Coordination Chemistry Reviewscbs.ewha.ac.kr/pub/data/2020_08_CCR_2020_421_213443.pdf · 2020. 11....

Coordination Chemistry Reviews 421 (2020) 213443

Contents lists available at ScienceDirect

Coordination Chemistry Reviews

journal homepage: www.elsevier .com/ locate/ccr

Artificial nonheme iron and manganese oxygenases for enantioselectiveolefin epoxidation and alkane hydroxylation reactions

https://doi.org/10.1016/j.ccr.2020.2134430010-8545/� 2020 Elsevier B.V. All rights reserved.

⇑ Corresponding authors.E-mail addresses: [email protected] (S. Fukuzumi), [email protected] (W. Nam), [email protected] (B. Wang).

Jie Chen a, Zhankun Jiang a, Shunichi Fukuzumi b,c,⇑, Wonwoo Nama,b,⇑, Bin Wang a,⇑a School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, ChinabDepartment of Chemistry and Nano Science, Ewha Womans University, Seoul 03760, Koreac Faculty of Science and Engineering, Meijo University, Nagoya, Aichi 468-8502, Japan

a r t i c l e i n f o

Article history:Received 11 January 2020Accepted 8 June 2020

Keywords:Enantioselective epoxidation andhydroxylationBioinspired catalysisNonheme iron and manganese catalystsMechanism

a b s t r a c t

The development of sustainable enantioselective olefin epoxidation and alkane oxidation reactions underenvironmentally friendly conditions is an ultimate goal that has long been pursued in chemistry.Excellent examples are naturally occurring monooxygenases, which are able to catalyze a variety of bio-logical oxidation reactions using molecular oxygen (O2) that afford high chemo-, regio-, and/or stereos-electivities. Inspired by the oxidation reactions of iron-containing monooxygenases, substantial effortshave been made towards the development of efficient catalysis for the enantioselective oxidation ofhydrocarbons using bioinspired nonheme iron and manganese catalysts under mild conditions. In thisreview, we describe synthetic models that functionally mimic these monooxygenases. There are a largenumber of nonheme iron and manganese complexes that can epoxidize olefins with high enantioselec-tivities, whereas only a few examples are reported for nonheme iron- and manganese-catalyzed enan-tioselective oxidation of inert C(sp3)–H bonds. In addition to its great achievement for syntheticapplications, mechanistic studies in biomimetic oxidation systems have also been intensively investi-gated, providing important insights into the understanding of the nature of active oxidants and the for-mation of the intermediates via OAO bond activation and the design of more elegant biomimeticoxidation catalysts. Thus, these bioinspired nonheme iron and manganese complexes used as catalystsin the enantioselective C@C epoxidation and aliphatic C(sp3)–H oxidation are the focus of discussion inthis review.

� 2020 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22. Enantioselective C¼C epoxidation with nonheme iron complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2.1. H2O2 as the oxygen source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.2. PhIO as the oxygen source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82.3. Peracid as the oxygen source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102.4. Mechanistic aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

3. Enantioselective C¼C epoxidation with nonheme manganese complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

3.1. Peracid as the oxygen source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133.2. H2O2 as the oxygen source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133.3. H2O as the oxygen source. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193.4. Mechanistic aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

4. Enantioselective C(sp3)�H oxidation with nonheme iron and manganese complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

4.1. Enantioselective C(sp3)AH oxidation with nonheme iron complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224.2. Enantioselective C(sp3)AH oxidation with nonheme manganese complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

http://crossmark.crossref.org/dialog/?doi=10.1016/j.ccr.2020.213443&domain=pdfhttps://doi.org/10.1016/j.ccr.2020.213443mailto:[email protected]:[email protected]:[email protected]://doi.org/10.1016/j.ccr.2020.213443http://www.sciencedirect.com/science/journal/00108545http://www.elsevier.com/locate/ccr

2 J. Chen et al. / Coordination Chemistry Reviews 421 (2020) 213443

Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

1. Introduction

Enantiomerically enriched epoxides are found in a diverse rangeof biologically active molecules, pharmaceuticals, agrochemicalsand advanced materials [1–15]. Also, enantioenriched epoxidesare highly versatile building blocks from the perspective of syn-thetic chemists. Since the catalytic enantioselective epoxidationof C@C bonds represents the most straightforward and efficientmethod for the synthesis of enantioenriched epoxides [1–15]. Asa result, enantioselective epoxidation by synthetic metal catalysts,especially those using earth-abundant metal ions and environmen-tally benign oxidant, is of fundamental interest in the communityof synthetic organic chemistry.

Alkanes are inert compounds and require further chemicalfunctionalization (e.g., oxygenation) to be used as starting materi-als in the synthesis of value-added chemical products. The func-tionalization of aliphatic C(sp3)AH bonds is of general interestand significance, but remains as a challenge for modern chemistry[16–23], in which the catalytic oxidation of unactivated C(sp3)AHbonds is highly important because the oxidation of these bondsprovides versatile intermediates for further use [22,23]. Moreover,enantioselective oxidation of aliphatic C(sp3)AH bonds under envi-ronmentally benign conditions represents one of the most chal-lenging tasks in organic synthesis [2,3,20]. The oxidation ofaliphatic C(sp3)AH bonds is thermodynamically favorable; how-ever, the large bond dissociation energy (BDE) of aliphatic C(sp3)AH bonds makes the activation of C–H bonds difficult becauseof the strong C(sp3)AH bonds, which are non-polarized, localizedand kinetically stable with large HOMO–LUMO gaps. Therefore,highly reactive oxidizing species are required to overcome thesebarriers. In addition, in order to achieve the selective oxidation ofC(sp3)AH bonds, several challenges should be overcome [2,3,23],such as (1) chemoselectivity, i.e., to direct the oxidation towardinert C(sp3)AH bonds in the presence of more reactive functional-ities in a molecule, (2) regioselectivity, i.e., to discriminate amongthe various C(sp3)AH bonds with only slight electronic and stericdifferences present in a molecule, (3) enantioselectivity, which isquite difficult to achieve during the oxidation of aliphatic C(sp3)AH bonds, and (4) overoxidation, which is the more facile inoxidation of secondary alcohols to ketones to eliminate the result-ing chiral center [21]. Given the above difficulties, enantioselectiveC(sp3)AH oxidation is rarely found in complex molecule synthesis.Instead, the preoxygenated fragments are employed in the con-struction of more complex molecules, relying on unproductive pro-tecting and deprotecting sequences. In this regard, enantioselectiveoxidation that introduces oxidized functional groups directly into C(sp3)AH bonds is envisioned as a more powerful and efficient strat-egy. This translates into the late-stage oxidation of aliphatic C(sp3)AH bonds with a predictive manner, avoiding the use of pro-tecting and directed groups.

Monooxygenases catalyze the oxidation of organic substrates inliving organisms. The rich chemistry of redox-active manganese-,iron-, or copper-containing complexes, which can have multipleoxidation states and different coordination geometries, allowsthe enzymes to perform a variety of biological transformationsassociated with their functions and play a pivotal role in highlysophisticated enzymatic reactions, such as O2 activation and oxida-tion reactions [24]. The active sites of monooxygenases can bemonometallic or polymetallic, and the common feature is that

nitrogen, oxygen or sulfur donors from amino acid residues areused to form metal complexes [24]. In specific cases, the positionof the coordination donors is controlled by the structure of theactive site, causing the metal ion at the active site to adopt partic-ular coordination number and geometry [24,25]. The reactivity ofthe metal-based oxidant is also tuned by the structure/geometryof the active site, such as the size, polarity and secondary coordina-tion sphere, for chemo-, regio-, and stereoselectivities [26,27].Additional advantages of the enzymatic reactions are that theycan be performed under mild conditions through inherently ‘green’processes with high atom economy [28]. For example, oxygenasesutilize O2 as oxidant to perform a variety of oxidation reactionswith high selectivity (Table 1), yielding only H2O as the byproduct,which is environmentally the most benign chemical [29–35].

Cytochromes P450 (CYP 450), one of the most well investigatedand understood monooxygenase enzymes, are thiolate-ligatedheme enzymes [29–31]. They use molecular oxygen (O2) and theformal equivalents of two hydrogen atoms (i.e., 2H+ and 2e–) toperform extensive oxidation reactions with high efficiency as wellas selectivity (Table 1). The most often-encountered oxidationreactions by CYP 450 are ranging from hydroxylation, epoxidation,and heteroatom oxidation to heteroatom dealkylation. [29–31].The catalytic cycle of the O2 activation by CYP 450 is now well-established [29–31], which is depicted in Scheme 1. The bindingof substrate to the active site of the low-spin iron(III) resting state(A) triggers spin crossover to a high-spin iron(III) porphyrin com-plex (B), followed by a one-electron reduction to give an iron(II)center (C). Then, the reaction of O2 with the iron(II) center affordsan iron(III)-superoxo complex (D), which becomes an iron(III)-peroxo complex (E) after the second one-electron reduction. Uponprotonation, the iron(III)-peroxo complex transforms into an iron(III)-hydroperoxo species (F), which is referred to as Compound0. The delivery of a second proton to the iron(III)-hydroperoxo spe-cies (F) results in the proton-assisted heterolytic OAO bond cleav-age of the hydroperoxide group, generating an iron(IV)-oxoporphyrin p-cation radical species (G) known as Compound I[36]. The oxygen atom is transferred from this high-valent iron-oxo species (G) to substrate through a two-step process knownas ‘‘oxygen rebound” [37]. This mechanism involves hydrogen-atom abstraction by the iron-oxo species (G) to form an iron(IV)-hydroxo species (H) known as Compound II and a short-lived alkylradical, followed by the ‘‘oxygen rebound” to give the alcohol pro-duct (I). Finally, dissociation of the oxidized product and the regen-eration of the resting state (A) complete the catalytic cycle [34].The formation of high-valent iron-oxo species (G) from the ferricstate (B) can also be achieved by using artificial oxidants such ashydrogen peroxide, alkyl hydroperoxides, peracids, iodosylarenesand sodium hypochlorite. Such a shortcut pathway is known asthe ‘‘peroxide shunt”, and this peroxide shunt pathway can be uti-lized in bioinspired oxidation catalysis by bypassing the intermedi-ates (C)–(F) in Scheme 1 [37].

The enzymatic oxidation reactions have inspired us for thedesign of efficient synthetic models, and much efforts have beendevoted to the development of synthetic catalysts that mimic thechemistry of monooxygenase enzymes [38–60]. In the particularcase of oxidation catalysis, bioinspiration from nature providesimportant insights into the design of metal-based catalysts, whichare composed of biologically relevant transition metals, such asiron, manganese and copper, bearing nitrogen, oxygen or sulfur

Table 1Oxidation reactions by O2 activation catalyzed by iron-containing enzymes.

