Halling, P. J. Kinetics of Enzyme-Catalysed Desymmetrisation of Prochiral Substrates: Product Enantiomeric Excess Is Not Always Constant. Beilstein J. Org. Chem. 2021, 17 (1), 873– 884,  DOI: 10.3762/bjoc.17.73
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    Kinetics of enzyme-catalysed desymmetrisation of prochiral substrates: product enantiomeric excess is not always constant
    Halling, Peter J.
    Beilstein Journal of Organic Chemistry (2021), 17 (), 873-884CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
    The kinetics of enzymic desymmetrisation were analyzed for the most common kinetic mechanisms: ternary complex ordered (prochiral ketone redn.); ping-pong second (ketone amination, diol esterification, desymmetrisation in the second half reaction); ping-pong first (diol ester hydrolysis) and ping-pong both (prochiral diacids). For plausible values of enzyme kinetic parameters, the product enantiomeric excess (ee) can decline substantially as the reaction proceeds to high conversion. For example, an ee of 0.95 at the start of the reaction can decline to less than 0.5 at 95% of equil. conversion, but for different enzyme properties it will remain almost unchanged. For most mechanisms a single function of multiple enzyme rate consts. (which can be termed ee decline parameter, eeDP) accounts for the major effect on the tendency for the ee to decline. For some mechanisms, the concns. or ratios of the starting materials have an important influence on the fall in ee. For the application of enzymic desymmetrisation it is important to study if and how the product ee declines at high conversion.
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    Sanfilippo, C.; Nicolosi, G.; Delogu, G.; Fabbri, D.; Dettori, M. A. Synthesis and Biocatalytic Resolution of a New Atropisomeric Thiobiphenyl: (2,2′,6,6′-Tetramethoxybiphenyl- 3,3′-Diyl)Dimethanethiol. Tetrahedron: Asymmetry 2005, 16, 1079– 1084,  DOI: 10.1016/j.tetasy.2005.01.028
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    Synthesis and biocatalytic resolution of a new atropisomeric thiobiphenyl: (2,2',6,6'-tetramethoxybiphenyl-3,3'-diyl)dimethanethiol
    Sanfilippo, Claudia; Nicolosi, Giovanni; Delogu, Giovanna; Fabbri, Davide; Dettori, Maria Antonietta
    Tetrahedron: Asymmetry (2005), 16 (6), 1079-1084CODEN: TASYE3; ISSN:0957-4166. (Elsevier B.V.)
    Both atropisomers of racemic thiobiphenyl (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol were obtained in enantiopure form using lipase catalyzed procedures. The esterification reaction of (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol in the presence of vinyl acetate gave in a one-pot reaction (+)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol and (-)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol via a lipase assisted dynamic kinetic resoln. of epimerizing hemithioacetal intermediates. The alcoholysis of the diacetyl thioester, (±)-of ethanethioic acid S,S'-[2,2',6,6'-tetra(methoxy)[1,1'-biphenyl]-3,3'-diyl] ester is an alternative strategy for access to the enantiomers of (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol with high enantiomeric excess.
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    Skrobo, B.; Deska, J. On the Lipase-Catalyzed Resolution of Functionalized Biaryls. Tetrahedron: Asymmetry 2013, 24 (17), 1052– 1056,  DOI: 10.1016/j.tetasy.2013.07.014
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    On the lipase-catalyzed resolution of functionalized biaryls
    Skrobo, Benedikt; Deska, Jan
    Tetrahedron: Asymmetry (2013), 24 (17), 1052-1056CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
    The implementation of lipase catalysis as a tool for the prepn. of optically active biaryls is discussed. While attempts toward dynamic kinetic resoln. based on the catalytic ring opening of configurationally unstable biaryl lactones were fruitless, kinetic resoln. via transesterification of hydroxymethyl-decorated substrates was successfully employed in the generation of optically enriched, axially chiral biaryls.
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    Ahmed, A.; Bragg, R. A.; Clayden, J.; Lai, L. W.; McCarthy, C.; Pink, J. H.; Westlund, N.; Yasin, S. A. Barriers to Rotation about the Chiral Axis of Tertiary Aromatic Amides. Tetrahedron 1998, 54 (43), 13277– 13294,  DOI: 10.1016/S0040-4020(98)00814-X
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    Barriers to rotation about the chiral axis of tertiary aromatic amides
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    Tetrahedron (1998), 54 (43), 13277-13294CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
    The barrier to rotation about the aryl-carbonyl bond in 40 tertiary arom. amides was detd. by variable-temp. NMR spectroscopy (for rapid rotations) or by following the interconversion of atropisomers (for slower rotations). Empirical guidelines to the rate of Ar-CO bond rotation in hindered tertiary arom. amides, and hence the stability of the atropisomeric stereoisomers of axially chiral amides, are presented.
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    Clayden, J.; Lai, L. W.; Helliwell, M. Dynamic Resolution of Atropisomeric Amides Using Proline-Derived Imidazolines and Ephedrine-Derived Oxazolidines. Tetrahedron 2004, 60 (20), 4399– 4412,  DOI: 10.1016/j.tet.2004.01.101
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    Dynamic resolution of atropisomeric amides using proline-derived imidazolines and ephedrine-derived oxazolidines
    Clayden, Jonathan; Lai, Lai Wah; Helliwell, Madeleine
    Tetrahedron (2004), 60 (20), 4399-4412CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science B.V.)
    Condensation of atropisomeric tertiary 2-formylnaphthamides or 2-formylbenzamides with some chiral diamines and amino alcs. leads, via a dynamic resoln. process, to single atropisomers of tertiary amides bearing chiral imidazolidines or oxazolidines. Hydrolysis of the new heterocycle competes a dynamic thermodn. resoln. of the starting aldehyde, and rapid redn. allows the isolation of atropisomeric amides bearing 2-hydroxymethyl substituents in enantiomerically enriched form. Evidence that the reactions are under thermodn. control is presented.
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    Ruzziconi, R.; Lepri, S.; Buonerba, F.; Schlosser, M.; Mancinelli, M.; Ranieri, S.; Prati, L.; Mazzanti, A. Long-Range Bonding/Nonbonding Interactions: A Donor–Acceptor Resonance Studied by Dynamic NMR. Org. Lett. 2015, 17 (11), 2740– 2743,  DOI: 10.1021/acs.orglett.5b01152
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    Long-Range Bonding/Nonbonding Interactions: A Donor-Acceptor Resonance Studied by Dynamic NMR
    Ruzziconi, Renzo; Lepri, Susan; Buonerba, Federica; Schlosser, Manfred; Mancinelli, Michele; Ranieri, Silvia; Prati, Luca; Mazzanti, Andrea
    Organic Letters (2015), 17 (11), 2740-2743CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    Long-range bonding interactions were evaluated using variable-temp. NMR spectroscopy and suitable 2'-CH2X-substituted phenylpyridines (X = Me, NMe2, OMe, F). It was found that the arylpyridyl rotational barriers were lower when electroneg. atoms were bound to the α carbon of the 2' moiety. This effect was ascribed to a stabilizing interaction in the transition state due to the lone pair of the heterocyclic nitrogen with the α carbon. Computational support for this hypothesis came from CCSD(T)/6-31+G(d) calcns. Steric effects of the X moiety were ruled out by comparison of the rotational barriers of analogous biphenyls.
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    Snodgrass, H. M.; Mondal, D.; Lewis, J. C. Directed Evolution of Flavin-Dependent Halogenases for Site- and Atroposelective Halogenation of 3-Aryl-4(3H)-Quinazolinones via Kinetic or Dynamic Kinetic Resolution. J. Am. Chem. Soc. 2022, 144 (36), 16676– 16682,  DOI: 10.1021/jacs.2c07422
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    Directed Evolution of Flavin-Dependent Halogenases for Site- and Atroposelective Halogenation of 3-Aryl-4(3H)-Quinazolinones via Kinetic or Dynamic Kinetic Resolution
    Snodgrass, Harrison M.; Mondal, Dibyendu; Lewis, Jared C.
    Journal of the American Chemical Society (2022), 144 (36), 16676-16682CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    In this study, we engineer a variant of the flavin-dependent halogenase RebH that catalyzes site- and atroposelective halogenation of 3-aryl-4(3H)-quinazolinones via kinetic or dynamic kinetic resoln. The required directed evolution uses a combination of random and site-satn. mutagenesis, substrate walking using two probe substrates, and a two-tiered screening approach involving the anal. of variant conversion and then enantioselectivity of improved variants. The resulting variant, 3-T, provides >99:1 e.r. for the (M)-atropisomer of the major brominated product, 25-fold improved conversion, and 91-fold improved site selectivity relative to the parent enzyme on the probe substrate used in the final rounds of evolution. This high activity and selectivity translate well to several addnl. substrates with varied steric and electronic properties. Computational modeling and docking simulations are used to rationalize the effects of key mutations on substrate binding. Given the range of substrates that have been used for atroposelective synthesis via electrophilic halogenation in the literature, these results suggest that flavin-dependent halogenases (FDHs) could find many addnl. applications for atroposelective catalysis. More broadly, this study highlights how RebH can be engineered to accept structurally diverse substrates that enable its use for enantioselective catalysis.
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  • Abstract

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    Figure 1

    Figure 1. Examples of important atropisomeric molecules. Atropisomeric bonds are highlighted in red.

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    Scheme 1

    Scheme 1. Cytochrome P450 Enzyme-Mediated Atroposelective Oxidative Homocoupling and Cross-Coupling of Its Native Substrate 5 with Phenol Derivatives
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    Scheme 2

    Scheme 2. Early Example of Biocatalytic Atroposelective Ester Hydrolysis Reported by Miyano and Co-workers, in Which Valeric Diester rac-12 Was Selectively Hydrolyzed to Afford (Sa)-BINOL 11
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    Scheme 3

    Scheme 3. Early Example of Biocatalytic KR of rac-BINOL 11via Acylation by a Variety of Vinyl Ester Acyl Donors to Form Monoesters 13
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    Scheme 4

    Scheme 4. PPL-Catalyzed Stereoselective Transesterification of Butyl Ester 14 and Indanol 15
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    Scheme 5

    Scheme 5. (a) Early Example of a Biocatalytic KR of a Biphenyl Diol rac-17 by PCL-Mediated Acylation, (b) KR of Bipyridinyl N-Oxide Atropisomers by MML-Mediated Acylation, and (c) Further Enantioenrichment of Synthetic Intermediate (Sa)-22 during the Asymmetric Synthesis of JNJ-4355 by Biocatalytic Acylation
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    Scheme 6

    Scheme 6. (a) Lipase-Catalyzed Atroposelective Amidation Reactions of Binaphthyl-Based Amines and (b) Biocatalytic Enantioselective Transamidation of Binaphthyl-Based Carboxylate Esters
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    Scheme 7

    Scheme 7. (a) Kinetic Resolutions of Acetylated Binaphthyl Oxime Derivatives by Atroposelective Enzymatic Hydrolysis and (b) Enantiopreference of the CHIRAZYME-L2-Mediated Hydrolysis of 31 Based on the E and Z Configurations of the Ketoxime Double Bond
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    Scheme 8

    Scheme 8. (a) Atroposelective Hydrolytic KR of Thioester 32 in the Presence of Cholesterol Esterase and (b) Enantioseparation of Thiol 34 by Lipase-Catalyzed DKR of Hemithioacetal Groups and Subsequent Hydrolysis
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    Scheme 9

    Scheme 9. Early Example of the Enantioselective Biocatalytic Reduction of Binaphthyl Aldehydes in the Presence of Baker’s Yeast
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    Scheme 10

    Scheme 10. (a–c) Selected Reported Examples of Atroposelective Lipase-Catalyzed Desymmetrization Reactions of Prochiral Biaryl Compounds, Including Highly Hindered Tetra-ortho-Substituted Substrates 41 and 43 and (d, e) Examples of Enantioselective Total Syntheses of Atropisomeric Natural Products Employing a Biocatalytic Desymmetrization Step
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    Scheme 11

    Scheme 11. KRED-Mediated Enantioselective Desymmetrization of Pro-atropisomeric Compounds by Aldehyde Reduction
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    Scheme 12

    Scheme 12. GOase-Mediated Enantioselective Desymmetrization of Pro-atropisomeric Bisbenzylic Alcohol Compounds 56 by Oxidation, Which Can Be Followed by a Second Enantioselective Oxidation to the Corresponding Dialdehyde 58
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    Scheme 13

    Scheme 13. Ring Opening of Lactone 59 Using PLE
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    Figure 2

    Figure 2. Experimentally determined barriers to rotation and half-lives of racemization at 20 °C of selected 1-naphthamide derivatives. The dashed red line indicates a barrier-lowering n → π* interaction.

