Recent Advances in Asymmetric Iron Catalysis

molecules

Review Recent Advances in Asymmetric Iron Catalysis

1, 2, 3, Alessandra Casnati † , Matteo Lanzi † and Gianpiero Cera * 1 Laboratoire des Systèmes Complexes en Synthèse et Catalyse, Institut de Science et d’Ingénierie Supramoléculaires, Université de Strasbourg &CNRS, 8 Allèe Gaspard Monge, BP 70028, F-67083 Strasbourg, France; [email protected] 2 Laboratoire de Chemie Moléculaire (UMR CNRS 7509), Université de Strasbourg, ECPM 25 Rue Becquerel, 67087 Strasbourg, France; [email protected] 3 Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale, Università di Parma, Parco Area delle Scienze 17/A, I-43124 Parma, Italy * Correspondence: [email protected]; Tel.: +39-0521-905-294 These authors contributed equally to this work. † Academic Editor: Fabio Marchetti Received: 28 July 2020; Accepted: 25 August 2020; Published: 26 August 2020 Abstract: Asymmetric transition-metal catalysis represents a fascinating challenge in the field of organic chemistry research. Since seminal advances in the late 60s, which were finally recognized by the Nobel Prize to Noyori, Sharpless and Knowles in 2001, the scientific community explored several approaches to emulate nature in producing chiral organic molecules. In a scenario that has been for a long time dominated by the use of late-transition metals (TM) catalysts, the use of 3d-TMs and particularly iron has found, recently, a widespread application. Indeed, the low toxicity and the earth-abundancy of iron, along with its chemical versatility, allowed for the development of unprecedented and more sustainable catalytic transformations. While several competent reviews tried to provide a complete picture of the astounding advances achieved in this area, within this review we aimed to survey the latest achievements and new concepts brought in the field of enantioselective iron-catalyzed transformations.

Keywords: iron; enantioselective; catalysis

1. Introduction Transition metal catalysis represents a powerful tool for the construction of highly functionalized molecules in organic synthesis. Among others, iron-catalyzed reactions [1–5] have recently become the most attractive alternative to the well-established palladium [6], rhodium [7], iridium [8] and ruthenium ones [9]. As a result of its low cost, compared to other d-metals, iron represents the most prominent metal for innovative and sustainable catalysis [10]. In addition, life evolution has integrated iron compounds in biological systems, thus resulting in low toxicity and therefore allowing high concentrations (>1300 ppm) of this metal in pharmaceuticals [11,12]. The chemistry of iron complexes is vast. Its position in the periodic table, just above ruthenium, justiﬁes its wide applicability, mostly due to the various accessible oxidation states (from II to +VI). Low-valent iron − complexes proved to be active for catalytic nucleophilic substitutions, hydrogenation/hydrosilylation and cycloisomerization reactions [13,14]. Parallelly, the more common +II and +III iron species exhibit Lewis acidity that has been exploited in the electrophilic aromatic substitutions, such as Friedel–Crafts reactions [15]. Radical reactions and two electron couplings are also feasible under iron catalysis. The latter, in particular, involves a Fe(I)/Fe(III) manifold that parallels [16], in terms of reactivity, those operating in palladium-catalyzed cross-couplings [17]. The stereochemical control of chiral centers during chemical reactions is fundamental to access enantiopure compounds and thus avoiding tedious puriﬁcations. As a matter of fact, asymmetric

Molecules 2020, 25, 3889; doi:10.3390/molecules25173889 www.mdpi.com/journal/molecules Molecules 2020, 25, 3889 2 of 29

Molecules 2020, 25, x FOR PEER REVIEW 2 of 30 catalysis withThe stereochemical transition metals control proved of chiral to be centers one of duri theng most chemical economical, reactions environmentally is fundamental to friendly access and efficientenantiopure approaches compounds for the synthesisand thus av ofoiding enantiomerically tedious purifications. pure molecules As a matter [18]. of fact, asymmetric Iron-catalyzedcatalysis with transition enantioselective metals proved reactions to be historically one of the most were economical, inspired by environmentally biological processes. friendlyIron is presentand in efficient several approaches enzymes, for such the as synthesis for instance, of enantiomerically the heme containing pure molecules cytochrome [18]. P450, known for its capabilityIron-catalyzed to promote C-H enantioselective oxygenations reactions [19] and historical carbenely were transfer inspired reactions by biological [20]. The processes. chemist’s Iron need to emulateis present nature in several led to enzymes, the development such as for ofinstance, a remarkable the heme number containing of iron-catalyzedcytochrome P450, enantioselective known for methodologies,its capability initiallyto promote using C‒H chiraloxygenations iron porphyrin [19] and carbene complexes transfer [21 reactions–23]. Major[20]. The advances chemist’s were need to emulate nature led to the development of a remarkable number of iron-catalyzed subsequently achieved with the introduction of chiral ligands such as oxazolines (i), NHCs (ii) or enantioselective methodologies, initially using chiral iron porphyrin complexes [21–23]. Major phosphine-basedadvances were ligands subsequently (iii) that achieved for a long with time the introd representeduction of the chiral most ligands commonly such as employed oxazolines approach (i), for highlyNHCs enantioselective (ii) or phosphine-based transformations. ligands (iii) More that recently,for a long new time strategies represented have the been most introduced commonly by the chemicalemployed community. approach For for example, highly enantioselective the use of achiral transformations. ligands, asymmetrically More recently, coordinatednew strategies around have the metalbeen center, introduced opened by access the chemical to catalytically community. active For exam chiral-at-metalple, the use of iron achiral complexes ligands, asymmetrically (iv). Additionally, asymmetriccoordinated induction around could the metal be also center, induced opened by a secondaccess to coordination catalytically sphereactive chiral-at-metal (v), usually constituted iron by biocomplexes macromolecules, (iv). Additionally, namely asymmetric enzymes or induction DNAs. could be also induced by a second coordination Thesphere aim (v), of usually this review constituted is to provide by bio an macromolecules, overview of the namely last advances enzymes in or enantioselective DNAs. iron-catalyzed reactions describingThe aim of theirthis review different is to working-modes provide an overview (i–v) toof inducethe last enantioselectivity.advances in enantioselective The last three iron- years catalyzed reactions describing their different working-modes (i–v) to induce enantioselectivity. The (2018, 2019 and 2020) will be covered with few references from the previous two years. last three years (2018, 2019 and 2020) will be covered with few references from the previous two years. 2. Chiral Oxazolines 2. Chiral Oxazolines ChiralChiral oxazolines oxazolines are a familyare a family of ligands of thatligands has beenthat extensivelyhas been extensively employed employed to develop to enantioselective develop transformations.enantioselective In transformations. the past three decades, In the past they thre receivede decades, remarkable they received attention remarkable due attention to their e duefficiency and versatilityto their efficiency [24–26 and]. Examples versatility including [24–26]. Examples early transition including metals, early transition such as metals, iron, are such however as iron,more recentare [27 however]. A chiral more spiro recent bisoxazoline [27]. A chiral ironspiro complex bisoxazoline was iron found complex catalytically was found active catalytically in promoting active the intramolecularin promoting enantioselective the intramolecular cyclopropanation enantioselective cy ofclopropanation indoles [28]. of This indole methodologys [28]. This methodology gives access to polycyclicgives compoundsaccess to polycyclic2 with two compounds contiguous 2 with all-carbon two contiguous quaternary all-ca stereogenicrbon quaternary centers. Chiralstereogenic ligand L1 was alsocenters. active Chiral in the ligand presence L1 was of also copper active precatalysts. in the presence Diff erentof copperα-aryl- precatalysts.α-diazoesters Different were α evaluated-aryl-α- in diazoesters were evaluated in the intramolecular cyclopropanation reaction providing high yields the intramolecular cyclopropanation reaction providing high yields and enantioselectivities (Scheme1). and enantioselectivities (Scheme 1).

Scheme 1. Enantioselective intramolecular cyclopropanation of indoles. NaBARF = sodium tetrakis [3,5-bis(triﬂuoromethyl)phenyl]borate. Molecules 2020, 25, x FOR PEER REVIEW 3 of 30

MoleculesScheme2020, 251. ,Enantioselective 3889 intramolecular cyclopropanation of indoles. NaBARF = sodium tetrakis3 of 29 [3,5-bis(trifluoromethyl)phenyl]borate.

TheThe cyclopropane-containing cyclopropane-containing final ﬁnal product 2, due due to to its its donor-acceptor donor-acceptor feature, feature, allowed allowed multiple multiple additionaladditional transformations transformations to to access access complex complex polycy polycyclicclic scaffolds. scaﬀolds. The The same same class class of of chiral ligands α was selected selected for for iron-catalyzed iron-catalyzed asymmetric asymmetric Si‒ Si-HH insertions insertions of α of-diazoesters-diazoesters [29]. [In29 particular,]. In particular, chiral hexamethyl-1,1chiral hexamethyl-1,1′-spirobiindane-based0-spirobiindane-based bisoxazoline bisoxazoline ligands ligands (L2, HMSI-BOX) (L2, HMSI-BOX) proved proved to be to superior be superior to otherto other bisoxazoline bisoxazoline ligands ligands in ensuring in ensuring high high levels levels of ofstereoinduction stereoinduction (Scheme (Scheme 2).2 ).

SchemeScheme 2. 2. EnantioselectiveEnantioselective Si Si-H‒H insertion of α-diazoesters-diazoesters..

Here,Here, the the product product selectivity selectivity is is determined determined by by a a concerted concerted Si Si-H‒H bond bond oxidative oxidative addition/hydride addition/hydride insertioninsertion sequence. sequence. The The relative relative Gibbs Gibbs free-energy free-energy ba barriersrriers associated associated to to the the two two transition transition states states at at alternativealternative spinspin states states were were measured measured via DFTvia DFT calculations. calculations. The quintet-state The quintet-state spin configuration spin configuration resulted resultedas the lowest as the in lowest terms in of terms energy of barrier, energy and barrier, the stereocontrol and the stereocontrol is induced is by induced steric repulsions by steric repulsions present in presentone of the in one two of transition the two statestransition between states the between phenyl the group phenyl on thegroup ligand on the and ligand ester moieties and ester of moieties starting ofmaterials starting 3materials. The substrate 3. The substrate scope was scope investigated was invest andigated a variety and a variety of alkyl ofα alkyl-diazoarylacetates α-diazoarylacetates3 was 3successfully was successfully silylated silylated with Et with3SiH Et or3SiH Me2 PhSiHor Me2 withPhSiH high with enantioselectivities high enantioselectivities (up to 90% (upee to). 90% Another ee). Anotherstrategy tostrategy obtain chiralto obtain organosilanes, chiral organosilanes, involved alkene involved hydrosilylation. alkene hydrosilylation. In 2018 Lu’sresearch In 2018 group Lu’s researchreported group a Markovnikov-selective reported a Markovnikov-selective and enantioselective and enantioselective hydrosilylation hydrosilylation of challenging of unactivatedchallenging unactivatedterminal alkenes terminal6 [30 alkenes]. Chiral 6 [30]. oxazolineiminopyridine Chiral oxazolineiminopyridine iron complexes iron complexes (L3 FeCl2 )(L3 were.FeCl selected2) were · selectedas promising as promising catalysts catalysts to promote to promote the desired the desired reactivity. reactivity. The presence The presence of ortho ofsubstituents ortho substituents on the onimine the fragmentimine fragment of the ligand of the was ligand crucial was to obtaincrucial highto obtain branched high vs. branched linear selectivity. vs. linear Particularly,selectivity. Particularly,the presence ofthe large presence CHPh of2 groups large CHPh at both2 groups the ortho atpositions both theof ortho the arylpositions ring was of the essential aryl ring to obtain was essentialthe transformation to obtain withthe transformation excellent enantioselectivities. with excellent Subsequently,enantioselectivities. the authors Subsequently, explored thethe substrate authors exploredscope; remarkably the substrate in all scope; the examples remarkably they in obtained all the examples high regioselectivities they obtained (> high96/4 branchedregioselectivities vs. linear) (> 96/4and enantiocontrolbranched vs. linear) (>97% andee). Dienantiocontrolfferent functional (>97% groups ee). Different were well functional tolerated, groups and the were late stagewell tolerated,functionalization and the late of bioactive stage functionalization molecules, such of bioactive as naproxen molecules, and ibuprofen, such as naproxen was accomplished and ibuprofen, (8f,g; wasScheme accomplished3). (8f,g; Scheme 3). The proposed mechanism goes through the formation of an iron silyl intermediate (A) rather than an iron-hydride species due to the easy β-hydride elimination that eventually occurs with in-situ formed secondary alkyl-iron compounds. The alkene inserts into the iron-silyl bond (C) and then reacts with PhSiH3 to regenerate the Fe-Si active species A, affording the final product 8 (Scheme4).

Molecules 2020, 25, x FOR PEER REVIEW 4 of 30

Molecules 2020, 25, 3889 4 of 29 Molecules 2020, 25, x FOR PEER REVIEW 4 of 30

Scheme 3. Markovnikov-selective and enantioselective hydrosilylation of unactivated terminal alkenes.

The proposed mechanism goes through the formation of an iron silyl intermediate (A) rather than an iron-hydride species due to the easy β-hydride elimination that eventually occurs with in- situ formed secondary alkyl-iron compounds. The alkene inserts into the iron-silyl bond (C) and then reacts with PhSiH3 to regenerate the Fe‒Si active species A, affording the final product 8 (Scheme 4). SchemeScheme 3.3. Markovnikov-selectiveMarkovnikov-selective and and enantioselective enantioselective hydrosilylation hydrosilylation of unactivated of unactivated terminal terminal alkenes. alkenes.

