Iridium-Catalyzed Asymmetric Allylic Substitution Reactions

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Iridium-Catalyzed Asymmetric Allylic Substitution Reactions Qiang Cheng,†,∥ Hang-Fei Tu,†,∥ Chao Zheng,† Jian-Ping Qu,‡ Günter Helmchen,*,§ and Shu-Li You*,†

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State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China ‡ Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China § Organisch-Chemisches Institut der Ruprecht-Karls, Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany ABSTRACT: In this review, we summarize the origin and advancements of iridiumcatalyzed asymmetric allylic substitution reactions during the past two decades. Since the first report in 1997, Ir-catalyzed asymmetric allylic substitution reactions have attracted intense attention due to their exceptionally high regio- and enantioselectivities. Ircatalyzed asymmetric allylic substitution reactions have been significantly developed in recent years in many respects, including ligand development, mechanistic understanding, substrate scope, and application in the synthesis of complex functional molecules. In this review, an explicit outline of ligands, mechanism, scope of nucleophiles, and applications is presented.

CONTENTS 1. Introduction 2. Ligands for Ir-Catalyzed Asymmetric Allylic Substitutions 3. Mechanistic Studies of Ir-Catalyzed Allylic Substitutions 3.1. Origin of Enantioselectivity 3.2. Origin of Regioselectivity 4. Ir-Catalyzed Asymmetric Allylic Alkylations 4.1. Stabilized Enolates 4.1.1. Malonic Acid Derivatives as Pronucleophiles 4.1.2. Malononitrile and Masked Acyl Cyanide Reagents 4.1.3. Diastereoselective Alkylations with Prochiral Stabilized Enolates 4.1.4. Sulfonylacetic Esters and Disulfones as Pronucleophiles 4.2. Aliphatic Nitro Compounds 4.3. Glycine Equivalents 4.4. Unstabilized Ester and Ketone Enolates 4.4.1. Decarboxylative Alkylation 4.4.2. Silyl Enol Ethers and Related Compounds as Pronucleophiles 4.4.3. Allylic Alkylations with Lithium, Barium, and Copper Enolates 4.4.4. Allylic Alkylations of Ketones via Dual, Synergistic, and Stereodivergent Catalysis 4.4.5. Allylic Alkylations with Trimethyl Orthoacetate and Ethylene Glycol Monovinyl Ether 4.5. Aldehydes and Enamines © XXXX American Chemical Society

AB

4.5.1. Preformed Enamines from Methyl Ketones as Nucleophiles 4.5.2. Dual Catalysis and Stereodivergence in Ir-Catalyzed Allylic Substitutions via Enamines 4.5.3. Diastereoselective Intramolecular Allylic Alkylations via Enamines 4.6. Electron-Rich Arenes 4.6.1. Indoles 4.6.2. Pyrroles 4.6.3. Phenols and Naphthols 4.6.4. Anilines 4.7. Organometallic Reagents 5. Ir-Catalyzed Asymmetric Allylic Substitutions with Olefins as Nucleophiles 5.1. Olefins via C−H Activation 5.2. Alkenes in Polyene Cyclization 5.3. Intermolecular Allylic Substitution with Alkenes as Nucleophiles 6. Ir-Catalyzed Asymmetric Allylic Substitutions with Hydrazones and Imines 6.1. Hydrazones 6.2. Umpolung of Imines 7. Ir-Catalyzed Asymmetric Allylic Aminations 7.1. Aliphatic Amines and Arylamines 7.1.1. Intermolecular Allylic Aminations with Alkyl- and Arylamines 7.1.2. Intramolecular and Sequential Interand Intramolecular Aminations 7.2. Sulfonamides

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Received: August 9, 2018

B B B E J K K K Q R U V V X X X AB

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AG AJ AJ AJ AR AR AT AV AY AY BA BA BB BB BC BD BD BD BJ BK

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Chemical Reviews 7.3. Carboxamides 7.3.1. N,N-Diacylamines 7.3.2. Carbamates via Decarboxylative Allylic Amidations 7.3.3. Primary Amides and Urethanes as Nucleophiles 7.3.4. Hydroxamic Acid Derivatives 7.3.5. Intramolecular Allylic Amidations 7.4. Nitrogen-Containing Heteroarenes 7.4.1. Intermolecular Aminations with Heterocycles 7.4.2. Intramolecular Aminations with Heterocycles 7.5. Ammonia and Sulfamic Acid as an Ammonia Surrogate 7.6. Guanidines 8. Ir-Catalyzed Asymmetric Allylic Substitutions with Oxygen Nucleophiles 8.1. Phenolates in Direct Substitutions and Decarboxylative Allylic Alkylations 8.2. Alcohols and Alkoxides 8.3. Hydroxylamine Derivatives 8.4. Silanolates and Hydroxide 8.5. Carboxylates and Carbamates 9. Ir-Catalyzed Asymmetric Allylic Substitutions with Sulfur, Selenium, and Halogen Nucleophiles 9.1. Sulfinates and Sulfites 9.2. Carbamothioates 9.3. Thiolates and Thioates 9.4. Selenide 9.5. Fluoride 10. Applications of Ir-Catalyzed Asymmetric Allylic Substitutions in Total Synthesis 11. Conclusions and Perspectives Author Information Corresponding Authors ORCID Author Contributions Notes Biographies Acknowledgments Abbreviations References

Review

ligands. Catalysts derived from other metals, including W,5 Mo,6−14 Ru,15−20 Rh,21−27 Ni,28−30 and Cu,31−39 were relatively less explored, but showed promising regio- and enantioselective control. Since the first report on an Ircatalyzed allylic substitution reaction by Takeuchi and Kashio,40 iridium complexes were found to be efficient catalysts for allylic substitution reactions. Compared with Pd catalysis, Ir catalysis has its own unique features. Particularly, allylic electrophiles with one terminal substituent usually yield achiral linear products with Pd catalysts, while Ir catalysts normally furnish branched products with excellent regio- and enantioselectivities. The most significant factor that accelerated the advancement of Ir-catalyzed asymmetric allylic substitution reactions was the discovery of the efficiency induced by chiral phosphoramidite ligands. The contributors include the groups of Hartwig, Helmchen, Carreira, Alexakis, You, and many others. The mechanistic understanding, mainly derived from efforts of the groups of Hartwig, Helmchen, Carreira, and You, have further shed light on the design of ligands and expanded the substrate scope in this field. However, a comprehensive review containing ligand and reaction development, mechanistic investigations, and synthetic applications, particularly those reported over the recent five years, is elusive.41−49 Herein we summarize the development of ligands and nucleophiles, mechanistic studies, and synthetic applications of Ir-catalyzed allylic substitution reactions from the very beginning of the discovery to the most recent results. Please note that the Krische reactions, i.e., Ir-catalyzed allylation reactions of carbonyl compounds via σ-allyliridium intermediates,50,51 will not be discussed herein.