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    Scheme 14

    Scheme 14. Kinetic Resolution of Biaryl rac-66 by KRED-Catalyzed Stereoselective Aldehyde Reduction
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    Figure 3

    Figure 3. Experimentally determined barriers to rotation and half-lives of racemization at 20 °C of selected biaryl aldehydes and alcohols. The dashed red line indicates a barrier-lowering n → π* interaction.

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    Scheme 15

    Scheme 15. Dynamic Kinetic Resolution of Biaryls 67 and 68 by KRED-Catalyzed Stereoselective Aldehyde Reduction
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    Scheme 16

    Scheme 16. (a) DYKAT of BINOL Derivatives rac-71 by Concurrent Ru(II)-Catalyzed Racemization and Lipase-Mediated Acylation and (b) Proposed Mechanism of the Ru(II)-Catalyzed Racemization
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    Figure 4

    Figure 4. Important classes of atropisomeric compounds that have or have not yet been made enantioselectively by biocatalytic methods (green and red boxes, respectively).

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  • References

    This article references 75 other publications.

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      Xiao, Yumei; Sun, Zhanhu; Guo, Hongchao; Kwon, Ohyun
      Beilstein Journal of Organic Chemistry (2014), 10 (), 2089-2121, 33 pp.CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
      A review. This review discusses the tertiary phosphines possessing various chiral skeletons that have been used in asym. nucleophilic organocatalytic reactions, including annulations of allenes, alkynes, and Morita-Baylis-Hillman (MBH) acetates, carbonates, and ketenes with activated alkenes and imines, allylic substitutions of MBH acetates and carbonates, Michael addns., γ-umpolung addns., and acylations of alcs.
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    6. 6
      Akiyama, T.; Mori, K. Stronger Brønsted Acids: Recent Progress. Chem. Rev. 2015, 115 (17), 9277– 9306,  DOI: 10.1021/acs.chemrev.5b00041
      6
      Stronger Bronsted Acids: Recent Progress
      Akiyama, Takahiko; Mori, Keiji
      Chemical Reviews (Washington, DC, United States) (2015), 115 (17), 9277-9306CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. The synthetic utility of Bronsted acid as a catalyst for the C-C bond formation reaction has seen significant growth in the 21st century, and a range of stronger Bronsted-acid-catalyzed reactions have been developed. Strong Bronsted acids, such as TfOH and Tf2NH, efficiently activated carbonyl groups, alkenes, alkynes, in addn. to hydroxy groups. They sometimes functioned complementarily to Lewis-acid catalysts. Chiral Bronsted acid has become one of the most attractive subjects in organocatalysis in the past decade because of the versatility for a wide range of reactions. In addn. to the chiral phosphoric acids, chiral dicarboxylic acids, chiral disulfonic acids, and chiral sulfonimides have emerged as stronger Bronsted acids, and their synthetic utility has gained wide acceptance.
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    7. 7
      Mondal, A.; Toyoda, R.; Costil, R.; Feringa, B. L. Chemically Driven Rotatory Molecular Machines. Angew. Chem., Int. Ed. 2022, 61 (40), e202206631,  DOI: 10.1002/anie.202206631
      7
      Chemically Driven Rotatory Molecular Machines
      Mondal, Anirban; Toyoda, Ryojun; Costil, Romain; Feringa, Ben L.
      Angewandte Chemie, International Edition (2022), 61 (40), e202206631CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Mol. machines are at the frontier of biol. and chem. The ability to control mol. motion and emulating the movement of biol. systems are major steps towards the development of responsive and adaptive materials. Amazing progress has been seen for the design of mol. machines including light-induced unidirectional rotation of overcrowded alkenes. However, the feasibility of inducing unidirectional rotation about a single bond as a result of chem. conversion has been a challenging task. In this Review, an overview of approaches towards the design, synthesis, and dynamic properties of different classes of atropisomers which can undergo controlled switching or rotation under the influence of a chem. stimulus is presented. They are categorized as mol. switches, rotors, motors, and autonomous motors according to their type of response. Furthermore, we provide a future perspective and challenges focusing on building sophisticated mol. machines.
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    8. 8
      Smyth, J. E.; Butler, N. M.; Keller, P. A. A Twist of Nature – the Significance of Atropisomers in Biological Systems. Nat. Prod. Rep. 2015, 32 (11), 1562– 1583,  DOI: 10.1039/C4NP00121D
      8
      A twist of nature - the significance of atropisomers in biological systems
      Smyth, Jamie E.; Butler, Nicholas M.; Keller, Paul A.
      Natural Product Reports (2015), 32 (11), 1562-1583CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
      Covering: up to mid-2015Recently identified natural atropisomeric compds. with potential medicinal applications are presented. The ability of natural receptors to possess differential binding between atropisomers is an important factor when considering active and inactive atropisomeric drugs, and has required the development of new techniques for atropselective synthesis of desired targets. Advances in this field therefore have significant relevance to modern pharmaceutical and medicinal chem. The atropisomeric natural products discussed include hibarimicinone, flavomannins, talaromannins, viriditoxin, rugulotrosin A, abyssomicin C, marinopyrroles, dixiamycins, streptorubin B, ustiloxins A-F, haouamine A, bisnicalaterines, and tedarene B, all of which show significant potential as leads in antibiotic, antiviral and anticancer studies. The importance for the development of common practices regarding atropisomer recognition and classification is also emphasized.
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    9. 9
      Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angew. Chem., Int. Ed. 2005, 44 (34), 5384– 5427,  DOI: 10.1002/anie.200462661
      9
      Atroposelective synthesis of axially chiral biaryl compounds
      Bringmann, Gerhard; Mortimer, Anne J. Price; Keller, Paul A.; Gresser, Mary J.; Garner, James; Breuning, Matthias
      Angewandte Chemie, International Edition (2005), 44 (34), 5384-5427CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. A rotationally hindered and thus stereogenic biaryl axis is the structurally and stereochem. decisive element of a steadily growing no. of natural products, chiral auxiliaries, and catalysts. Thus, it is not surprising that significant advances have been made in the asym. synthesis of axially chiral biaryl compds. over the past decade. In addn. to the classic approach (direct stereoselective aryl-aryl coupling), innovative concepts have been developed in which the asym. information is introduced into a preformed, but achiral-i.e., sym. or configurationally labile-biaryl compd., or in which an aryl-C single bond is stereoselectively transformed into an axis. This review classifies these strategies according to their underlying concepts and critically evaluates their scope and limitations with ref. to selected model reactions and applications. Furthermore, the preconditions required for the existence of axial chirality in biaryl compds. are discussed.
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    10. 10
      Clayden, J. Atropisomers and Near-Atropisomers: Achieving Stereoselectivity by Exploiting the Conformational Preferences of Aromatic Amides. Chem. Commun. 2004, 2, 127– 135,  DOI: 10.1039/b307976g
      There is no corresponding record for this reference.
    11. 11
      Adler, T.; Bonjoch, J.; Clayden, J.; Font-Bardía, M.; Pickworth, M.; Solans, X.; Solé, D.; Vallverdú, L. Slow Interconversion of Enantiomeric Conformers or Atropisomers of Anilide and Urea Derivatives of 2-Substituted Anilines. Org. Biomol. Chem. 2005, 3 (17), 3173– 3183,  DOI: 10.1039/b507202f
      11
      Slow interconversion of enantiomeric conformers or atropisomers of anilide and urea derivatives of 2-substituted anilines
      Adler, Thomas; Bonjoch, Josep; Clayden, Jonathan; Font-Bardia, Merce; Pickworth, Mark; Solans, Xavier; Sole, Daniel; Vallverdu, Lluis
      Organic & Biomolecular Chemistry (2005), 3 (17), 3173-3183CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
      N-Acylated 2-substituted anilines undergo slow Ar-N bond rotation, allowing in some cases isolation of enantiomeric or diastereoisomeric atropisomers and in others the detn. of the rate of Ar-N bond rotation by NMR. 2-Iodoanilides bearing a branched N-substituent demonstrate sufficient enantiomeric stability to be resolvable, either by HPLC or by formation of diastereoisomeric lactanilide derivs. For the first time, the rates of Ar-N rotation in 2-substituted N,N'-diarylureas have been established: they mainly fall in the region of 50-70 kJ mol-1 with a relatively weak dependence on substituent size.
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    12. 12
      Clayden, J.; Turner, H.; Helliwell, M.; Moir, E. N,N′-Diarylureas: A New Family of Atropisomers Exhibiting Highly Diastereoselective Reactivity. J. Org. Chem. 2008, 73 (12), 4415– 4423,  DOI: 10.1021/jo702706c
      12
      N,N'-Diarylureas: A New Family of Atropisomers Exhibiting Highly Diastereoselective Reactivity
      Clayden, Jonathan; Turner, Hazel; Helliwell, Madeleine; Moir, Elizabeth
      Journal of Organic Chemistry (2008), 73 (12), 4415-4423CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      2,6-Disubstituted N-aryl ureas rotate slowly about their Ar-N bonds and can exist as separable atropisomers. They also react remarkably diastereoselectively, with the urea axis controlling new stereogenic centers with high fidelity in a variety of nucleophilic and electrophilic addn. reactions. The sense of diastereoselectivity in lateral lithiation-electrophilic quench reactions is electrophile-dependent and appears to be the result of stereospecific reaction with one of two interconvertible diastereoisomeric organolithiums.
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    13. 13
      Clayden, J.; Turner, H. Enantiomerically Enriched Atropisomeric N,N′-Diaryl Ureas by Oxidative Kinetic Resolution of Their 2-Sulfanyl Derivatives. Tetrahedron Lett. 2009, 50 (26), 3216– 3219,  DOI: 10.1016/j.tetlet.2009.02.021
      13
      Enantiomerically enriched atropisomeric N,N'-diarylureas by oxidative kinetic resolution of their 2-sulfanyl derivatives
      Clayden, Jonathan; Turner, Hazel
      Tetrahedron Letters (2009), 50 (26), 3216-3219CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
      Atropisomeric N-methyl-N,N'-diarylureas may be obtained in enantiomerically enriched form by oxidative kinetic resoln. of their sulfide derivs. The atropisomeric sulfides may be obtained in up to 97:3 er and display high stability to racemization (half-lives at 25 °C of up to 500 years). Unlike related fully alkylated ureas, the product sulfoxides exhibit relatively weak thermodn. conformational selectivity.
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    14. 14
      Costil, R.; Sterling, A. J.; Duarte, F.; Clayden, J. Atropisomerism in Diarylamines: Structural Requirements and Mechanisms of Conformational Interconversion. Angew. Chem., Int. Ed. 2020, 59 (42), 18670– 18678,  DOI: 10.1002/anie.202007595
      14
      Atropisomerism in diarylamines: structural requirements and mechanisms of conformational interconversion
      Costil, Romain; Sterling, Alistair J.; Duarte, Fernanda; Clayden, Jonathan