Scheme 4. ProposedProposed mechanism mechanism for for the hydrosilylation of alkenes.

3. N-Heterocyclic Carbenes (NHCs) N-Heterocyclic carbenes (NHCs) are currently in use as both nucleophilic organocatalysts [31] and as electron-rich neutral ligands in combination with several transition metals [32]. The large

Scheme 4. Proposed mechanism for the hydrosilylation of alkenes.

Molecules 2020, 25, x FOR PEER REVIEW 5 of 30

3. N-Heterocyclic Carbenes (NHCs) Molecules 2020, 25, 3889 5 of 29 N-Heterocyclic carbenes (NHCs) are currently in use as both nucleophilic organocatalysts [31] and as electron-rich neutral ligands in combination with several transition metals [32]. The large success ofof achiralachiral NHCs NHCs ligands ligands led led to theto developmentthe development of chiral of chiral equivalents equivalents as stereodirecting as stereodirecting ligands ligandsfor enantioselective for enantioselective transformations transformations [33]. The [33]. construction The construction of their of sca theirﬀold scaffold is easily is easily achieved achieved from fromimidazolium imidazolium salt precursors, salt precursors, thus favoring thus favoring the access the to access a vast libraryto a vast of tailor-madelibrary of tailor-made chiral compounds. chiral compounds.In 2017 Ackermann’s In 2017 groupAckermann’s reported angroup iron-NHC reported catalyzed an iron-NHC enantioselective catalyzed C-H enantioselective alkylation of indoles C‒H alkylation9 [34]. Among of indoles all the 9 NHCs [34]. Among ligands all tested, the NHCs the meta ligands-substituted tested,N the,N0 -diarylatedmeta-substituted NHC N proved,N’-diarylated to be the NHCmost active,proved providing to be the most high levelsactive, ofprovidin enantioselectivities.g high levels of A enantioselectivities.meta-1-adamantyl derivative A meta-1-adamantylL4 ensured derivativean er of 96:4 L4 for ensured the C-H an alkylation er of 96:4 of indolefor the9 Cwith‒H alkenylalkylation ferrocenes, of indole signiﬁcant 9 with alkenyl building ferrocenes, blocks in significantmaterial sciences building and blocks bioinorganic in material chemistry sciences [35 ].and The bioinorganic optimized reaction chemistry conditions [35]. The allowed optimized us to reactionfunctionalize conditions diversely allowed substituted us to indolesfunctionalize with a diversely variety of styrenessubstituted10 includingindoles with styryl a ferrocenesvariety of styrenesand ruthenocenes, 10 including among styryl others ferrocenes (Scheme and5). ruthenocenes, among others (Scheme 5).

Scheme 5. EnantioselectiveEnantioselective C C-H‒H alkylation of indolesindoles withwith styrenestyrene derivatives.derivatives. Fc = ferrocenyl.ferrocenyl. TMEDA = N,N,NN,N,N′0,N,N′0-Tetramethylethylenediamine.-Tetramethylethylenediamine.

To elucidate the mechanism of this highly positional selective C C-H‒H alkylation, ﬁrstfirst isotopically labeled substrates were investigated.investigated. Deuterium Deuterium wa wass transferred transferred to to the the terminal terminal position of the alkene supporting supporting an an inner inner sphere sphere C C-H‒H activation. activation. This This mode mode of ofaction action can can be rationalized be rationalized with with the Cthe‒H C-H cleavage cleavage occurring occurring by lig byand-to-ligand ligand-to-ligand H-transfer H-transfer (G, LLHT) (G, LLHT) or by or C by‒H C-Hoxidative oxidative addition. addition. The Theproposed proposed catalytic catalytic cycle cycle starts starts with with the the reduction reduction ofof the the iron(III) iron(III) precatalyst precatalyst via ββ-hydrogen elimination, triggered by the action of CyMgCl. Th Thee so-formed iron-NHC coordinates in a reversible th manner the alkene (D, zero th-order-order dependence). dependence). The The substrate substrate undergoes undergoes C C-H‒H metalation via LLHT (G)[) [36].36]. Then Then the the stereo-determining stereo-determining migratory migratory insert insertionion takes takes place place and and it itis isinduced induced by by ligation ligation of theof the substrate substrate 9. Here,9. Here, the thestereoinduction stereoinduction is controlled is controlled by dispersive by dispersive secondary secondary interactions interactions [37]; [one37]; sideone sideof the of double the double bond bond suffers su ﬀfromers from steric steric clashes clashes with withthe meta the-bulkymeta-bulky group group of the of NHC the NHC ligand, ligand, thus favoringthus favoring a unilateral a unilateral coordination coordination to the to metal the metal center center (Scheme (Scheme 6). 6).

Molecules 2020, 25, 3889 6 of 29 Molecules 2020, 25, x FOR PEER REVIEW 6 of 30

SchemeScheme 6.6. ProposedProposed mechanismmechanism forfor thethe alkylationalkylation ofof indolesindoles featuring a ligand-to-ligand H-transfer (LLHT) type C-H activation. (LLHT) type C‒H activation.

4.4. P-Based-Ligands PhosphinePhosphine chiralchiral ligands ligands covered covered an importantan important role inrole enantioselective in enantioselective transition transition metal-catalyzed metal- reactions.catalyzed Despitereactions. a widespread Despite a widespread application of application iron catalysis of iniron cross-couplings catalysis in cross-couplings [38], an enantioselective [38], an protocolenantioselective remained, protocol for a long remained, time, elusive for a long [39 ].time, In this elusive context, [39]. recently In this context, Nakamura recently and co-workers Nakamura pioneeredand co-workers this field pioneered reporting this the firstfield example reporting of enantioselectivethe first example iron-catalyzed of enantioselective Kumada iron-catalyzed coupling [40]. BasedKumada on thesecoupling studies, [40]. last Based year theon samethese group studies, described last year anenantioconvergent the same groupconstruction described an of 3 3 C(spenantioconvergent)-C(sp ) bonds construction through an of iron-catalyzed C(sp3)‒C(sp3 Suzuki-Miyaura) bonds through reactionan iron-catalyzed [41]. Chiral Suzuki-Miyaura diphosphines α werereaction found [41]. as Chiral suitable diphosphines ligands for the were conversion found as of suitabletert-butyl ligands-bromo for propionate the conversion12 in theof tert presence-butyl ofα- lithiumbromo propionate aryl boronates 12 in13 .the Bidentate presence aliphatic of lithium and aryl benzene boronates bridged 13 chiral. Bidentate ligands aliphatic did not and provide benzene any stereocontrol,bridged chiral albeit ligands ensuring did highnot provide reaction yields.any stereoco Contrary,ntrol, excellent albeit yieldensuring and highhigh enantioselectivity reaction yields. wereContrary, achieved excellent with yieldC1-symmetric and high enantioselectivity quinoxaline L5. Thewere addition achieved of with TFA C at1-symmetric the end of thequinoxaline reaction α enabledL5. The addition the isolation of TFA of at the the optical end of active the reacti-arylatedon enabled carboxylic the isolation acid of through the optical a one-pot active procedureα-arylated (Schemecarboxylic7). acid through a one-pot procedure (Scheme 7). Mechanistic investigations were performed to elucidate the enantioselective induction showed by (R,R)-quinoxP* L5. Complex FeCl2/(R,R)-quinoxP* I, synthetized separately, was reacted with phenyl boronate 13a (5 equiv) and MgBr2 (1 equiv) to form complex J, within 2 h. This manifold was compared to the one constituted by the FeCl2/(R,R)-BenzP* complex, previously employed for the enantioselective Kumada reaction. Indeed, after 62 hrs, only 60% of the starting iron complex was consumed. This finding highlighted how the electron withdrawing nature of the ligand renders the iron center more electrophilic, hence accelerating the transmetalation step. On the basis of several

Molecules 2020, 25, x FOR PEER REVIEW 7 of 30

Molecules 2020, 25, 3889 7 of 29 experimental evidences, a plausible catalytic cycle was proposed. The in-situ formed iron(I) complex H can reduce the alkyl bromide to form an alkyl radical and the iron(II) species I. The subsequent transmetalation provides intermediate J, which through radical recombination forms an iron(III) intermediate K. DFT calculations proved this step as enantio-determining in the catalytic cycle. Finally, the desired product 14a is formed after reductive elimination from complex K and eventual acidic

Moleculeshydrolysis 2020 (Scheme, 25, x FOR8 PEER). REVIEW 7 of 30

Scheme 7. Selected examples of enatioconvergent iron-catalyzed Suzuki–Miyaura reaction.

Mechanistic investigations were performed to elucidate the enantioselective induction showed by (R,R)-quinoxP* L5. Complex FeCl2/(R,R)-quinoxP* I, synthetized separately, was reacted with phenyl boronate 13a (5 equiv) and MgBr2 (1 equiv) to form complex J, within 2 h. This manifold was compared to the one constituted by the FeCl2/(R,R)-BenzP* complex, previously employed for the enantioselective Kumada reaction. Indeed, after 62 hrs, only 60% of the starting iron complex was consumed. This finding highlighted how the electron withdrawing nature of the ligand renders the iron center more electrophilic, hence accelerating the transmetalation step. On the basis of several experimental evidences, a plausible catalytic cycle was proposed. The in-situ formed iron(I) complex H can reduce the alkyl bromide to form an alkyl radical and the iron(II) species I. The subsequent transmetalation provides intermediate J, which through radical recombination forms an iron(III) intermediate K. DFT calculations proved this step as enantio-determining in the catalytic cycle. Finally, the desired product 14a is formed after reductive elimination from complex K and eventual acidic hydrolysisScheme 7. (Scheme SelectedSelected 8).examples examples of of enatioconvergent enatioconvergent iron-catalyzed iron-catalyzed Suzuki Suzuki–Miyaura–Miyaura reaction.

SchemeScheme 8. 8. ProposedProposed mechanism mechanism for for enantioconvergent enantioconvergent iron-catalyzed iron-catalyzed Suzuki–Miyaura reaction.

Directing group (DG)-assisted C-H activation methodologies represent an important synthetic tool with the aim to functionalize organic molecules in a site-selective manner [41]. In this context, triazole TAM DGs introduced by the group of Ackermann are gaining increasing attention in promoting iron-catalyzed C-H functionalizations [4]. Inspired by earlier contributions [42,43], Schmiel and Buthenshön disclosed an enantioselective iron-catalyzed C-H arylation [44], setting the stage for the synthesis of planar chiral ferrocenamides 17, 18 (Scheme9).

Scheme 8. Proposed mechanism for enantioconvergent iron-catalyzed Suzuki–Miyaura reaction.

Molecules 2020, 25, x FOR PEER REVIEW 8 of 30

Directing group (DG)-assisted C‒H activation methodologies represent an important synthetic tool with the aim to functionalize organic molecules in a site-selective manner [41]. In this context, triazole TAM DGs introduced by the group of Ackermann are gaining increasing attention in promoting iron-catalyzed C‒H functionalizations [4]. Inspired by earlier contributions [42,43], MoleculesSchmiel2020, 25and, 3889 Buthenshön disclosed an enantioselective iron-catalyzed C‒H arylation [44], setting the8 of 29 stage for the synthesis of planar chiral ferrocenamides 17, 18 (Scheme 9).

Molecules 2020, 25, x FOR PEER REVIEW 9 of 30

that subsequently undergoes ligand exchange with 19 and peroxide-mediated bond cleavage to provide intermediate M. Transfer of the electron density from the naphtholate ligand (N) enabled a radical-anion coupling with a second naphthol unit 19, leading to O. Finally, radical abstraction