Iron-containing enzymes Oxidation reactions

The heme paradigmCytochromes P450

Nonheme systemsMononuclear center

Iron(II) enzymes with the 2-His-1-Carboxylate facial triad motifExtradiol-cleaving catechol dioxygenases

Rieske dioxygenases

Pterin-dependent aromatic amino acid hydroxylases

a-Ketoglutarate dependent hydroxylases

Iron(III) dioxygenasesIntradiol-cleaving catechol dioxygenases

Lipoxygenases

Dinuclear centerMethane monooxygenase

Scheme 1. Proposed catalytic cycle of Cytochrome P450.

J. Chen et al. / Coordination Chemistry Reviews 421 (2020) 213443 3

donor ligands. These catalysts activate O2 or peroxides (e.g., hydro-gen peroxide or alkyl hydroperoxide) to generate high-valentmetal–oxygen intermediates in a controlled manner that performselective oxidation of various substrates, reproducing the catalyticfunction of monooxygenases [38–60]. Inspired by the active sitesof monooxygenase enzymes, bioinorganic chemists have designedand synthesized biomimetic catalysts mimicking the chemistry ofmonooxygenase enzymes for highly efficient and selectivecatalytic oxidation systems.

This review is focused on the biomimetic oxidation systemsinspired by monooxygenase enzymes. A large number of examplesfor the nonheme iron and manganese complexes, which can epox-idize olefins with high yields and enantioselectivities are discussed[40–52], together with a few examples of nonheme iron and man-ganese complexes that catalyze enantioselective C(sp3)–H oxida-tion [56–60]. These biomimetic oxidation systems are consideredto be environmentally benign because of the use of H2O2 as oxidantand earth-abundant metals (e.g., iron and manganese) as catalysts;in particular, these processes can be readily expanded to the large-scale production of oxygen-containing hydrocarbons. Besides itspotential usefulness in synthetic oxidation chemistry, mechanisticstudies in biomimetic catalytic oxidation systems will providevaluable insights into understanding biological oxidation reactions[60,61]. In this review, we will particularly focus on the discussionof bioinspired nonheme iron and manganese complexes as cata-lysts in enantioselective C@C epoxidation and aliphatic C(sp3)–Hoxidation (Fig. 1).

2. Enantioselective C¼C epoxidation with nonheme ironcomplexes

The peroxide shunt pathway shown in the catalytic cycle of CYP450 (Scheme 1) promoted the development of catalytic oxidationreactions by synthetic metalloporphyrins. One notable examplereported by Groves and co-workers was the catalytic oxidation ofalkanes and alkenes by Fe(TPP)Cl (TPP = 5,10,15,20-tetraphenylporphyrin) and iodosylbenzene (PhIO) [62]. The first catalytic enan-tioselective epoxidation by an iron porphyrin complex was alsoreported by Groves and co-workers in 1983 [63]. Employing theiron complexes of abab-tetrakis(o-(R)-hydratropamidophenyl)por

Fig. 1. Lessons from nature: Bioinspired enantioselective epoxidation and inert C(sp3)AH oxidation.

Scheme 2. Discovery of novel catalysts for alkene epoxidation from metal-bindingcombinatorial libraries.


phyrin and abab-tetrakis(o-[(S)-20-carboxymethyl-1,10-binaphthyl-2-carboxamido]phenyl)porphyrin as catalyst afforded theepoxidation of styrene derivatives and aliphatic alkenes with0–51% enantiomeric excess (ee) [63]. Although moderate enantios-electivities were achieved, the discovery by Groves and co-workersdisclosed a new approach and propelled active research in thisarea. Since then, numerous chiral iron porphyrins have been stud-ied in enantioselective epoxidation [64–67], but only a few of themafforded satisfactory enantioselectivities. The main drawback ofthe above catalytic systems is the laborious synthesis and modifi-cation of chiral porphyrins, which promoted the development ofnonheme iron catalysts not only for enantioselective epoxidationbut also for a variety of oxidation reactions [38–60].

2.1. H2O2 as the oxygen source

Date back to 1999, combinatorial chemistry was applied to dis-cover novel and efficient catalysts for enantioselective epoxidationwith H2O2 by Jacobsen and co-workers [68]. This was the first para-

Scheme 3. A synthetically useful nonheme iron catalyti

digm shift from the traditional approach through finely tuning thesteric and electronic effects of the metal catalysts. The ligands wereprepared from amino acids with a great diversity of donor sidechains, and these amino acids were connected to aminomethylpolystyrene by standard peptide coupling strategies (Scheme 2)[68]. The other end of the peptide chain was attached to a hetero-cycle containing end cap. As a result, a library of ligands were pre-pared and iron-based catalysts were obtained from metalation ofthese ligands with iron(II) or iron(III) ion, and a library of 5760metal–ligand complexes were investigated for epoxidation oftrans-b-methylstyrene with H2O2 as an oxidant. As a result, threemoderately enantioselective catalysts were discovered (Scheme 2)[68].

A synthetically useful catalytic system with the combination ofa nonheme iron catalyst and aqueous H2O2 for efficient alkeneepoxidation was reported by Jacobsen and co-workers in 2001[69]. Employing low loadings of a readily accessible nonheme ironcomplex, [Fe(mep)(CH3CN)2](SbF6)2 (mep = N,N0-bis(2-pyridylmethyl)-N,N0-dimethyl-1,2-ethylenediamine), aqueousH2O2 and acetic acid, aliphatic alkenes were found to be epoxidizedwithin 5 min, affording 60–90% isolated yields (Scheme 3) [69].

The first promising nonheme iron-catalyzed enantioselectiveepoxidation using H2O2 as an oxidant was reported by Beller andco-workers in 2007 [70]. The catalysts were generated in situ con-sisting of FeCl3�6H2O, pyridine-2.6-dicarboxylic acid as co-ligand,and chiral 1,2-diphenylethylenediamine derivatives as ligands(Scheme 4) [70]. para-Substituted trans-stilbenes were epoxidizedwith excellent enantioselectivities (up to 97% ee) [70]. It wasshown that the yields and enantioselectivities were dependenton the substrate symmetry and bulkiness and that trans-stilbeneswith substituents at the para position were more reactive andstereoselective than the meta- and ortho-substituted analogous,thus the best enantioselectivities were achieved with stericallymore demanding 4,40-dialkylsubstituted stilbenes (Scheme 4)[70]. Beller and co-workers also extended the catalytic oxidationsystem to the common alkenes [71]. However, the enantioselectiv-ities obtained for small alkenes, such as styrenes (8–26% ee), were

c system for olefin epoxidation with aqueous H2O2.

Scheme 4. Iron-catalyzed asymmetric epoxidation of aromatic alkenes usinghydrogen peroxide.

Scheme 5. Proposed mechanistic pathway to explain the enantioselectivity of iron-catalyzed epoxidation.


lower than those of larger ones. A mechanism for the olefin epox-idation was proposed as shown in Scheme 5, where the initiallygenerated [Fe(III)(L*)2(Pydic)] reacted with H2O2 to form an iron(III)-hydroperoxo species, [Fe(III)(L*)2(OOH)(Pydic)], which wasthen converted to a reactive iron(IV)- or iron(V)-oxo species viathe homolytic or heterolytic OAO bond cleavage of the hydroper-oxide ligand, respectively [71]. These high-valent iron-oxo speciesappeared to be a more plausible oxidant than the iron(III)-hydroperoxide and �OH radical. The epoxidation reaction was pro-posed to occur via the formation of radical intermediates, asdepicted in Scheme 5 [71]. It was further assumed that such an oxi-

Scheme 6. Asymmetric epoxidation with

dation proceeded with a preference for a top-on approach of thealkene over the side-on approach [71].

In 2008, Kwong and co-workers reported the epoxidation of ole-fins with an iron(III) complex bearing a chiral sexipyridine ligandin the presence of acetic acid [72]. Treatment of oligopyridineswith FeCl2 in a molar ratio of 1:2 afforded a chiral l-oxo diferriccomplex, [Fe2(l-O)(Cl)4(SPP)] (SPP = 6,6000-bis((5R,7R,8S)-6,6,8-trimethyl-5,6,7,8-tetrahydro-5,7-methanoquinolin-2-yl)-2,20:60,200:600,2000-quaterpyridine), which showed the reactivity towards olefinepoxidation [72]. Low enantioselectivities (31–43%) were obtainedin the epoxidation of terminal alkenes (Scheme 6) [72]. Intermolec-ular competitive reactions and Hammett analysis were employedto probe the nature of the responsible oxidant, which exhibitedthe electrophilic character of the active oxidant [72]. It is notewor-thy that no epoxide was yielded when peracetic acid wasemployed as an oxidant. This result rules out a possibility of theformation of peracetic acid from H2O2 and HOAc in the course ofolefin epoxidation [72], in contrast with the epoxidation mecha-nism via the in situ formation of peracetic acid in nonheme iron-catalyzed epoxidation by H2O2 in the presence of acetic acid, asproposed by Que and co-workers [73].

Initial use of [Fe(OTf)2(R,R-mcp)] (mcp = N,N0-bis-(2-pyridylmethyl)-N,N0-dimethyl-1,2-cyclohexanediamine) in asym-metric epoxidation with H2O2 met with little success; for example,a relatively low ee (~12%) was obtained in the epoxidation of trans-2-heptene [74]. Under such circumstances, Sun and co-workersdeveloped a nonheme iron(II) complex [Fe(OTf)2(R,R,R,R-BPMCP)](BPMCP = N,N0-dimethyl-N,N0-bis[4-tert-butylphenyl(2-pyridinylmethyl)]cyclohexanediamine), which is an analogue of [Fe(OTf)2(R,R-mcp)], to perform the asymmetric epoxidation of electron-deficient a,b-enones with H2O2 or peracetic acid as oxidant toobtain epoxy ketones in moderate to good yields and 50–87% ee(Scheme 7) [75]. They synthesized another catalyst [Fe(OTf)2(S-PEB)] (PEB = N-methyl-1-(1-ethyl-1H-benzo[d]imidazol-2-yl)-N-((1-((1-ethyl-1Hbenzo[d]imidazol-2-yl)methyl)pyrrolidin-2-yl)methyl)methanamine) bearing a rigid chiral tetradentate sp2-N/sp3-Nhybrid tetradentate nitrogen ligand derived from naturally occur-ring L-proline and benzimidazole [76]. With 2 mol% catalyst load-ing, the new catalytic system enabled the nonheme iron-catalyzedasymmetric epoxidation of electron-deficient multi-substitutedenones with H2O2 in the presence of 3 equiv. of acetic acid, yieldingenantiomerically pure epoxy ketones in good yields, along withhigh enantioselectivities (up to 98% ee) (Scheme 7) [76]. Moreover,an iron(II) complex bearing a C2-symmetric tetradentate N4 ligandderived from the readily available (R,R)-cyclohexane-1,2-diamineand 2-chloromethyl-1-methyl-benzimidazole was also shown tobe a highly efficient catalyst for enantioselective epoxidation[77]; the results were similar to those obtained with [Fe(OTf)2(S-PEB)] (Scheme 7).