      Angewandte Chemie, International Edition (2020), 59 (42), 18670-18678CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      In common with other hindered structures contg. two arom. rings linked by a short tether, diarylamines may exhibit atropisomerism (chirality due to restricted rotation). Previous examples have principally been tertiary amines, esp. those with cyclic scaffolds. Little is known of the structural requirement for atropisomerism in structurally simpler secondary and acyclic diarylamines. In this paper we describe a systematic study of a series of acyclic secondary diarylamines, and we quantify the degree of steric hindrance in the ortho positions that is required for atropisomerism to result. Through a detailed exptl. and computational anal., the role of each ortho-substituent on the mechanism and rate of conformational interconversion is rationalized. We also present a simple predictive model for the design of configurationally stable secondary diarylamines.
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    15. 15
      Clayden, J.; Worrall, C. P.; Moran, W. J.; Helliwell, M. Enantioselective Synthesis of an Atropisomeric Diaryl Ether. Angew. Chem., Int. Ed. 2008, 47 (17), 3234– 3237,  DOI: 10.1002/anie.200705660
      15
      Enantioselective synthesis of an atropisomeric diaryl ether
      Clayden, Jonathan; Worrall, Christopher P.; Moran, Wesley J.; Helliwell, Madeleine
      Angewandte Chemie, International Edition (2008), 47 (17), 3234-3237CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Introduction of a bulky alkylsulfinyl substituent ortho to the C-O axis of a diaryl ether imposes a powerful conformational preference. The preference persists upon oxidn. of the sulfoxide to a sulfone, leading to dynamic thermodn. resoln. of the atropisomeric ether. This is the first enantioselective synthesis of an atropisomeric diaryl ether not forming part of a macrocyclic ring.
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    16. 16
      Clayden, J.; Senior, J.; Helliwell, M. Atropisomerism at C-S Bonds: Asymmetric Synthesis of Diaryl Sulfones by Dynamic Resolution Under Thermodynamic. Control. Angew. Chem. Int. Ed. 2009, 48 (34), 6270– 6273,  DOI: 10.1002/anie.200901718
      There is no corresponding record for this reference.
    17. 17
      Clayden, J.; Fletcher, S. P.; Senior, J.; Worrall, C. P. Hindered Diarylether and Diarylsulfone Bisphosphine Ligands: Atropisomerism and Palladium Complexes. Tetrahedron: Asymmetry 2010, 21 (11), 1355– 1360,  DOI: 10.1016/j.tetasy.2010.06.017
      17
      Hindered diarylether and diarylsulfone bisphosphine ligands: atropisomerism and palladium complexes
      Clayden, Jonathan; Fletcher, Stephen P.; Senior, James; Worrall, Christopher P.
      Tetrahedron: Asymmetry (2010), 21 (11-12), 1355-1360CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
      Phosphines and bisphosphines derived from hindered ortho-substituted diaryl ethers and diarylsulfones by lithiation are, with appropriate substitution patterns, resolvable atropisomeric ligands which form cryst. complexes with Pd dichloride. The racemization kinetics of o-diphenylphosphinophenyl 2-diphenylphosphino-6-methoxymethylphenyl ether and the crystal structures of palladium complexes with Me substituted bis(o-diphenylphosphinophenyl) ethers are reported.
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    18. 18
      Steinreiber, J.; Faber, K.; Griengl, H. De-Racemization of Enantiomers versus De-Epimerization of Diastereomers─Classification of Dynamic Kinetic Asymmetric Transformations (DYKAT). Chem.─Eur. J. 2008, 14 (27), 8060– 8072,  DOI: 10.1002/chem.200701643
      18
      De-racemization of enantiomers versus de-epimerization of diastereomers - classification of dynamic kinetic asymmetric transformations (DYKAT)
      Steinreiber, Johannes; Faber, Kurt; Griengl, Herfried
      Chemistry - A European Journal (2008), 14 (27), 8060-8072CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The isolation of single stereoisomers from a racemic (or diastereomeric) mixt. by enzymic or chem. resoln. techniques goes in hand with the disposal of 50% (racemate) or more (diastereomeric mixts.) of the "undesired" substrate isomer(s). In order to circumvent this drawback, dynamic systems have been developed for the de-racemization of enantiomers and the de-epimerizations of diastereomers. Key strategies within this area are discussed and are classified according to their underlying kinetics, i.e., dynamic kinetic resoln. (DKR), dynamic kinetic asym. transformations (DYKAT), and hybrids between both of them. Finally, two novel types of DYKAT are defined.
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    19. 19
      Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F. Recent Advances and New Concepts for the Synthesis of Axially Stereoenriched Biaryls. Chem. Soc. Rev. 2015, 44, 3418– 3430,  DOI: 10.1039/C5CS00012B
      19
      Recent advances and new concepts for the synthesis of axially stereoenriched biaryls
      Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F.
      Chemical Society Reviews (2015), 44 (11), 3418-3430CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Axial chirality was a key feature of many important org. mols., such as biol. active compds., stereogenic ligands and optically pure materials. Significant efforts in the field of the atropisomeric synthesis of biaryls was hence undertaken over the past decade. Several major improvements of the already known methods to build up such chiral backbones (e.g. oxidative couplings and stereoselective Suzuki-Miyaura arylations) were achieved and, in parallel, novel concepts were emerged enabling unprecedented synthetic routes toward mols. of this kind. These outstanding steps further unlocked the door to the prepn. of previously difficult-to-access precursors of privileged ligands like BINOL, BINAM, QUINAP and many other mols. of interest.
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    20. 20
      Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel, D. J.; Weisenburger, G. A. Dynamic Thermodynamic Resolution: Control of Enantioselectivity through Diastereomeric Equilibration. Acc. Chem. Res. 2000, 33 (10), 715– 727,  DOI: 10.1021/ar000077s
      20
      Dynamic Thermodynamic Resolution: Control of Enantioselectivity through Diastereomeric Equilibration
      Beak, Peter; Anderson, David R.; Curtis, Michael D.; Laumer, Jason M.; Pippel, Daniel J.; Weisenburger, Gerald A.
      Accounts of Chemical Research (2000), 33 (10), 715-727CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A theor. foundation, tools for recognition and control, and recent examples of a class of asym. transformation termed dynamic thermodn. resoln. are presented. Enantioselective reaction pathways that involve an induced diastereomeric equilibration to intermediates, which are configurationally stable on the time scale of a subsequent reaction, are illustrated. Dynamic thermodn. resoln. differs from the classic, well-documented pathways of kinetic resoln. and dynamic kinetic resoln. in that equilibration and resoln. can be operative on one system in sep. controllable steps. This approach offers a high level of flexibility and provides multiple opportunities for optimization of enantioselectivity; 38 refs.
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    21. 21
      Bell, E. L.; Finnigan, W.; France, S. P.; Green, A. P.; Hayes, M. A.; Hepworth, L. J.; Lovelock, S. L.; Niikura, H.; Osuna, S.; Romero, E.; Ryan, K. S.; Turner, N. J.; Flitsch, S. L. Biocatalysis. Nat. Rev. Methods Primers 2021, 1 (1), 1– 21,  DOI: 10.1038/s43586-021-00044-z
      There is no corresponding record for this reference.
    22. 22
      Hall, M. Enzymatic Strategies for Asymmetric Synthesis. RSC Chem. Biol. 2021, 2 (4), 958– 989,  DOI: 10.1039/D1CB00080B
      22
      Enzymatic strategies for asymmetric synthesis
      Hall, Melanie
      RSC Chemical Biology (2021), 2 (4), 958-989CODEN: RCBSBP; ISSN:2633-0679. (Royal Society of Chemistry)
      Enzymes, at the turn of the 21st century, are gaining a momentum. Esp. in the field of synthetic org. chem., a broad variety of biocatalysts are being applied in an increasing no. of processes running at up to industrial scale. In addn. to the advantages of employing enzymes under environmentally friendly reaction conditions, synthetic chemists are recognizing the value of enzymes connected to the exquisite selectivity of these natural (or engineered) catalysts. The use of hydrolases in enantioselective protocols paved the way to the application of enzymes in asym. synthesis, in particular in the context of biocatalytic (dynamic) kinetic resolns. After two decades of impressive development, the field is now mature to propose a panel of catalytically diverse enzymes for (i) stereoselective reactions with prochiral compds., such as double bond redn. and bond forming reactions, (ii) formal enantioselective replacement of one of two enantiotopic groups of prochiral substrates, as well as (iii) atroposelective reactions with noncentrally chiral compds. In this review, the major enzymic strategies broadly applicable in the asym. synthesis of optically pure chiral compds. are presented, with a focus on the reactions developed within the past decade.
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    23. 23
      Zetzsche, L. E.; Narayan, A. R. H. Broadening the Scope of Biocatalytic C–C Bond Formation. Nat. Rev. Chem. 2020, 4 (7), 334– 346,  DOI: 10.1038/s41570-020-0191-2
      23
      Broadening the scope of biocatalytic C-C bond formation
      Zetzsche, Lara E.; Narayan, Alison R. H.
      Nature Reviews Chemistry (2020), 4 (7), 334-346CODEN: NRCAF7; ISSN:2397-3358. (Nature Research)
      Abstr.: Enzymes exercise impeccable control over chemoselectivity, site selectivity and stereoselectivity in reactions they mediate, such that we have witnessed a surge in the development of new biocatalytic methods. Although carbon-carbon (C-C) bonds are the central framework of org. mols., biocatalytic methods for their formation have largely been limited to a select few lyase enzymes. Thus, despite several decades of research, there are not many biocatalytic C-C-bond-forming transformations at our disposal. This Review describes the suite of enzymes available for highly selective, biocatalytic C-C bond formation. We discuss each class of enzyme in terms of native activity, alteration of this activity through protein or substrate engineering, and its utility in abiotic synthesis. [graphic not available: see fulltext].
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    24. 24
      Hüttel, W.; Müller, M. Regio- and Stereoselective Intermolecular Phenol Coupling Enzymes in Secondary Metabolite Biosynthesis. Nat. Prod. Rep. 2021, 38 (5), 1011– 1043,  DOI: 10.1039/D0NP00010H
      24
      Regio- and stereoselective intermolecular phenol coupling enzymes in secondary metabolite biosynthesis
      Huettel, Wolfgang; Mueller, Michael
      Natural Product Reports (2021), 38 (5), 1011-1043CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
      Covering: 2005 to 2020Phenol coupling is a key reaction in the biosynthesis of important biopolymers such as lignin and melanin and of a plethora of biarylic secondary metabolites. The reaction usually leads to several different regioisomeric products due to the delocalization of a radical in the reaction intermediates. If axial chirality is involved, stereoisomeric products are obtained provided no external factor influences the selectivity. Hence, in non-enzymic org. synthesis it is notoriously difficult to control the selectivity of the reaction, in particular if the coupling is intermol. From biosynthesis, it is known that esp. fungi, plants, and bacteria produce biarylic compds. regio- and stereoselectively. Nonetheless, the involved enzymes long evaded discovery. First progress was made in the late 1990s; however, the breakthrough came only with the genomic era and, in particular, in the last few years the no. of relevant publications has dramatically increased. The discoveries reviewed in this article reveal a remarkable diversity of enzymes that catalyze oxidative intermol. phenol coupling, including various classes of laccases, cytochrome P 450 enzymes, and heme peroxidases. Particularly in the case of laccases, the catalytic systems are often complex and addnl. proteins, substrates, or reaction conditions have a strong influence on activity and regio- and atroposelectivity. Although the field of (selective) enzymic phenol coupling is still in its infancy, the diversity of enzymes identified recently could make it easier to select suitable candidates for biotechnol. development and to approach this challenging reaction through biocatalysis.