operated by the peroxide (P), followed by transmetallation,2 releases product 20 restoring the iron SchemeScheme 9. Enantioselective 9. Enantioselective iron-catalyzed iron-catalyzed C(sp C(sp2)–H arylation arylation of of ferrocenes ferrocenes aromatic aromatic rings rings with withTAM TAM catalystand (Scheme Q DGs. 2,3-DCB 11). = 2,3-Dichlorobutane. and QMore DGs. recently, 2,3-DCB also= 2,3-Dichlorobutane. chiral diphosphine oxide ligands were found as suitable ligands for the enantioselectiveThe use of commercially synthesis of BINOLs. available Hence, P,P-chiral Ishiha ligandra and L6 co-workers allowed for reported the synthesis a stable of 17diphosphino, 18 in high The use of commercially available P,P-chiral ligand L6 allowed for the synthesis of 17, 18 in high oxideyields. iron(II) Although complex, the enantioselection which acts as is a just better modera oxidantte, this for represents the radical-anion the first examplecoupling of [51]. asymmetric Various yields. Although the enantioselection is just moderate, this represents the ﬁrst example of asymmetric chiraliron-catalyzed diphosphines C‒H functionalizationligands were tested using in the bidentate presence DGs. of Fe(OTf) 2 and tert-butyl peroxide. BINOLs- iron-catalyzedbasedChiral backbone C-Hphosphoric functionalizationligands failedacids to areinduce usinglargely any bidentate stereocoused inntrol, DGs. enantioselective while high yields transformations and enantioselectivities either in Chiralwerecombination observed phosphoric with with a acidsligandsmetal areor L8 under largely and L9 metal-free used. The in-situ in enantioselectivecondit formedions L8[45]..Fe(OTf) Their transformations2 synthesicomplexs, was which either found suffers in active combination from for withthetedious a metaloxidative multistep or coupling under syntheticmetal-free of a largesequences, family conditions principall of 3,7- and [45y requires ].6-substituted Their the synthesis,use 2-naphthols of enantiomerically which 19 (Scheme suffers pure 12). fromC 1-chiral tedious multistepBINOLTosynthetic structures.shed light sequences, A on step-economica the mode principally ofl approachaction requires of forthethe BINOLs, iron use catalysis, of starting enantiomerically mechanistic from commercially pureexperimentsC available1-chiral were BINOL2- structures.conducted.naphthols A step-economical 19 Interestingly,, was achieved anapproach byenantioselective Katsuki, for Pappo BINOLs, non-liner and Bryliakov starting positive from under effect commercially iron was catalysis observed available[46–48]. for the Recently, reaction 2-naphthols . 19, waswithPappo achieved ligand and co-workers L8. byIn addition,Katsuki, developed a Pappostoichiometric an iron-catalyzed and Bryliakov reaction chiral-anion conducted under iron instrategy the catalysis presence for the [46 ofenantio-construction– 48L8].Fe(OTf) Recently,2 with Pappo1 equiv of tBuOOH, led to2 the desired2 product in moderate yield (47%), suggesting the consumption and co-workersof atropoisomeric developed C(sp )‒C(sp an iron-catalyzed) bonds (Scheme chiral-anion 10) [49]. strategy for the enantio-construction of of partVarious of the 3,3oxidant′-disubstituted to generate phosphoric the active spacidsecies weFe(III)re foundfrom Fe(II). active This and finding promoted confirms the a atropoisomeric C(sp2)-C(sp2) bonds (Scheme 10)[49]. Fe(III)/Fe(IV)enantioselective catalytic transformation, manifold as albeit previous withly low described ees, suggesting by Pappo the and formation Katsuki of[49,50]. a labile chiral iron intermediate. Indeed, using catalyst (L7)3Fe, previously prepared from the corresponding chiral phosphoric acid and Fe(ClO4)3 in the presence of di-tertt-butylBu peroxide, the desired BINOL was delivered in 86% yield and 94:6 er. Since the metal center in complex L7 does not present any vacant coordination site, the reaction was conducted with different ratios of iron and ligands (1:1; 1:2 and 1:3) in order to identify the catalytic active OspeciesO during the transformation. The low P Fe enantioselectivity demonstrated with 5 mol% of ligandO O with respect to 10 or 15 mol%, suggested the 3 presence of a catalytically operative (L7)2Fe complex, which undergoes ligand exchange with 2- naphthol 19 to form an (Lx)3Fe species that finally enabled the transformation. A broad scope for chiral 7,7′-BINOLs 20 was reported with high yields and goodtBu to excellent enantioselectivities. These R OH (L7) .Fe (2.5 mol%) latter were found affected by the electronic 3nature of substrates; thus, electron-poorOH reagents were R converted with higher enantioselectivity comparedtBuOOtBu (1 to equiv) electron-rich ones. OH The erosion of the enantiopurity of theDCE:HFIP products (1:1),, in r.t. the presenceR of catalytic amounts of FeCl3 19 was hypothesized to be promoted by a reversible single electron transfer (SET) process involving the 20 binaphthyl metal complex that generated a delocalized biaryloxy radical. These evidences supported the hypothesis of a radical anion coupling mechanism to be operative [50]. On the basis of these experimental results, the catalytic cycle wasCF proposed.3 Coordination of peroxide to iron(III) forms L

C8H17 F3C OH iPr OH OH OH iPr OH OH

F3C C8H17

20a, 88% 20b, 94% 20c, 77% CF3 er 87:13 er 84:16 er 86:14 SchemeScheme 10. Selected10. Selected examples examples of of chiral chiral phosphoric phosphoric iron-catalyzed enan enantioselectivetioselective construction construction of of BINOLs.BINOLs. HFIP HFIP= 1,1,1,3,3,3-Hexaﬂuoro-2-propanol. = 1,1,1,3,3,3-Hexafluoro-2-propanol.

Molecules 2020, 25, 3889 9 of 29

Various 3,30-disubstituted phosphoric acids were found active and promoted the enantioselective transformation, albeit with low ees, suggesting the formation of a labile chiral iron intermediate. Indeed, using catalyst (L7)3Fe, previously prepared from the corresponding chiral phosphoric acid and Fe(ClO4)3 in the presence of di-tert-butyl peroxide, the desired BINOL was delivered in 86% yield and 94:6 er. Since the metal center in complex L7 does not present any vacant coordination site, the reaction was conducted with different ratios of iron and ligands (1:1; 1:2 and 1:3) in order to identify the catalytic active species during the transformation. The low enantioselectivity demonstrated with 5 mol% of ligand with respect to 10 or 15 mol%, suggested the presence of a catalytically operative (L7)2Fe complex, which undergoes ligand exchange with 2-naphthol 19 to form an (Lx)3Fe species that finally enabled the transformation. A broad scope for chiral 7,70-BINOLs 20 was reported with high yields and good to excellent enantioselectivities. These latter were found affected by the electronic nature of substrates; thus, electron-poor reagents were converted with higher enantioselectivity compared to electron-rich ones. The erosion of the enantiopurity of the products, in the presence of catalytic amounts of FeCl3 was hypothesized to be promoted by a reversible single electron transfer (SET) process involving the binaphthyl metal complex that generated a delocalized biaryloxy radical. These evidences supported the hypothesis of a radical anion coupling mechanism to be operative [50]. On the basis of these experimental results, the catalytic cycle was proposed. Coordination of peroxide to iron(III) forms L that subsequently undergoes ligand exchange with 19 and peroxide-mediated bond cleavage to provide intermediate M. Transfer of the electron density from the naphtholate ligand (N) enabled a radical-anion coupling with a second naphthol unit 19, leading to O. Finally, radical abstraction operated by the peroxide (P), followed by transmetallation, releases product 20 restoring the iron catalyst (Scheme 11). Molecules 2020, 25, x FOR PEER REVIEW 10 of 30

Scheme 11.11.Plausible Plausible mechanism mechanism for ironfor phosphate-catalyzediron phosphate-catalyzed enantioselective enantioselective construction construction of BINOLs. of BINOLs.

Molecules 2020, 25, 3889 10 of 29

More recently, also chiral diphosphine oxide ligands were found as suitable ligands for the enantioselective synthesis of BINOLs. Hence, Ishihara and co-workers reported a stable diphosphino oxide iron(II) complex, which acts as a better oxidant for the radical-anion coupling [51]. Various chiral diphosphines ligands were tested in the presence of Fe(OTf)2 and tert-butyl peroxide. BINOLs-based backbone ligands failed to induce any stereocontrol, while high yields and enantioselectivities were observed with ligands L8 and L9. The in-situ formed L8 Fe(OTf) complex was found active for the · 2 Moleculesoxidative 2020 coupling, 25, x FOR of PEER a large REVIEW family of 3,7- and 6-substituted 2-naphthols 19 (Scheme 12). 11 of 30

SchemeScheme 12. 12. DiphosphineDiphosphine oxide oxide ligands ligands in iniron-catalyzed iron-catalyzed.. enantioselective enantioselective synthesis synthesis of BINOLs; of BINOLs; (a) selected(a) selected examples examples of 3,7-naphthols of 3,7-naphthols and and (b) (selectedb) selected examples examples of 6-naphthols. of 6-naphthols.

5. Chiral-to-MetalTo shed light on the mode of action of the iron catalysis, mechanistic experiments were conducted. Interestingly, an enantioselective non-liner positive eﬀect was observed for the reaction with ligand Commonly, enantioselective transformations are designed using a catalytic system composed by a metal center and cost-effective chiral ligands. In the last years, appealing alternatives have been developed and involve the use of readily available achiral ligands arranged into an asymmetric octahedral coordination sphere around the metal. Despite various chiral-at-metal catalysts have been reported for the 4d and 5d transition metals [52,53], 3d chiral complexes remain less investigated. Meggers and co-workers pioneered this field presenting the synthesis and the catalytic activity of chiral-to-metal iron catalysts [54]. The synthesis of iron compounds was accomplished by an electrolysis reaction of the corresponding in situ-generated PyNHC silver salt, in MeCN, with an iron sacrificial anode. Thus, the racemic iron intermediate L10.Fe(PF6)2(MeCN)2 was delivered in good yield. Separation of diastereoisomers, obtained by complexation with a chiral oxazoline and

Molecules 2020, 25, 3889 11 of 29

L8. In addition, a stoichiometric reaction conducted in the presence of L8 Fe(OTf) with 1 equiv of · 2 tBuOOH, led to the desired product in moderate yield (47%), suggesting the consumption of part of the oxidant to generate the active species Fe(III) from Fe(II). This ﬁnding conﬁrms a Fe(III)/Fe(IV) catalytic manifold as previously described by Pappo and Katsuki [49,50].

5. Chiral-to-Metal Commonly, enantioselective transformations are designed using a catalytic system composed by a metal center and cost-effective chiral ligands. In the last years, appealing alternatives have been developed and involve the use of readily available achiral ligands arranged into an asymmetric octahedral coordination sphere around the metal. Despite various chiral-at-metal catalysts have been reported for the 4d and 5d transition metals [52,53], 3d chiral complexes remain less investigated. Meggers and co-workers pioneered this field presenting the synthesis and the catalytic activity of chiral-to-metal iron catalysts [54]. The synthesis of iron compounds was accomplished by an electrolysis reaction of the corresponding in situ-generated PyNHC silver salt, in MeCN, with an iron sacrificial anode. Thus, the racemic iron intermediate L10 Fe(PF ) (MeCN) was delivered in good Molecules 2020, 25, x FOR PEER REVIEW · 6 2 2 12 of 30 yield. Separation of diastereoisomers, obtained by complexation with a chiral oxazoline and subsequent subsequenttreatment with treatment NH PF , yieldedwith NHd-(4SPF)-L106, yieldedFe(PF ) (MeCN)D-(S)-L10.(Fe(PFΛ-Fe)6) and2(MeCN)l-(R)-2 L10(ΛFe(PF-Fe) and) (MeCN) L-(R)- 4 6 · 6 2 2 · 6 2 2 L10(∆-Fe.Fe(PF) chiral6)2(MeCN) catalysts.2 (Δ These-Fe) chiral bench catalysts. stable Lewis These acids bench resulted stable Lewis in being acids highly resulted enantiopure in being (highly>99:1) enantiopureand showed mirror-imagine(>99:1) and showed CD spectra mirror-imagine proving the CD presence spectra of theproving two corresponding the presence enantiomersof the two corresponding(Scheme 13). enantiomers (Scheme 13).

Scheme 13. Chiral-to-metalChiral-to-metal iron complexes synthesis.

Chiral Lewis acid iron(II) complexes ΛΛ-Fe-Fe and Δ∆-Fe-Fe demonstrated peculiar peculiar catalytic catalytic activities. activities. The asymmetric conversion of phenylglyoxal 2121 toto mandelate ester ester 22 proceeded in high yield and enantioselectivity (Scheme 14a).14a). As As expected, expected, Δ∆-Fe-Fe catalyzedcatalyzed the the formation formation of the corresponding mirror-imagine of 22 with comparable yield and stereoselection.stereoselection. These complexes were also found active in promoting the asymmetric Nazarov reaction of 23 providing the formation of (1 R, 2 2S)-24 in high dr and ee (Scheme 1414b).b). Although the precise mechan mechanismism is unknown, the high enantiocontrol displayed by the catalysts, suggested iron-substrate interactions to occur into the chiralchiral pocket.pocket.

Scheme 14. Examples of enantioselective reactions with iron-based chiral-to-metal catalysts.

More recently, Che and co-workers described the catalytic application of iron(II) complexes with metal- and ligand-chirality [55]. The reaction of different N4-type chiral ligands, such as bis(quinolyl)diamine with the Fe(OTf)2(MeCN)2 precatalyst, allowed for the synthesis of a family of bench stable iron complexes, where the octahedral coordination provided a metal chirality feature to

Molecules 2020, 25, x FOR PEER REVIEW 12 of 30 subsequent treatment with NH4PF6, yielded D-(S)-L10.Fe(PF6)2(MeCN)2 (Λ-Fe) and L-(R)- L10.Fe(PF6)2(MeCN)2 (Δ-Fe) chiral catalysts. These bench stable Lewis acids resulted in being highly enantiopure (>99:1) and showed mirror-imagine CD spectra proving the presence of the two corresponding enantiomers (Scheme 13).

Scheme 13. Chiral-to-metal iron complexes synthesis.

Chiral Lewis acid iron(II) complexes Λ-Fe and Δ-Fe demonstrated peculiar catalytic activities. The asymmetric conversion of phenylglyoxal 21 to mandelate ester 22 proceeded in high yield and enantioselectivity (Scheme 14a). As expected, Δ-Fe catalyzed the formation of the corresponding mirror-imagine of 22 with comparable yield and stereoselection. These complexes were also found active in promoting the asymmetric Nazarov reaction of 23 providing the formation of (1R, 2S)-24 in highMolecules dr and2020, ee25 ,(Scheme 3889 14b). Although the precise mechanism is unknown, the high enantiocontrol12 of 29 displayed by the catalysts, suggested iron-substrate interactions to occur into the chiral pocket.

Scheme 14. ExamplesExamples of of enantioselective enantioselective reactions reactions wi withth iron-based chiral-to-metal catalysts.

More recently, Che and co-workers described the ca catalytictalytic application of iron(II) complexes with metal- andand ligand-chirality ligand-chirality [55 ].[55]. The The reaction reaction of diﬀ erentof differentN4-type chiralN4-type ligands, chiral such ligands, as bis (quinolyl)such as bisMoleculesdiamine(quinolyl)diamine 2020 with, 25 the, x FOR Fe(OTf) PEER with REVIEW2 (MeCN)the Fe(OTf) 2 precatalyst,2(MeCN)2 allowedprecatalyst, for theallowed synthesis for the of asynthesis family of of bench a family13 stable of of30 benchiron complexes, stable iron where complexes, the octahedral where the coordination octahedral coordination provided a metal provided chirality a metal feature chirality to the feature catalyst. to Thethe catalyst. catalytic The activity catalytic was activity subsequently was subsequently demonstrated demonstrated in FC-type alkylationin FC-type reactionsalkylation of reactions indoles 26of withindolesα,β 26-unsaturated with α,β-unsaturated acyl imidazoles acyl imidazoles25 (Scheme 25 15 (Scheme). 15).