In 2012, Talsi and coworkers employed [Fe(OTf)2(S,S-PDP)](PDP = N,N0-bis (2-pyridylmethyl)-2,20-bipyrrolidine) in asymmet-ric epoxidation of chalcone using H2O2 and a stoichiometric

a chiral iron-sexipyridine complex.

Scheme 7. Asymmetric epoxidation of enones with different nonheme iron complexes.

Fig. 2. Typical carboxylic acids used in bioinspired oxidation systems.


amount of carboxylic acid as additive [78]. It was shown that theenantioselectivities increased as the steric bulkiness of thecarboxylic acid increased (Fig. 2, Scheme 8), indicating that the car-

Scheme 8. Asymmetric epoxidation with [Fe(OTf)2(S,S-PDP)] and H

boxylic acid molecule was incorporated into the active oxidant asan auxiliary ligand at the enantioselectivity-determining step. Inaddition, based on the EPR data obtained in the reaction of the non-heme iron(II) complex and H2O2 in the presence of acetic acid atlow temperature, a low-spin (S = 1/2) oxoiron(V) species, such as[((S,S)-PDP)FeV=O(OC(O)CH3)]2+, was suggested as an active oxi-dant that is responsible for the oxygen atom transfer [78].

In 2013, a family of 2,20-bipyrrolidine-based complexes [Fe(OTf)2(XPDP)] (X = Me2N, dMM, MeO, Me, H, Cl and CO2Et) weredeveloped by Costas and co-workers [79]. By investigating theelectronic effect of the pyridine group on the ligand and the impactof the carboxylic acid (Scheme 9), [Fe(OTf)2(Me2NPDP)] (Me2N = dimethylamino) was identified as a highly efficient and enantiose-lective catalyst for olefin epoxidation with H2O2 in the presenceof a catalytic amount of steric bulky carboxylic acid (2-eha;

2O2 in the presence of HOAc or 2-ethylhexanoic acid (2-eha).

Scheme 9. Enantioselective epoxidation with H2O2 by modulating the electronic properties of nonheme iron catalysts.

Scheme 10. Asymmetric epoxidation of a-alkyl-substituted styrenes with a nonheme iron complex synergistically cooperated with N-protected amino acid.


2-ethylhexanoic acid or S-ibp; (S)-ibuprofen, Fig. 2) [79]. Goodyields and excellent enantioselectivities were achieved forelectron-poor substrates such as cis-cinnamic esters, cis-cinnamicamides, chromenes and substituted aromatic enones (up to 99%ee) [79]. However, modest yields and low ee’s were obtained withunfunctionalized alkenes, such as trans-b-methylstyrene and a-methyl styrene (7–45% ee) [79].

Mechanistic studies have shown four notable features regardingthe epoxidizing species as follows [79]. (1) When the cis-b-methylstyrene epoxidation was performed using the same catalystand acetic acid as an additive but different oxidants, such as H2O2,tBuOOH, and peracetic acid, the enantiomeric excess of the epoxi-dation product was virtually the same irrespective of the oxidantsemployed [79]. This observation suggests that a common interme-diate was responsible for the oxygen atom transfer reaction. (2)The presence of an electrophilic oxidant is evidenced by competi-tive epoxidation of cis-b-methylstyrene and cis-ethyl cinnamate,

Scheme 11. Enantioselective epoxidation of cyclic enon

in which the electron-rich cis-b-methylstyrene was more reactivethan the electron-poor cis-ethyl cinnamate [79]. (3) Isotopic label-ing experiments indicated that the source of oxygen atom incorpo-rated into the epoxide product was the oxidant and the oxygenatom from water was not incorporated [79]. (4) A plot of the log(ee) of asymmetric induction in epoxidation of trans-chalcone,cis-b-methylstyrene, 6-cyano-2,2-dimethylchromene and trans-methyl cinnamate vs. the Hammett constant of the X group in[Fe(OTf)2(XPDP)] (X = Me2N, MeO, Me, H, Cl, CO2Et) exhibited a lin-ear correlation, where the more electron rich was the ligand, theless was the electrophilicity of the metal-oxo species [79]. Basedon these observations, the electronic effect imposed by the ligandon the metal center was proposed to synergistically cooperate witha catalytic amount of carboxylic acids in promoting OAO bondcleavage in a controlled manner, which resulted in generation ofhighly enantioselective epoxidizing species, thus providing a widerange of epoxides in synthetically useful yields [79].

es with H2O2 catalyzed by nonheme iron catalysts.

N N

[Fe(OTf)2(S,S-PDBzL)]

N NFe

TfO OTf

O

[Fe(OTf)2(S,S-PDBzL)] (1.0-4.0 mol%)2-eha, H2O2

CH3CN, -30 oC, 30 min

up to 98% yield and 97% ee

N N

Ph

O

R

R1 R2

O O

Ph

O

R

R1 R2

O

O

O

O

O

Scheme 12. Enantioselective epoxidation with [Fe(OTf)2(S,S-PDBzL)].

Scheme 13. Asymmetric epoxidation with a nonheme iron complex and a peptide.


a-Alkyl-substituted styrenes are particularly challenging termi-nal olefins for enantioselective epoxidation due to the difficulty indifferentiating between the enantiotopic faces of these substrates[80–83]. In 2015, Costas and co-workers reported highly enantios-elective epoxidation of a-alkyl-substituted styrenes with H2O2 cat-alyzed by bioinspired iron catalysts in the presence of a catalyticamount of N-protected amino acids (Fig. 2) [84]. It was shown thatthe amino acids synergistically cooperated with the metal center infacilitating the activation of H2O2 efficiently in a controlled mannerto catalyze the epoxidation of the challenging substrates with goodyields and enantioselectivities (up to 97% ee) (Scheme 10) [84].

In 2016, a nonheme iron complex bearing a C1-symmetrictetradentate nitrogen-donor ligand that contains a bulky pyridineand a N-methylbenzimidazole was identified as a highly efficientand enantioselective catalyst for epoxidation of cyclic aliphaticenones with H2O2 (Scheme 11) [85]. Mechanistic studies have pro-vided three important features of the active oxidant for oxygenatom transfer [85]: (1) The implication of an electrophilic oxidantwas evidenced by carrying out competitive reaction of a substratemixture of 2-cyclohexenone and cyclohexene under oxidant-limiting conditions, in which electron-rich cyclohexene was pre-ferred over electron-deficient 2-cyclohexenone. (2) 18O-Labelingexperiments supported that the oxygen atom in the epoxide pro-duct derived from the terminal oxidant H2O2. (3) Virtually, thesame ee values were achieved when different terminal oxidantswere used in the catalytic oxidation of 2-cyclohexenone, suggest-ing that a common active oxidant was responsible for the epoxida-tion reactions.

The combination of two N-methylbenzimidazole and S,S-dipyrrolidine leads to a new chiral tetradentate nitrogen ligand(Scheme 12). Then, a nonheme iron complex bearing this S,S-PDBzL

Scheme 14. Asymmetric epoxidation with an iron

ligand was synthesized and investigated in enantioselective epox-idation using H2O2 as oxidant in the presence of carboxylic acid[86]. While moderate enantioselectivities for 2-cyclohexen-1-oneand cis-b-methylstyrene were obtained, high enantioselectivitieswere achieved for chalcones and tetralone derivatives [86].

In 2017, Costas described a conceptually different strategy forasymmetric epoxidation using a supramolecular system containinga nonheme iron complex [Fe(OTf)2(S,S-Me2NPDP)] and a peptidewith a b-turn design (Scheme 13) [87]. Epoxidation of a-alkyl-substituted and cis-substituted styrenes took place with good toexcellent yields and high enantioselectivities. The peptide wasshown to play a multifunctional role in this catalytic system, inwhich the terminal carboxylic acid promotes the iron center inthe activation of H2O2, while its b-turn structure is crucial for theasymmetric induction [87]. The authors claimed that this catalyticsystem reproduced the key structural properties of numerous non-heme iron oxygenases to provide a bottom up strategy towards thedevelopment of artificial oxygenases, since it contains the firstcoordination sphere including heterocyclic amines, carboxylateanions and labile sites, and the carboxylate group connects the ironcenter to an amino acid chain that contributes to shaping the sec-ond coordination sphere [87]. The synergistic cooperation of thesecomponents is indispensable to enable the efficient activation ofH2O2 and the highly enantioselective oxygen atom transferreaction.

2.2. PhIO as the oxygen source

In 2012, an iron(III) complex bearing a 1,8-(bisoxazolyl)-carbazole ligand, which exhibited porphyrin-like properties, wassynthesized by Niwa and Nakada [88]; this iron(III) complex was

(III) complex with porphyrin-like properties.

Scheme 15. Proposed mechanism of asymmetric epoxidation by Nakada and Niwa.

Scheme 16. A chiral dinuclear iron catalyst for enantioselective epoxidation.

Scheme 17. Asymmetric epoxidation with the combination of iron(II) triflate and a phenanthroline ligand.


a good catalyst for enantioselective epoxidation of (E)-alkenes byiodosylbenzene (PhIO) in the presence of NaBARF (sodiumtetrakis[3,5-bis(trifluoromethyl)phenyl] borate) and SIPrAgCl(SIPr = N,N0-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene) (Scheme 14). It was shown from the X-ray crystal structure

Scheme 18. Asymmetric epoxidation of tetralone der

that the tridentate carbazole ligand and two chloride groups coor-dinate to the iron(III) center in a five-coordinated trigonal–bipyra-midal topology [88]. The two chloride ligands could be removed byadding NaBARF and SIPrAgCl, thus generating an intermediate-spin(S = 3/2) iron(III) species that undergoes two-electron oxidation by

ivatives with a porphyrin-inspired iron catalyst.


PhIO to form an iron(IV)-oxo cation radical (S = 1/2) as an activeoxidant (Scheme 15) [88].

2.3. Peracid as the oxygen source

Ménage and co-workers synthesized a chiral l-oxo diferriccomplex, Fe2O(bisPB)4(X)2(ClO4)4 (PB = 4,5-pinene-2,20-bipyridine;X = H2O or CH3CN), with a chiral pinene appended ligand based on2,20-bipyridine [89]. This nonheme chiral diiron complex catalyzedepoxidation of alkenes with peracetic acid efficiently with up to850 TON, but the enantioselectivity was moderate and olefins thatcan be epoxidized were limited to electron-poor olefins, such astrans-chalcones and trans-cinnamates (Scheme 16) [89].