BL BL BO BP BP BP BQ BQ BT BW BX BY BY CB CF CF CF CF CF CH CH CJ CJ

2. LIGANDS FOR IR-CATALYZED ASYMMETRIC ALLYLIC SUBSTITUTIONS To date, various chiral ligands have been applied in Ircatalyzed asymmetric allylic substitution reactions (Figure 1). Among these, phosphoramidite ligands unarguably are the most useful ones. The phosphoramidite ligands, introduced by Feringa and co-workers,52,53 were first applied in Ir-catalyzed allylic alkylation by the Helmchen54 group and in allylic amination by the Hartwig55 group. In addition, another efficient type of phosphoramidite ligand is a (P,olefin)-ligand developed by the Carreira group, now known as the Carreira ligand.56 Ir complexes containing these ligands as well as other established ligands are summarized in Figure 2.

CL CX CY CY CY CY CY CY CY CY CZ

1. INTRODUCTION Transition-metal-catalyzed coupling reactions are highly important for the construction of carbon−carbon and carbon−heteroatom bonds. Among these, asymmetric allylic substitution reactions (Tsuji−Trost reactions) have evolved into reliable methods for the synthesis of enantiomerically pure organic compounds (Scheme 1). Early studies of Tsuji−Trost reactions were mainly focused on palladium catalysts,1−4 which feature a broad scope of both electrophiles and nucleophiles and readily available chiral

3. MECHANISTIC STUDIES OF IR-CATALYZED ALLYLIC SUBSTITUTIONS The first Ir-catalyzed allylic alkylation reaction was reported by Kashio and Takeuchi in 1997.40 The phosphite P(OPh)3 was found to be an efficient ligand to form an active catalyst in situ with [Ir(cod)Cl]2, which induced reactions favoring branched products (Table 1). Sodium malonates were typically employed as nucleophiles in these reactions (Scheme 2). Acetates and carbonates were found to be suitable substrates. The reaction could occur even with trisubstituted allylic acetates to form products with a quaternary stereogenic center. In addition, the cyclic allylic carbonate 4 furnished product 5 with full retention of configuration, albeit in poor yield because of lower reactivity. This supported a double inversion or double retention pathway (Scheme 3).57 The decision in favor of the double inversion pathway was provided by Helmchen et al. by means of a Fiaud test in 2002.58

Scheme 1. Transition-Metal-Catalyzed Allylic Substitution

B

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Figure 1. Chiral ligands used in Ir-catalyzed asymmetric allylic substitutions.

the following conclusions: (a) Solvents affected both the reactivity and regioselectivity of the reaction, with polar solvents providing better yields and branched:linear (b:l) selectivity. (b) With primary amines, no diallylation was observed, which is in marked contrast to Pd catalysis. (c) Arylsubstituted allylic carbonates produced amination products with higher regioselectivity than alkyl-substituted ones. (d) Allylic acetates were less reactive than allylic carbonates. (e) Allylic amination of (Z)-2-alkenyl carbonates mainly afforded (Z)-linear products. Helmchen and co-workers investigated the possible intermediates to figure out the active catalyst as well as the detailed mechanism (Scheme 5).58 Mixing [Ir(cod)Cl]2 and 2 equiv of P(OPh)3 formed the complex K1a, which, however, is

At this early stage, an important stereochemical issue was clarified by the Helmchen group to explain the observation that under basic reaction conditions branched allylic substrates are generally less suitable in enantioselective allylic substitutions than linear substrates. Alkylations using an achiral catalyst in combination with enantiomerically pure substrates 6 and 8 revealed a high degree of stereospecificity, i.e., conservation of enantiomeric purity (Scheme 4).54 This result proved that the rate of nucleophilic attack is faster than the rate of isomerization of intermediary allyl complexes. An explicit investigation of allylic amination reactions catalyzed by the iridium/P(OPh)3 catalyst was carried out by the Takeuchi group.59 After screening various reaction parameters, ranging from solvents to substrates, they reached C

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Figure 2. Ir complexes.

not reactive toward allylic substrates. When the nucleophile NaCH(CO2Me)2 was added to K1a combined with P(OPh)3,

an Ir(I) complex, K2a, was formed via C−H activation at the phenyl group of the phosphite ligand. As complex K2a is D

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Table 1. First Report on the Ir-Catalyzed Allylic Substitution Reaction

entry

ligand

T (°C)

time (h)

yield (%)

b:l

1 2 3 4 5

P(OPh)3 P(OEt)3 P(O-i-Pr)3 PPh3 P(n-Bu)3

rt 65 65 65 65

3 3 9 16 16

89 81 44 6 0

96:4 59:41 53:47 24:76

Scheme 2. Substrate Scope for the Allylic Alkylation Reaction

Scheme 5. Cyclometalated Species of Ir Complexes with P(OPh)3

high regio- and enantioselectivities in allylic alkylation reactions. To gain insight into the reaction mechanism, the crystal structure of the (π-allyl)(PHOX)IrIII complex was prepared by Helmchen and co-workers (Scheme 7).61 Testing the complex as a catalyst led to lower regio- and enantioselectivities. It was found that complex K3a reacted with NaCH(CO2CH3)2 to yield complex K4, which was formed via nucleophilic addition at the central allylic carbon to give the iridacyclobutane complex (Scheme 8). This result may account for the observed discrepancy between the in situ generated catalyst and the complex K3a. A landmark contribution to the field of Ir-catalyzed enantioselective allylic substitution reactions was made by the Hartwig group in 2003. Feringa-type ligands52,53 were introduced to an Ir-catalyzed asymmetric allylic amination reaction, which was used as the model reaction to investigate the key intermediates involved in the processes. The initially formed complex K1b, prepared by mixing [Ir(cod)Cl]2 with ligand L1, was not an active catalyst (Scheme 9). It was later found that the metallacyclic iridium complex K6a was the active catalyst, which was formed via a C−H bond activation of the methyl group of the ligand upon addition of the amine.62 The residual ligand L1 in K6a could be exchanged by a more strongly coordinating dative ligand, PMe3 or PPh3, to generate complexes K6c and K6d. In addition, when these pendent ligands in K6a and K6b were replaced with ethylene, complexes K6e and K6f were prepared, which displayed improved efficiency in allylic substitution reactions, as elucidated later by Hartwig and co-workers by kinetic studies.63 Hartwig and co-workers further studied the ligands and the iridacyclic complexes.64 The functions of different parts of the phosphoramidite ligands were investigated.65 It was found that the configuration of the binaphthol part determined the configuration of the allylic substitution products. In addition, ligand L6a bearing a single phenethyl stereogenic center was shown to give results similar to those of the more complex ligand L1. Furthermore, by investigation of an iridacyclic catalyst derived from ligand L4, a diastereoisomer of L1, they found that the origin of the divergent reactivity displayed by