Scheme 15. SelectedSelected examples examples of of chiral-to-metal chiral-to-metal iron iron-catalyzed-catalyzed FC alkylations of indoles.

The iron complex L11.Fe(OTf) , bearing quinoline fused pentane rings, proved to be the best The iron complex L11·Fe(OTf)22, bearing quinoline fused pentane rings, proved to be the best catalyst, leading to 27 inin highhigh yieldyield andand enantioselectivity.enantioselectivity. Interestingly, usingusing 2,3-di-substituted2,3-di-substituted substrates, N-alkylated indoles were obtained with comparable yields and stereoselection (27d,e, Scheme 15). The Fe(II) chiral catalyst L11.Fe(OTf)2 was also found active for the alkylation of electron- rich anilines 28 and pyrroles 29. High enantioselectivities were obtained for the positional selective C-2 and C-3 alkylation of pyrroles, with these latter achieved in the presence of 2,5-disubstitued substrates 31b,c (Scheme 16).

Molecules 2020, 25, 3889 13 of 29 substrates, N-alkylated indoles were obtained with comparable yields and stereoselection (27d,e, Scheme 15). The Fe(II) chiral catalyst L11 Fe(OTf) was also found active for the alkylation of · 2 electron-rich anilines 28 and pyrroles 29. High enantioselectivities were obtained for the positional selective C-2 and C-3 alkylation of pyrroles, with these latter achieved in the presence of 2,5-disubstitued Moleculessubstrates 202031b,c, 25, x FOR(Scheme PEER 16REVIEW). 14 of 30

Scheme 16. SelectedSelected examples examples of of chiral-to-metal chiral-to-metal iron-c iron-catalyzedatalyzed anilines and pyrroles alkylations.

To shedshed lightlight onon the the mechanism mechanism and and on on the the origin orig ofin theof the enantioselectivity, enantioselectivity, DFT DFT calculations calculations were wereconducted. conducted. The lowestThe lowest energy energy catalytic catalytic pathway pathwa is depictedy is depicted below below (Scheme (Scheme 17) and17) and begins begins with with the thecoordination coordination of 25 ofto 25 the to chiral the chiral metal metal center center (Q). A bidentate(Q). A bidentate coordination coordination of 25 to theof 25 catalyst to the preserves catalyst preservesthe Si-prochiral the Si-prochiral face and enables face and the enables interaction the interaction of the indole of the to the indoleRe-face. to the In Re addition,-face. In πaddition,–π stacking π– πinteractions stacking interactions between the between indole andthe indole the quinoline and the ligandquinoline moieties ligand reduce moieties the reduce energy the of theenergy transition of the transitionstate. The state. subsequent The subsequent proton transfer proton and transfer the exothermic and the exothermic tautomerization tautomerization ﬁnally generate finally product generate27 product(Scheme 2717 ).(Scheme 17).

Molecules 2020, 25, 3889 14 of 29 Molecules 2020, 25, x FOR PEER REVIEW 15 of 30

Scheme 17. Lowest energy catalytic cycle for chiral-to-metalchiral-to-metal iron-catalyzed alkylationalkylation ofof indoles.indoles.

6.6. Second Coordination Sphere InIn transitiontransition metalmetal catalysis,catalysis, the catalyticcatalytic activityactivity of thethe metalmetal centercenter isis oftenoften controlledcontrolled byby thethe ligands,ligands, whichwhich constituteconstitute the the first first coordination coordination sphere. sphere In. In this this context, context, enantioselectivity enantioselectivity isachieved is achieved by directingby directing the the incoming incoming reagent reagent to one to one prochiral prochiral side, side, by blocking,by blocking, often often sterically, sterically, the otherthe other one. one. EnzymaticEnzymatic catalysiscatalysis featuresfeatures hybridhybrid catalystscatalysts composedcomposed ofof aa catalyticallycatalytically activeactive transitiontransition metalmetal complexcomplex integrated in in a abiomolecular biomolecular scaffold, scaffold, usually usually a protein a protein [56] [ 56or] DNA or DNA [57]. [In57 ].this In case, this chiral case, chiraldiscrimination discrimination is induced is induced by the by thesecond second coordination coordination sphere sphere [58,59], [58,59 ],with with the the chiral chiral environment providedprovided byby biobio macromolecules.macromolecules. In this way, biomolecularbiomolecular scascaffoldsffolds cancan directdirect thethe reactivityreactivity toto oneone prochiralprochiral faceface ofof thethe boundedbounded reactantreactant oror favorfavor thethe structure ofof oneone enantiomer’senantiomer’s transition state [60]. [60]. IronIron playsplays aa crucialcrucial rolerole inin enzymaticenzymatic catalysiscatalysis becausebecause most of thethe studiesstudies are focusedfocused onon thethe modificationmodification ofof enzymesenzymes containingcontaining iron-hemeiron-heme complexescomplexes [[61–63].61–63]. OneOne ofof thethe undisputed undisputed leaders leaders in in this this field field is theis th 2018e 2018 Nobel Nobel laureate laureate Frances Frances Arnold Arnold [64,65 [64,65].]. In 2017 In Arnold’s2017 Arnold’s research research group group reported reported an enantioselective an enantioselective intermolecular intermolecular benzylic benzylic C–H C–H amination amination [66]. The[66]. active The active catalyst catalyst consists consists of the directed of the directed evolution evolution of an iron of containing an iron containing enzyme based enzyme on cytochrome based on P450cytochrome monooxygenase. P450 monooxygenase. This enzyme This is known enzyme to is nature known because to nature it promotes because theit promotes direct insertion the direct of oxygeninsertion into of C–Hoxygen bonds into [67 C–H]. By bonds just modifying [67]. By just the cysteinemodifying axial the ligand cysteine with axial a serine ligand one, with it is possiblea serine toone, obtain it is apossible class of to modified obtain a cytochromes class of modified called cytochromes P411s. This modificationcalled P411s. ofThis the modification axial ligand of thethe hemeaxial ligand cofactor of increases the heme the cofactor Fe(III)/ Fe(II)increases reduction the Fe potential.(III)/Fe(II) These reduction enzymes potential. are able These to catalyze enzymes nitrene are transferable to catalyze reactions nitrene (Scheme transfer 18)[68 reactions]. (Scheme 18) [68]. To probe the selected transformation, 4-ethylanisole 32a was reacted with tosyl azide with whole E. coli cells overexpressing P411. Other modifications (Enzyme P411CHA) were necessary in order to maximize the selectivity toward the desired product 34a over the reduction of the nitrenoid. Beneficial mutations were identified in the active site of the enzyme that mediates the substrate binding. The scope of the reaction was then investigated. Substitutions in para, meta and ortho- position of the aromatic ring were well tolerated (Scheme 19, 34a–c). Although the presence of electron-withdrawing groups decreased the reactivity, halogens substituents could be still successfully converted into the corresponding products with excellent enantioselectivity (34d). The enzyme active site could

Molecules 2020, 25, x FOR PEER REVIEW 16 of 30

Molecules 2020, 25, 3889 15 of 29 accommodate also larger substrates such as 4-propylanisole (34e), while tetraline and indane (34f,g) Moleculeswere suitable 2020, 25 candidates, x FOR PEER forREVIEW the enantioselective C–H amination, as well. 16 of 30

Scheme 18. Proposed mechanism for benzylic C‒H aminations.

To probe the selected transformation, 4-ethylanisole 32a was reacted with tosyl azide with whole E. coli cells overexpressing P411. Other modifications (Enzyme P411CHA) were necessary in order to maximize the selectivity toward the desired product 34a over the reduction of the nitrenoid. Beneficial mutations were identified in the active site of the enzyme that mediates the substrate binding. The scope of the reaction was then investigated. Substitutions in para, meta and ortho- position of the aromatic ring were well tolerated (Scheme 19, 34a–c). Although the presence of electron-withdrawing groups decreased the reactivity, halogens substituents could be still successfully converted into the corresponding products with excellent enantioselectivity (34d). The enzyme active site could accommodate also larger substrates such as 4-propylanisole (34e), while tetraline and indane (34fSchemeScheme,g) were 18. 18. Proposed Proposedsuitable mechanismcandidates mechanism for for benzylic benzylicthe enan C C-Htioselective‒H aminations. C–H amination, as well.

To probe the selected transformation, 4-ethylanisole 32a was reacted with tosyl azide with whole E. coli cells overexpressing P411. Other modifications (Enzyme P411CHA) were necessary in order to maximize the selectivity toward the desired product 34a over the reduction of the nitrenoid. Beneficial mutations were identified in the active site of the enzyme that mediates the substrate binding. The scope of the reaction was then investigated. Substitutions in para, meta and ortho- position of the aromatic ring were well tolerated (Scheme 19, 34a–c). Although the presence of electron-withdrawing groups decreased the reactivity, halogens substituents could be still successfully converted into the corresponding products with excellent enantioselectivity (34d). The enzyme active site could accommodate also larger substrates such as 4-propylanisole (34e), while tetraline and indane (34f,g) were suitable candidates for the enantioselective C–H amination, as well.

SchemeScheme 19. Selected 19. Selected example example of the of substrate the substrate scope scope for the for enzyme the enzyme P411CHA P411catalyzedCHA catalyzed C-H amination. C‒H amination. The same class of serine-ligated P411 enzymes was investigated for the catalytic carbene transfer to internal alkynes to aﬀord cyclopropene products 37 as a single enantiomer. A proper engineering of the active site of the enzyme was fundamental in order to avoid the steric clashes between the liner π-system and the planar heme cofactor (Scheme 20)[69].

Scheme 19. Selected example of the substrate scope for the enzyme P411CHA catalyzed C‒H amination.

Molecules 2020, 25, x FOR PEER REVIEW 17 of 30

The same class of serine-ligated P411 enzymes was investigated for the catalytic carbene transfer to internal alkynes to afford cyclopropene products 37 as a single enantiomer. A proper engineering ofMolecules the active2020, 25site, 3889 of the enzyme was fundamental in order to avoid the steric clashes between the16 liner of 29 π-system and the planar heme cofactor (Scheme 20) [69].

Scheme 20. CyclopropanationCyclopropanation of of internal internal alkynes via an iron-carbene intermediate.

The scope of the reaction was then evaluated and aromatic internal alkynes bearing different different substituents onon thethe aromaticaromatic ring ring were were tested. tested. Other Other modifications modifications were were needed needed in orderin order to expandto expand the thesubstrate substrate scope scope due todue the to hypothesized the hypothesized specificity specific acquiredity acquired from the from first the enzyme first enzyme modification modification towards towardsunsubstituted unsubstituted aromatic ringaromatic or electron-rich ring or electron alkynes.-rich Indeed, alkynes. replacing Indeed, a serinereplacing with a a serine glycine with in the a glycineactive site, in the allowed active one site, to allowed increase one the spaceto increase for substituted the space aromatic for substituted rings obtaining aromatic from rings moderate obtaining to fromgood moderate results with to good a broad results variety with of a all-substituted, broad variety of as all-substituted, well as disubstituted, as wellrings. as disubstituted, Internal aliphatic rings. Internalalkynes provedaliphatic to bealkynes more challenging proved to substrates. be more Nevertheless,challenging propersubstrates. modifications Nevertheless, revealed proper to be modificationsfundamental to revealed allow their to be reactivity. fundamental Moreover, to allow it was their possible reactivity. to tune Moreover, the chemoselectivity it was possible to to obtain tune theeither chemoselectivity the C-H insertion to orobtain the cyclopropenation. either the C‒H insertion Ultimately, or the they cyclopropenation. found that this enzymatic Ultimately, platform they foundallowed that one this to enzymatic readily scale-up platform the reaction.allowed one to readily scale-up the reaction. Very recently, thethe samesame researchresearch groupgroup proposedproposed a methodology to accessaccess aliphatic primary 3 amines via C(spC(sp3)–H aminationsaminations [[70].70]. TheThe directeddirected evolution evolution of of cytochrome cytochrome P411 P411 enzymes enzymes allowed allowed to toselectively selectively functionalize functionalize benzylic benzylic and and allylic allylic C–H C–H bonds bonds providing providing a broad a broad range ofrange primary of primary amines amines(39 and 41(39) throughand 41) thethrough formation the formation of high-valent of high-valent unprotected unprotected iron-nitrenoid iron-nitrenoid intermediates intermediates [71]. Several [71].mutations Several were mutations introduced were in theintroduced active site, in granting the active the formationsite, granting of the the desired formation products. of the Secondary desired products.benzylic C–H Secondary bonds ensuredbenzylic the C–H best bonds yields ensured with high the enantioselectivities best yields with high (Scheme enantioselectivities 21a). This class (Schemeof enzymes 21a). also This allowed class of for enzymes the C–H also amination allowed of for allylic thebonds C–H amination by an appropriate of allylic engineering bonds by an of appropriatethese former; engineering the modifications of these were former; aimed the at modi minimizingfications thewere possible aimed sideat minimizing reactions involving the possible the sideolefin. reactions The optimized involving new the enzyme olefin. The provided optimized high yieldsnew enzyme and selectivity provided for high a di ffyieldserent and range selectivity of allylic forsubstrates a different41 (Scheme range of 21 allylicb). substrates 41 (Scheme 21b). Non-heme iron enzymes were recently found as feasible catalysts for nitrene transfer reactions. Hence, in 2019, Arnold’s research group described olefin aziridinations and nitrene C–H insertions [72]. α-Ketoglutarate-dependent iron enzymes were selected as proper tool to investigate the aziridination of styrene 42. This family of enzymes binds iron through two histidines and one aspartate or glutamate. Of the three available coordination sites, two are occupied by the α-ketoglutarate and the third is required for the specific reactivity of the enzymes (often an iron-oxo intermediate). Due to the non-heme structure of the enzyme, the first coordination sphere of the metal can be modified with small molecules in order to tune the activity and the selectivity of the enzyme (Scheme 22).