In 2011, Yamamoto and Nishikawa reported the first iron-catalyzed enantioselective epoxidation of acyclic b,b-disubstituted enones (Scheme 17) [90]. A pseudo C2-symmetriciron(II) catalyst, [Fe(L*)2(CH3CN)(OTf)](OTf), was synthesizedin situ by mixing iron(II) triflate with axial chiral phenanthrolineligand binding to binaphthyl moieties in a molar ratio of 1 to 2in acetonitrile. Under the optimal conditions, the iron(II) complexcatalyzed the epoxidation of b,b-disubstituted enones to afford a,b-epoxyketones with good yields and high enantioselectivities(up to 92% ee) [90]. Moreover, trisubstituted a,b-unsaturated esterswere transformed into a,b-epoxy esters in moderate yields, alongwith excellent enantioselectivities [91]. In addition, this catalyticsystem can also be suitable for unactivated alkene, such astrans-a-methylstilbene (Scheme 17), affording the correspondingepoxide with a good enantioselectivity (87% ee) [90]. Further, anelectrophilic oxidant was proposed based on the intermolecularcompetitive reaction between electron-rich and electron-pooralkenes [91].

In 2015, Gao and co-workers developed a porphyrin-like ironcatalyst for enantioselective epoxidation of electron-deficientenones [92]. The epoxidation reaction was performed with an ironcomplex synthesized in situ by mixing equal amounts of iron(II)triflate and chiral oxazoline ligand in acetonitrile and using per-acetic acid as oxidant (Scheme 18), affording epoxides in highyields with excellent enantioselectivities (up to 94% yield and99% ee) [92]. When peracetic acid was replaced by other oxidants,such as H2O2 and tBuOOH, however, no epoxidation products wereobtained [92]. Competitive epoxidations of para-substituted cyclicenones were also performed to investigate the nature of theresponsible oxidant, affording a negative slope (q+ = �0.52) from

Scheme 19. Proposed mechanism for nonheme Fe and Mn catalyzed asymmetric epoxidperoxide, R1 = H, for alkyl hydroperoxide, R1 = alkyl.

Hammett analysis. The latter result indicates electrophilic charac-ter of the active oxidant [92].

2.4. Mechanistic aspects

The role of carboxylic acids in the catalytic epoxidation reac-tions has attracted much attention and has been discussed exten-sively but still needs to be clarified. As it has been shown in manycatalytic oxidation reactions, carboxylic acids played a pivotal rolein olefin epoxidation reactions with H2O2 catalyzed by iron com-plexes. Obviously, acetic acid increased both the activity and enan-tioselectivity of nonheme iron catalysts in olefin epoxidationreactions [69,78]. In addition, acetic acid inhibited iron-catalyzedcis-dihydroxylation to increase the chemoselectivity towardsepoxidation [93]. Talsi, Bryliakov and co-workers reported thatacetic acid was replaced by bulkier carboxylic acids (Fig. 2) withimproved enantioselectivities as well as product yields [78].Indeed, the first example utilizing acetic acid as an additive wasdemonstrated by Jacobsen and co-workers in the epoxidation ofolefins by [Fe(mep)(CH3CN)2](SbF6)2 and H2O2, showing a positiveeffect on the efficiency of the catalytic system [69]. Que and co-workers investigated the reactivity of nonheme iron complexes,[Fe(OTf)2(mep)] and [Fe(OTf)2(TPA)] (TPA = tris(2-pydidylmethyl)amine), in the presence of carboxylic acid, proposing that aceticacid promotes the OAO bond cleavage of iron(III)-hydroperoxospecies for the generation of an iron(V)-oxo species, [(TPA)FeV(O)(OAc)]2+, which is responsible for the epoxidation of olefins(Scheme 19, carboxylic acid-assisted pathway) [94–96]. The for-mation of an iron(V)-oxo species, [(TPA)FeV(O)(OAc)]2+, was sup-ported by the detection of cis-hydroxyacetoxylated product in [Fe(OTf)2(TPA)]-catalyzed olefin oxidations by H2O2 in the presenceof acetic acid [97].

Although it is difficult to trap an active intermediate during cat-alytic reaction because of the high reactivity and instability, Talsiand co-workers suggested FeV(O)(OAc) as a reactive intermediateon the basis of EPR experiments for the reaction between H2O2and [Fe(OTf)2(S,S-PDP)] in the presence of acetic acid [98]. Specifi-cally, they detected an iron intermediate with rhombic S = 1/2 EPRsignals with g values of 2.66, 2.42, and 1.71 in a solvent mixture ofCH3CN and CH2Cl2 at –70 �C [95]. The decay of this intermediatewas accelerated by the presence of cyclohexene, yielding cyclohex-ene oxide as the major product [98]. Nevertheless, this species wasformed with extremely low yield (~1%) of the total iron content in

ation with hydrogen peroxide and alkyl hydroperoxide, M = Fe or Mn, for hydrogen

N

N

N

NFe

OTf

OTf

[Fe(OTf)2(dMMPDP)]OMe

OMe

N

N

N

NFe

OTf

OTf

[Fe(OTf)2(dMMmep)]OMe

OMe

N

N

N

N

MeO OMe

MeO

FeOTf

OTf

[Fe(OTf)2(dMMTPA)]

H2O2/HOAcor mCPBA Fe

III

OO

O R

FeVO

OR

O

Scheme 20. Generation of iron(III)-acylperoxo species from iron(II) complex and H2O2/HOAc or peracid.

[Fe(OTf)2(S,S-dMMPDP)]

N

N

N

NFe

NMe2

NMe2

OTf

OTf

N

N

N

NFe

OMe

OMe

OTf

OTf

H2O2 or tBuOOH

RCO2HFeV

O

OR

O

[Fe(OTf)2(S,S-Me2NPDP)]

RC(O)OOHFeIV

O

OR

O

or

Scheme 21. The common oxidant in enantioselective epoxidations with Fe-PDP catalysts.


the sample [98]. Thus, more mechanistic studies are needed toclarify the actual reactive intermediate. In parallel efforts by Queand co-workers, [Fe(OTf)2(dMMmep)], [Fe(OTf)2(dMMTPA)], and [Fe(OTf)2(dMMPDP)] complexes, which contain electron-donatinggroups on pyridine ring (dMM = dimethylmethoxy in Scheme 20),were used as catalysts [94,95], since electron-rich complexes wereenvisioned to stabilize high-valent iron-oxo species. EPR studies onthe reactions with mCPBA, AcOOH and H2O2/AcOH exhibited anS = 1/2 EPR signal, while the visible absorption bands at kmax =465 nm for [Fe(dMMPDP)(CH3CN)2](ClO4)2 and [Fe(dMMmep)(CH3-CN)2](ClO4)2 and kmax = 460 nm for [Fe(OTf)2(dMMTPA)] wereobserved and the latter complex has been studied in details[94,95]. The reaction of [Fe(OTf)2(dMMTPA)] with mCPBA generateda metastable species that was characterized with various spectro-scopic techniques, such as ESI-MS, UV–vis, resonance Raman andMössbauer [94]. On the basis of the spectroscopic characterization,the intermediate was assigned as a low-spin iron(III)-acylperoxospecies [94]. Interestingly, kinetic studies demonstrated that thisspecies was not responsible for the oxygen atom transfer to thealkenes [94]. However, DFT calculations suggested that this specieswas involved in the rate-determining OAO bond cleavage to forman iron(V)-oxo species as an active oxidant [94].

Iron complexes bearing tetradentate aminopyridine ligandsbased on the PDP scaffold are among the most efficient and selec-tive catalysts for the highly enantioselective epoxidation of olefinswith H2O2 [2,3]. Besides H2O2, other oxidants (alkyl hydroperox-ides and peroxycarboxylic acids) can also be effectively used[79,99]. The nature of the active species responsible for oxygenatom transfer in these catalytic systems remains elusive. To obtainmore insights into the active species, the enantioselectivity of theepoxidation product has been examined as a mechanistic probeby Costas [79,99], by comparing enantioselectivities obtainedunder different reaction conditions for two iron catalysts, (S,S)-[Fe(OTf)2(Me2NPDP)] and (S,S)-[Fe(OTf)2(dMMPDP)] [99]. Reactionswere carried out with a series of peracids (RC(O)O2H) to comparethe enantioselectivities with the counterparts obtained by combin-ing peroxides, such as H2O2 and tBuOOH, and the carboxylic acids(RC(O)OH) [99]. Based on the mechanistic study, they reached to aconclusion that the same oxidant (i.e., FeIV(O)(�OC(O)R)) or FeV(O)

(OC(O)R) was responsible for the enantioselective epoxidation inboth scenarios (Schemes 19 and 21).

More recently, Talsi, Bryliakov and co-workers reported EPRspectroscopic studies of mononuclear iron(II) and dinuclear iron(III) complexes, such as [Fe(OTf)2(TPA)], [Fe(OTf)2(dMMTPA)], [Fe(OTf)2(S,S-PDP)], [Fe(OTf)2(S,S-dMMPDP)], [FeIII2 (OH)2(dMMTPA)2](OTf)4, [FeIII2 (OH)2(S,S-dMMPDP)2](OTf)4, and [FeIII2 (OH)2(S,S-Me2N-PDP)2](OTf)4, for epoxidation with H2O2 in the presence of aceticacid (Fig. 2, aa) or 2-eha (Fig. 2) [98,100,101]. At low temperatures,�75 to �85 �C, the highly reactive and extremely unstable iron-oxygen intermediates could directly react with the electron-richalkenes, affording epoxides with an excellent selectivity even at�85 �C [98,100,101]. With regards to iron-oxygen intermediatesbearing electron-donating p-OCH3 and m-CH3 substitutes on thepyridine ring [98,100,101], their EPR signals (g1 = 2.070–2.071,g2 = 2.005–2.008, g3 = 1.956–1.960) were quite similar to thereported low-spin (S = 1/2) iron(V)-oxo species [102], [(TMC)FeV=O(NC(O)CH3)]+ (g1 = 2.053, g2 = 2.010, g3 = 1.971, TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), while larger anisotropicg values (g1 = 2.63, g2 = 2.41, g3 = 1.72) were observed for iron-oxygen intermediates lacking of electron density at the unsubsti-tuted pyridine rings [98,100,101]. The EPR spectroscopic trappingof the iron-oxygen intermediates bearing the strongly electron-donating p-NMe2 substituents on the pyridine ring was also carriedout by Bryliakov and Talsi, in which EPR signals from an S = 3/2 (g1,g2 = 3.69, g3 = 1.96) species were observed [101]. Moreover, theabove two catalytic systems exhibiting S = 1/2 and S = 3/2 active spe-cies were also compared in the enantioselective epoxidation withchalcone as a model substrate; it was shown that the catalyst witha low-spin (S = 1/2) state exhibits higher activity with lower enan-tioselectivity, whereas the catalyst possessing a high-spin (S = 3/2)state exhibits lower activity with higher enantioselectivity(Scheme 22) [101]. Based on the EPR, catalytic reactivity, and DFTstudies, the authors proposed the iron-oxygen intermediate derivedfrom Fe-PDP with strongly electron-donating p-NMe2 substituentsas an unprecedented high-spin (S = 3/2) iron(V)-oxo species [101].