Scheme 3. Stereospecific Allylic Alkylation

Scheme 4. Stereospecificity of Allylic Alkylations with Enantiomerically Pure Allylic Substrates

coordinatively saturated, P(OPh)3 must dissociate to obtain a catalytically active species. 3.1. Origin of Enantioselectivity

In 1997, Helmchen and Jansen reported the first Ir-catalyzed enantioselective allylic alkylation reaction (Scheme 6).60 A chiral phosphinooxazoline ligand, L7b, was used in combination with [Ir(cod)Cl]2 to form the catalyst, which furnished E

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Scheme 6. First Report of Ir-Catalyzed Asymmetric Allylic Alkylation

At almost the same time, Helmchen and co-workers developed a more straightforward synthesis of the allyliridium intermediates by using allylic carbonates directly (Scheme 11).67,68 It was found that the complexes were air-stable and could be purified by silica gel column chromatography. The preparation according to Scheme 11 turned out to be applicable to a wide variety of allylic substrates and ligands and has become the standard procedure in this area. The very high yield of a single complex was astonishing, considering that 16 stereoisomers are possible. Density functional theory (DFT) calculations showed that the observed complex is the thermodynamically more stable one. The C−H activation step was proposed to be reversible, as the reformation of K1c was observed by 31P NMR spectroscopy upon addition of weak acids, such as ammonium halides, to the solution of complex K6b (Scheme 12). On the basis of DFT calculations, the 16 valence electron (VE) intermediate K5b was postulated as the active species in the catalytic cycle. As described above, K8 was synthesized in a convenient, onepot procedure and characterized by X-ray crystal structure analysis. During the study of the formation of K8 (Scheme 11), a mixture of diastereomeric hydridoiridium complexes K6g was observed by NMR spectroscopy. The base generated from the alkyl carbonate drives the reaction equilibrium toward K8. The asymmetric allylic alkylation reactions catalyzed by complex K8 gave results similar to those of the in situ generated catalyst. On the basis of an NMR study, it was found that complexes K8 and K9 are the resting states of the reaction, mainly depending on the nucleophiles employed and reaction conditions (Scheme 12). In addition, it was found that π-allyl complexes obtained by replacing cod in K8 with dbcot could catalyze the asymmetric allylic alkylation reaction under aerobic conditions, yielding the products in high enantioselectivity and usually with improved regioselectivity.

Scheme 7. Synthesis of Chiral Allyliridium(III) Complexes K3a and K3b

Scheme 8. An Unexpected Result for the Reaction of Complex K3a with Sodium Dimethyl Malonate

the diastereomeric catalysts was probably due to differing rates of catalyst activation. In 2009, Hartwig and co-workers synthesized and characterized π-allyliridium intermediates (Scheme 10) by treating the metallacyclic iridium complex K6e with the corresponding allylic halides in benzene, followed by an exchange of the counteranion with silver salts at room temperature.66 Structures of the π-allyliridium complexes K7a·OTf and K7b·SbF6 were confirmed by X-ray diffraction analysis. The reactions of stoichiometric amounts of K7a·OTf and K7b·SbF6 with carbon and heteroatom nucleophiles were also investigated. The yields, regioselectivities, and enantioselectivities (for K7b·SbF6) of these reactions were similar to those of the catalytic reactions of allyl methyl carbonates promoted by Ir complex K6e.

Scheme 9. Cyclometalated Species of Ir Complexes with Phosphoramidites

F

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Scheme 10. Preparation of π-Allyliridium Complexes

Scheme 11. A Straightforward Synthesis of π-Allyliridium Complexes

mechanistic studies revealed that the active metallacyclic iridium complex was formed via C(sp2)−H bond activation of the phenyl group, different from that of Feringa-type ligands. DFT calculations also supported the understanding that this C(sp2)−H activation mode is responsible for the excellent selectivity in the allylic alkylation reactions. Hartwig and co-workers took a further step in the investigation of the origin of the high enantioselectivity of Ircatalyzed allylic substitutions.70 Using allylic amination as a model reaction system, they first synthesized both the thermodynamically more stable π-allyliridium complex and a less stable one, via the reaction of a linear and branched allylic ester, respectively, with the complex K6e (Scheme 14). A comparison between the rates of epimerization of the πallyliridium complexes containing weakly coordinating anions and the rates of nucleophilic attack was conducted. These results revealed that the epimerization process (from the less to more stable one) occurred with a rate constant of 5.4 × 10−5 s−1 at −40 °C, while nucleophilic attack was found to be an order of magnitude faster (2.5 × 10−3 s−1). Thus, the oxidative addition step is the stereodetermining step, as the more stable π-allyliridium intermediate leads to the major enantiomer of the product. In addition, the rates of nucleophilic attack on both π-allyliridium diastereomers were compared (Scheme 15). Though the less stable intermediate reacted faster, the stereoselectivity of the oxidative addition step is sufficiently high to cause the overall process to occur with high enantioselectivity. Reactions with enantioenriched, monodeuterated allylic carbonates catalyzed by the enantiomers of the cyclometalated Ir catalyst K6e were carried out to determine the changes in configuration through the catalytic cycle (Scheme 16). The oxidative addition proceeded predominantly with inversion of configuration, forming allyliridium complexes in an 83:17 ratio. The authors proposed that the lack of exclusive formation of

Scheme 12. Proposed Catalytic Cycle for Ir-Catalyzed Allylic Substitution Reactions

In 2012, You and co-workers introduced N-arylphosphoramidite ligands in Ir-catalyzed asymmetric allylic alkylation reactions with nucleophiles derived from malonate diesters.69 Among these ligands, (R,Ra)-Me-THQphos (L12b) was found to be the optimal one considering both reactivity and selectivity. It is noteworthy that, with this ligand, the unfavorable ortho-substituent effect observed for many different types of nucleophiles in conjunction with the use of Feringa-type ligands could be overcome (Scheme 13). Further G

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Scheme 13. Preparation of an Iridium Complex Containing Me-THQphos (L12b) and Allylic Alkylation Reactions with orthoSubstituted Cinnamyl Electrophiles