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    25. 25
      Wu, J.; Kozlowski, M. C. Catalytic Oxidative Coupling of Phenols and Related Compounds. ACS Catal. 2022, 12 (11), 6532– 6549,  DOI: 10.1021/acscatal.2c00318
      25
      Catalytic Oxidative Coupling of Phenols and Related Compounds
      Wu, Jingze; Kozlowski, Marisa C.
      ACS Catalysis (2022), 12 (11), 6532-6549CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      A review. Phenols and their derivs. are the elementary building blocks for several classes of complex mols. that play essential roles in biol. systems. Nature has devised methods to selectively couple phenolic compds., and many efforts have been undertaken by chemists to mimic such coupling processes. A range of mechanisms can be involved with well-studied catalysts, and the reaction outcomes in phenol-phenol oxidative coupling reactions can be predicted with a good level of fidelity. However, reactions with catalysts that have not been studied or that do not behave similarly to known catalysts can be hard to predict and control. This perspective provides an overview of catalytic methods for the oxidative coupling of phenols, focusing on the last 10 years, and summarizes current challenges.
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    26. 26
      Zetzsche, L. E.; Chakrabarty, S.; Narayan, A. R. H. The Transformative Power of Biocatalysis in Convergent Synthesis. J. Am. Chem. Soc. 2022, 144 (12), 5214– 5225,  DOI: 10.1021/jacs.2c00224
      26
      The Transformative Power of Biocatalysis in Convergent Synthesis
      Zetzsche, Lara E.; Chakrabarty, Suman; Narayan, Alison R. H.
      Journal of the American Chemical Society (2022), 144 (12), 5214-5225CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A review. Achieving convergent synthetic strategies has long been a gold std. in constructing complex mol. skeletons, allowing for the rapid generation of complexity in comparatively streamlined synthetic routes. Traditionally, biocatalysis has not played a prominent role in convergent lab. synthesis, with the application of biocatalysts in convergent strategies primarily limited to the synthesis of chiral fragments. Although the use of enzymes to enable convergent synthetic approaches is relatively new and emerging, combining the efficiency of convergent transformations with the selectivity achievable through biocatalysis creates new opportunities for efficient synthetic strategies. This Perspective provides an overview of recent developments in biocatalytic strategies for convergent transformations and offers insights into the advantages of these methods compared to their small mol.-based counterparts.
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    27. 27
      Paniagua, C.; Bilkova, A.; Jackson, P.; Dabravolski, S.; Riber, W.; Didi, V.; Houser, J.; Gigli-Bisceglia, N.; Wimmerova, M.; Budínská, E.; Hamann, T.; Hejatko, J. Dirigent Proteins in Plants: Modulating Cell Wall Metabolism during Abiotic and Biotic Stress Exposure. J. Exp. Bot. 2017, 68 (13), 3287– 3301,  DOI: 10.1093/jxb/erx141
      27
      Dirigent proteins in plants: modulating cell wall metabolism during abiotic and biotic stress exposure
      Paniagua, Candelas; Bilkova, Anna; Jackson, Phil; Dabravolski, Siarhei; Riber, Willi; Didi, Vojtech; Houser, Josef; Gigli-Bisceglia, Nora; Wimmerova, Michaela; Budinska, Eva; Hamann, Thorsten; Hejatko, Jan
      Journal of Experimental Botany (2017), 68 (13), 3287-3301CODEN: JEBOA6; ISSN:1460-2431. (Oxford University Press)
      Dirigent (DIR) proteins were found to mediate regio- and stereoselectivity of bimol. phenoxy radical coupling during lignan biosynthesis. Here we summarize the current knowledge of the importance of DIR proteins in lignan and lignin biosynthesis and highlight their possible importance in plant development. We focus on the still rather enigmatic Arabidopsis DIR gene family, discussing the few members with known functional importance. We comment on recent discoveries describing the detailed structure of two DIR proteins with implications in the mechanism of DIR-mediated catalysis. Further, we summarize the ample evidence for stress-induced dirigent gene expression, suggesting the role of DIRs in adaptive responses. In the second part of our work, we present a preliminary bioinformatics-based characterization of the AtDIR family. The phylogenetic anal. of AtDIRs complemented by comparison with DIR proteins of mostly known function from other species allowed us to suggest possible roles for several members of this family and identify interesting AtDIR targets for further study. Finally, based on the available metadata and our in silico anal. of AtDIR promoters, we hypothesize about the existence of specific transcriptional controls for individual AtDIR genes and implicate them in various stress responses, hormonal regulations, and developmental processes.
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    28. 28
      Zetzsche, L. E.; Yazarians, J. A.; Chakrabarty, S.; Hinze, M. E.; Murray, L. A. M.; Lukowski, A. L.; Joyce, L. A.; Narayan, A. R. H. Biocatalytic Oxidative Cross-Coupling Reactions for Biaryl Bond Formation. Nature 2022, 603 (7899), 79– 85,  DOI: 10.1038/s41586-021-04365-7
      28
      Biocatalytic oxidative cross-coupling reactions for biaryl bond formation
      Zetzsche, Lara E.; Yazarians, Jessica A.; Chakrabarty, Suman; Hinze, Meagan E.; Murray, Lauren A. M.; Lukowski, April L.; Joyce, Leo A.; Narayan, Alison R. H.
      Nature (London, United Kingdom) (2022), 603 (7899), 79-85CODEN: NATUAS; ISSN:1476-4687. (Nature Portfolio)
      Biaryl compds., with two connected arom. rings, are found across medicine, materials science and asym. catalysis1,2. The necessity of joining arene building blocks to access these valuable compds. has inspired several approaches for biaryl bond formation and challenged chemists to develop increasingly concise and robust methods for this task3. Oxidative coupling of two C-H bonds offers an efficient strategy for the formation of a biaryl C-C bond; however, fundamental challenges remain in controlling the reactivity and selectivity for uniting a given pair of substrates4,5. Biocatalytic oxidative cross-coupling reactions have the potential to overcome limitations inherent to numerous small-mol.-mediated methods by providing a paradigm with catalyst-controlled selectivity6. Here we disclose a strategy for biocatalytic cross-coupling through oxidative C-C bond formation using cytochrome P 450 enzymes. We demonstrate the ability to catalyze cross-coupling reactions on a panel of phenolic substrates using natural P 450 catalysts. Moreover, we engineer a P 450 to possess the desired reactivity, site selectivity and atroposelectivity by transforming a low-yielding, unselective reaction into a highly efficient and selective process. This streamlined method for constructing sterically hindered biaryl bonds provides a programmable platform for assembling mols. with catalyst-controlled reactivity and selectivity.
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    29. 29
      Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis: Regio- and Stereoselective Biotransformations; Wiley, 2006.
      There is no corresponding record for this reference.
    30. 30
      Fujimoto, Y.; Iwadate, H.; Ikekawa, N. Preparation of Optically Active 2,2′-Dihydroxy-l,1 ′mbinaphthyl via Microbial Resolution of the Corresponding Racemic Diester. J. Chem. Soc. Chem. Commun. 1985, 19, 1333– 1334,  DOI: 10.1039/C39850001333
      There is no corresponding record for this reference.
    31. 31
      Miyano, S.; Kawahara, K.; Inoue, Y.; Hashimoto, H. A Convenient Preparation of Optically Active 1,1′-Binaphthyl-2,2′-Diol via Enzymatic Hydrolysis of the Racemic Diester. Chem. Lett. 1987, 16 (2), 355– 356,  DOI: 10.1246/cl.1987.355
      There is no corresponding record for this reference.
    32. 32
      Kazlauskas, R. J. Resolution of Binaphthols and Spirobiindanols Using Cholesterol Esterase. J. Am. Chem. Soc. 1989, 111 (13), 4953– 4959,  DOI: 10.1021/ja00195a059
      32
      Resolution of binaphthols and spirobiindanols using cholesterol esterase
      Kazlauskas, Romas J.
      Journal of the American Chemical Society (1989), 111 (13), 4953-9CODEN: JACSAT; ISSN:0002-7863.
      Simple, synthetic-scale procedures (200 g) procedures are detailed for the resoln. of [1,1'-binaphthalene]-2,2'-diol (I) and 2,2',3,3'-tetrahydro-2,2',3,3'-tetramethyl-1,1'spirobi[1H-indene]-6,6'-diol (II) using cholesterol esterase-catalyzed hydrolysis of their diesters. Resoln. of I involved hydrolysis of the dipentanoate ester catalyzed by crude , inexpensive enzyme (bovine pancreas acetone powder) and yielded each enantiomer in >60% of theor. yield with ≥99% enantiomeric purity.n. Similar resoln. of II by hydrolysis of the dihexanoate ester yielded each enantioimer in >50% of theor. yield with >95% enantiomeric purity. These resolns. involve 2 enzymic reactions: hydrolysis of the diester to the monoester followed by the hydrolysis of the monoester the diol. A theor. anal. of such 2-step resolns. suggests that 2-step resolns. can yield products with higher enantiomeric purity than 1-step resolns.
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    33. 33
      Kazlauskas, R. J. (S)-(−)- and (R)-(+)-1,1′-Bi-2-Naphthol. Org. Synth. 1992, 70, 60,  DOI: 10.15227/orgsyn.070.0060
      33
      (S)-(-)- and (R)-(+)-1,1'-Bi-2-naphthol
      Kazlauskas, Romas J.
      Organic Syntheses (1992), 70 (), 60-7CODEN: ORSYAT; ISSN:0078-6209.
      Esterification of racemic 1,1'-bi-2-naphthol with pentanoyl chloride gave racemic binaphthol dipentanoate, which when treated with cholesterol esterase (as bovine pancreas acetone powder) gave 64-67% highly pure (S)-(-)-1,1'-bi-2-naphthol by fractional crystn. Concn. of the filtrate gave (R)-binaphthol dipentanoate, which was sapond. with NaOMe in MeOH to give enantiomerically pure (R)-(+)-1,1'-bi-2-naphthol.
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    34. 34
      Furutani, T.; Hatsuda, M.; Imashiro, R.; Seki, M. Facile Synthesis of Enantiopure 1,1′-Binaphthyl-2,2′-Dicarboxylic Acid via Lipase-Catalyzed Kinetic Resolution. Tetrahedron: Asymmetry 1999, 10 (24), 4763– 4768,  DOI: 10.1016/S0957-4166(99)00555-8
      34
      Facile synthesis of enantiopure 1,1'-binaphthyl-2,2'-dicarboxylic acid via lipase-catalyzed kinetic resolution
      Furutani, Toshiyuki; Hatsuda, Masanori; Imashiro, Ritsuo; Seki, Masahiko
      Tetrahedron: Asymmetry (1999), 10 (24), 4763-4768CODEN: TASYE3; ISSN:0957-4166. (Elsevier Science Ltd.)
      Enantiopure (R)- and (S)-1,1'-binaphthyl-2,2'-dicarboxylic acid have been synthesized through the lipase-catalyzed kinetic resoln. of racemic 2,2-bis(hydroxymethyl)-1,1'-binaphthyl and subsequent oxidn. of the hydroxymethyl groups.
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    35. 35
      Seki, M.; Furutani, T.; Hatsuda, M.; Imashiro, R. Facile Synthesis of C2-Symmetric Chiral Binaphthyl Ketone Catalysts. Tetrahedron Lett. 2000, 41 (13), 2149– 2152,  DOI: 10.1016/S0040-4039(00)00120-9
      35
      Facile synthesis of C2-symmetric chiral binaphthyl ketone catalysts
      Seki, Masahiko; Furutani, Toshiyuki; Hatsuda, Masanori; Imashiro, Ritsuo