Molecules 2020, 25, 3889 17 of 29 Molecules 2020, 25, x FOR PEER REVIEW 18 of 30

Scheme 21.21. FormationFormation of of benzyl benzyl amines amines (a) and(a) allyland aminesallyl amines (b) catalyzed (b) catalyzed by cythocrome by cythocrome P411 variants. P411 variants. Several small molecules related to α-ketoglutarate were investigated and it was found that the presenceNon-heme of a carboxylate iron enzymes was beneficialwere recently for the found reactivity. as feasible The catalysts selected ligandfor nitrene species transfer was acetate reactions. for itsHence, ubiquity in 2019, and Arnold’s inexpensiveness. research Ofgroup course, described some mutations olefin aziridinations in the binding and pocket nitrene were C–H required insertions to obtain[72]. α high-Ketoglutarate-dependent enantioselectivity for 44–46iron enzymes(88% and 64%wereee serespectively,lected as proper Scheme tool 22). to investigate the aziridinationAs mentioned of styrene above, 42 the. This second family coordination of enzymes sphere binds interactions iron through can involvetwo histidines DNA structures and one asaspartate a biomolecular or glutamate. scaffold Of around the three the metalavailable complex, coordination providing sites, a chiral two environmentare occupied toby develop the α- enantioselectiveketoglutarate and transformations. the third is required In 2016, for the Roefels specif andic reactivity co-workers of the disclosed enzymes a DNA (often/cationic-iron- an iron-oxo porphyrin-basedintermediate). Due catalytic to the non-heme system structure for the styrenesof the enzyme, cyclopropanation the first coordinati via carbeneon sphere transfer of the metal [73]. Meso-tetrakis(N-alkylpyridyl)porphyrins L13 FeCl, well-established DNA binders, were chosen as can be modified with small molecules in order· to tune the activity and the selectivity of the enzyme a(Scheme model catalytic22). system to study the reactivity. Their binding properties depend on the type and length of the alkylic chain. Among all the porphyrins tested, those bringing 2-N-methyl pyridines gave the best enantioselectivity together with a marked acceleration effect in the presence of the DNA. The porphyrin’s interaction with DNA mostly occurs through groove binding in AT-rich areas. The groove binding makes the catalytic site more accessible to the substrate, being at the periphery of the structure of the DNA. Moreover, the iron porphyrins binding with the DNA forms hydrophobic pockets where the reagents are concentrated. For this reason, the concentration plays an important role to exploit the desired reactivity and the rate acceleration due to the DNA (Scheme 23).

Molecules 2020, 25, 3889 18 of 29 Molecules 2020, 25, x FOR PEER REVIEW 19 of 30

SchemeScheme 22. 22.Nitrene Nitrene transfer transfer catalyzed catalyzed by non-hemeby non-heme enzymes. enzymes.α-KG α=-KGα-ketoglutarate; = α-ketoglutarate; NOG =NOGN-oxalyl = N- Moleculesglycine;oxalyl 2020 glycine;, Ac25, x= FORacetate. Ac PEER = acetate. REVIEW 20 of 30

Several small molecules related to α-ketoglutarate were investigated and it was found that the presence of a carboxylate was beneficial for the reactivity. The selected ligand species was acetate for its ubiquity and inexpensiveness. Of course, some mutations in the binding pocket were required to obtain high enantioselectivity for 44–46 (88% and 64% ee respectively, Scheme 22). As mentioned above, the second coordination sphere interactions can involve DNA structures as a biomolecular scaffold around the metal complex, providing a chiral environment to develop enantioselective transformations. In 2016, Roefels and co-workers disclosed a DNA/cationic-iron- porphyrin-based catalytic system for the styrenes cyclopropanation via carbene transfer [73]. Meso- tetrakis(N-alkylpyridyl)porphyrins L13.FeCl, well-established DNA binders, were chosen as a model catalytic system to study the reactivity. Their binding properties depend on the type and length of the alkylic chain. Among all the porphyrins tested, those bringing 2-N-methyl pyridines gave the best enantioselectivity together with a marked acceleration effect in the presence of the DNA. The porphyrin’s interaction with DNA mostly occurs through groove binding in AT-rich areas. The groove binding makes the catalytic site more accessible to the substrate, being at the periphery of the structure of the DNA. Moreover, the iron porphyrins binding with the DNA forms hydrophobic Scheme 23. DNA/cationic-iron-porphyrin-basedDNA/cationic-iron-porphyrin-based catalytic system for styrenes cyclopropanations. pockets where the reagents are concentrated. For this reason, the concentration plays an important role to exploit the desired reactivity and the rate acceleration due to the DNA (Scheme 23). 7. Others Despite notable advances obtained for the enantioselectiveenantioselective synthesis of BINOL derivatives, strategies for chiralchiral 2-amino-22-amino-20′-hydroxy-1,1′0-dinaphtyl-dinaphtyl (NOBIN) (NOBIN) ligands ligands are are limited to multistep synthetic approaches [74]. [74]. Moreover, Moreover, these protocol protocolss do not allow the presence of substitutions at 3,30′-positions,-positions, often often important important for for the design of eeffeﬀectivective chiralchiral catalystscatalysts [[75].75]. To To overcome these limitations, an enantioselective protocol for the synthesis of NOBIN derivatives 49 has been recently devised by Pappo and co-workers through a peculiar point-to-axial chiral transfer approach [[76]76] (Scheme 2424).).

Molecules 2020, 25, x FOR PEER REVIEW 20 of 30

Scheme 23. DNA/cationic-iron-porphyrin-based catalytic system for styrenes cyclopropanations.

7. Others Despite notable advances obtained for the enantioselective synthesis of BINOL derivatives, strategies for chiral 2-amino-2′-hydroxy-1,1′-dinaphtyl (NOBIN) ligands are limited to multistep synthetic approaches [74]. Moreover, these protocols do not allow the presence of substitutions at 3,3′-positions, often important for the design of effective chiral catalysts [75]. To overcome these limitations, an enantioselective protocol for the synthesis of NOBIN derivatives 49 has been recently devisedMolecules 2020by ,Pappo25, 3889 and co-workers through a peculiar point-to-axial chiral transfer approach19 [76] of 29 (Scheme 24).

Scheme 24. NOBINs synthesis via iron-catalyzed point-to-axial chiral approach.

An iron(III)-catalyzed reaction between 2-naphthols 19 and chiral labeled 2-aminonaphthalenes 48 enabled the access to a separable mixture of diastereoisomers 49. The reaction required the presence of trifluoroacetic acid without the need of any additional expensive chiral ligand. The unique possible side products of the reaction, BINOL and the 48 homocoupling product, were absent. This highlighted the chemoselectivity of the method, further suggesting the presence of a naphthoxyl radical intermediate. A large family of NOBIN derivatives 50 was efficiently accessible with moderate to high yields. The presence of substituents at the C-3 position of starting materials ensured higher enantioselectivities and allowed for the formation of a single product; this could be rationalized by the high steric hindrance present in the inner sphere transition state. The involvement of a naphthoxyl radical was confirmed by the complete racemization of Ra-NOBIN with a catalytic amount of FeCl3 (10 mol%) within 5 h. The following removal of the chiral auxiliary afforded (+)-Ra-50e and ( )-(Sa)-50e in high − enantioselectivity (up to 99% ee). The utility of the methodology was also reported with the large-scale synthesis of a NOBIN-backboned phosphoric acid 51 (Scheme 25). Enantiopure chiral substrates were also used by Baik, Cook and co-workers to develop iron(III)-catalyzed stereospecific nucleophilic substitutions [77]. Preliminary studies on intermolecular amination reactions of secondary and tertiary alcohols demonstrated the efficiency of iron catalysts, which afforded the corresponding desired products in high yields. In contrast, an enantioselective stereoinverting pathway was observed for the intramolecular amination reaction. The Fe(SbF6)3 complex, formed in situ from FeCl3 and AgSbF6, catalyzed the stereoinverting amination reaction of enantiopure secondary alcohols 52 with high enantiospecificity and quantitative yields (Scheme 26). Molecules 2020, 25, x FOR PEER REVIEW 21 of 30

Scheme 24. NOBINs synthesis via iron-catalyzed point-to-axial chiral approach.

MoleculesSchemeScheme 2020, 25.25 25., (xa( aFOR) )Purification Puriﬁcation PEER REVIEW and and deprotection deprotection of of 50e50e andand (b ()b derivatization) derivatization of of49e49e toto phosphoric phosphoric acid acid 51e51e. 22. of 30

Enantiopure chiral substrates were also used by Baik, Cook and co-workers to develop iron(III)- catalyzed stereospecific nucleophilic substitutions [77]. Preliminary studies on intermolecular amination reactions of secondary and tertiary alcohols demonstrated the efficiency of iron catalysts, which afforded the corresponding desired products in high yields. In contrast, an enantioselective stereoinverting pathway was observed for the intramolecular amination reaction. The Fe(SbF6)3 complex, formed in situ from FeCl3 and AgSbF6, catalyzed the stereoinverting amination reaction of enantiopure secondary alcohols 52 with high enantiospecificity and quantitative yields (Scheme 26).

Scheme 26. Iron-catalyzedIron-catalyzed enantiospecific enantiospeciﬁc aminat aminationion reaction of secondary alcohols.

Intuitively, lowerlower temperatures temperatures ( 20(−◦20C) °C) and theand use the of use an apolar of an solvent apolar (toluene) solvent were(toluene) mandatory were − mandatoryto promote theto promote stereochemical the stereochemical control of the nucleophiliccontrol of the attack nucleophilic when chiral attack tertiary when alcohols chiral 54tertiarywere alcoholsemployed 54 as were reactants. employed Here, as thereactants. enantiospeciﬁcity Here, the enantios is due topecificity the nucleophilic is due to the attack nucleophilic occurring attack at the occurringopposite face at the of anopposite oxo-iron face intermediate of an oxo-iron resulting intermediate in an inversion resulting of in conﬁguration an inversion of of the configuration stereogenic ofcenter the stereogenic (Scheme 27 b).center (Scheme 27b). TMs-catalyzed asymmetric hydrogenations are among the most important synthetic transformations and constitute, currently, a routine methodology in industrial organic chemistry [78,79]. In this context, asymmetric transfer hydrogenation (ATH) has played an important role for the synthesis of enantiopure alcohols [80]. Iron-catalyzed ATH has found wide applicability in the development of sustainable hydrogenation reactions mainly due to the low cost with respect to the ruthenium catalysts [81]. Mezzetti and co-workers reported on a (NH) P macrocyclic-based iron(II) catalysts L14 Fe(CNR) (BF ) for 2 2 · 2 4 2 the asymmetric hydrogenation of ketones and 1,2-diketones [82,83]. More recently, the authors investigated on the mode of action of complex L14 Fe(CNR) (BF ) through NMR spectroscopy and · 2 4 2

Scheme 27. (a) Iron-catalyzed enantiospecific amination reaction of tertiary alcohols and (b) mechanistic rationale.

TMs-catalyzed asymmetric hydrogenations are among the most important synthetic transformations and constitute, currently, a routine methodology in industrial organic chemistry [78,79]. In this context, asymmetric transfer hydrogenation (ATH) has played an important role for the synthesis of enantiopure alcohols [80]. Iron-catalyzed ATH has found wide applicability in the development of sustainable hydrogenation reactions mainly due to the low cost with respect to the

Molecules 2020, 25, x FOR PEER REVIEW 22 of 30

Molecules 2020, 25, 3889 21 of 29

DFT calculations [84]. The catalytic activity of L14 Fe(CNR) (BF ) (T) and L14 FeH(CNR)(BF )(U) was Scheme 26. Iron-catalyzed enantiospecific· amination2 reaction4 2 of secondary· alcohols. 4 tested in the hydrogenation of various ketones in the presence of 2-propanol, with and without the use of additionalIntuitively, bases lower respectively, temperatures providing (−20 a°C) comparable and the outcome.use of an In orderapolar to solvent elucidate (toluene) the activation were mandatoryprocess, complex to promoteT was titratedthe stereochemical with NaOiPr (10control equiv) of/ iPrOH;the nucleophilic the resulting attack equilibrium when chiral demonstrated tertiary alcoholsthe formation 54 were of employed the hydride as reactants. complex UHere,through the enantios intermediatepecificityT’ is(Scheme due to the28a). nucleophilic The reaction attack of complex U with acetophenone at 40 C enabled the NMR identiﬁcation of two diastereoisomeric occurring at the opposite face of an− oxo-iron◦ intermediate resulting in an inversion of configuration ofphenylethanolate the stereogenic complexescenter (Scheme (a)-V 27b).and (b)-V in the 2.2:1 ratio (Scheme 28b).