Scheme 14. Synthesis of Both Diastereomers of π-Allyliridium Complexes

Scheme 15. Relative Rates of Nucleophilic Attack on Diastereomers of π-Allyliridium Complexes

Scheme 16. Stoichiometric Reactions of Complex K6e with an Enantioenriched, Deuterium-Labeled Electrophile

H

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Scheme 17. Synthesis of Iridium Intermediates Containing the Carreira Ligand

same product distribution, which was consistent with their prior experimental and computational72 results. The major diastereomer was assigned as an exo-configuration by X-ray crystal structure analysis and NMR studies. The Ir−C benzylic carbon bond is longer than that of the terminal carbon, which may be due to the strong trans influence of the phosphorus, rendering this position more electrophilic against nucleophilic attack, yielding the branched product preferentially. Complexes K12a and K13 were demonstrated to be catalytically and kinetically competent intermediates in the asymmetric allylic substitution reaction. Remarkably, addition of a nucleophile at the major exo-isomers with inversion, i.e., from the face opposite to Ir, would give rise to the minor enantiomers of the products. Thus, if direct addition to complexes K13 was product determining, either faster reaction of the minor endo-allyl complexes K13 or an inner sphere mechanism with retention must be invoked. Further experiments, such as those described above (cf. Scheme 16), need to be carried out. Furthermore, prolonged reaction time during catalyst formation led to the complex K14a with two chiral ligands in bidentate mode bound at iridium (Scheme 18). Treating complex K14a with an excess of allylic alcohol did not furnish

one stereoisomer was likely due to partial racemization of the substrate during esterification of the alcohol.70 The subsequent nucleophilic attack also proceeded with inversion of configuration. Thus, the Helmchen group’s previous conclusions (cf. Scheme 3) for alkylations58 were corroborated for aminations. The key points for enantioselective allylic substitution reactions catalyzed by cyclometalated Ir complexes can be summarized as follows: (a) The reactions proceed with inversion of configuration of both oxidative addition and attack of the nucleophile, i.e., overall retention of configuration. (b) π−σ−π-Isomerization of the allyliridium intermediates is slow compared to the rate of attack of the nucleophile. (c) The stereodetermining step is the oxidative addition of the catalyst. Previous studies by Helmchen, Hartwig, and You have demonstrated that the active Ir catalysts are the cyclometalated iridium complexes generated via C(sp3)−H activation or C(sp2)−H activation. Two obvious features are noticeable: First, the frequently employed electrophiles in these reactions are linear allylic carbonates, while branched allylic substrates usually provide low enantioselectivity. Second, basic reaction conditions are needed to promote the reaction effectively. In 2007, the Carreira group reported a new variant of Ircatalyzed allylic substitution reaction, in which branched allylic alcohols were used as the electrophiles in combination with an acid promoter.56 An Ir complex derived from (P,olefin)-ligand L8 was found to be a powerful catalyst for asymmetric allylic substitution reactions. In 2017, the Carreira group isolated and characterized two important intermediates, diastereoisomers of an (η2-allylic alcohol)iridium(I) complex (K12a) and an η3allyliridium(III) complex (K13) (Scheme 17).71 According to the X-ray crystal structure of complex K12a, the two ligands are bound differently to iridium, with one coordinated in a bidentate (η2-κP) fashion, whereas the other is bound solely at phosphorus. The double bond of the allylic alcohol of K12a is coordinated with iridium to form a distorted trigonal bipyramidal geometry. In the presence of triflic acid, both the diastereomers of complex K12a could be transformed to the η3-allyliridium(III) complex K13 in an identical diastereomer ratio by oxidative addition of the protonated allylic alcohol. The authors postulated that rapid isomerization of the two diastereomeric allyl complexes occurred to give the

Scheme 18. Iridium Complexes K14a and K23

I

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Scheme 19. Proposed Catalytic Cycle of the Allylic Substitution Reaction Catalyzed by the Carreira Ir Complex

Scheme 20. X-ray Crystal Structure of π-Allyliridium Complex K15

Scheme 21. Kinetic Study of the Oxidative Addition Process

the catalytically active complex K12a. Thus, catalyst preparation requires great care to avoid slow formation of the complex K14a; Carreira et al. recommend to include the allylic alcohol from the outset upon in situ catalyst preparation. It was further observed that molecular oxygen gave rise to the complex K23 (Scheme 18). Binding of oxygen is reversible, and the complex K12a is formed from K23 in the presence of branched allylic alcohol; as a consequence, the allylic substitution reaction is only slowed rather than fully inhibited by molecular oxygen. This result explains the observed air tolerance of the catalyst system. On the basis of these results, Carreira and co-workers proposed the following reaction mechanism: at the outset, coordination of the allylic alcohol to the Ir catalyst generates the η2-complex K12a, which undergoes acid-promoted oxidative addition to give the η3-allyliridium(III) complex K13. Subsequent nucleophilic attack and ligand exchange with allylic alcohol complete the catalytic cycle (Scheme 19). Note

that Carreira et al. have chosen to present the pathway via the minor allylic isomers endo-K13. 3.2. Origin of Regioselectivity

Early on, several hypotheses were proposed for rationalization of the marked regioselectivity of Ir-catalyzed allylic substitutions, for example, invoking preferred reaction at the site with the longer metal−carbon bond66 or with the higher positive charge of the allyliridium complex.57,59 The first systematic evaluation was carried out by the Helmchen group in 2010 (cod complexes)68 and 2012 (dbcot complexes),73 based on DFT calculations for aminations with Ir complexes K8. While the calculations qualitatively reproduced enantio- and regioselectivity, no simple answer on the origin of the preferred formation of branched isomers was found. Product development control was excluded, i.e., stability of the product complexes; charges, lowest unoccupied molecular orbital (LUMO) coefficients, and C−Ir bond J

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Scheme 22. DFT Calculations of the Nucleophilic Attack of Trifluoroacetate on the π-Allyliridium Complexes