      Tetrahedron Letters (2000), 41 (13), 2149-2152CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
      C2-sym. chiral binaphthyl ketones I (R = H, Cl), efficient catalysts for asym. epoxidn., were synthesized through an intramol. Ullmann reaction and/or a lipase-catalyzed enantioselective hydrolysis of the resp. 11-membered cyclic binaphthyl acetate.
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    36. 36
      Juárez-Hernandez, M.; Johnson, D. V.; Holland, H. L.; McNulty, J.; Capretta, A. Lipase-Catalyzed Stereoselective Resolution and Desymmetrization of Binaphthols. Tetrahedron: Asymmetry 2003, 14 (3), 289– 291,  DOI: 10.1016/S0957-4166(02)00792-9
      36
      Lipase-catalyzed stereoselective resolution and desymmetrization of binaphthols
      Juarez-Hernandez, Marcela; Johnson, Dean V.; Holland, Herbert L.; McNulty, James; Capretta, Alfredo
      Tetrahedron: Asymmetry (2003), 14 (3), 289-291CODEN: TASYE3; ISSN:0957-4166. (Elsevier Science Ltd.)
      We have investigated the use of lipoprotein lipase enzymes from Pseudomonas sp. and Pseudomonas fluorescens for the enantioselective resoln. and desymmetrization of racemic binaphthols I (R = H, Br, OMe). The reactions were carried out using a non-aq. environment (iPr2O/acetone/vinyl acetate), and yielded mono-acetate ester products of the parent unsubstituted substrate, the 6,6'-dibromo-substrate, and the 6,6'-dimethoxy-substrate with high enantiomeric selectivity.
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    37. 37
      Tanaka, K.; Furuta, T.; Fuji, K.; Miwa, Y.; Taga, T. Preparation and Absolute Configuration of Hexahydroxyter- and Octahydroxyquaternaphthalene Derivatives. Tetrahedron: Asymmetry 1996, 7 (8), 2199– 2202,  DOI: 10.1016/0957-4166(96)00270-4
      37
      Preparation of absolute configuration of hexahydroxyternaphthalene and octahydroxyquaternaphthalene derivatives
      Tanaka, Kiyoshi; Furuta, Takumi; Fuji, Kaoru; Miwa, Yoshihisa; Taga, Tooru
      Tetrahedron: Asymmetry (1996), 7 (8), 2199-2202CODEN: TASYE3; ISSN:0957-4166. (Elsevier)
      Oxidative coupling reactions of the stereochem. defined tetrahydroxybinaphthalene derivs. gave a separable mixt. of two diastereomers of (S,S,S)-quaternaphthalenes and (S,R.S)-quaternaphthalenes, whose structures were confirmed by an alternative chem. transformation through the ternaphthalenes as well as the X-ray structure anal. The CD spectra of the corresponding diastereomers were indicative of the stereochem. across the axis.
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    38. 38
      Banerjee, S.; Riggs, B. E.; Zakharov, L. N.; Blakemore, P. R. Synthesis, Properties, and Enantiomerization Behavior of Axially Chiral Phenolic Derivatives of 8-(Naphth-1-Yl)Quinoline and Comparison to 7,7′-Dihydroxy-8,8′-Biquinolyl and 1,1′-Bi-2-Naphthol. Synthesis 2015, 47 (24), 4008– 4016,  DOI: 10.1055/s-0035-1560640
      38
      Synthesis, Properties, and Enantiomerization Behavior of Axially Chiral Phenolic Derivatives of 8-(Naphth-1-yl)quinoline and Comparison to 7,7'-Dihydroxy-8,8'-biquinolyl and 1,1'-Bi-2-naphthol
      Banerjee, Somdev; Riggs, Brian E.; Zakharov, Lev N.; Blakemore, Paul R.
      Synthesis (2015), 47 (24), 4008-4016CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)
      An aza-analog of 1,1'-bi-2-naphthol (BINOL, III), 7-hydroxy-8-(2-hydroxynaphth-1-yl)quinoline (8-azaBINOL, II), was prepd. in 3 steps and 49% yield from N,N-di-Et O-(7-hydroxy-8-iodoquinolyl)carbamate via Suzuki coupling with 1-naphthylboronic acid followed by Sanford oxidn. and sapon. II was resolved into (-)-(aS) and (+)-(aR) atropisomers via enzymic hydrolysis of its racemic divalerate deriv. with bovine pancreas acetone powder. The configurational stability of diol II was found to be intermediate to that of 7,7'-dihydroxy-8,8'-biquinolyl (least stable) and BINOL (most stable). Eyring plot anal. of the enantiomerization kinetics of I, II, and III, in DMSO soln. revealed activation parameters of ΔH⧺ = +27.4, +19.9, +23.2 kcal mol-1, and ΔS⧺ = +3.8, -27.9, -25.3 cal mol-1 K-1, resp. The unique character of ΔH⧺ and ΔS⧺ values for biquinolyl I suggests that the enantiomerization mechanism for I is distinct to that for naphthalenes II and III. Monohydroxy analogs of II, 7-hydroxy-8-(naphth-1-yl)quinoline (IV) and 8-(2-hydroxynaphth-1-yl)quinoline (V), were similarly prepd. and their racemization half-lives at room temp. were detd.; τ1/2(rac) was strongly dependent on solvent for naphthol V [τ1/2(rac) at 24°: in CHCl3 = 2.7 h, in MeOH = 89 h] but not for the quinol IV [τ1/2(rac) at 24°: in CHCl3 = 106 h, in MeOH = 120 h].
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    39. 39
      Blakemore, P. R.; Milicevic, S. D.; Zakharov, L. N. Enzymatic Resolution of 7,7′-Dihydroxy-8,8′- Biquinolyl Dipentanoate and Its Conversion to 2,2′-Di-Tert-Butyl-7,7′-Dihydroxy-8,8′-Biquinolyl. J. Org. Chem. 2007, 72 (24), 9368– 9371,  DOI: 10.1021/jo701611u
      39
      Enzymatic resolution of 7,7'-dihydroxy-8,8'-biquinolyl dipentanoate and its conversion to 2,2'-Di-tert-butyl-7,7'-dihydroxy-8,8'-biquinolyl
      Blakemore, Paul R.; Milicevic, Selena D.; Zakharov, Lev N.
      Journal of Organic Chemistry (2007), 72 (24), 9368-9371CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Incubation of (±)-7,7'-di(pentanoyloxy)-8,8'-biquinolyl (I) with a crude cholesterol esterase prepn. (from bovine pancreas) yielded highly enantioenriched unreacted dextrorotatory material, (+)-(aR)-I (46%, ≥99% ee), accompanied by the expected diol product, (-)-(aS)-7,7'-dihydroxy-8,8'-biquinolyl, in modest enantiomeric excess (≥37%, ≥77% ee). Treatment of scalemic diester I with t-BuLi, followed by sapon. in the presence of air, gave 2,2'-di-tert-butyl-7,7'-dihydroxy-8,8'-biquinolyl (II) in enantio enriched form. Biquinolyl II is less configurationally stable than I, racemizing rapidly in CHCl3 (t1/2(rac) = 1.9 h, rt), and with a moderate rate in MeOH (t1/2(rac) = 30.5 h, rt).
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    40. 40
      Inagaki, M.; Hiratake, J.; Nishioka, T.; Jun’ichi, O. Lipase-Catalyzed Stereoselective Acylation of [1,1′-Binaphthyl]-2,2′-Diol and Deacylation of Its Esters in an Organic Solvent. Agric. Biol. Chem. 1989, 53 (7), 1879– 1884,  DOI: 10.1080/00021369.1989.10869551
      40
      Lipase-catalyzed stereoselective acylation of [1,1'-binaphthyl]-2,2'-diol and deacylation of its esters in an organic solvent
      Inagaki, Minoru; Hiratake, Jun; Nishioka, Takaaki; Oda, Junichi
      Agricultural and Biological Chemistry (1989), 53 (7), 1879-84CODEN: ABCHA6; ISSN:0002-1369.
      A kinetic resoln. of [1,1'-binaphthyl]-2,2'-diol (binaphthol) [(±)-I) and its esters was first accomplished by lipase-catalyzed transesterification in an org. solvent. Acylation of binaphthol with enol esters in diisopropyl ether-acetone (9:1) gave solely (R)-2-acyloxy-2'-hydroxy-1,1'-binaphthyl (binaphthyl monoesters) having 90 ∼ 95% optical purities. The unreacted binaphthol, which was also recovered in high chem. yields, was the S enantiomer with 69 ∼ 89% (enantiomeric excess). On the other hand, the lipase-catalyzed deacylation or alcoholysis of racemic binaphthyl monoesters gave (S)-monoesters and (R)-I in high chem. and optical yields (>90% enantiomeric excess). In deacylation, the reaction period was much shortened by introducing the more electroneg. Cl atom into the acetyl group of the substrate.
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    41. 41
      Moustafa, G. A. I.; Kasama, K.; Higashio, K.; Akai, S. Base-Promoted Lipase-Catalyzed Kinetic Resolution of Atropisomeric 1,1′-Biaryl-2,2′-Diols. RSC Adv. 2019, 9 (3), 1165– 1175,  DOI: 10.1039/C8RA09070J
      41
      Base-promoted lipase-catalyzed kinetic resolution of atropisomeric 1,1'-biaryl-2,2'-diols
      Moustafa, Gamal A. I.; Kasama, Kengo; Higashio, Koichi; Akai, Shuji
      RSC Advances (2019), 9 (3), 1165-1175CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      A dramatic acceleration of the lipase-catalyzed kinetic resoln. of atropisomeric 1,1'-biaryl-2,2'-diols sym. R-R (R = 7-bromo-2-hydroxynaphthalen-1-yl, 2-hydroxy-6-methylphenyl, 3-bromo-2-hydroxynaphthalen-1-yl, etc.) and non sym. R1-R2 (R1 = 6-[ethoxy(carbonyl)]-2-hydroxynaphthalen-1-yl, 3-bromo-2-hydroxynaphthalen-1-yl, 2,5-dichloro-6-hydroxy-3-methoxyphenyl, etc.; R2 = 2-hydroxynaphthalen-1-yl, 6-bromo-2-hydroxynaphthalen-1-yl) by the addn. of sodium carbonate has been reported. This result likely originates from the increased nucleophilicity of the phenolic hydroxyl group toward the acyl-enzyme intermediate. Under these conditions, various substituted C2-sym. and non-C2-sym. binaphthols and biphenols were efficiently resolved with ∼50% conversion in only 13-30 h with excellent enantioselectivity.
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    42. 42
      Lin, G.; Chen, S.-J.; Sun, H.-L. Multiple Enantioselection by an Enzyme-Catalyzed Transacylation Reaction. J. Chin. Chem. Soc. 1994, 41 (4), 459– 465,  DOI: 10.1002/jccs.199400060
      42
      Multiple enantioselection by an enzyme-catalyzed transacylation reaction
      Lin, Gialih; Chen, Show-Jane; Sun, Hwey-Lin
      Journal of the Chinese Chemical Society (Taipei, Taiwan) (1994), 41 (4), 459-65CODEN: JCCTAC; ISSN:0009-4536.
      Multiply enantioselective enzyme-catalyzed transacylation reactions are described. Two instances of triply enantioselective enzyme-catalyzed transacylations are (1) the reaction of rac-1-indanol (rac-1) with rac-1,1'-bi-2-naphthyl-2,2'-dibutyrate to afford (S)-1, (R)-1-indanyl butyrate (R-3), (S)-1,1'-bi-2-naphthyl-2,2'-diol, and (R)-1,1'-bi-2-naphthyl-2,2'-dibutyrate and (2) the reaction of rac-1 with rac-2,2'-bis(butyroxymethyl)biphenyl to afford (S)-1, (R)-3, (S)-2,2'-biphenyldimethanol, and (R)-2,2'-bis(butyroxymethyl)biphenyl. Doubly enantioselective enzyme-catalyzed transacylations are described according to two instances: (1) the reaction of rac-1 with rac-1,1'-bi-2-naphthyl-2-ol-2'-butyrate afforded (S)-1, (R)-3, (S)-1,1'-bi-2-naphthyl-2,2'-diol, and (R)-1,1'-bi-2-naphthyl-2-ol-2'-butyrate, and (2) the reaction of rac-1 with 1,3,5-O-methylidyne-2,4,6-tri-O-butyrate-myo-inositol to afford (S)-1, (R)-3, and 1,3,5-O-methylidyne-2,6-di-O-butyrate-myo-inositol. Multiply enantioselective enzyme-catalyzed reactions have a merit of the enhancement of enantiomeric excess over singly enantioselective ones.
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    43. 43
      Sanfilippo, C.; Nicolosi, G.; Delogu, G.; Fabbri, D.; Dettori, M. A. Access to Optically Active 2,2′-Dihydroxy-6,6′-Dimethoxy-1,1′-Biphenyl by a Simple Biocatalytic Procedure. Tetrahedron: Asymmetry 2003, 14 (21), 3267– 3270,  DOI: 10.1016/j.tetasy.2003.08.002
      43
      Access to optically active 2,2'-dihydroxy-6,6'-dimethoxy-1,1'-biphenyl by a simple biocatalytic procedure
      Sanfilippo, Claudia; Nicolosi, Giovanni; Delogu, Giovanna; Fabbri, Davide; Dettori, Maria Antonietta
      Tetrahedron: Asymmetry (2003), 14 (21), 3267-3270CODEN: TASYE3; ISSN:0957-4166. (Elsevier Science B.V.)
      Lipase from Pseudomonas cepacia was found to catalyze acetylation in tert-Bu Me ether of the title alc. The action of four different P. cepacia prepns. was compared, all possessing high steric recognition, that results in an efficient kinetic resoln. of this atropisomeric biphenyl.
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    44. 44
      Sanfilippo, C.; D’Antona, N.; Nicolosi, G. Lipase-Catalysed Resolution by an Esterification Reaction in Organic Solvent of Axially Chiral (±)-3,3′-Bis(Hydroxymethyl)-2,2′-Bipyridine N,N-Dioxide. Tetrahedron: Asymmetry 2006, 17 (1), 12– 14,  DOI: 10.1016/j.tetasy.2005.11.028
      44
      Lipase-catalysed resolution by an esterification reaction in organic solvent of axially chiral (±)-3,3'-bis(hydroxymethyl)-2,2'-bipyridine N,N-dioxide
      Sanfilippo, Claudia; D'Antona, Nicola; Nicolosi, Giovanni
      Tetrahedron: Asymmetry (2006), 17 (1), 12-14CODEN: TASYE3; ISSN:0957-4166. (Elsevier B.V.)