Scheme 27. ((a)a) Iron-catalyzedenantiospecificaminationreactionoftertiaryalcoholsand(Iron-catalyzed enantiospecific amination reaction of tertiary alcoholsb)mechanisticrationale. and (b) mechanistic rationale. The catalytic cycle was investigated by DFT calculations using the hydride complex U since it resultedTMs-catalyzed as the most asymmetric stable species. hydrogenations The lowest energyare among pathway the is depictedmost important below (Scheme synthetic 29). transformationsAcetophenone approaches and constitute, complex currently,U where a routin the N-H–Oe methodology bond directs in industrial and activates organic the chemistry carbonyl. [78,79].The subsequent In this context, hydride asymmetric transfer, which transfer is enantiodetermining, hydrogenation (ATH) generates has played the phenylethanoate an important role bonded for theto intermediate synthesis of U’enantiopure. The hydride alcohols transfer [80]. resulted Iron-catalyzed in being ATH barrierless, has found therefore wide the applicability enantioselection in the developmentis determined of by sustainable the Boltzmann hydrogenation distribution reactions of TS-( bmainly)-V and dueTS -(toa )-theV, low where cost the with latter respect is the to most the stable. This model justiﬁes the high enantioselectivities achieved by the iron-catalyzed ATH. Then, two reaction pathways can be followed: (a) a barrierless proton transfer that occurs from the solvent (2-propanol) to the phenylethanoate providing intermediate U”’, or otherwise, (b) the formation of an amido-iron complex U”, which engages a new hydrogen bond with 2-propanol (U”’), through product release. A ﬁnal proton elimination from intermediate U”’ forms acetone regenerating catalyst U for both depicted pathways. Interestingly, in the catalytic cycle, intermediate U”’ resulted the highest in energy and its formation is guaranteed only in the presence of an excess of 2-propanol. Contrarily, the observed (a)-V and T’ intermediates were lower in energy with respect to U”’, suggesting these complexes as resting species in the catalytic cycle. Molecules 2020, 25, x FOR PEER REVIEW 23 of 30

ruthenium catalysts [81]. Mezzetti and co-workers reported on a (NH)2P2 macrocyclic-based iron(II) catalysts L14.Fe(CNR)2(BF4)2 for the asymmetric hydrogenation of ketones and 1,2-diketones [82,83]. More recently, the authors investigated on the mode of action of complex L14.Fe(CNR)2(BF4)2 through NMR spectroscopy and DFT calculations [84]. The catalytic activity of L14.Fe(CNR)2(BF4)2 (T) and L14.FeH(CNR)(BF4) (U) was tested in the hydrogenation of various ketones in the presence of 2- propanol, with and without the use of additional bases respectively, providing a comparable outcome. In order to elucidate the activation process, complex T was titrated with NaOiPr (10 equiv)/iPrOH; the resulting equilibrium demonstrated the formation of the hydride complex U through intermediate T’ (Scheme 28a). The reaction of complex U with acetophenone at −40 °C Molecules 2020, 25, 3889 22 of 29 enabled the NMR identification of two diastereoisomeric phenylethanolate complexes (a)-V and (b)- V in the 2.2:1 ratio (Scheme 28b).

Molecules 2020, 25, x FOR PEER REVIEW 24 of 30

determined by the Boltzmann distribution of TS-(b)-V and TS-(a)-V, where the latter is the most stable. This model justifies the high enantioselectivities achieved by the iron-catalyzed ATH. Then, two reaction pathways can be followed: a) a barrierless proton transfer that occurs from the solvent (2-propanol) to the phenylethanoate providing intermediate U’’’, or otherwise, b) the formation of an amido-iron complex U’’, which engages a new hydrogen bond with 2-propanol (U’’’), through product release. A final proton elimination from intermediate U’’’ forms acetone regenerating catalyst U for both depicted pathways. Interestingly, in the catalytic cycle, intermediate U’’’ resulted

the highest in energy and its formation is guaranteed only in the presence of an excess of 2-propanol. SchemeContrarily,Scheme 28. NMR the28. studiesNMRobserved studies of (a the )-ofV the ironand iron catalyzedT’ catalyzed intermediates asymmetricasymmetric were transfer lower transfer hydrogenation in hydrogenationenergy with (ATH) respect reaction. (ATH) to reaction.U’’’, (a) NMRsuggesting( titrationa) NMR these withtitration complexes NaO withiPr as andNaO restini (Prb) g identiﬁcationand species (b) identificationin the ofcatalytic diastereoisomeric of cycle.diastere oisomeric phenylethanolate phenylethanolate complexes. complexes.

The catalytic cycle was investigated by DFT calculations using the hydride complex U since it resulted as the most stable species. The lowest energy pathway is depicted below (Scheme 29). Acetophenone approaches complex U where the N‒H–O bond directs and activates the carbonyl. The subsequent hydride transfer, which is enantiodetermining, generates the phenylethanoate bonded to intermediate U’. The hydride transfer resulted in being barrierless, therefore the enantioselection is

SchemeScheme 29. Calculated 29. Calculated catalytic catalytic cycle cycle of of iron-based iron-based complex U Uin thein theATH ATH reaction reaction of acetophenone. of acetophenone.

Mechanistic studies on N2P2 macrocyclic-based iron(II) complexes, active for the asymmetric hydrogenation of ketones, were performed by Zuo [84]. The amido-ene(amido) carbonyl iron(II) complex L15.Fe(II)CO was reported to efficiently oxidize 2-propanol through the formation of an amino hydrido iron(II) species L15.Fe(II)H(CO) (Scheme 30) [85]. Both iron(II) species are stabilized by covalent π-backdonation interactions between the ene(amido) fragment and the iron center. This stabilization is the reason for the high catalytic activity observed compared to other N2P2 complexes that do not present the ene(amido) group.

Molecules 2020, 25, x FOR PEER REVIEW 24 of 30 determined by the Boltzmann distribution of TS-(b)-V and TS-(a)-V, where the latter is the most stable. This model justifies the high enantioselectivities achieved by the iron-catalyzed ATH. Then, two reaction pathways can be followed: a) a barrierless proton transfer that occurs from the solvent (2-propanol) to the phenylethanoate providing intermediate U’’’, or otherwise, b) the formation of an amido-iron complex U’’, which engages a new hydrogen bond with 2-propanol (U’’’), through product release. A final proton elimination from intermediate U’’’ forms acetone regenerating catalyst U for both depicted pathways. Interestingly, in the catalytic cycle, intermediate U’’’ resulted the highest in energy and its formation is guaranteed only in the presence of an excess of 2-propanol. Contrarily, the observed (a)-V and T’ intermediates were lower in energy with respect to U’’’, suggesting these complexes as resting species in the catalytic cycle.

Molecules 2020, 25, 3889 23 of 29 Scheme 29. Calculated catalytic cycle of iron-based complex U in the ATH reaction of acetophenone.

Mechanistic studies on N P macrocyclic-based iron(II) complexes, active for the asymmetric Mechanistic studies on N2P22 macrocyclic-based iron(II) complexes, active for the asymmetric hydrogenation of ketones, were performed by Zuo [[84].84]. The The amido- amido-ene(amido)ene(amido) carbonyl carbonyl iron(II) iron(II) complex L15 Fe(II)CO was reported to eﬃciently oxidize 2-propanol through the formation of an amino complex L15·.Fe(II)CO was reported to efficiently oxidize 2-propanol through the formation of an hydrido iron(II) species L15 Fe(II)H(CO) (Scheme 30)[85]. Both iron(II) species are stabilized by covalent amino hydrido iron(II) species· L15.Fe(II)H(CO) (Scheme 30) π -backdonation[85]. Both iron(II) interactions species between are stabilized the ene(amido) by covalent fragment π-backdonation and the iron interactions center. This between stabilization the ene(amido)is the reason fragment for the high and catalyticthe iron center. activity This observed stabiliz comparedation is the to reason other for N2 Pthe2 complexes high catalytic that activity do not present the ene(amido) group. observed compared to other N2P2 complexes that do not present the ene(amido) group.

Molecules 2020, 25, x FOR PEER REVIEW 25 of 30

SchemeScheme 30. 30. ActivationActivation of of precatalyst precatalyst L15L15.Fe(II)COFe(II)CO to to form form the the active active intermediate intermediate L15L15.Fe(II)H(CO).Fe(II)H(CO). · ·

Knölker-typeKnölker-type iron iron complexes complexes are are known known to to efficien efficientlytly catalyze catalyze hydrogen hydrogen transfer transfer reactions reactions [86]; [86]; however,however, despitedespite their their wide wide application, application, this this class class of catalysts of catalysts suffered suffered from a from poor stereocontrol.a poor stereocontrol. Recently, the design of a new Knölker-type catalyst L16 Fe(0)(CO) , featuring. a C2-symmetric cyclopentadienone Recently, the design of a new Knölker-type· catalyst3 L16 Fe(0)(CO)3, featuring a C2-symmetric cyclopentadienoneligand bearing chiral ligand substituents bearing atchiral the 2substi and 5tuents positions, at the provided 2 and 5 positions,ees up to 70%provided for the ees asymmetric up to 70% forhydrogenation the asymmetric of di hydrogenationﬀerent ketones of (Scheme different 31 ketones)[87]. (Scheme 31) [87].

SchemeScheme 31. 31. ATHATH of different diﬀerent ketones catalyzed by Knölker type complexes (R33 = Me,Me, Ph; R 44 == TIPS,TIPS, TBDPS).TBDPS). TMAO TMAO == trimethylaminetrimethylamine NN-oxide.-oxide.

WhenWhen new chiralchiral ligands ligands are are designed designed for for asymmetric asymmetric transformations, transformations, a rigid a backbonerigid backbone is usually is usuallypursued pursued to ensure to ensure a successful a successful chiral inductionchiral induction to the to products. the products. Recently, Recently, Feng Feng introduced introduced a new a newclass class of conformationally of conformational ﬂexible,ly flexible, C2 symmetric C2 symmetricN,N0-dioxide N,N’-dioxide chiral chiral ligands, ligands, able to able promote to promote highly highlyenantiocontrolled enantiocontrolled catalytic catalytic transformations transformations [88]. These [88]. These ligands ligands display display two alkyl two aminealkyl amine oxide–amide oxide– amidesubunits subunits separated separated by an alkylby an spacer alkyl andspacer they and are they easily are synthesized easily synthesized from commercially from commercially available, available,optically pureoptically amino pure acids. amino In acids. 2020 Feng’sIn 2020 research Feng’s research group showed group showed the versatility the versatility of this classof this of classligands of inligands combination in combination with iron with salts. iron Indeed, salts. they Indeed, reported they the reported halohydroxylation the halohydroxylation of α,β unsaturated of α,β unsaturatedketones 58 using ketones water 58 asusing a nucleophile water as a [nucleophile89]. The use [89]. of a lThe-ramipril use of derivativea L-ramipril ligand derivative (L17), ligand able to (coordinateL17), able to the coordinate Fe(II) center the inFe(II) a tetradentate center in amanner, tetradentate led to manner, the desired led to transformation the desired transformation with ees up to with98%. ee Disﬀ uperent to substituents98%. Different on thesubstituents chalcone derivative on the chalcone were well derivative tolerated; wereortho -substitutedwell tolerated; aryls ortho (59b-) substitutedgave lower drarylsthan (59b the) corresponding gave lower drmeta than- and thepara corresponding-substituted ones, meta- probably and para due-substituted to the increased ones, probablysteric hindrance due to the between increased the substratessteric hindrance and the betw catalysteen the (Scheme substrates 32). and the catalyst (Scheme 32).

Molecules 2020, 25, x FOR PEER REVIEW 25 of 30

Scheme 30. Activation of precatalyst L15.Fe(II)CO to form the active intermediate L15.Fe(II)H(CO).

Knölker-type iron complexes are known to efficiently catalyze hydrogen transfer reactions [86]; however, despite their wide application, this class of catalysts suffered from a poor stereocontrol. Recently, the design of a new Knölker-type catalyst L16.Fe(0)(CO)3, featuring a C2-symmetric cyclopentadienone ligand bearing chiral substituents at the 2 and 5 positions, provided ees up to 70% for the asymmetric hydrogenation of different ketones (Scheme 31) [87].

Scheme 31. ATH of different ketones catalyzed by Knölker type complexes (R3 = Me, Ph; R4 = TIPS, TBDPS). TMAO = trimethylamine N-oxide.

When new chiral ligands are designed for asymmetric transformations, a rigid backbone is usually pursued to ensure a successful chiral induction to the products. Recently, Feng introduced a new class of conformationally flexible, C2 symmetric N,N’-dioxide chiral ligands, able to promote highly enantiocontrolled catalytic transformations [88]. These ligands display two alkyl amine oxide– amide subunits separated by an alkyl spacer and they are easily synthesized from commercially available, optically pure amino acids. In 2020 Feng’s research group showed the versatility of this class of ligands in combination with iron salts. Indeed, they reported the halohydroxylation of α,β unsaturated ketones 58 using water as a nucleophile [89]. The use of a L-ramipril derivative ligand (L17), able to coordinate the Fe(II) center in a tetradentate manner, led to the desired transformation with ees up to 98%. Different substituents on the chalcone derivative were well tolerated; ortho- substitutedMolecules 2020 , aryls25, 3889 (59b) gave lower dr than the corresponding meta- and para-substituted 24ones, of 29 probably due to the increased steric hindrance between the substrates and the catalyst (Scheme 32).

Molecules 2020, 25, x FOR PEER REVIEW 26 of 30

Scheme 32. HalohydroxylationHalohydroxylation of of αα,β,β unsaturatedunsaturated ketones ketones 5858 usingusing water water asas a nucleophile. a nucleophile. NBS NBS = N=-

bromosuccinimide.N-bromosuccinimide.