4. IR-CATALYZED ASYMMETRIC ALLYLIC ALKYLATIONS

lengths at the allylic termini could not be correlated with regioselectivity. The origin of the high regioselectivity for Ir-catalyzed allylic alkylation reactions with malonates as nucleophiles was investigated by Hartwig and co-workers in 2015,74 using iridium catalysts derived from P(OPh)3. The allylic metallacyclic iridium complexes were synthesized with the method developed by Helmchen and co-workers.58 Though two diastereomers were generated at room temperature, the major diastereomer K15 could be obtained as a single isomer at low temperature and was characterized by X-ray crystallographic analysis (Scheme 20). These π-allyliridium complexes were active species for both stoichiometric and catalytic reactions, preferentially giving rise to branched products. The Ir−C bond lengths of the allylic termini were both 2.28 Å, indicating that the difference of these bond lengths should not be the major reason for the regioselectivity. By a kinetic study of the oxidative addition reaction of metallacyclic iridium complex K2b with branched or linear allylic trifluoacetate 12l or 12b, respectively, the branched substrate was found to react approximately 170 times faster than the linear one (Scheme 21). According to the principle of microscopic reversibility, it could be deduced that the nucleophilic attack to form the branched product should also be faster than that of the linear one, which was supported by DFT calculations (Scheme 22). Since, in the crystal structure of K15, CH···F attractive interactions between the cod ligand and the tetrafluoroborate were observed, Hartwig and co-workers proposed that, during the process of nucleophilic attack, the oxygen atom on the nucleophile could interact with the C−H bond of the cod ligand, which might determine the regioselectivity. This hypothesis was supported by calculations which showed that attractive C H···O interactions between the cod ligand and the oxygen atom of the nucleophile in the transition state are a major factor favoring the formation of the branched product. A corresponding interaction was not seen in the transition states of aminations by Helmchen et al.68,73 Overall, this work underlines that a general explanation of the observed regioselectivites remains elusive.

4.1. Stabilized Enolates

4.1.1. Malonic Acid Derivatives as Pronucleophiles. The first nucleophiles used, by Takeuchi as well as Helmchen, in Ir-catalyzed allylic substitution reactions were malonic acid diesters.40,60 In 1997, the Helmchen group reported the first Ir-catalyzed enantioselective alkylation reactions of monosubstituted allylic acetates 10 (Scheme 23).60 It was found that with arylallyl Scheme 23. First Ir-Catalyzed Asymmetric Allylic Alkylations

acetates and phosphinooxazoline ligand L7b, the desired branched products could be obtained in excellent yields and regio- and enantioselectivities. These results indicated a great potential of iridium catalysis for asymmetric allylic substitution and opened up a new field for Tsuji−Trost-type reactions. Further studies showed that phosphinooxazolines are not suitable ligands in the case of substrates with aliphatic substituents.54,75 For example, using ligand L7b, it was found that branched allylic acetates furnished products in high regioselectivity (b:l) but low enantioselectivity (Table 2, entries 1 and 3). The reason was outlined above: slow isomerization of intermediary π-allyliridium complexes. Linear substrates gave better results with respect to enantioselectivity, but relatively low regioselectivity for aliphatically substituted ones (Table 2, entries 2 and 4). More promising results were obtained with phosphoramidites, ligands that had been introduced by Feringa and coworkers three years prior to this work.52 With the easily accessible phosphoramidite L24, excellent regioselectivity with only moderate enantioselectivity was obtained from linear allylic acetates (Table 2, entries 5 and 6).76 A better result was obtained with the branched acetate rac-11b (entry 7). Speculating that the moderate ee with the branched substrate might be due to slow isomerization of intermediary πK

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Table 2. Ir-Catalyzed Allylic Alkylation with Phosphoramidites as Ligands

entry

substrate

ligand

1 2 3 4 5 6 7 8 9 10 11

rac-11a 10a rac-11b 10b 10b 10a rac-11b (R)-11b (99.5% ee) (R)-11b (91% ee) (R)-11b (91% ee) (S)-11b (98% ee)

L7b L7b L7b L7b L24 L24 L24 L24 L23 L23

additive

LiCl LiCl

yield (%)

3:4

ee (%) of 3

99 99 99 93 54 99 92 99 98 61 67

95:5 95:5 95:5 62:38 95:5 98:2 98:2 99:1 99:1 79:21 91:9

15 (S) 91 (R) 8 (S) 78 (R) 43 (R) 37 (R) 69 (R) 93 (R) 39 (R) 34 (R) 85 (S)

obtained for both monoarylallyl acetates and carbonates (Scheme 25). As expected, racemic branched allylic substrate led to products in poor enantioselectivity, and a stereospecific reaction was observed when enantiomerically pure substrate 11a was applied. A highly efficient asymmetric allylic alkylation reaction of linear aryl and alkyl carbonates with sodium dimethyl malonate in the presence of Ir catalyst was reported by Polet and Alexakis in 2004.79 The phosphoramidite ligand L2, developed in their group, was used in combination with the reaction conditions worked out by the Helmchen group76 (Scheme 26). The corresponding phosphoramidite derived from biphenol also served as an excellent ligand for this reaction, leading to a result similar to that obtained with L2. LiCl played a key role in the control of both reactivity and selectivity, which was attributed to the strong salt effect found by Helmchen52 and Fuji.77 A further investigation revealed that LiCl may break the aggregates of the sodium salt of the malonate anion to promote the reaction.80 The scope of stabilized enolate nucleophiles was further expanded (Table 3). Trisubstituted malonates as well as βketoesters yielding a prochiral enolate were also tolerated, affording the corresponding allylated products in good to excellent yields, with high regio- and enantioselectivities; however, diastereoselectivity was very low (Table 3, entries 3 and 4). The catalytic system was also applicable to linear allylic acetates 10, though with a slight decrease in reactivity (Scheme 27). With the branched allylic acetate 11a as a substrate, low enantioselectivity was expected and was indeed observed. Upon decreasing the rate of nucleophilic attack at the πallyliridium complex, by decreasing the concentration of the

allyliridium complexes, studies on salt effects were initiated, aimed at maximum erosion of the enantioselectivity for reactions with enantiomerically enriched branched allylic substrates (entries 8−11). In a series of reactions with lithium halides, maximal erosion of enantiomeric purity was found when LiCl was used as an additive alongside ligand L23. The final optimal reaction conditions are given in Scheme 24. These conditions were applicable to aminations; however, enantioselectivity was low with ligand L24. Scheme 24. Ir-Catalyzed Asymmetric Allylic Alkylation and Amination Reactions

In 1999, allylic alkylations with chiral phosphites as ligands were reported by Fuji and co-workers.77 Dimethyl malonate (15) was used as the pronucleophile, and L9a was the optimal ligand. The countercation of the stabilized enolate played a crucial role for the control of enantioselectivity.78 When a mixture of n-BuLi/ZnCl2 was used as the base, products with excellent yields and regio- and enantioselectivities were L

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Scheme 25. Asymmetric Allylic Alkylation with Chiral Phosphite Ligands