      The enzymic kinetic resoln. of atropisomeric (±)-3,3'-bis(hydroxymethyl)-2,2'-bipyridine N,N-dioxide (±)-3 was investigated via enantioselective esterification in the unusual medium of alc./vinyl acetate (20:80). Lipase from Mucor miehei (immobilized lipase prepn., Lipozyme) was found to give good enantioselectivity with an (aS)-enantiopreference in the axial recognition, and allowed to efficiently perform the prepn. of both enantioforms with ee >98%. Lipase from Pseudomonas cepacia (immobilized lipase prepn., PS-D) also catalyzed the reaction although with low enantioselectivity and showing opposite stereopreference.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XotFKguw%253D%253D&md5=9eddf50b04c8486c2abad0fc0577726d
    45. 45
      Takemura, T.; Emoto, G.; Satoh, J.; Kobayashi, Y.; Yaginuma, C.; Takahashi, Y.; Utsukihara, T.; Horiuchi, C. A. Optical Resolution of Hexamethylbiphenol by Cholesterol Esterase and Porcine Pancreas Lipase. J. Mol. Catal. B Enzym. 2008, 55 (3–4), 104– 109,  DOI: 10.1016/j.molcatb.2008.02.007
      45
      Optical resolution of hexamethylbiphenol by cholesterol esterase and porcine pancreas lipase
      Takemura, Tetsuo; Emoto, Go; Satoh, Jun; Kobayashi, Yoshitaka; Yaginuma, Chihiro; Takahashi, Yuta; Utsukihara, Takamitsu; Horiuchi, C. Akira
      Journal of Molecular Catalysis B: Enzymatic (2008), 55 (3-4), 104-109CODEN: JMCEF8; ISSN:1381-1177. (Elsevier B.V.)
      Both enantiomers of 2,2'-dihydroxy-4,4',5,5',6,6'-hexamethybiphenyl (2), a potentially useful chiral synthon, were obtained with >99% ee in high enantioselectivity by cholesterol esterase or porcine pancreas lipase (PPL)-mediated hydrolysis of the corresponding (±)-dipentanoate or (±)-dihexanoate, resp. Abs. configuration of (S)-3-bromo-2,6'-dimethoxy-4,5,6,2',3',4'-hexamethyl-biphenyl (2h) was detd. by X-ray anal.
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    46. 46
      Jouffroy, M.; Neufeld, K. Synthesis of Atropisomeric Biaryls via Chiral Suzuki–Miyaura/Enzymatic Kinetic Resolution. ACS Catal. 2022, 12 (14), 8380– 8385,  DOI: 10.1021/acscatal.2c02090
      46
      Synthesis of Atropisomeric Biaryls via Chiral Suzuki-Miyaura/Enzymatic Kinetic Resolution
      Jouffroy, Matthieu; Neufeld, Katharina
      ACS Catalysis (2022), 12 (14), 8380-8385CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      An unprecedented chiral Suzuki-Miyaura/enzymic kinetic resoln. sequence for the synthesis of JNJ-4355 (I) and other atropisomeric biaryls yielding the targets in high enantiopurity without chiral sepn. was reported.
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    47. 47
      Aoyagi, N.; Izumi, T. Kinetic Resolution of 1,1′-Binaphthylamines via Lipase-Catalyzed Amidation. Tetrahedron Lett. 2002, 43 (32), 5529– 5531,  DOI: 10.1016/S0040-4039(02)01162-0
      47
      Kinetic resolution of 1,1'-binaphthylamines via lipase-catalyzed amidation
      Aoyagi, Naoto; Izumi, Taeko
      Tetrahedron Letters (2002), 43 (32), 5529-5531CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
      Lipase-catalyzed N-acylation of binaphthyl-substituted amine I (n = 2) with aliph. esters gave optically active binaphthyls (R)-II (n = 2; R = Me, Et, Pr) with high enantiomeric excess. The analog with shorter aliph. chain, I (n = 1), was less reactive and under similar conditions gave the corresponding amides II (n = 1; R = Me, F3C, Pr) with lower enantioselectivity.
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    48. 48
      Aoyagi, N.; Kawauchi, S.; Izumi, T. Effect of the Alkyl Chain Length of 1,1′-Binaphthyl Esters in Lipase-Catalyzed Amidation. Tetrahedron Lett. 2003, 44 (30), 5609– 5612,  DOI: 10.1016/S0040-4039(03)01373-X
      48
      Effect of the alkyl chain length of 1,1'-binaphthyl esters in lipase-catalyzed amidation
      Aoyagi, Naoto; Kawauchi, Shinji; Izumi, Taeko
      Tetrahedron Letters (2003), 44 (30), 5609-5612CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science B.V.)
      Lipase-catalyzed amidation of 2-[2-(ethoxycarbonyl)ethyl]-1,1'-binaphthyl [(±)-I] yielded optically active (S)-I and (R)-2-[2-(2-cyanoethylaminocarbonyl)ethyl]-1,1'-binaphthyl with high enantiomeric excess. For these lipase-catalyzed amidations, the optimal alkyl chain length between the binaphthyl ring and the ester group was detd. to be an ethylene spacer.
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    49. 49
      Aoyagi, N.; Kawauchi, S.; Izumi, T. Different Recognitions of (E)- and (Z)-1,1′-Binaphthyl Ketoximes Using Lipase-Catalyzed Reactions. Tetrahedron Lett. 2004, 45 (27), 5189– 5192,  DOI: 10.1016/j.tetlet.2004.05.051
      49
      Different recognitions of (E)- and (Z)-1,1'-binaphthyl ketoximes using lipase-catalyzed reactions
      Aoyagi, Naoto; Kawauchi, Shinji; Izumi, Taeko
      Tetrahedron Letters (2004), 45 (27), 5189-5192CODEN: TELEAY; ISSN:0040-4039. (Elsevier)
      Lipase-catalyzed hydrolysis of (E)-2-[α-(acetoxyimino)benzyl]-1,1'-binaphthyl (I) [(E)-(±)-I] and (Z)-2-[α-(acetoxyimino)benzyl]-1,1'-binaphthyl [(Z)-(±)-I] yielded optically active (E)-2-[α-(hydroxyimino)benzyl]-1,1'-binaphthyl (II) [(E,S)-II] and (Z)-2-[α-(hydroxyimino)benzyl]-1,1'-binaphthyl [(Z,R)-II], resp., with high enantiomeric excess. Selectivity for the opposite enantiomer of the axial binaphthyl skeleton was shown by (Z)-isomer I against (E)-isomer I.
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    50. 50
      Kiefer, M.; Vogel, R.; Helmchen, G.; Nuber, B. Resolution of (1,1′-Binaphthalene)-2,2′-Dithiol by Enzyme Catalysed Hydrolysis of a Racemic Diacyl Derivative. Tetrahedron 1994, 50 (24), 7109– 7114,  DOI: 10.1016/S0040-4020(01)85237-6
      50
      Resolution of (1,1'-binaphthalene)-2,2'-dithiol by enzyme catalyzed hydrolysis of a racemic diacyl derivative
      Kiefer, Matthias; Vogel, Rainer; Helmchen, Guenter; Nuber, Bernhard
      Tetrahedron (1994), 50 (24), 7109-14CODEN: TETRAB; ISSN:0040-4020.
      Both enantiomers of (1,1'-binaphthalene)-2,2'-dithiol (1) can be obtained with 98% ee by enzymic (cholesterol esterase) resoln. of the corresponding S,S'-dipentanoate. Abs. configuration and enantiomeric purity were detd. by crystal structure and 1H NMR anal., resp., of a diastereomeric deriv. of 1.
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    51. 51
      Sanfilippo, C.; Nicolosi, G.; Delogu, G.; Fabbri, D.; Dettori, M. A. Synthesis and Biocatalytic Resolution of a New Atropisomeric Thiobiphenyl: (2,2′,6,6′-Tetramethoxybiphenyl-3,3′-Diyl)Dimethanethiol. Tetrahedron: Asymmetry 2005, 16 (6), 1079– 1084,  DOI: 10.1016/j.tetasy.2005.01.028
      51
      Synthesis and biocatalytic resolution of a new atropisomeric thiobiphenyl: (2,2',6,6'-tetramethoxybiphenyl-3,3'-diyl)dimethanethiol
      Sanfilippo, Claudia; Nicolosi, Giovanni; Delogu, Giovanna; Fabbri, Davide; Dettori, Maria Antonietta
      Tetrahedron: Asymmetry (2005), 16 (6), 1079-1084CODEN: TASYE3; ISSN:0957-4166. (Elsevier B.V.)
      Both atropisomers of racemic thiobiphenyl (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol were obtained in enantiopure form using lipase catalyzed procedures. The esterification reaction of (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol in the presence of vinyl acetate gave in a one-pot reaction (+)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol and (-)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol via a lipase assisted dynamic kinetic resoln. of epimerizing hemithioacetal intermediates. The alcoholysis of the diacetyl thioester, (±)-of ethanethioic acid S,S'-[2,2',6,6'-tetra(methoxy)[1,1'-biphenyl]-3,3'-diyl] ester is an alternative strategy for access to the enantiomers of (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol with high enantiomeric excess.
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    52. 52
      Kawahara, K.; Matsumoto, M.; Hashimoto, H.; Miyano, S. Kinetic Resolution of 2-Formyl-1,1′-Binaphthyls by Baker’s-Yeast Reduction of the Formyl Function. Chem. Lett. 1988, 17 (7), 1163– 1164,  DOI: 10.1246/cl.1988.1163
      There is no corresponding record for this reference.
    53. 53
      Csuk, R.; Glänzer, B. I. Baker’s Yeast Mediated Transformations in Organic Chemistry. Chem. Rev. 1991, 91 (1), 49– 97,  DOI: 10.1021/cr00001a004
      53
      Baker's yeast mediated transformations in organic chemistry
      Csuk, Rene; Glaenzer, Brigitte I.
      Chemical Reviews (Washington, DC, United States) (1991), 91 (1), 49-97CODEN: CHREAY; ISSN:0009-2665.
      A review with 508 refs. The transformations include redns., oxidns., C-C bond-forming and -breaking reactions, are hydrolysis of esters.
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    54. 54
      Staniland, S.; Yuan, B.; Giménez-Agulló, N.; Marcelli, T.; Willies, S. C.; Grainger, D. M.; Turner, N. J.; Clayden, J. Enzymatic Desymmetrising Redox Reactions for the Asymmetric Synthesis of Biaryl Atropisomers. Chem.─Eur. J. 2014, 20 (41), 13084– 13088,  DOI: 10.1002/chem.201404509
      54
      Enzymatic Desymmetrising Redox Reactions for the Asymmetric Synthesis of Biaryl Atropisomers
      Staniland, Samantha; Yuan, Bo; Gimenez-Agullo, Nelson; Marcelli, Tommaso; Willies, Simon C.; Grainger, Damian M.; Turner, Nicholas J.; Clayden, Jonathan
      Chemistry - A European Journal (2014), 20 (41), 13084-13088CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Atropisomeric biaryls carrying ortho-hydroxymethyl and formyl groups were made enantioselectively by desymmetrization of dialdehyde or diol substrates. The oxidn. of the sym. diol substrates was achieved using a variant of galactose oxidase (GOase), and the redn. of the dialdehydes using a panel of ketoreductases (KREDs). Either M or P enantiomers of the products could be formed, with abs. configurations assigned by time-dependent DFT calcns. of CD spectra. The differing selectivities obsd. with different biaryl structures offer an insight into the detailed structure of the active site of the GOase enzyme.
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    55. 55
      Matsumoto, T.; Konegawa, T.; Nakamura, T.; Suzuki, K. Facile and Highly Enantioselective Synthesis of Axially Chiral Biaryls by Enzymatic Desymmetrization. Synlett 2002, 2002 (1), 0122– 0124,  DOI: 10.1055/s-2002-19349
      There is no corresponding record for this reference.
    56. 56
      Okuyama, K.; Shingubara, K.; Tsujiyama, S.; Suzuki, K.; Matsumoto, T. Enantiodivergent Synthesis of Tetra-Ortho-Substituted Biphenyls by Enzymatic Desymmetrization. Synlett 2009, 2009 (6), 941– 944,  DOI: 10.1055/s-0028-1088215
      There is no corresponding record for this reference.
    57. 57
      Takahashi, N.; Kanayama, T.; Okuyama, K.; Kataoka, H.; Fukaya, H.; Suzuki, K.; Matsumoto, T. Enantioselective Total Synthesis of (−)-Euxanmodin B: An Axially Chiral Natural Product with an Anthraquinone–Xanthone Composite Structure. Chem.─Asian J. 2011, 6 (7), 1752– 1756,  DOI: 10.1002/asia.201100187
      57
      Enantioselective Total Synthesis of (-)-Euxanmodin B: An Axially Chiral Natural Product with an Anthraquinone-Xanthone Composite Structure
      Takahashi, Nobuyuki; Kanayama, Takeshi; Okuyama, Kumi; Kataoka, Hiroko; Fukaya, Haruhiko; Suzuki, Keisuke; Matsumoto, Takashi
      Chemistry - An Asian Journal (2011), 6 (7), 1752-1756CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The first total synthesis of (-)-euxanmodin B (I) was achieved starting from an axially chiral, enantiomerically pure biphenyl substrate II. Further studies are in progress, including the biol. assay for nonracemic and racemic materials.
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    58. 58
      Yamaguchi, S.; Takahashi, N.; Yuyama, D.; Sakamoto, K.; Suzuki, K.; Matsumoto, T. First Total Synthesis of Dermocanarin 2. Synlett 2016, 27 (8), 1262– 1268,  DOI: 10.1055/s-0035-1561417
      58
      First Total Synthesis of Dermocanarin 2
      Yamaguchi, Satoru; Takahashi, Nobuyuki; Yuyama, Daisuke; Sakamoto, Kayo; Suzuki, Keisuke; Matsumoto, Takashi