Talsi and co-workers also studied the effect of carboxylic acidon the electronic structure of the active species formed in Fe(PDP)-catalyzed epoxidation by EPR spectroscopy [100]. The

Scheme 22. High-spin and low-spin iron(V)-oxo in enantioselective epoxidations with Fe-PDP catalysts.

Scheme 23. Effect of carboxylic acid on the electronic structure of the responsible oxidant in Fe(PDP)-catalyzed asymmetric epoxidation.

Scheme 24. Different active species in nonheme iron-catalyzed asymmetric epoxidation with various oxidants.


electronic structure of the active species is dependent on the nat-ure of acid used in the enantioselective epoxidation reaction byFe(PDP)/H2O2/RC(O)OH. That is, two different active species wereobserved (Scheme 23) [100]. The use of unbranched carboxylicacids (acetic acid, butyric acid, and hexanoic acid) led to the forma-

tion of intermediates with a large g-factor anisotropy(g1 � 2.7 g2 � 2.4, g3 � 1.7), whereas branched acids with tertiarya-carbon atoms (valproic acid, 2-ethylbutyric acid, and 2-ethylhexanoic acid) promoted the formation of the intermediateswith a small g-factor anisotropy (g1 = 2.07, g2 = 2.01, g3 = 1.96)


[100]. The latter species was more enantioselective, being assignedto iron(V)-oxo species with iron in the formal + 5 oxidation state,[((S,S)-PDP)FeIV=O(�OC(O)R)]2+ or [((S,S)-PDP)FeV=O(OC(O)R)]2+,and the higher enantioselectivity could be ascribed to the addi-tional stabilization via unpaired electron delocalization over thecarboxylic moiety (Scheme 23) [100].

Talsi and Bryliakov further investigated the nature of active spe-cies of a mononuclear iron complex, [Fe(OTf)2(S,S-PDP)], and a din-uclear ferric complex, [FeIII2 (OH)2(S,S-dMMPDP)2](OTf)4, with variousoxidants (H2O2, tBuOOH, CmOOH, CH3C(O)OOH and mCPBA) [103].Based on the EPR experiments, Hammett analysis, enantioselectivity,stereoselectivity of cis-stilbene epoxidation and 18O-labeling data,the authors proposed that the active species and epoxidation mech-anisms were different depending on the oxidants used (Scheme 24)[103], and the following three points were noted: (1) Oxygen atomtransfer from an iron(III)-alkylperoxo species [(L)FeIII(OOR)]2+ to ole-fins resulted in generation of acyclic, presumptively radical interme-diate when alkyl hydroperoxides were used as oxidant. (2) An iron(V)-oxo species, [(L)FeV=O(OC(O)R)]2+, was responsible for the olefinepoxidation in the system of H2O2/RC(O)OH and alkyl hydroperox-ide/RC(O)OH, accompanying with the formation of presumablycationic acyclic intermediate. (3) Concerted oxygen atom transferfrom iron(III)-acylperoxo [(L)FeIII(OOC(O)R)]2+ to olefins occurredin the system of RC(O)OOH/RC(O)OH.

3. Enantioselective C¼C epoxidation with nonheme manganesecomplexes

3.1. Peracid as the oxygen source

The efficient and selective epoxidation catalyzed by bioinspiredmanganese complexes was pioneered by Stack and co-workers[104]. In 2003, they reported a manganese complex bearing a lin-ear tetradentate nitrogen ligand, [Mn(OTf)2(R,R-mcp)], which hasthe topology of cis-a coordination containing two CF3SO3— labileanions (Scheme 25) [104]. The geometry is C2-symmetric, withtwo pyridine groups coordinate trans to each other and the two ali-phatic diamines are oriented anti to each other, leaving two labilecis sites at the manganese center, which are occupied by triflate(OTf) anions and can be replaced by exogenous ligands [104]. Thiscationic manganese complex can rapidly (

Scheme 26. Asymmetric epoxidation with [Mn(OTf)2(R,R,S,S)-mcpp]] and AcOOH.

Scheme 27. Asymmetric epoxidation of trans-b-methylstyrene with [Mn(CH3CN)2(S,R,R,S-bomcn)](SbF6)2 and AcOOH.

Scheme 28. Epoxidation of different olefins with [Mn(OTf)2(PyTACN)] and H2O2 in the presence of AcOH.

Scheme 29. Asymmetric epoxidation with [Mn(OTf)2(R,R,R,R-BPMCP)] and H2O2 in the presence of HOAc.


was involved in the oxygen delivering species at theenantioselectivity-determining step [78,109]. Based on the EPRand enantioselectivity data, these active species were proposedto be manganese(V)-oxo, such as [((S,S)-PDP)MnV=O(OC(O)R)]2+

(R = alkyl) [78,109].Costas and co-workers also developed manganese complexes

bearing tetradentate nitrogen-donor ligands composed by a 2,20-bipyrrolidine backbone and two 4,5-pinene-appended pyridinerings, in which pinene groups are connected to the 4 and 5 posi-tions of the pyridine rings of [Mn(OTf)2(R,R-PDP)] to obtain [Mn(OTf)2(R,R,R-BPBPP)]) (BPBPP = 1,10-bis((6,6-dimethyl-5,6,7,8-tetrahydro-5,7-methanoisoquinolin-3-yl)methyl)-2,20-bipyrrolidine)(Scheme 31) [110]. The combination of the chirality of the diaminebackbone together with that of a-pinene groups resulted in twodiastereoisomers of the chiral metal complexes (K and D) [110].

In the case of the K isomer, the CH3 groups of the pinene ringsare oriented towards the OTf groups, whereas the opposite orien-tation was observed in the case of D isomer [110]. Complex D-[Mn(OTf)2(R,R,R-BPBPP)] catalyzed the epoxidation of a series ofolefins with a low catalyst loading (0.1 mol%) and only slightexcess of H2O2 (1.2 equiv.) as oxidant, achieving good yields (60–100%) and moderate enantioselectivities (up to 73% ee) [110].The D-[Mn(OTf)2(R,R,R-BPBPP)] provided better enantioselectivi-ties than the K isomer, while reactivities of two diastereoisomersremained similar [110].

Sun and co-workers further reported a nonheme manganesecomplex, [Mn(OTf)2(S-PEP)] (PEP = N-methyl-1-(pyridin-2-yl)-N-((1-(pyridin-2-ylmethyl)pyrrolidin-2-yl)methyl)methanamine),based on a more rigid diamine from naturally occurring L-prolineand pyridine [111]. Modest enantioselectivities were obtained in

Scheme 30. Asymmetric epoxidation with [Mn(OTf)2(S,S-PDP)] and H2O2 in the presence of carboxylic acids.

Scheme 31. Asymmetric epoxidation with [Mn(OTf)2(R,R,R-BPBPP)] and H2O2 in the presence of AcOH.

Scheme 32. Asymmetric epoxidation with nonheme manganese complexes derived from L-proline.

Scheme 33. Enantioselective epoxidation with H2O2 catalyzed by [Mn(OTf)2(S,S-Me2NPDP)].



the epoxidation of a,b-enones [111]. A similar nonheme man-ganese complex, [Mn(OTf)2(S-PEB)], in which pyridine groups arereplaced by benzimidazole groups, has also been explored by thesame group [112]. Highly efficient asymmetric epoxidation wasperformed with 0.01–0.2 mol% catalyst loading, 2.0 equiv. ofH2O2 as oxidant and 5.0 equiv. of HOAc as additive to obtain upto 95% ee (Scheme 32), and TOFs and TONs reached to 59000 h�1

and 9600, respectively [112]. To the best of our knowledge, thiscatalyst is the most efficient catalyst for enantioselective epoxida-tion reported so far.

In 2013, Costas and co-workers systematically studied theelectronic effect of nonheme manganese complexes [Mn(OTf)2(S,S-xPDP)] (X = CO2Et, Cl, H, Me, MeO and Me2N) on asymmetricepoxidation reactions using H2O2 as oxidant [113]. For this pur-pose, a range of substituents with different electronic propertieswere introduced into the para-position of the pyridine group(Scheme 33) [113]. All the newly designed complexes were inves-tigated in asymmetric epoxidation with cis-b-methylstyrene as amodel substrate and H2O2 as oxidant in the presence of acetic acid[113]. As a result, the reactivity and enantioselectivity were foundto be sensitive to the electronic properties of the ligands, and theyield and enantioselectivity were improved substantially as theligand became electron-rich [113]. In addition, further studiesdirected at the selection of carboxylic acid additives revealed adirect dependence between the size of carboxylic acids and theenantioselectivity of the epoxidation products, such as 2-eha thatprovides the best result.

Recently, Gao and co-workers described a series of porphyrin-like tetradentate nitrogen donor ligands based ono-phenylenediamine and chiral oxazoline, possessing a long conju-gation and strong donor moieties (Scheme 34) [114]. The mainadvantages of these ligands are readily prepared, structurallydiverse, sterically tunable due to the abundant amino acid sourcesavailable to construct oxazolines. The corresponding manganesecomplexes were synthesized in situ by mixing manganese(II) tri-flate and the ligands just before initiating the epoxidation reactions[114]. After investigating a large number of ligands bearing differ-ent bulky groups, those containing i-Pr groups were found to givethe better results (Scheme 34) [114]. Under optimal conditions,with H2O2 as a terminal oxidant and acetic acid as an additive,excellent yields and enantioselectivities (up to 99% ee) wereachieved for electron-deficient olefins, such as chromenes, trans-stilbenes, indene and 1,2-dihydronaphthalene [111]. Moreover,intermolecular competitive reaction studies suggested that anelectrophilic oxidant was responsible for the epoxidation [114].Further, the authors studied the acid effect of carboxylic acids tooptimize the reaction conditions and found that adamantane-1-carboxylic acid (ACA) improved the enantioselectivity remarkably

Scheme 34. In situ generated manganese comp

[115]. It should be noted that this catalytic system was toleratedfrom the presence of water, when the reaction was performed with1% wt H2O2, the reactivity and stereoselectivity remained unmod-ified [115].

Abdi and co-workers developed a recyclable nonheme man-ganese complex structurally related to [Mn(OTf)2(mcp)], by intro-ducing methyl groups in pseudo-benzylic positions [116]. Whenthe epoxidation was carried out with H2O2 in the presence of aceticacid in acetonitrile at 0 �C, reactions with trans-chalcones, indeneand chromenes were completed within one hour and afforded withgood conversions and enantioselectivities (up to 88% ee)(Scheme 35) [116]. A preliminary kinetic study revealed that thereaction rate was the first order with respect to the concentrationsof the catalyst and oxidant but independent on the substrate con-centration [116]. Moreover, the catalyst was recyclable with 3cycles in the epoxidation of styrene [116].