Scheme 26. Allylic Alkylation Using L2 as the Ligand

Table 3. Allylic Alkylation with Malonates and β-Ketoesters as Nucleophiles

maintain a low concentration led to moderate enantioselectivity after full conversion (Scheme 27). The substrate 19 is privileged in Pd-catalyzed enantioselective allylic substitution. Under Ir catalysis, the alkylation reaction of 19 with sodium malonate afforded 20 in high ee but gave only 80% conversion due to the lower reactivity of the disubstituted allylic acetate 19 compared with the monosubstituted allylic acetates (Scheme 28). Scheme 28. Ir-Catalyzed Asymmetric Allylic Alkylation with (E)-1,3-Diphenylallyl Acetate (19)

In 2004, Helmchen and co-workers further investigated Ircatalyzed allylic alkylation of malonates.81 It was found that reactions of linear acetates promoted by ligand L1 were slow, which was attributed to the formation of the coordinatively

nucleophile, i.e., increasing the relative rate of π−σ−π interconversion, an increase of the overall enantioselectivity was expected. Indeed, slow addition of the nucleophile to

Scheme 27. Ir-Catalyzed Asymmetric Allylic Alkylation with Allylic Acetates as Substrates

M

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Scheme 29. Ir-Catalyzed Highly Regio- and Enantioselective Allylic Alkylation Using a Catalyst with Improved Activity

saturated complex K6a. Improvement was gained by using TBD as the base for in situ catalyst activation82 and addition of THT (tetrahydrothiophene) and CuI as scavengers for the selective removal of the auxiliary ligand, avoiding the formation of K6a. With the new catalyst, various allylic acetates were transformed into the desired alkylated products in good to excellent yields and enantioselectivity within less than 1 h at room temperature (Scheme 29). After ligand L2 became known, Helmchen and co-workers were able to further improve the alkylation reaction and apply it to more challenging substrates (Scheme 30).83 The catalyst

Scheme 32. First Ir-Catalyzed Intramolecular Allylic Alkylation Reaction

without additives such as CuI and THT (see above). In addition, alkylated cyanoacetates and vinylcyclopropanes were obtained in good yields and excellent enantioselectivity under these salt-free conditions, which were previously inaccessible under the alkali-metal salt reaction conditions (Scheme 33).

Scheme 30. An Optimal Catalyst for Highly Regio- and Enantioselective Allylic Alkylation

Scheme 33. Salt-Free Allylic Alkylation with Methyl Cyanoacetate and Malononitrile and Cyclization Reaction

loading could be as low as 0.1 mol %. With the enantiomerically enriched products 21 in hand, carbocycles 22 were prepared by ring closing metathesis (RCM) (Scheme 31). The Scheme 31. Synthesis of Unsaturated Carbocycles from Alkylation Products via Ring Closing Metathesis PHOX (phosphinooxazoline) ligands were previously applied in Ir-catalyzed allylic alkylation reactions by Helmchen and co-workers.60 Later, Moberg and co-workers tried PHOX ligands modified by the incorporation of an OH or an OCH3 group.87 Regioselectivity was low for both ligands. Higher enantioselectivity was obtained by the use of L18b, indicating that the free hydroxyl group might be detrimental (Scheme 34). DIAPHOX ligands developed by Hamada and co-workers88 were also applied to Ir-catalyzed allylic alkylation reactions with stabilized enolates.89 Good reactivity was achieved with NaPF6 as an additive. Additionally, LiOAc was an advantageous additive for both reactivity and enantioselectivity. With ligand L10a under the optimal conditions, various substituted methyl cinnamyl carbonates and their derivatives were used as allylic electrophiles, affording the alkylated products with good to excellent yields and regio- and enantioselectivities (Scheme 35). Product 29 was applied to a formal asymmetric total synthesis of (−)-paroxetine (Scheme 36).90

first Ir-catalyzed intramolecular allylic alkylation reaction was realized using a lithium malonate, which furnished the vinylcyclopentane and vinylcyclohexane 24 with excellent enantioselectivity (Scheme 32). Allylic alkylation reactions were usually carried out with alkali-metal salts as nucleophiles. At a multigram scale, difficulties are often encountered because of low solubility of the substrates. Helmchen and co-workers solved this problem by application of the Tsuji conditions,84 i.e., use of the conjugate acid of an anionic nucleophile, because the alkoxide generated in situ from an allylic carbonate can function as a base.85 These “salt-free conditions” 86 gave distinctly better results than the reaction with sodium dimethyl malonate, even N

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Scheme 34. Allylic Alkylations Using PHOX Ligands Bearing a Hydroxyl or a Methoxy Group

Scheme 35. DIAPHOX Ligands in Ir-Catalyzed Allylic Alkylation Reactions

Scheme 36. Formal Synthesis of (−)-Paroxetine

Scheme 37. Phosphoramidite Ligands L11 in Ir-Catalyzed Allylic Alkylation

Phosphoramidite ligands bearing an amide moiety were developed for Ir-catalyzed allylic substitution reactions by Takeuchi and co-workers in 2008.91 Various sodium malonates were tested, dimethyl and diethyl malonates of which provided products with the best yields and selectivities. Then the substrate scope of various allylic acetates 10 was investigated using either L11a or L11b as the ligand; branched products were obtained in high yields and regioselectivity and moderate to excellent enantioselectivity (Scheme 37). In most cases, LiCl was not necessary for good results. The ligands were proposed to function as bidentate ligands with both phosphine and oxygen binding to the iridium as depicted in Scheme 38. Cyclopentenones are important structural motifs in natural products and pharmaceuticals. The Helmchen group has

Scheme 38. Proposed Transition States of Nucleophilic Attack to the π-Allyliridium Intermediates Containing Ligand L11a

O

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Scheme 39. Modular Synthesis of Chiral Cyclopentenones by Ir-Catalyzed Allylic Alkylation with a Weinreb-Type Malonic Amide

Scheme 40. Enantioselective Synthesis of (R)-TEI-9826

Scheme 41. Enantioselective Synthesis of 2′-Methylcarbovir

Scheme 42. Allylic Alkylation with ω-Ethylenic Allylic Carbonates

developed a highly enantioselective modular synthesis of 2,4disubstituted cyclopentenones, based on an Ir-catalyzed asymmetric allylic alkylation of Weinreb-type malonic amides 30 (Scheme 39).92 The branched substitution products 31,

obtained with up to 99% ee, were subjected to saponification/ decarboxylation reactions. The resultant Weinreb amides 32 were reacted with alkenylmagnesium halides to give dienes 33, which could be transformed to the enantiomerically enriched P