The same research group also reported a chiral chiral NN,,N’-dioxide-iron(III)0-dioxide-iron(III) catalyst catalyst for for the the asymmetric asymmetric oxidation of sulfides to chiral sulfoxides 61 [90]. A high-spin L18 Fe(III)-OOH intermediate was oxidation of sulfides to chiral sulfoxides 61 [90]. A high-spin L18·.Fe(III)-OOH intermediate was proposed toto be be the the most most probable probable active active species spec in theies catalytic in the cycle,catalytic while cycle, the enantio-discrimination while the enantio- discriminationof heterotopic loneof heterotopic pairs, was lone determined pairs, was by determined steric repulsions by steric between repulsions sulfides between60 and sulfides the spatially 60 and theencumbered spatially ligandsencumbered (L18,19 ligands). The (L18 procedure,19). The gave procedure access togave a broad access range to a ofbroad chiral range sulfoxides of chiral61, sulfoxideswith high 61 functional, with high group functional tolerance. group The tolerance. biologically The biologically active sulfoxide active( Rsulfoxide)-modafinil (R)-modafinil (61a) was (synthesized61a) was synthesized on a gram on scale a gram (Scheme scale 33 (Scheme). 33).

Scheme 33. Iron-catalyzedIron-catalyzed asymmetric asymmetric oxidation oxidation of sulfides: sulﬁdes: synthesis synthesis of of ( (R)-modafinil.)-modaﬁnil.

Molecules 2020, 25, 3889 25 of 29

8. Conclusions The development of more sustainable, cheaper and stereoselective synthetic methodologies are crucial for the future. As emerged by this review, asymmetric iron catalysis represents a clear and potentially ground-breaking alternative to the well-established 4d and 5d metals-catalyzed reactions. This has been made possible by controlling the catalytic activity of iron catalysts through a proper choice of ligands. Particularly, we summarized the recent advances focusing on the mode of action of chiral iron catalysts. Different approaches have been envisioned for controlling the enantioselectivity of the transformation; the most common involve the use of chiral ligands in combination with iron precursors salts. Among them, chiral oxazoline-containing ligands received remarkable attention for the enantioselective construction of carbon-silicon bonds. These ligands proved their efficiency also in cyclopropanation reactions. Another interesting class of emerging ligands is represented by NHCs; in combination with an iron catalyst, they promoted the C-H hydroarylation of alkenes. Of course, phosphorous containing ligands are still the most utilized for enantiocontrolled reactions. Bidentate chiral phosphines were found active for the enantioconvergent construction of chiral C-C bonds via Suzuki–Miyaura cross-coupling or for DG-mediated C-H functionalization reactions. Chiral phosphoric acids, on the other hand, were found suitable for the synthesis of axially chiral molecules derivatives through radical iron catalysis. The same approach could be developed through the aid of chiral diphospine oxide ligands or using chiral auxiliaries. Recently, it has been proved that ligands featuring rigid backbones are not strictly required for ensuring high levels of asymmetric induction. In fact, conformationally flexible C2 symmetric N,N0-dioxide chiral ligands were found suitable for the asymmetric halohydroxylation of α,β unsaturated ketones as well as for the oxidation of sulfides to chiral sulfoxides. Chiral N2P2 complexes and Knölker-type catalysts have been extensively investigated for the asymmetric transfer hydrogenation of ketones with a sacrificial hydrogen source. A more recent approach, to promote enantioselective reactions, consists of chiral-at-metal catalysis. In this case, asymmetric coordination of achiral ligands at the iron center generated chiral octahedral iron catalysts. These complexes were found active in the asymmetric Nazarov reaction or FC-type alkylations. Asymmetric transformations could be developed by exploiting second coordination spheres usually consisting of a protein or DNA strands. Different enzymes containing cytochrome P450 were modified to promote nitrene or carbene transfer reactions. Moreover, the DNA/iron-porphyrin catalytic system was found active for the cyclopropanation of alkenes. In this scenario, many other challenges need to be addressed, particularly with the aim to design new chiral ligands to expand the portfolio of asymmetric iron-catalyzed C-C bond forming reactions as in example (reductive) cross-coupling [91] or C-H functionalization reactions. Furthermore, a deeper understanding of reaction mechanism and particularly of the role played by additives and ligands, will be crucial for the application of stereoselective iron-catalyzed transformations in continuous-flow processes [92] or the development of photoredox iron-catalyzed transformations [93].

Author Contributions: Conceptualization, G.C.; writing-original draft preparation, A.C. and M.L.; writing-review and editing, A.C., M.L. and G.C. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References

1. Bauer, I.; Knölker, H.-J. Iron Catalysis in Organic Synthesis. Chem. Rev. 2015, 115, 3170–3387. [CrossRef] [PubMed] 2. Fürstner, A. Iron catalysis in organic synthesis: A critical assessment of what it takes to make this base metal a multitasking champion. Acs Cent. Sci. 2016, 2, 778–789. [CrossRef][PubMed] 3. Cera, G.; Ackermann, L. Iron-Catalyzed C–H Functionalization Processes. Top. Curr. Chem. 2016, 374, 57. [CrossRef][PubMed] Molecules 2020, 25, 3889 26 of 29

4. Lanzi, M.; Cera, G. Iron-Catalyzed C–H Functionalizations under Triazole-Assistance. Molecules 2020, 25, 1806. [CrossRef] 5. Guðmundsson, A.; Bäckvall, J.-E. On the Use of Iron in Organic Chemistry. Molecules 2020, 25, 1349. [CrossRef] 6. Biﬃs, A.; Centomo, P.; Del Zotto, A.; Zecca, M. Pd Metal Catalysts for Cross-Couplings and Related Reactions in the 21st Century: A Critical Review. Chem. Rev. 2018, 118, 2249–2295. [CrossRef] 7. Tanaka, K. Rhodium Catalysis in Organic Synthesis: Methods and Reactions; Wiley-VCH Verlag GmbH & Co KGaA: Weinheim, Germany, 2019. 8. Andersson, P.G. Iridium Catalysis; Springer: Berlin/Heidelberg, Germany; Cham, Switzerland, 2011. 9. Dixneuf, P.H.; Bruneau, C. Ruthenium in Catalysis; Springer: Cham, Switzerland, 2014. 10. Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Iron-Catalyzed Reactions in Organic Synthesis. Chem. Rev. 2004, 104, 6217–6254. [CrossRef] 11. Darwish, M.; Wills, M. Asymmetric catalysis using iron complexes-Ruthenium Lite? Catal. Sci. Technol. 2012, 2, 243–255. [CrossRef] 12. Kaplan, J.; Ward, D.M. The Essential Nature of Iron Usage and Regulation. Curr. Biol. 2013, 23, 642–646. [CrossRef] 13. Enthaler, S.; Junge, K.; Beller, M. Sustainable Metal Catalysis with Iron: From Rust to a Rising Star? Angew. Chem. Int. Ed. 2008, 47, 3317–3321. [CrossRef] 14. Teske, J.; Plietker, B. Fe-Catalyzed Cycloisomerizations. Isr. J. Chem. 2017, 57, 1082–1089. [CrossRef] 15. Rueping, M.; Nachtsheim, B.J. A review of new developments in the Friedel–Crafts alkylation-From green chemistry to asymmetric catalysis. Beilstein J. Org. Chem. 2010, 6, 6. [CrossRef][PubMed] 16. Czaplik, W.M.; Mayer, M.; Cvengroš, J.; Jacobi von Wangelin, A. Coming of Age: Sustainable Iron-Catalyzed Cross-Coupling Reactions. ChemSusChem 2009, 2, 396–417. [CrossRef][PubMed] 17. Johansson Seechurn, C.C.C.; Kitching, M.O.; Colacot, T.J.; Snieckus, V. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize. Angew. Chem. Int. Ed. 2012, 51, 5062–5085. [CrossRef] 18. Cherney, A.H.; Kadunce, N.T.; Reisman, S.E. Enantioselective and Enantiospeciﬁc Transition-Metal-Catalyzed Cross-Coupling Reactions of Organometallic Reagents to Construct C–C Bonds. Chem. Rev. 2015, 115, 9587–9652. [CrossRef][PubMed] 19. Hrycay, E.G.; Bandiera, S.M. Monooxygenase, Peroxidase and Peroxygenase Properties and Mechanisms of Cytochrome P450; Springer: Cham, Switzerland, 2015. 20. Singh, R.; Kolev, J.N.; Sutera, P.A.; Fasan, R. Enzymatic C(sp3)-H Amination: P450-Catalyzed Conversion of Carbonazidates into Oxazolidinones. Acs Catal. 2015, 5, 1685–1691. [CrossRef] 21. Groves, J.T.; Viski, P. Asymmetric hydroxylation, epoxidation, and sulfoxidation catalyzed by vaulted binaphthyl metalloporphyrins. J. Org. Chem. 1990, 55, 3628–3634. [CrossRef] 22. Gopalaiah, K. Chiral Iron Catalysts for Asymmetric Synthesis. Chem. Rev. 2013, 113, 3248–3296. [CrossRef] 23. Pellissier, H. Recent developments in enantioselective iron-catalyzed transformations. Coord. Chem. Rev. 2019, 386, 1–31. [CrossRef] 24. McManus, H.A.; Guiry, P.J. Recent Developments in the Application of Oxazoline-Containing Ligands in Asymmetric Catalysis. Chem. Rev. 2004, 104, 4151–4202. [CrossRef]

25. Desimoni, G.; Faita, G.; Jørgensen, K.A. C2-Symmetric Chiral Bis(oxazoline) Ligands in Asymmetric Catalysis. Chem. Rev. 2006, 106, 3561–3651. [CrossRef][PubMed] 26. Yang, G.; Zhang, W. Renaissance of pyridine-oxazolines as chiral ligands for asymmetric catalysis. Chem. Soc. Rev. 2018, 47, 1783–1810. [CrossRef][PubMed] 27. Loup, J.; Dhawa, U.; Pesciaioli, F.; Wencel-Delord, J.; Ackermann, L. Enantioselective C-H Activation with Earth-Abundant 3d. Angew. Chem. Int. Ed. 2019, 58, 12803–12818. [CrossRef][PubMed] 28. Xu, H.; Li, Y.-P.; Cai, Y.; Wang, G.-P.; Zhu, S.-F.; Zhou, Q.-L. Highly Enantioselective Copper- and Iron-Catalyzed Intramolecular Cyclopropanation of Indoles. J. Am. Chem. Soc. 2017, 139, 7697–7700. [CrossRef] 29. Gu, H.; Han, Z.; Xie, H.; Lin, X. Iron-Catalyzed Enantioselective Si–H Bond Insertions. Org. Lett. 2018, 20, 6544–6549. [CrossRef] 30. Cheng, B.; Liu, W.; Lu, Z. Iron-Catalyzed Highly Enantioselective Hydrosilylation of Unactivated Terminal Alkenes. J. Am. Chem. Soc. 2018, 140, 5014–5017. [CrossRef] Molecules 2020, 25, 3889 27 of 29

31. Flanigan, D.M.; Romanov-Michailidis, F.; White, N.A.; Rovis, T. Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes. Chem. Rev. 2015, 115, 9307–9387. [CrossRef] 32. Lin, J.C.Y.; Huang, R.T.W.; Lee, C.S.; Bhattacharyya, A.; Hwang, W.S.; Lin, I.J.B. Coinage Metal N − -Heterocyclic Carbene Complexes. Chem. Rev. 2009, 109, 3561–3598. [CrossRef][PubMed] 33. Janssen-Müller, D.; Schlepphorst, C.; Glorius, F. Privileged chiral N-heterocyclic carbene ligands for asymmetric transition-metal catalysis. Chem. Soc. Rev. 2017, 46, 4845–4854. [CrossRef][PubMed] 34. Loup, J.; Zell, D.; Oliveira, J.C.A.; Keil, H.; Stalke, D.; Ackermann, L. Asymmetric Iron-Catalyzed C H − Alkylation Enabled by Remote Ligand meta-Substitution. Angew. Chem. Int. Ed. 2017, 56, 14197–14201. [CrossRef][PubMed] 35. Dai, L.; Hou, X. Chiral Ferrocenes in Asymmetric Catalysis: Synthesis and Applications; Wiley-VCH: Weinheim, Germany, 2010. 36. Ackermann, L. Carboxylate-Assisted Transition-Metal-Catalyzed C H Bond Functionalizations: Mechanism − and Scope. Chem. Rev. 2011, 111, 1315–1345. [CrossRef][PubMed] 37. Sunoj, R.B. Transition State Models for Understanding the Origin of Chiral Induction in Asymmetric Catalysis. Acc. Chem. Res. 2016, 49, 1019–1028. [CrossRef][PubMed] 38. Tamura, M.; Kochi, J.K. Vinylation of Grignard reagents. Catalysis by Iron. J. Am. Chem. Soc. 1971, 93, 1487–1489. [CrossRef] 39. Crockett, M.P.; Tyrol, C.C.; Wong, A.S.; Li, B.; Byers, J.A. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling Reactions between Alkyl Halides and Unactivated Arylboronic Esters. Org. Lett. 2018, 20, 5233–5237. [CrossRef][PubMed] 40. Jin, M.; Adak, L.; Nakamura, M. Iron-Catalyzed Enantioselective Cross-Coupling Reactions of α-Chloroesters with Aryl Grignard Reagents. J. Am. Chem. Soc. 2015, 137, 7128–7134. [CrossRef][PubMed] 41. Iwamoto, T.; Okuzono, C.; Adak, L.; Jin, M.; Nakamura, M. Iron-catalysed enantioselective Suzuki–Miyaura coupling of racemic alkyl bromides. Chem. Commun. 2019, 55, 1128–1131. [CrossRef] 42. Sambiagio, C.; Schönbauer, D.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M.F.; Wencel-Delord, J.; Besset, T.; et al. A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry. Chem. Soc. Rev. 2018, 47, 6603–6743. [CrossRef] 43. Gu, Q.; Al Mamari, H.H.; Graczyk, K.; Diers, E.; Ackermann, L. Iron-Catalyzed C(sp2) H and C(sp3) H − − Arylation by Triazole Assistance. Angew. Chem. Int. Ed. 2014, 53, 3868–3871. [CrossRef] 44. Cera, G.; Haven, T.; Ackermann, L. Expedient Iron-Catalyzed C H Allylation/Alkylation by Triazole − Assistance with Ample Scope. Angew. Chem. Int. Ed. 2016, 55, 1484–1488. [CrossRef] 45. Schmiel, D.; Butenschön, H. Directed Iron-Catalyzed ortho-Alkylation and Arylation: Toward the Stereoselective Catalytic Synthesis of 1,2-Disubstituted Planar-Chiral Ferrocene Derivatives. Organometallics 2017, 36, 4979–4989. [CrossRef] 46. Fang, G.-C.; Cheng, Y.-F.; Yu, Z.-L.; Li, Z.-L.; Liu, X.-Y. Recent Advances in First-Row Transition Metal/Chiral Phosphoric Acid Combined Catalysis. Top. Curr. Chem. 2019, 377, 23. [CrossRef] 47. Matsumoto, K.; Egami, H.; Oguma, T.; Katsuki, T. What factors inﬂuence the catalytic activity of iron–salan complexes for aerobic oxidative coupling of 2-naphthols? Chem. Commun. 2012, 48, 5823–5825. [CrossRef] [PubMed] 48. Egami, H.; Katsuki, T. Iron-Catalyzed Asymmetric Aerobic Oxidation: Oxidative Coupling of 2-Naphthols. J. Am. Chem. Soc. 2009, 131, 6082–6083. [CrossRef][PubMed] 49. Tkachenko, N.V.; Lyakin, O.Y.; Samsonenko, D.G.; Talsi, E.P.; Bryliakov, K.P. Highly eﬃcient asymmetric aerobic oxidative coupling of 2-naphthols in the presence of bioinspired iron aminopyridine complexes. Catal. Commun. 2018, 104, 112–117. [CrossRef] 50. Narute, S.; Parnes, R.; Toste, F.D.; Pappo, D. Enantioselective Oxidative Homocoupling and Cross-Coupling of 2-Naphthols Catalyzed by Chiral Iron Phosphate Complexes. J. Am. Chem. Soc. 2016, 138, 16553–16560. [CrossRef][PubMed]