Bryliakov and co-workers developed manganese catalysts usingthe [Mn(OTf)2(S,S-PDP)] catalyst, in which the electronic and stericproperties of aminopyridine ligands were systematically changed[117]. These catalysts were similar to those studied previously byCostas and co-workers [113]. The authors found that the use ofsterically hindered aromatic groups appended on the pyridinegroups of the ligand resulted in no improvement of the catalyticactivity as compared to the parent catalyst, [Mn(OTf)2(S,S-PDP)][117]. However, the manganese catalysts with electron-donatingligands exhibited better catalytic activities and enantioselectivitiesfor a broad substrate scope (Scheme 36) [117]. Additionally, iso-topically labeled water (H218O) experiments were performed forepoxidation of styrenes with H218O2 as oxidant in the absence ofcarboxylic acid, catalyzed by the manganese complexes withelectron-donating substituents to confirm the formation of 18O-labeled styrene epoxide and 1,2-diols, suggesting that the activeoxidant responsible for olefin epoxidation does exchange its oxy-gen atomwith H218O [117]. Hammett analysis from the competitiveoxidations of para-substituted trans-chalcones exhibited preferen-tial oxidation of the more electron-rich substrate, demonstratingthe electrophilic character of the active oxidant [117]. Moreover,the authors proposed that the transition state for the oxygen atomtransfer step became more product-like as the ligand became moreelectron-donating [117]. This translates into a closer substrate-catalyst interaction that justifies a more enantioselective oxygenatom transfer. Finally, the authors suggested that a carbocationicintermediate was generated, since the formation of trans-epoxides was observed with a partial erosion of stereochemistryduring the epoxidation of cis-stilbene [117].

Sun and co-workers reported a comprehensive comparison ofmanganese aminobenzimidazole complexes bearing three differ-ent chiral diamine backbones, (1R,2R)-1,2-diaminocyclohexane,

lex as catalyst for asymmetric epoxidation.

Scheme 35. Asymmetric epoxidation with Abdi’s catalyst.

Scheme 36. Asymmetric epoxidation with [Mn(OTf)2(S,S-dmpdpn)] and H2O2 in the presence of 2-eha.

R2

R1R3

[Mn(OTf)2(S,S-PDBzL)] (0.3 mol%)2-eha (2.0 equiv.)H2O2 (1.2 equiv.)

CH3CN, -30 oC, 0.5 h R2

R1R3

O

PhO

O

ONC

PhO

72% yield96% ee

90% yield93% ee

79% yield56% ee

92% yield81% ee

PhO

O

Ph

up to 96% eeN N

[Mn(OTf)2(S,S-PDBzL)]

N NMn

TfO OTfN N

Scheme 37. Asymmetric epoxidation with [Mn(OTf)2(S,S-PDBzL)] and H2O2 in the presence of 2-eha.

Scheme 38. Asymmetric epoxidation with [Mn(OTf)2(R,R,R,R-Me2NPMCP)] and H2O2 in the presence of DMBA.


(2S,20S)-2,20-bipyrrolidine and (R)-2-methylaminomethylpyrrolidine derived from proline, in asymmetric epoxidation [118]. Whencis-b-methylstyrene was employed as a model substrate, a man-

ganese catalyst, [Mn(OTf)2(S,S-PDBzL)], derived from (2S,20S)-2,20-bipyrrolidine gave better activities and enantioselectivities underthe optimal conditions (Scheme 37) [118]. However, the good

REWG

Mn cat. (0.05-0.3 mol%)HOAc (17 or 35 equiv.)H2O2 (1.2 equiv.)

CH3CN/CH2Cl2-40 oC, 35 min

REWG

O

PhO

NBn

Bn81% yield>99% ee

PhO

Ph

O

85% yield96% ee

PhO

NH2

O

80% yield>97% ee

PhO

NHMe

O

82% yield97% ee

up to 99.9% ee

PhO

OPh

O

77% yield62% ee

N N

N NMn

TfO OTfN N

O

Scheme 39. Enantioselective epoxidation of electron-deficient alkenes with a manganese complex.


selectivity was limited to electron-deficient chromenes and trans-chalcone derivatives, and a poor enantioselectivity was obtainedin the case of simple aliphatic alkenes although the conversionsand selectivities were excellent [118].

By introducing bulky aromatic groups in 2-pyridylmethyl posi-tions and electron-donating NMe2 groups on pyridine rings(Scheme 38), a series of manganese complexes structurally relatedto the parent [Mn(OTf)2(R,R-mcp)] were synthesized and charac-terized by Sun and co-workers [119]. These manganese complexesafforded better activities and the enantioselectivities in the epoxi-dation of styrene derivatives (up to 93% ee) with H2O2 as oxidant inthe presence of a catalytic amount of bulky carboxylic acid (25 mol% DMBA, DMBA = 2,2-dimethylbutyric acid, Fig. 2) [119].

A series of nonheme manganese complexes bearing tetraden-tate sp2N/sp3N hybrid chiral N4 ligands derived from rigid chiraldiamines were prepared and found to be efficient catalysts forthe enantioselective epoxidation of electron-deficient olefins withH2O2 [120]. With low catalyst loading (0.05–0.3 mol%) and nearlystoichiometric amount of H2O2 (1.2 equiv.), enantioenriched epoxyketones, epoxy amides and epoxy esters were obtained with excel-lent enantioselectivities (up to 99.9% ee) (Scheme 39) [120]. Pre-liminary investigation on the structure-activity relationship (SAR)revealed that higher electron-donating ability of sp2-N and lowerelectron-donating ability of sp3-N of the ligands were the key toobtain higher catalytic activity and enantioselectivity, thus leadingto a new understanding of biomimetic epoxidation with H2O2[120].

Sun and co-workers reported that addition of a catalyticamount of graphene oxide resulted in the improvement of boththe reactivity and the enantioselectivity compared with the tradi-tional stoichiometric carboxylic acid additive [121]. However, alarge amount of H2O2 (8.0 equiv.) was required to achieve highyields and high enantioselectivities, which reduced the merits of

Scheme 40. Asymmetric epoxidation with [Mn(OTf)2(R,R,R,R

this elegant catalytic epoxidation process significantly (Scheme 40)[121].

Interestingly, addition of a catalytic amount of H2SO4 (1.0 mol%) was found to improve the yields and enantioselectivitiesgreatly in the asymmetric epoxidation by H2O2 catalyzed by anonheme manganese complex (Scheme 41) [122]. When H2SO4was replaced by other Brønsted acids, such as HClO4, H3PO4 orCF3SO3H, the yields and enantioselectivities were much lowerthan the reaction with H2SO4, demonstrating that the existenceof SO42� anion was a crucial factor to enhance the catalytic activityand the enantioselectivity of the nonheme manganese catalyst[122]. The role(s) of H2SO4 was proposed to facilitate the genera-tion of a high-valent Mn-oxo species via OAO bond heterolysis ofa presumed Mn(III)-hydroperoxo precursor to enhance the oxidiz-ing ability and enantioselectivity of the Mn-oxo species in olefinsepoxidation [122]. The involvement of a high-valent Mn-oxo spe-cies as an active oxidant, which was formed via heterolytic cleav-age of the OAO bond in the presence of protons, was suggestedfrom isotopically labeled water experiments [122]. In addition,the proton effect on the reactivity of the Mn-oxo species in epox-idation reactions was proposed to be consistent with the previousstudies on the effect of Brønsted acids on the oxidation of organiccompounds by high-valent iron and manganese-oxo complexes[123–128].

b,b-Disubstituted enamides have been recognized as notori-ously difficult substrates for epoxidation [129]. In this context,Costas and co-workers described a new nonheme manganesecatalyst based on a chiral 1,10,2,20,3,30,4,40-octahydro-1,40-biisoquinoline backbone (Ohq) to achieve enantioselective epoxi-dation of b,b-disubstituted enamides using H2O2 as an oxidant(Scheme 42) [129]. It was shown that the carboxylic acid as anadditive and the amide moiety in the substrate were key in secur-ing the high enantioselectivity [129].

-DBPMCP)] and H2O2 in the presence of graphene oxide.

Scheme 41. Nonheme manganese-catalyzed asymmetric epoxidation with H2O2 in the presence of H2SO4.

Scheme 42. Enantioselective epoxidation of b,b-disubstituted enamides catalyzed by a nonheme manganese catalyst.

Scheme 43. Photocatalytic asymmetric epoxidation using H2O as an oxygen source.


3.3. H2O as the oxygen source

As described above, H2O2 has been used as oxidant for enantios-elective epoxidation, which is catalyzed by nonheme manganeseand iron complexes bearing chiral tetradentate nitrogen ligands.Recently, H2O, which is one of the most environmentally benignchemicals, was used as an oxygen source in photocatalytic enan-tioselective epoxidation of terminal olefins with a nonheme man-ganese complex, [Mn(OTf)2(R,R-BQCN)] (BQCN = N,N0-dimethyl-N,N0-bis(8-quinolyl)cyclohexanediamine), using [RuII(bpy)3]2+

(bpy = 2,20-bipyridine) as a photoredox catalyst and [CoIII(NH3)5-Cl]2+ as a weak one-electron oxidant [130]. Under the optimizedconditions, epoxides were obtained with 24–65% yields and 43–60% ee (Scheme 43) [130]. 18O-Enriched epoxide was obtainedwhen the photocatalytic epoxidation was carried out in thepresence of H218O, suggesting that the oxygen atom in the epox-ide product came from water [130]. The involvement of a Mn(IV)-oxo species as a reactive intermediate was proposed from

the comparable enantioselectivities achieved in photocatalyticepoxidation reactions and stoichiometric reactions betweenthe synthetic Mn(IV)-oxo and olefins [130]. In addition, the pho-tocatalytic mechanism was elucidated through a combination ofnanosecond laser flash photolysis and some other spectroscopicmeasurements [130]. It is desired that [CoIII(NH3)5Cl]2+ used asan oxidant can be replaced by O2 to achieve photocatalytic enan-tioselective epoxidation using O2 as an oxidant and H2O as anoxygen source, both of which are environmentally benign [131].

3.4. Mechanistic aspects

Two plausible mechanisms were proposed for the epoxidationreactions catalyzed by nonheme manganese complexes bearingtetradentate nitrogen-donor ligands: One involves Lewis acid acti-vation of the oxidant by a manganese complex, whereas the otherfavors high-valent Mn(IV)-oxo or Mn(V)-oxo species (vide infra).For the Lewis acid activation mechanism, Busch and co-workers

Scheme 44. Olefin epoxidation by the hydroperoxide adduct of a nonheme Mn(IV)-oxo complex.