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nucleophiles in Ir-catalyzed allylic substitutions (Scheme 45).98 As 3,3-disubstituted allylic substrates display low reactivity,

cyclopentenones 34 by ring closing metathesis in high overall yields. With the enantiomerically enriched cyclopentenones in hand, concise syntheses of prostaglandin analogue TEI-9826 (Scheme 40) and the carbonucleoside 2′-methylcarbovir (Scheme 41) were carried out.93 In 2010, Alexakis et al. used ω-ethylenic allylic carbonates 44 as electrophiles for the Ir-catalyzed allylic alkylation of dimethyl malonate.94,95 Products 45 were obtained with excellent regioselectivity. These alkylation products were further subjected to ring closing metathesis to yield five- and six-membered carbocycles 46 in 48−52% yields and excellent enantioselectivity (Scheme 42). Three-membered rings appear in many pharmaceuticals and natural products with interesting bioactivities. Accordingly, cyclopropane-containing building blocks are of great importance. In 2010, You and co-workers reported an asymmetric allylic alkylation of the cyclopropylallyl methyl carbonate (47) with sodium dimethyl malonate affording cyclopropanecontaining building blocks. The Ir catalyst generated from [Ir(cod)Cl]2 and the Alexakis ligand L2 was employed (Scheme 43).96

Scheme 45. Ir-Catalyzed Asymmetric Allylic Alkylation with Fluoride-Containing 3,3-Disubstituted Allylic Substrates

leaving groups of high fugacity, such as a dialkyl phosphate or trifluoroacetate, were required. Furthermore, products with an acidic hydrogen in the β-position relative to fluorine are prone to E1cB-type elimination; this was avoided by using 2substituted malonic acid derivatives or β-ketoesters as pronucleophiles. The results presented in Scheme 45 demonstrate that excellent regio- and enantioselectivities were achieved with a variety of malonic acid derivatives and arylallylic substrates not substituted in the o-aryl position. Particularly valuable are products derived from (methoxymethoxy)malonitrile, which constitutes an acyl equivalent. It was also demonstrated that the reaction with prochiral nucleophile 56 could provide either diastereomer of the product predominately by choosing different bases (Scheme 46).

Scheme 43. Ir-Catalyzed Enantioselective Synthesis of Chiral Cyclopropane-Containing Building Blocks

Scheme 46. Ir-Catalyzed Diastereoselective Fluoroalkylation of Ethyl 2-Oxocyclohexanecarboxylate

Chiral allylboronates are important reagents for the addition to carbonyl compounds, yielding chiral homoallylic alcohols. In 2007, Peng and Hall developed an Ir-catalyzed allylic alkylation reaction for the synthesis of α-substituted allylboronates.97 The major challenge they encountered was the regioselectivity, as under most conditions tried formation of the linear product was favored. After various ligands and boronic esters were screened, the combination of L2 with substrate 49 was found to be suitable for the production of branched allylic boronates. As product 50 is unstable to silica gel purification, a one-pot procedure of allylic alkylation followed by allylboration of aldehyde was developed. Homoallylic alcohol 51 was obtained in 51% yield, with an E:Z ratio of 8:1 and 80% ee for the Eisomer (Scheme 44). The construction of a stereogenic center with a fluorine substituent at an allylic position is difficult because of facile cleavage of the C−F bond and poor nucleophilicity of the fluoride anion. In 2018, Butcher and Hartwig reported a novel approach by placing fluorine into the 3-position of an allylic electrophile and using conventional stabilized enolates as

4.1.2. Malononitrile and Masked Acyl Cyanide Reagents. The cyano group is a useful functional moiety for organic synthesis. In 2008, Helmchen and co-workers utilized malononitrile (58) as a pronucleophile for Ir-catalyzed allylic alkylation reactions (Scheme 47).99 Excellent enantioselectivity and moderate to good regioselectivity were obtained using various allylic carbonates. The products 59 could be degraded by oxidation with magnesium monoperoxyphthalate, affording methyl esters 60 in high yield without loss of

Scheme 44. One-Pot Allylic Alkylation/Allylboration for the Synthesis of Homoallylic Alcohols

Q

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Scheme 47. Allylic Alkylation of Malononitrile and Oxidative Degradation of the Products To Give Methyl Esters

Scheme 49. Reactions with Further Trisubstituted Allylic Electrophiles

LiBr as an additive, this reaction did not proceed with ligand L12b or L1. Ligand L8, however, provided the desired product 64 in 13% yield with a moderate enantiomeric excess (Table 4, entries 1−3). Then triethylborane was used as a Lewis acid for the activation of the allylic carbonate (E)-63a, giving rise to both improved reactivity and improved enantioselectivity (Table 4, entries 4−6). However, substrate (Z)-63a displayed low reactivity, while branched substrate 65 afforded nearly racemic product 64, though in high yield (Scheme 49). Finally, deprotection by treatment of the allylated products derived from (E)-63 with acid produced various α-chiral carboxylic acids 66 with an all-carbon quaternary stereogenic center in good to excellent yields and with high enantioselectivity (Scheme 50). However, a variety of products derived from non-aryl-substituted or sterically hindered allylic electrophiles were obtained either in low yield or with low enantioselectivity. In 2018, Stoltz and co-workers further expanded the substrate scope of the MAC reagents in Ir-catalyzed asymmetric allylic alkylation reactions with trisubstituted allylic electrophiles 63 (Scheme 51).103 In this case, additional base (DABCO) was required for the high enantioselectivity. Under the optimal reaction conditions, various alkyl group substituted MAC nucleophiles 61 were tolerated, leading to the formation of products 68 with vicinal all-carbon quaternary centers in good to excellent yields and enantioselectivity, while the phenyl-substituted MAC proved unreactive. 4.1.3. Diastereoselective Alkylations with Prochiral Stabilized Enolates. Prochiral nucleophiles were rarely used in Ir-catalyzed allylic alkylation reactions. This was because the

enantiomeric purity (Scheme 47). Thus, the malononitrile group was shown to function as an acylanion equivalent according to this strategy. A masked acyl cyanide (MAC) reagent,100 a carbon monoxide equivalent, was first used as a nucleophile in Ircatalyzed asymmetric allylic alkylation reactions by Stoltz and co-workers in 2017.101 The protecting group of the MAC nucleophile was crucial to the reactivity, and the methoxymethyl ether 61 was the only identified nucleophile to be suitable after screening (Scheme 48). Under the optimal conditions, the alkylated products 62 could be obtained in good to excellent yields and with high enantioselectivity. Scheme 48. MAC as the Nucleophile in Ir-Catalyzed Allylic Alkylation Reaction

The MAC nucleophile 61 was also applied in the alkylation reaction with a trisubstituted allylic electrophile, a challenging substrate due to the steric hindrance hampering the oxidative addition to iridium and the formation of vicinal quaternary carbon centers (Table 4, Scheme 49).102 Upon application of