      Synlett (2016), 27 (8), 1262-1268CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
      The first total synthesis of dermocanarin 2 (I) is described. The synthesis features the construction of the anthraquinone and naphthoquinone frameworks through annulation reactions onto an axially chiral biphenyl intermediate, obtained by an enzyme-catalyzed enantioselective desymmetrization of a σ-sym. precursor, followed by a stereoselective aldol reaction to construct the stereogenic center in the side chain.
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    59. 59
      Ochiai, M.; Akisawa, Y.; Kajiyama, D.; Matsumoto, T. Desymmetrization of σ-Symmetric Biphenyl-2,6-Diyl Diacetate Derivatives by Lipase-Catalyzed Hydrolysis: Unexpected Effect of C(3′)-Substituent on the Enantiotopic Group Selectivity. Synlett 2019, 30 (5), 557– 562,  DOI: 10.1055/s-0037-1611701
      59
      Desymmetrization of σ-Symmetric Biphenyl-2,6-diyl Diacetate Derivatives by Lipase-Catalyzed Hydrolysis: Unexpected Effect of C(3')-Substituent on the Enantiotopic Group Selectivity
      Ochiai, Mio; Akisawa, Yuki; Kajiyama, Daichi; Matsumoto, Takashi
      Synlett (2019), 30 (5), 557-562CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
      Highly enantioselective desymmetrization of σ-sym. 3'-substituted 2',6'-dimethoxybiphenyl-2,6-diyl diacetate derivs. I (R = CO2CH3, C(O)CH3, 2-furanyl, etc.) to the corresponding monoacetates II and III was effected by using Rhizopus oryzae lipase (ROL) and porcine pancreatic lipase (PPL), despite the remoteness of the C(3') substituent from the acetate groups. ROL promoted hydrolysis of the pro-S-acetates, irresp. of the type of C(3') substituent, whereas PPL promoted hydrolysis of the pro-R-acetates, and selectivity was only attainable when the C(3') substituent was a polar group.
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    60. 60
      Kasama, K.; Aoyama, H.; Akai, S. Enantiodivergent Synthesis of Axially Chiral Biphenyls from σ-Symmetric 1,1′-Biphenyl-2,6-Diol Derivatives by Single Lipase-Catalyzed Acylative and Hydrolytic Desymmetrization. Eur. J. Org. Chem. 2020, 2020 (6), 654– 661,  DOI: 10.1002/ejoc.201901583
      60
      Enantiodivergent Synthesis of Axially Chiral Biphenyls from σ-Symmetric 1,1'-Biphenyl-2,6-diol Derivatives by Single Lipase-Catalyzed Acylative and Hydrolytic Desymmetrization
      Kasama, Kengo; Aoyama, Hiroshi; Akai, Shuji
      European Journal of Organic Chemistry (2020), 2020 (6), 654-661CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The enzymic acylative desymmetrization of σ-sym. 2'-halo-1,1'-biphenyl-2,6-diols was achieved for the first time using com. available Burkholderia cepacia lipase immobilized on diatomaceous earth to give (S)-mono esters. The hydrolytic desymmetrization of the corresponding diacetates was also achieved using the same lipase to give (R)-mono esters. The authors' results, therefore, demonstrate that a single lipase can conduct the enantiodivergent synthesis of axially chiral biphenyl compds. in high chem. and optical yields.
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    61. 61
      Dong, J.; Fernández-Fueyo, E.; Hollmann, F.; Paul, C. E.; Pesic, M.; Schmidt, S.; Wang, Y.; Younes, S.; Zhang, W. Biocatalytic Oxidation Reactions: A Chemist’s Perspective. Angew. Chem., Int. Ed. 2018, 57 (30), 9238– 9261,  DOI: 10.1002/anie.201800343
      61
      Biocatalytic Oxidation Reactions: A Chemist's Perspective
      Dong, JiaJia; Fernandez-Fueyo, Elena; Hollmann, Frank; Paul, Caroline E.; Pesic, Milja; Schmidt, Sandy; Wang, Yonghua; Younes, Sabry; Zhang, Wuyuan
      Angewandte Chemie, International Edition (2018), 57 (30), 9238-9261CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Oxidn. chem. using enzymes is approaching maturity and practical applicability in org. synthesis. Oxidoreductases (enzymes catalyzing redox reactions) enable chemists to perform highly selective and efficient transformations ranging from simple alc. oxidns. to stereoselective halogenations of non-activated C-H bonds. For many of these reactions, no "classical" chem. counterpart is known. Hence oxidoreductases open up shorter synthesis routes based on a more direct access to the target products. The generally very mild reaction conditions may also reduce the environmental impact of biocatalytic reactions compared to classical counterparts. In this Review, we critically summarize the most important recent developments in the field of biocatalytic oxidn. chem. and identify the most pressing bottlenecks as well as promising solns.
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    62. 62
      Escalettes, F.; Turner, N. J. Directed Evolution of Galactose Oxidase: Generation of Enantioselective Secondary Alcohol Oxidases. ChemBioChem. 2008, 9 (6), 857– 860,  DOI: 10.1002/cbic.200700689
      62
      Directed evolution of galactose oxidase: generation of enantioselective secondary alcohol oxidases
      Escalettes, Franck; Turner, Nicholas J.
      ChemBioChem (2008), 9 (6), 857-860CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A colorimetric solid phase assay which allowed to assess the activity of individual clones when grown on agar plates is described. This screening method which relies upon capture of the hydrogen peroxide byproducts produced in the oxidn. reaction, is versatile, in that different substrate can easily be introduced into the assay and also reasonably high-throughput allowing up to 100,000 clones to be readily screened per round of evolution. Libraries of M3 GOase were generated using error-prone PCR in which the av. no. of amino acids mutations per gene was about 3-4. These libraries were used to transform E. coli and the resulting colonies screened on solid phase against but-3-en-2-ol as substrate. Variants of GOase were identified that possess good activity towards a range of secondary alcs. based upon the 1-phenylethanol template and high enantioselectivity in the kinetic resoln. of (±)-3 fluoro-1-phenylethanol.
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    63. 63
      Nicolaou, K. C.; Boddy, C. N. C.; Bräse, S.; Winssinger, N. Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics. Angew. Chem., Int. Ed. 1999, 38 (15), 2096– 2152,  DOI: 10.1002/(SICI)1521-3773(19990802)38:15<2096::AID-ANIE2096>3.0.CO;2-F
      63
      Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics
      Nicolaou; Boddy; Brase; Winssinger
      Angewandte Chemie (International ed. in English) (1999), 38 (15), 2096-2152 ISSN:.
      The war against infectious bacteria is not over! Although vancomycin and glycopeptide antibiotics have provided a strong last line of defence against many drug-resistant bacteria, their overuse has given rise to more dangerous strains of bacteria. An understanding of the chemistry and biology of these highly complex glycopeptides are destined to play a crucial role in the discovery of new antibiotics.
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    64. 64
      Halling, P. J. Kinetics of Enzyme-Catalysed Desymmetrisation of Prochiral Substrates: Product Enantiomeric Excess Is Not Always Constant. Beilstein J. Org. Chem. 2021, 17 (1), 873– 884,  DOI: 10.3762/bjoc.17.73
      64
      Kinetics of enzyme-catalysed desymmetrisation of prochiral substrates: product enantiomeric excess is not always constant
      Halling, Peter J.
      Beilstein Journal of Organic Chemistry (2021), 17 (), 873-884CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
      The kinetics of enzymic desymmetrisation were analyzed for the most common kinetic mechanisms: ternary complex ordered (prochiral ketone redn.); ping-pong second (ketone amination, diol esterification, desymmetrisation in the second half reaction); ping-pong first (diol ester hydrolysis) and ping-pong both (prochiral diacids). For plausible values of enzyme kinetic parameters, the product enantiomeric excess (ee) can decline substantially as the reaction proceeds to high conversion. For example, an ee of 0.95 at the start of the reaction can decline to less than 0.5 at 95% of equil. conversion, but for different enzyme properties it will remain almost unchanged. For most mechanisms a single function of multiple enzyme rate consts. (which can be termed ee decline parameter, eeDP) accounts for the major effect on the tendency for the ee to decline. For some mechanisms, the concns. or ratios of the starting materials have an important influence on the fall in ee. For the application of enzymic desymmetrisation it is important to study if and how the product ee declines at high conversion.
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    65. 65
      Sanfilippo, C.; Nicolosi, G.; Delogu, G.; Fabbri, D.; Dettori, M. A. Synthesis and Biocatalytic Resolution of a New Atropisomeric Thiobiphenyl: (2,2′,6,6′-Tetramethoxybiphenyl- 3,3′-Diyl)Dimethanethiol. Tetrahedron: Asymmetry 2005, 16, 1079– 1084,  DOI: 10.1016/j.tetasy.2005.01.028
      65
      Synthesis and biocatalytic resolution of a new atropisomeric thiobiphenyl: (2,2',6,6'-tetramethoxybiphenyl-3,3'-diyl)dimethanethiol
      Sanfilippo, Claudia; Nicolosi, Giovanni; Delogu, Giovanna; Fabbri, Davide; Dettori, Maria Antonietta
      Tetrahedron: Asymmetry (2005), 16 (6), 1079-1084CODEN: TASYE3; ISSN:0957-4166. (Elsevier B.V.)
      Both atropisomers of racemic thiobiphenyl (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol were obtained in enantiopure form using lipase catalyzed procedures. The esterification reaction of (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol in the presence of vinyl acetate gave in a one-pot reaction (+)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol and (-)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol via a lipase assisted dynamic kinetic resoln. of epimerizing hemithioacetal intermediates. The alcoholysis of the diacetyl thioester, (±)-of ethanethioic acid S,S'-[2,2',6,6'-tetra(methoxy)[1,1'-biphenyl]-3,3'-diyl] ester is an alternative strategy for access to the enantiomers of (±)-2,2',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-dimethanethiol with high enantiomeric excess.
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    66. 66
      Skrobo, B.; Deska, J. On the Lipase-Catalyzed Resolution of Functionalized Biaryls. Tetrahedron: Asymmetry 2013, 24 (17), 1052– 1056,  DOI: 10.1016/j.tetasy.2013.07.014
      66
      On the lipase-catalyzed resolution of functionalized biaryls
      Skrobo, Benedikt; Deska, Jan
      Tetrahedron: Asymmetry (2013), 24 (17), 1052-1056CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
      The implementation of lipase catalysis as a tool for the prepn. of optically active biaryls is discussed. While attempts toward dynamic kinetic resoln. based on the catalytic ring opening of configurationally unstable biaryl lactones were fruitless, kinetic resoln. via transesterification of hydroxymethyl-decorated substrates was successfully employed in the generation of optically enriched, axially chiral biaryls.
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    67. 67
      Ahmed, A.; Bragg, R. A.; Clayden, J.; Lai, L. W.; McCarthy, C.; Pink, J. H.; Westlund, N.; Yasin, S. A. Barriers to Rotation about the Chiral Axis of Tertiary Aromatic Amides. Tetrahedron 1998, 54 (43), 13277– 13294,  DOI: 10.1016/S0040-4020(98)00814-X
      67
      Barriers to rotation about the chiral axis of tertiary aromatic amides
      Ahmed, Anjum; Bragg, Ryan A.; Clayden, Jonathan; Lai, Lai Wah; McCarthy, Catherine; Pink, Jennifer H.; Westlund, Neil; Yasin, Samreen A.
      Tetrahedron (1998), 54 (43), 13277-13294CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)
      The barrier to rotation about the aryl-carbonyl bond in 40 tertiary arom. amides was detd. by variable-temp. NMR spectroscopy (for rapid rotations) or by following the interconversion of atropisomers (for slower rotations). Empirical guidelines to the rate of Ar-CO bond rotation in hindered tertiary arom. amides, and hence the stability of the atropisomeric stereoisomers of axially chiral amides, are presented.