Scheme 45. Proposed mechanism in the catalytic epoxidation of cis-stilbene by Mn(III)(Cz) and PhIO.


demonstrated that a nonheme Mn(IV)-oxo complex, [MnIV(Me2-EBC)(O)(OH)]+ (Me2EBC = 4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane), showed no capability to transfer its oxygenatom to olefins but that a hydrogen peroxide adduct of a nonhemeMn(IV)-oxo complex, [MnIV(Me2EBC)(O)(OOH)]+, which was gener-ated by ligand exchange between [MnIV(Me2EBC)(O)(OH)]+ andH2O2 (Scheme 44), promoted the electrophilic epoxidation ofthe olefins when the Mn(IV) ion acted as a Lewis acid to polarizeand activate the OAO bond of H2O2 synergistically [132]. Anotherexample is the binding of an oxidant by a high-valent Mn-oxospecies, which was reported by Goldberg and co-workers whoisolated a stable Mn(V)-oxo complex with a corrolazine (Cz)ligand [133]. The isolated Mn(V)-oxo complex exhibited no capa-bility of transferring its oxo ligand to cis-stilbene, ruling out Mn(V)-oxo as a plausible oxidant in the catalytic oxidation reactions(Scheme 45) [133]. In contrast, the catalytic epoxidation of cis-stilbene with Mn(III) triazacorrole complex and PhIO providedcis-epoxide preferentially over the trans isomer, and the totalyield of epoxidation product was 29% based on the oxidant used

Scheme 46. Proposed mechanisms for nonheme manganese-catalyzed asymmetric

[133]. Such observations implied that a ‘‘second oxidant”, ratherthan Mn(V)-oxo, was responsible for the oxygen atom transfer.A plausible mechanism is shown in Scheme 45, where the firststep involves rapid formation of a Mn(V)-oxo species, followedby coordination of PhIO to generate a PhIO adduct of Mn(V)-oxo. Finally, the coordinated PhIO transfers its oxygen atomdirectly to the olefin [133]. These results suggest that the high-valent manganese-oxo species serves as a Lewis acid that bindsand activates PhIO towards oxygen atom transfer to thesubstrate.

Along the same vein, a Mn(IV)-oxo complex were inactive inepoxidizing olefins but it formed adducts with acyl and alkylhydroperoxides or iodosylarenes, which were active for the enan-tioselective epoxidation [134]. For example, when peracids, alkylhydroperoxides and iodosylarenes were employed as terminal oxi-dants, [MnIV(O)OOAcyl]+, [MnIV(O)(OOAlkyl)]+ and [MnIV(O)(OIAr)]2+ were proposed to transfer oxygen atom from the coordi-nated oxidant, rather than the oxo group of Mn(IV)-oxo, to the sub-strate (Scheme 46) [134].

epoxidations with iodosylarenes (left) and alkyl or acyl hydroperoxides (right).

Scheme 47. Generation of Mn(V)-oxo species in the reactions of [MnII(OTf)2(LN4)] with H2O2, alkyl hydroperoxides or PhIO.


When hydrogen peroxide or alkyl hydroperoxides were used asoxidant in the presence of carboxylic acid [78,117,135], a car-boxylic acid-assisted OAO bond cleavage pathway was proposed[93,96,136,137], in which a highly reactive nonheme Mn(V)-oxospecies was generated via a heterolytic OAO bond cleavage of aputative Mn(III)-hydroperoxo precursor in the presence of car-boxylic acid (Scheme 19). Similarly, a water-assisted OAO bondcleavage pathway was proposed in the absence of carboxylic acid(Scheme 19), in which a five-membered ring species was generatedby pre-equilibrium with water that binds to the adjacent labile siteof the putative Mn(III)-hydroperoxo intermediate, thus promotingheterolytic OAO bond cleavage to generate cis-HO-MnV=O as theactive oxidant [78,117,135].

Recently, Sun, Nam and co-workers investigated themanganese-catalyzed enantioselective epoxidation with nonhememanganese complexes bearing tetradentate nitrogen (LN4) andpentadentate nitrogen (LN5) ligands and using various oxidants,such as H2O2, alkyl hydroperoxides, and PhIO [138]. It was shownthat [Mn(OTf)2(LN4)] was a good enantioselective epoxidation cat-alyst when H2O2, tert-butyl hydroperoxide (TBHP), cumenehydroperoxide (CHP) and PhIO were used as oxidant in the pres-ence of carboxylic acid (Scheme 47) [138]. High product yieldsand the virtually same enantioselectivities were obtained irrespec-tive of the oxidants used. In addition, the ratios of cis- to trans-stilbene oxides were the same in the competitive epoxidation ofcis- versus trans-stilbenes as well as in the cis-stilbene epoxidation

Scheme 48. Generation of Mn(V)-oxo species in the reactions of [MnII(OTf)(LN5)](OTf) anreactions of H2O2 and alkyl hydroperoxides.

[138]. These results demonstrated unambiguously that a commonintermediate (e.g., Mn-oxo) was generated as an active oxidant inthe catalytic reactions. In contrast, [Mn(OTf)(LN5)](OTf) was notan efficient catalyst when H2O2, TBHP and CHP were employedas terminal oxidants in the presence of carboxylic acid (Scheme 47)[138]. The latter result can be explained by the lack of one labilecis-binding site for carboxylic acid to promote the heterolyticOAO bond cleavage of the putative manganese(III)-hydro(alkyl)peroxo precursors, leading to the formation of a high-valentmanganese(V)-oxo species as an actual oxidant via the ‘‘carboxylicacid-assisted” pathway (Scheme 19) [138]. When PhIO wasemployed as oxidant, [Mn(OTf)(LN5)](OTf) was demonstrated tobe a good enantioselective epoxidation catalyst in the presenceof carboxylic acid [138]. These results indicate that the enantiose-lectivity is improved by the noncoordinated carboxylic acid mole-cule(s), probably via a second-sphere hydrogen-bondinginteraction of the carboxylic acid with the oxo group of themanganese(V)-oxo species (Scheme 48) [138]. Sun, Nam and co-workers demonstrated that the enantioselectivity of epoxidationwas modulated by the presence of noncoordinated carboxylicacid(s), whereas the reactivity of high-valent metal-oxo specieswas dramatically enhanced by the presence of protons that forma hydrogen bond, as shown in the stoichiometric reactions ofMn-oxo species in the presence of protons [123–128]. Moreover,a synthetic Mn(IV)-oxo complex, [MnIV(O)(LN4)]2+, showed no reac-tivity in olefin epoxidation, ruling out the possibility of the Mn(IV)-

d PhIO, and cis-binding site required for the formation of Mn(V)-oxo species in the

Scheme 49. A chiral l-oxo diferric complex in enantioselective C–H oxidation.


oxo species acting as an active oxidant. The latter result led themto propose the Mn(V)-oxo species as the most plausible oxidantin the catalytic epoxidation reactions of olefins [138].

4. Enantioselective C(sp3)�H oxidation with nonheme iron andmanganese complexes

4.1. Enantioselective C(sp3)AH oxidation with nonheme ironcomplexes

Biologically inspired nonheme iron complexes catalyze the oxi-dation of nonactivated aliphatic C(sp3)AH bonds [38–44,139–148].However, only a few examples of enantioselective oxidation of ali-phatic C(sp3)�H bonds by transition metal complexes have beenreported so far [149–159], but nonheme iron-catalyzed enantiose-lective oxidation of C(sp3)AH bonds by H2O2 has been rarelyreported. The enantioselective benzylic hydroxylation by H2O2 cat-alyzed by a chiral diferric l-oxo complex, [((PB)2(H2O)FeIII)2(l-O)](ClO4)4, with 4,5-(-)-pinene-2,20-bipyridine (PB) as the supportingligand has been developed by Ménage and co-workers [160]. Thisstructural feature is reminiscent of the active site of methanemonooxygenase (MMO) and the related dinuclear iron oxygenases(Scheme 49). Ethylbenzene and 1,1-dimethylindane were oxidizedto the corresponding alcohols in 7% and 15% ee, respectively [160].However, this catalytic system was neither selective nor efficient,and the alcohol/ketone ratio was nearly 1/1 when a large excessamount of alkanes was used [160].

Itoh and co-workers synthesized a dinuclear iron(III) complexbearing a BINOL-containing ligand, [FeIII2 (O)(L)(OBz)](ClO4), whichhas a l-oxo and a l-carboxylato doubly bridged dinuclear iron(III)core, and the structural feature resembles that of the active site ofMMO and related diiron enzymes (Scheme 50) [161]. Enantioselec-tive benzylic hydroxylation of tetralin by this iron catalyst with alimited amount of mCPBA was examined, affording only 9.9% eeand alcohol/ketone ratio of 8.8 [161].

4.2. Enantioselective C(sp3)AH oxidation with nonheme manganesecomplexes

Significant advance has been made in nonheme manganese-catalyzed C(sp3)AH oxidation in the past decades [162–165]; how-

Scheme 50. Enantioselective C–H oxidatio

ever, there were no reports of manganese-catalyzed enantioselec-tive hydroxylation with H2O2 in water until Simonneaux andco-workers reported a chiral water-soluble manganeseporphyrin-catalyzed enantioselective hydroxylation of arylalkaneswith H2O2 to produce optically active alcohols (up to 57% ee) [166].

A landmark achievement of using H2O2 as terminal oxidant innonheme manganese-catalyzed regio- and enantioselective C(sp3)–H oxidation was reported by Costas and co-workers(Scheme 51) [167], representing the first instance of enantioselec-tive oxidation of unactivated aliphatic C(sp3)AH via a desym-metrization strategy to afford chiral carbonyl compound asoveroxidation product (up to 96% ee), rather than chiral alcohol.When N-cyclohexylalkanamides were used as substrates, highregioselectivity toward C3 was achieved with up to 96% ee(Scheme 51) [167]. In general, high-valent metal-oxo speciesabstract a hydrogen atom from C(sp3)AH bond to generate a car-bon radical, followed by enantioselectivity-delivering oxygen atomrebound to the carbon radical through a-face (or b-face) to formenantioenriched alcohol (Scheme 52a) [167]. The current method-ology produced the optically active overoxidation products via adesymmetrization strategy, in which the chirality was inducedduring the hydrogen atom transfer (HAT) step (Scheme 52b) [167].

The bond strength and the effects of electron, steric, stereoelec-tronic and torsion are considered to be the determinants of CAHrelative reactivity [22,23]. Taking advantage of torsional effects,Costas and co-workers developed nonheme manganese-catalyzedsite selective and enantioselective oxidation of a series of N-cyclohexyl amides [168]. Kinetic resolution in C(sp3)AH bond oxi-dation of cyclohexane derivatives was demonstrated to be a newstrategy in synthetic chemistry, when trans-1,3-, cis-1,4-, and cis-1,2-cyclohexanediamides were selectively oxidized over the corre-sponding diastereoisomers to obtain the oxidation productsderived from the cis isomers, thus allowing the isolation of theunreacted trans ones in good to excellent yields (Scheme 53)[168]. Oxidation of the trans isomers can afford ketoamides inwhich a methylene group was oxidized with excellent site-selectivity and high enantioselectivities (up to 90% ee) (Scheme 54)[168]. As far as we know, this report represents the first example ofenantioselective oxidation of cyclohexane derivatives takingadvantage of torsional effects to isolate diastereoisomericmixtures.

n with a dinuclear iron(III) complex.