51. Egami, H.; Matsumoto, K.; Oguma, T.; Kunisu, T.; Katsuki, T. Enantioenriched Synthesis of C 1 -Symmetric BINOLs: Iron-Catalyzed Cross-Coupling of 2-Naphthols and Some Mechanistic Insight. J. Am. Chem. Soc. 2010, 132, 13633–13635. [CrossRef] 52. Horibe, T.; Nakagawa, K.; Hazeyama, T.; Takeda, K.; Ishihara, K. An enantioselective oxidative coupling reaction of 2-naphthol derivatives catalyzed by chiral diphosphine oxide–iron(ii) complexes. Chem. Commun. 2019, 55, 13677–13680. [CrossRef][PubMed] Molecules 2020, 25, 3889 28 of 29

53. Zhang, L.; Meggers, E. Steering Asymmetric Lewis Acid Catalysis Exclusively with Octahedral Metal-Centered Chirality. Acc. Chem. Res. 2017, 50, 320–330. [CrossRef] 54. Zhang, L.; Meggers, E. Stereogenic-Only-at-Metal Asymmetric Catalysts. Chem. Asian J. 2017, 12, 2335–2342. [CrossRef] 55. Hong, Y.; Jarrige, L.; Harms, K.; Meggers, E. Chiral-at-Iron Catalyst: Expanding the Chemical Space for Asymmetric Earth-Abundant Metal Catalysis. J. Am. Chem. Soc. 2019, 141, 4569–4572. [CrossRef] 56. Wei, J.; Cao, B.; Tse, C.-W.; Chang, X.-Y.; Zhou, C.-Y.; Che, C.-M. Chiral cis -iron(ii) complexes with metal- and ligand-centered chirality for highly regio- and enantioselective alkylation of N-heteroaromatics. Chem. Sci. 2020, 11, 684–693. [CrossRef] 57. Steinreiber, J.; Ward, T.R. Artificial metalloenzymes as selective catalysts in aqueous media. Coord. Chem. Rev. 2008, 252, 751–766. [CrossRef] 58. Ringenberg, M.R.; Ward, T.R. Merging the best of two worlds: Artificial metalloenzymes for enantioselective catalysis. Chem. Commun. 2011, 47, 8470–8476. [CrossRef][PubMed] 59. Leenders, S.H.A.M.; Gramage-Doria, R.; de Bruin, B.; Reek, J.N.H. Transition metal catalysis in confined spaces. Chem. Soc. Rev. 2015, 44, 433–448. [CrossRef][PubMed] 60. Rosati, F.; Roelfes, G. Artificial Metalloenzymes. ChemCatChem 2010, 2, 916–927. [CrossRef] 61. Leveson-Gower, R.B.; Mayer, C.; Roelfes, G. The importance of catalytic promiscuity for enzyme design and evolution. Nat. Rev. Chem. 2019, 3, 687–705. [CrossRef] 62. Kan, S.B.J.; Huang, X.; Gumulya, Y.; Chen, K.; Arnold, F.H. Genetically programmed chiral organoborane synthesis. Nature 2017, 552, 132–136. [CrossRef] 63. Kan, S.B.J.; Lewis, R.D.; Chen, K.; Arnold, F.H. Directed evolution of cytochrome c for carbon–silicon bond formation: Bringing silicon to life. Science 2016, 354, 1048–1051. [CrossRef] 64. Chen, K.; Arnold, F.H. Engineering new catalytic activities in enzymes. Nat. Catal. 2020, 3, 203–213. [CrossRef] 65. Zhang, R.K.; Romney, D.K.; Kan, S.B.J.; Arnold, F.H. Artificial Metalloenzymes and MetalloDNAzymes in Catalysis. From Design to Applications; Dieguez, M., Bäckvall, J.-E., Pamies, O., Eds.; Wiley-VCH: Weinheim, Germany, 2018. 66. Prier, C.K.; Zhang, R.K.; Buller, A.R.; Brinkmann-Chen, S.; Arnold, F.H. Enantioselective, intermolecular benzylic C–H amination catalysed by an engineered iron-haem enzyme. Nat. Chem. 2017, 9, 629–634. [CrossRef] 67. De Montellano, P.R.O. Hydrocarbon Hydroxylation by Cytochrome P450 Enzymes. Chem. Rev. 2010, 110, 932–948. [CrossRef][PubMed] 68. Coelho, P.S.; Wang, Z.J.; Ener, M.E.; Baril, S.A.; Kannan, A.; Arnold, F.H.; Brustad, E.M. A serine-substituted P450 catalyzes highly efficient carbene transfer to olefins in vivo. Nat. Chem. Biol. 2013, 9, 485–487. [CrossRef] [PubMed] 69. Chen, K.; Arnold, F.H. Engineering Cytochrome P450s for Enantioselective Cyclopropenation of Internal Alkynes. J. Am. Chem. Soc. 2020, 142, 6891–6895. [CrossRef][PubMed] 70. Jia, Z.-J.; Gao, S.; Arnold, F.H. Enzymatic Primary Amination of Benzylic and Allylic C(sp3)–H Bonds. J. Am. Chem. Soc. 2020, 142, 10279–10283. [CrossRef][PubMed] 71. Park, Y.; Kim, Y.; Chang, S. Transition Metal-Catalyzed C–H Amination: Scope, Mechanism, and Applications. Chem. Rev. 2017, 117, 9247–9301. [CrossRef] 72. Goldberg, N.W.; Knight, A.M.; Zhang, R.K.; Arnold, F.H. Nitrene Transfer Catalyzed by a Non-Heme Iron Enzyme and Enhanced by Non-Native Small-Molecule Ligands. J. Am. Chem. Soc. 2019, 141, 19585–19588. [CrossRef] 73. Rioz-Martínez, A.; Oelerich, J.; Ségaud, N.; Roelfes, G. DNA-Accelerated Catalysis of Carbene-Transfer Reactions by a DNA/Cationic Iron Porphyrin Hybrid. Angew. Chem. Int. Ed. 2016, 55, 14136–14140. [CrossRef] 74. Ding, K.; Guo, H.; Li, X.; Yuan, Y.; Wang, Y. Synthesis of NOBIN Derivatives for Asymmetric Catalysis. Top. Catal. 2005, 35, 105–116. [CrossRef] 75. Bringmann, G.; Price Mortimer, A.J.; Keller, P.A.; Gresser, M.J.; Garner, J.; Breuning, M. Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angew. Chem. Int. Ed. 2005, 44, 5384–5427. [CrossRef]

76. Forkosh, H.; Vershinin, V.; Reiss, H.; Pappo, D. Stereoselective Synthesis of Optically Pure 2-Amino-20- hydroxy-1,10-binaphthyls. Org. Lett. 2018, 20, 2459–2463. [CrossRef] Molecules 2020, 25, 3889 29 of 29

77. Marcyk, P.T.; Jeﬀeries, L.R.; AbuSalim, D.I.; Pink, M.; Baik, M.; Cook, S.P. Stereoinversion of Unactivated Alcohols by Tethered Sulfonamides. Angew. Chem. Int. Ed. 2019, 58, 1727–1731. [CrossRef][PubMed] 78. Knowles, W.S. Asymmetric Hydrogenations (Nobel Lecture). Angew. Chem. Int. Ed. 2002, 41, 1998–2007. [CrossRef] 79. Noyori, R. Asymmetric Catalysis: Science and Opportunities (Nobel Lecture 2001). Adv. Synth. Catal. 2003, 345, 1–2. [CrossRef] 80. Wang, D.; Astruc, D. The Golden Age of Transfer Hydrogenation. Chem. Rev. 2015, 115, 6621–6686. [CrossRef] 81. Morris, R.H. Asymmetric hydrogenation, transfer hydrogenation and hydrosilylation of ketones catalyzed by iron complexes. Chem. Soc. Rev. 2009, 38, 2282–2291. [CrossRef] 82. De Luca, L.; Mezzetti, A. Base-Free Asymmetric Transfer Hydrogenation of 1,2-Di- and Monoketones Catalyzed

by a (NH)2P2-Macrocyclic Iron(II) Hydride. Angew. Chem. Int. Ed. 2017, 56, 11949–11953. [CrossRef] 83. Bigler, R.; Huber, R.; Mezzetti, A. Highly Enantioselective Transfer Hydrogenation of Ketones with Chiral

(NH)2P2 Macrocyclic Iron(II) Complexes. Angew. Chem. Int. Ed. 2015, 54, 5171–5174. [CrossRef] 84. Xue, Q.; Wu, R.; Wang, D.; Zhu, M.; Zuo, W. The Stabilization Eﬀect of π-Backdonation Ligands on the Catalytic Reactivities of Amido-Ene(amido) Iron Catalysts in the Asymmetric Transfer Hydrogenation of Ketones. Eur. J. Inorg. Chem. 2020.[CrossRef] 85. Zuo, W.; Lough, A.J.; Li, Y.F.; Morris, R.H. Amine(imine)diphosphine iron catalysts for asymmetric transfer hydrogenation of ketones and imines. Science 2013, 324, 1080–1083. [CrossRef] 86. Casey, C.P.; Guan, H. An Eﬃcient and Chemoselective Iron Catalyst for the Hydrogenation of Ketones. J. Am. Chem. Soc. 2007, 129, 5816–5817. [CrossRef] 87. Van Slagmaat, C.A.M.R.; Chou, K.C.; Morich, L.; Hadavi, D.; Blom, B.; De Wildeman, S.M.A. Synthesis and Catalytic Application of Knölker-Type Iron Complexes with a Novel Asymmetric Cyclopentadienone Ligand Design. Catalysts 2019, 9, 790. [CrossRef]

88. Liu, X.; Lin, L.; Feng, X. Chiral N,N0-dioxide ligands: Synthesis, coordination chemistry and asymmetric catalysis. Org. Chem. Front. 2014, 1, 298–302. [CrossRef] 89. Li, W.; Zhou, P.; Li, G.; Lin, L.; Feng, X. Catalytic Asymmetric Halohydroxylation of α,β-Unsaturated Ketones with Water as the Nucleophile. Adv. Synth. Catal. 2020, 362, 1982–1987. [CrossRef]

90. Wang, F.; Feng, L.; Dong, S.; Liu, X.; Feng, X. Chiral N,N0-dioxide–iron(III)-catalyzed asymmetric sulfoxidation with hydrogen peroxide. Chem. Commun. 2020, 56, 3233–3236. [CrossRef] 91. Pang, H.; Wang, Y.; Gallou, F.; Lipshutz, B.H. Fe-Catalyzed Reductive Couplings of Terminal (Hetero)Aryl Alkenes and Alkyl Halides under Aqueous Micellar Conditions. J. Am. Chem. Soc. 2019, 141, 17117–17124. [CrossRef][PubMed] 92. Yu, T.; Ding, Z.; Nie, W.; Jiao, J.; Zhang, H.; Zhang, Q.; Xue, C.; Duan, X.; Yamada, Y.A.Y.; Li, P. Recent Advances in Continuous-Flow Enantioselective Catalysis. Chem. Eur. J. 2020, 26, 5729–5747. [CrossRef] 93. Neumeier, M.; Chakraborty, U.; Schaarschmidt, D.; de la Pena O’Shea, V.; Perez-Ruiz, R.; Jacobi von Wangelin, A. Combined Photoredox and Iron Catalysis for the Cyclotrimerization of Alkynes. Angew. Chem. Int. Ed. 2020, 59, 1–7. [CrossRef]

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).