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    68. 68
      Clayden, J.; Lai, L. W.; Helliwell, M. Dynamic Resolution of Atropisomeric Amides Using Proline-Derived Imidazolines and Ephedrine-Derived Oxazolidines. Tetrahedron 2004, 60 (20), 4399– 4412,  DOI: 10.1016/j.tet.2004.01.101
      68
      Dynamic resolution of atropisomeric amides using proline-derived imidazolines and ephedrine-derived oxazolidines
      Clayden, Jonathan; Lai, Lai Wah; Helliwell, Madeleine
      Tetrahedron (2004), 60 (20), 4399-4412CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science B.V.)
      Condensation of atropisomeric tertiary 2-formylnaphthamides or 2-formylbenzamides with some chiral diamines and amino alcs. leads, via a dynamic resoln. process, to single atropisomers of tertiary amides bearing chiral imidazolidines or oxazolidines. Hydrolysis of the new heterocycle competes a dynamic thermodn. resoln. of the starting aldehyde, and rapid redn. allows the isolation of atropisomeric amides bearing 2-hydroxymethyl substituents in enantiomerically enriched form. Evidence that the reactions are under thermodn. control is presented.
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    69. 69
      Ruzziconi, R.; Lepri, S.; Buonerba, F.; Schlosser, M.; Mancinelli, M.; Ranieri, S.; Prati, L.; Mazzanti, A. Long-Range Bonding/Nonbonding Interactions: A Donor–Acceptor Resonance Studied by Dynamic NMR. Org. Lett. 2015, 17 (11), 2740– 2743,  DOI: 10.1021/acs.orglett.5b01152
      69
      Long-Range Bonding/Nonbonding Interactions: A Donor-Acceptor Resonance Studied by Dynamic NMR
      Ruzziconi, Renzo; Lepri, Susan; Buonerba, Federica; Schlosser, Manfred; Mancinelli, Michele; Ranieri, Silvia; Prati, Luca; Mazzanti, Andrea
      Organic Letters (2015), 17 (11), 2740-2743CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      Long-range bonding interactions were evaluated using variable-temp. NMR spectroscopy and suitable 2'-CH2X-substituted phenylpyridines (X = Me, NMe2, OMe, F). It was found that the arylpyridyl rotational barriers were lower when electroneg. atoms were bound to the α carbon of the 2' moiety. This effect was ascribed to a stabilizing interaction in the transition state due to the lone pair of the heterocyclic nitrogen with the α carbon. Computational support for this hypothesis came from CCSD(T)/6-31+G(d) calcns. Steric effects of the X moiety were ruled out by comparison of the rotational barriers of analogous biphenyls.
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    70. 70
      Snodgrass, H. M.; Mondal, D.; Lewis, J. C. Directed Evolution of Flavin-Dependent Halogenases for Site- and Atroposelective Halogenation of 3-Aryl-4(3H)-Quinazolinones via Kinetic or Dynamic Kinetic Resolution. J. Am. Chem. Soc. 2022, 144 (36), 16676– 16682,  DOI: 10.1021/jacs.2c07422
      70
      Directed Evolution of Flavin-Dependent Halogenases for Site- and Atroposelective Halogenation of 3-Aryl-4(3H)-Quinazolinones via Kinetic or Dynamic Kinetic Resolution
      Snodgrass, Harrison M.; Mondal, Dibyendu; Lewis, Jared C.
      Journal of the American Chemical Society (2022), 144 (36), 16676-16682CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      In this study, we engineer a variant of the flavin-dependent halogenase RebH that catalyzes site- and atroposelective halogenation of 3-aryl-4(3H)-quinazolinones via kinetic or dynamic kinetic resoln. The required directed evolution uses a combination of random and site-satn. mutagenesis, substrate walking using two probe substrates, and a two-tiered screening approach involving the anal. of variant conversion and then enantioselectivity of improved variants. The resulting variant, 3-T, provides >99:1 e.r. for the (M)-atropisomer of the major brominated product, 25-fold improved conversion, and 91-fold improved site selectivity relative to the parent enzyme on the probe substrate used in the final rounds of evolution. This high activity and selectivity translate well to several addnl. substrates with varied steric and electronic properties. Computational modeling and docking simulations are used to rationalize the effects of key mutations on substrate binding. Given the range of substrates that have been used for atroposelective synthesis via electrophilic halogenation in the literature, these results suggest that flavin-dependent halogenases (FDHs) could find many addnl. applications for atroposelective catalysis. More broadly, this study highlights how RebH can be engineered to accept structurally diverse substrates that enable its use for enantioselective catalysis.
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    71. 71
      Moustafa, G. A. I.; Oki, Y.; Akai, S. Lipase-Catalyzed Dynamic Kinetic Resolution of C1- and C2-Symmetric Racemic Axially Chiral 2,2′-Dihydroxy-1,1′-Biaryls. Angew. Chem., Int. Ed. 2018, 57 (32), 10278– 10282,  DOI: 10.1002/anie.201804161
      71
      Lipase-Catalyzed Dynamic Kinetic Resolution of C1- and C2-Symmetric Racemic Axially Chiral 2,2'-Dihydroxy-1,1'-biaryls
      Moustafa, Gamal A. I.; Oki, Yasuhiro; Akai, Shuji
      Angewandte Chemie, International Edition (2018), 57 (32), 10278-10282CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      We have discovered that the racemization of configurationally stable, axially chiral 2,2'-dihydroxy-1,1'-biaryls proceeds with a catalytic amt. of a cyclopentadienylruthenium(II) complex at 35-50 °C. Combining this racemization procedure with lipase-catalyzed kinetic resoln. led to the first lipase/metal-integrated dynamic kinetic resoln. of racemic axially chiral biaryl compds. The method was applied to the synthesis of various enantio-enriched C1- and C2-sym. biaryl diols in yields of up to 98 % and enantiomeric excesses of up to 98 %, which paves the way for new developments in the field of asym. synthesis.
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    72. 72
      Bhat, V.; Welin, E. R.; Guo, X.; Stoltz, B. M. Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations. Chem. Rev. 2017, 117 (5), 4528– 4561,  DOI: 10.1021/acs.chemrev.6b00731
      72
      Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations
      Bhat, Vikram; Welin, Eric R.; Guo, Xuelei; Stoltz, Brian M.
      Chemical Reviews (Washington, DC, United States) (2017), 117 (5), 4528-4561CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. Stereoconvergent catalysis is an important subset of asym. synthesis that encompasses stereoablative transformations, dynamic kinetic resolns., and dynamic kinetic asym. transformations. Initially, only enzymes were known to catalyze dynamic kinetic processes, but recently various synthetic catalysts have been developed. This review summarizes major advances in nonenzymic, transition-metal-promoted dynamic asym. transformations reported between 2005 and 2015.
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    73. 73
      Aranda, C.; Oksdath-Mansilla, G.; Bisogno, F. R.; Gonzalo, G. de. Deracemisation Processes Employing Organocatalysis and Enzyme Catalysis. Adv. Synth. Catal. 2020, 362 (6), 1233– 1257,  DOI: 10.1002/adsc.201901112
      73
      Deracemisation Processes Employing Organocatalysis and Enzyme Catalysis
      Aranda, Carmen; Oksdath-Mansilla, Gabriela; Bisogno, Fabricio R.; de Gonzalo, Gonzalo
      Advanced Synthesis & Catalysis (2020), 362 (6), 1233-1257CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The focus of this comprehensive review is on the application of deracemization procedures in the present century in order to obtain optically active valuable compds. when employing non-metallic catalysts. Thus, the review will mainly focus on the use of different enzymic prepns. (purified enzymes, cell-free exts. or whole cell systems) and organocatalysts for the deracemization of racemic mixts.
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    74. 74
      Schwizer, F.; Okamoto, Y.; Heinisch, T.; Gu, Y.; Pellizzoni, M. M.; Lebrun, V.; Reuter, R.; Köhler, V.; Lewis, J. C.; Ward, T. R. Artificial Metalloenzymes: Reaction Scope and Optimization Strategies. Chem. Rev. 2018, 118 (1), 142– 231,  DOI: 10.1021/acs.chemrev.7b00014
      74
      Artificial Metalloenzymes: Reaction Scope and Optimization Strategies
      Schwizer, Fabian; Okamoto, Yasunori; Heinisch, Tillmann; Gu, Yifan; Pellizzoni, Michela M.; Lebrun, Vincent; Reuter, Raphael; Kohler, Valentin; Lewis, Jared C.; Ward, Thomas R.
      Chemical Reviews (Washington, DC, United States) (2018), 118 (1), 142-231CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. The incorporation of a synthetic, catalytically competent metallocofactor into a protein scaffold to generate an artificial metalloenzyme (ArM) has been explored since the late 1970's. Progress in the ensuing years was limited by the tools available for both organometallic synthesis and protein engineering. Advances in both of these areas, combined with increased appreciation of the potential benefits of combining attractive features of both homogeneous catalysis and enzymic catalysis, led to a resurgence of interest in ArMs starting in the early 2000's. Perhaps the most intriguing of potential ArM properties is their ability to endow homogeneous catalysts with a genetic memory. Indeed, incorporating a homogeneous catalyst into a genetically encoded scaffold offers the opportunity to improve ArM performance by directed evolution. This capability could, in turn, lead to improvements in ArM efficiency similar to those obtained for natural enzymes, providing systems suitable for practical applications and greater insight into the role of second coordination sphere interactions in organometallic catalysis. Since its renaissance in the early 2000's, different aspects of artificial metalloenzymes have been extensively reviewed and highlighted. Our intent is to provide a comprehensive overview of all work in the field up to Dec. 2016, organized according to reaction class. Because of the wide range of non-natural reactions catalyzed by ArMs, this was done using a functional-group transformation classification. The review begins with a summary of the proteins and the anchoring strategies used to date for the creation of ArMs, followed by a historical perspective. Then follows a summary of the reactions catalyzed by ArMs and a concluding crit. outlook. This anal. allows for comparison of similar reactions catalyzed by ArMs constructed using different metallocofactor anchoring strategies, cofactors, protein scaffolds, and mutagenesis strategies. These data will be used to construct a searchable Web site on ArMs that will be updated regularly by the authors.
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    75. 75
      Chatterjee, A.; Mallin, H.; Klehr, J.; Vallapurackal, J.; Finke, A. D.; Vera, L.; Marsh, M.; Ward, T. R. An Enantioselective Artificial Suzukiase Based on the Biotin–Streptavidin Technology. Chem. Sci. 2016, 7 (1), 673– 677,  DOI: 10.1039/C5SC03116H
      75
      An enantioselective artificial Suzukiase based on the biotin-streptavidin technology
      Chatterjee, Anamitra; Mallin, Hendrik; Klehr, Juliane; Vallapurackal, Jaicy; Finke, Aaron D.; Vera, Laura; Marsh, May; Ward, Thomas R.
      Chemical Science (2016), 7 (1), 673-677CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      Introduction of a biotinylated monophosphine palladium complex within streptavidin affords an enantioselective artificial Suzukiase. Site-directed mutagenesis allowed the optimization of the activity and the enantioselectivity of this artificial metalloenzyme. A variety of atropisomeric biaryls e.g., I were produced in good yields and up to 90% ee. The hybrid catalyst described herein shows comparable TOF to the previous aq.-asym. Suzuki catalysts, and excellent stability under the reaction conditions to realize higher TON through longer reaction time.
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