Scheme 51. Enantioselective C(sp3)-H oxidation of N-cyclohexyl amides with a nonheme manganese complex.

Scheme 52. Two distinct strategies for enantioselective oxidation of aliphatic C(sp3)AH bonds.

Scheme 53. Oxidation reactions of cis–trans mixtures of 4-X-substituted N-cyclohexyl amides.


The discovery of efficient and practical enantioselectiveC(sp3)–H oxidation methodologies utilizing aqueous H2O2 as ter-minal oxidant stands as a challenging task in synthetic chemistry[15,23]. Synthetically useful enantioselective oxidation of spiro-cyclic compounds with a nonheme manganese complex and aque-ous H2O2 was reported by Sun, Nam and co-workers [169]. Underthe optimized conditions, spirocyclic tetralones and indanoneswere transformed into their corresponding chiral spirocyclic b,b0-diketones with high regio- and enantioselectivities (Scheme 55)[169]. It is noteworthy that this catalytic system was shown to

be applicable to the gram-scale synthesis of chiral spirocyclic dike-tones, which were smoothly converted to diols further [169].Mechanistic studies with experimental and theoretical approachwere able to propose the reactive intermediate responsible forthe oxidation of spirocyclic hydrocarbons by nonheme manganesecatalyst and H2O2 as follows (Scheme 56) [169,170]. (1) Ketoneswere obtained as products via the initial generation of alcohols,which were followed by further oxidation to form spirocyclic dike-tones [169]. (2) Hydrogen atom transfer from the methylene CAHbonds of spirocyclic compounds to a presumed Mn(V)-oxo inter-

Scheme 54. Enantioselective oxidation of trans-4-X-substituted N-cyclohexyl amides.

Scheme 55. Highly enantioselective oxidation of spirocyclic hydrocarbons with a nonheme manganese complex.


mediate was proposed to be the rate-determining step [169]. (3) Ahigh-spin (S = 1) Mn(V)-oxo species is responsible for the enantios-elective C(sp3)AH bond hydroxylation of spirocyclic compoundsvia oxygen rebound mechanism [170]. According to the aboveobservations, a proposed mechanism for selective oxidation of C(sp3)AH bond by nonheme manganese complex and H2O2 in thepresence of carboxylic acid is depicted as shown in Scheme 56[169,170].

Sun and co-workers applied their nonhememanganese catalyticsystem to the enantioselective oxidation of methylene C(sp3)AHbonds in oxindoles or 2,3-dihydroquinolin-4-ones [171]. A varietyof spirocyclic oxindoles were oxidized into the correspondingketones in high product yields and enantioselectivities (up to 91%ee) (Scheme57) [171]. In comparison, the secondary alcohols,whichare the enantioselective hydroxylation products, were obtained asthe dominant product for the oxidation of prochiral spirocyclic2,3-dihydroquinolin-4-ones (up to 99% ee, Scheme 58) [171].

In 2017, Bryliakov and co-workers reported that the combina-tion of a nonheme Mn-aminopyridine complex [Mn(OTf)2(R,R-TFE-PDP)] (TFE = 2,2,2-trifluoroethoxy) and an enantioenrichedadditive N-Boc-(L)-proline was competent in catalyzing the enan-tioselective oxidation of arylalkanes with limited amount of H2O2as terminal oxidant, affording enantiomerically enriched 1-arylalkanols (up to 86% ee) and the corresponding ketones (A/K =0.5–3.4; Scheme 59) [172]. Oxidative kinetic resolution has been

found to have a minor contribution to the amplification of chiralityover the reaction course, whereas the major source of asymmetricinduction derives from enantioselective CAH oxidation itself [172].On the basis of the observed KIE values (3.5–3.6) and good linearBrown–Okamoto correlations (q+ = �1.4), either a hydrogen atomtransfer/oxygen rebound or hydride transfer/oxygen reboundmechanism was proposed for asymmetric hydroxylation of ary-lalkanes [172].

Fluorinated alcohols, such as 1,1,1,3,3,3-hexafluoro-2-propanol(HFIP) and 2,2,2-trifluoroethanol (TFE), are strong hydrogen bonddonor (HBD) solvents and exhibit a non-nucleophilic property toendow with the ability to stabilize charged intermediates [173–175]. It was demonstrated that these solvents exerted a polarityreversal on electron-donating functional groups, directing non-heme manganese-catalyzed oxidation toward an innate strongerand nonactivated CAH bonds [176]. Utilizing a polarity reversalstrategy, enantioselective hydroxylation of methylenic sites wasrealized employing aqueous H2O2 as oxidant in fluorinated alco-hols with a limited amount of oxidant [176]. For example, the oxi-dation of propylbenzene with 1.0 mol% Mn(dMMPDP) or Mn(Me2NPDP), 0.5 equiv. of H2O2, and 2 equiv. of 2-eha in TFE led tothe generation of 1-phenyl-1-propanol with excellent hydroxyla-tion selectivity (>90%) and moderate enantioselectivity of 66%and 60%, respectively (Table 2) [176]. In comparison, when ace-tonitrile was used as solvent, the hydroxylation selectivity and

Scheme 56. Proposed mechanism for C(sp3)-H oxidation by Mn/H2O2/RC(O)OH catalytic system.

Scheme 57. Enantioselective oxidation of spirocyclic oxindoles enabled by a biomimetic manganese complex.


enantioselectivity decreased significantly (7% yield and 39% ee; 7%yield and 10% ee), and the ketone was the dominant product(Table 2) [176]. Compared with previous reports of enantioselec-tive benzylic oxidation via hydrogen atom transfer, it is importantto note that the present results clearly demonstrate that the use offluorinated alcohols as solvent prevents the chiral alcohol gener-ated firstly from overoxidation, thus avoiding the use of largeexcess amount of substrates to obtain high TON [176].

5. Conclusion

In light of the increasing demand for sustainable chemistry andbetter understanding or replicating the catalytic function of natu-rally occurring metalloenzymes, substantial efforts have beenmade aiming at the development of novel catalytic systems forselective oxidation of hydrocarbons under mild conditions.Inspired by the oxidative transformations carried out by iron-

Scheme 58. Enantioselective oxidation of spirocyclic 2,3-dihydroquinolin-4(1H)-ones enabled by a biomimetic manganese complex.

Scheme 59. Asymmetric C–H oxidation of arylalkanes with a nonheme Mn-aminopyridine complex.


containing oxygenases, a plethora of iron and manganese com-plexes with non-porphyrinic ligands that can catalyze oxidationsof C@C and C(sp3)AH bonds using H2O2, PhIO or peracids as oxi-dants have been synthesized and investigated as catalysts in enan-tioselective oxidation reactions over the past two decades. For ironand manganese complex-catalyzed enantioselective epoxidationusing H2O2 as an environmentally friendly oxidant in the presenceof carboxylic acid or sulfuric acid as an additive, high to excellentenantioselectivities with excellent product yields were achievedfor electron-deficient alkenes, such as trans-chalcones, chromenes,a,b-unsaturated esters, a,b-unsaturated amides and para-substituted trans-stilbenes. However, the scope of ‘good’ substratesis rather narrow at present, and the liner and terminal aliphaticalkenes still remain as challenging substrates. Moreover, themajority of nonheme iron and manganese catalysts suffer fromlow catalytic efficiency and low turnover numbers (TON) (e.g.,850 and 9600 TON for nonheme iron and manganese catalytic sys-tems, respectively). Compared to the development of bioinspiredenantioselective epoxidation, enantioselective oxidation of unacti-

vated C(sp3)AH bonds is quite rare, and only a few examples havebeen reported in nonheme manganese catalytic systems, in whichketones rather than alcohols are the major product. Regarding thenonheme iron catalytic systems for selective C(sp3)–H oxidation,we look forward to witnessing future studies on the more appeal-ing and challenging nonheme iron-catalyzed enantioselective oxi-dation of aliphatic C(sp3)AH bonds to chiral alcohols, withpreventing the more facile overoxidation of secondary alcohols toketones. In terms of oxygen source used, a significant challengeis the use of abundant and more environmentally friendly O2 orH2O under mild conditions, such as the development of photocat-alytic oxidation reactions using O2.

Mechanistic studies have been performed to understand the nat-ure of the reactive intermediate(s) and the mechanism(s) of OAObond activation process based on spectroscopic characterization,kinetics study and enantioselectivity, revealing that carboxylic acidfacilitates the OAO bond cleavage of a putative iron(III)- ormanganese(III)-hydroperoxo species to generate an electrophiliciron(V)- ormanganese(V)-oxo species bearing a carboxylatemoiety

Table 2Oxidation of propylbenzene with Mn(dMMPDP) and Mn(Me2NPDP) in different solvent.

Catalyst Solvent Product yield (%) Hydroxylation selectivity (%) ee (%)

1-Phenyl-1-propanol Propiophenone

Mn(dMMPDP) CH3CN 7 26 37 39TFE 24 2 96 66HFIP 12 0.3 99 46

Mn(Me2NPDP) CH3CN 7 39 26 10TFE 44 7 93 60HFIP 12 1 96 40


that effect the enantioselective oxidation reactions. The carboxylicacidmolecule is proposed to be incorporated into the active oxidantfor the enantioselectivity-delivering step, presumably serving as anauxiliary ligand. To sum up, future efforts should be focused on elu-cidating the intriguing mechanism(s) using isolated synthetic non-heme iron(V)- or manganese(V)-oxo species.

Declaration of Competing Interest

The authors declare that they have no known competing finan-cial interests or personal relationships that could have appearedto influence the work reported in this paper.

Acknowledgements

We acknowledge financial support of this work from theNational Natural Science Foundation of China (21771087 to B.W.and 21703080 to J.C.), the NSF of Shandong Province(ZR2017MB007 to B.W. and ZR2017BB010 to J.C.), Taishan ScholarProgram of Shandong Province (tsqn201812078 to B.W.), the NRFof Korea through CRI(NRF-2012R1A3A2048842 to W.N.), the BasicScience Research Program (2017R1D1A1B03032615 to S.F.) and byMEXT (Grant-in-Aid16H02268 to S.F.).

References

[1] T. Katsuki, In Catalytic Asymmetric Synthesis; 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000, p 287.

[2] K. Muñiz, Catalytic Oxidation in Organic Synthesis, Thieme, 2018.[3] K.P. Bryliakov, Frontiers of Green Catalytic Selective Oxidations, Springer,

Singapore, 2019.[4] G. De Faveri, G. Ilyashenko, M. Watkinson, Chem.

Coordination Chemistry Reviewscbs.ewha.ac.kr/pub/data/2020_08_CCR_2020_421_213443.pdf · 2020. 11....

Documents

Transcript of Coordination Chemistry Reviewscbs.ewha.ac.kr/pub/data/2020_08_CCR_2020_421_213443.pdf · 2020. 11....