Table 4. Application of a MAC Nucleophile in Ir-Catalyzed Allylic Alkylation

entry

L

61:63a

additive

yield (%)

ee (%)

1 2 3 4 5 6

L12b L1 L8 L8 L8 L8

2:1 2:1 2:1 2:1 1:1.2 1:2

LiBr LiBr LiBr BEt3 BEt3 BEt3

0 0 13 34 74 99

79 93 92 94

R

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Scheme 50. Substrate Scope for Allylic Alkylation To Form a Carboxylic Acid Bearing a Quaternary Carbon Center

5H-Oxazol-4-ones and 5H-thiazol-4-ones were further successfully addressed as prochiral nucleophiles by the Hartwig group.105 However, direct application of the previous counterion strategy led to poor diastereoselectivity. After careful investigation of various reaction parameters, it was found that particular combinations of the base and a metallacyclic Ir catalyst (K6f) furnished excellent diastereoselectivity. Et2Zn and Mg(N-i-Pr2)2 were optimal bases for allylic alkylations of 5H-oxazol-4-ones and 5H-thiazol-4-ones, respectively (Scheme 54). Thus, for this reaction, the cation bound to the enolate could have a positive effect on the diastereoselectivity. Direct control of diastereoselectivity by a chiral catalyst was accomplished by Stoltz et al. in 2013, who reported Ircatalyzed enantio- and diastereoselective allylic alkylations to construct α-quaternary β-ketoesters 78 with vicinal stereocenters (Scheme 55).106 Excellent diastereoselectivity was achieved with an Ir catalyst prepared from ligand MeTHQphos (L12b)69 via in situ activation with TBD. Under the optimal reaction conditions, various cyclic β-ketoester derivatives were tested, most of which provided products with good to excellent yields and regio-, diastereo-, and enantioselectivities. Furthermore, with 2-(trimethylsilyl)ethyl β-ketoester 78a as the substrate, a sequential Pd-catalyzed decarboxylative allylic alkylation could be accomplished, providing access to the two diastereoisomers (Table 5). PHOX ligands with different configurations ((S)-L25/(R)-L26) led to diastereoisomeric products with excellent dr values in both cases (Table 5, entries 1 and 2). Additionally, other substituted allylic carbonates were shown to be compatible, affording products with excellent diastereoselectivity (Table 5, entries 3 and 4).

Scheme 51. Ir-Catalyzed Asymmetric Allylic Alkylation of MAC Reagents

configurational control by chiral catalysts was weak; i.e., moderate to poor diastereoselectivity was observed. In 2013, Chen and Hartwig applied counterion effects in reactions with azlactones, using silver salts to introduce the counterions.104 It was found that diastereoselectivity increased in correlation with the bulk of the counterion; eventually, silver phosphate 71 was identified as the optimal additive. Reactions of various αsubstituted azlactones and allylic carbonates were investigated, affording products with quaternary and vicinal tertiary carbon stereogenic centers (Scheme 52). To elucidate the function of the silver phosphate additive, mechanistic investigations were carried out. Control experiments with the neutral iridacyclic catalyst K6f were run without and with the additive 72, which furnished diastereoselectivities of 3:1 and >20:1, respectively (Scheme 53). In addition, the leaving group of the allylic substrate also affected the diastereoselectivity, which led to the conclusion that both the carbonate leaving group and the added counterion improved the selectivity at the faces of the prochiral nucleophile.

Scheme 52. Control of Diastereoselectivity by a Phosphate as the Counterion in Ir-Catalyzed Allylic Alkylation with a Prochiral Nucleophile

S

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Scheme 53. Control Experiments

Scheme 54. Cation Control of Diastereoselectivity in Ir-Catalyzed Allylic Alkylations

Scheme 55. Ir-Catalyzed Diastereo- and Enantioselective Allylic Alkylation with β-Ketoesters

Table 5. Sequential Pd-Catalyzed Decarboxylative Allylic Alkylation Reactions of 78a

entry

R

ligand

yield (%)

dr 81:82

1 2 3 4

H H Ph Me

(S)-L25 (R)-L26 (R)-L26 (R)-L26

91 85 87 70

1:8 18:1 12:1 13:1

Enolates of acyclic β-ketoesters are more challenging nucleophiles in Ir-catalyzed asymmetric allylic substitution reactions than those formed from cyclic β-ketoesters due to their higher degree of conformational multiplicity. In 2013, Stoltz and co-workers continued to apply the procedures employed previously to cyclic β-ketoesters to set up acyclic vicinal tertiary and quaternary centers for the first time.107 The

same ligand, L12b (Me-THQphos), was used, while LiO-t-Bu was chosen as the base to shorten the reaction time. The new procedure was applicable to a wide variety of allylic carbonates 16 and acyclic β-ketoesters 83 (Scheme 56). Substituted cinnamyl substrates with electron-withdrawing groups displayed diminished regioselectivity. This point was investigated by an analysis relating the logarithm of the ratio of branched to T

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Scheme 56. Ir-Catalyzed Allylic Alkylation of Acyclic βKetoesters

alkylated products 93 in good to excellent yields and selectivities (Scheme 60). Since a report from the Carreira group in 2013,110 dual and stereodivergent catalysts have become important innovations in the area of Ir-catalyzed allylic substitution reactions. In 2018, Hartwig and co-workers reported examples for reactions with stabilized enolates.111 Azaaryl acetamides and acetates were utilized as pronucleophiles, which were transformed into stereochemically well-defined copper(I) enolate chelate complexes. The combination of a copper(I) complex of the bisphosphine ligand L27 and the π-allyliridium complex K7c· BF4 as catalysts allowed the absolute and relative configurations of both new stereogenic centers of the products to be controlled almost to perfection. Various α-allylated azaaryl acetamides and acetates containing two adjacent tertiary stereocenters were obtained in excellent yields, and with high enantio- and diastereoselectivities (Scheme 61). In particular, each of the four stereoisomers of product 95a was prepared with excellent results upon permutation of the configurations of ligands in the Cu and Ir catalysts, as shown in Scheme 62. 4.1.4. Sulfonylacetic Esters and Disulfones as Pronucleophiles. An Ir-catalyzed highly enantioselective allylic alkylation of sulfonylacetic esters was reported by the Helmchen group in 2013.112 The allylic substitution products 96 were subjected to a Krapcho reaction and a Julia−Kocienski olefination subsequently to give trienes 98. Sequential selective hydroboration with 9-BBN and Suzuki−Miyaura coupling furnished trienoates, which by subsequent Lewis acid catalyzed IMDA reaction yielded the hexahydroindene moiety 100, a core structure of the antibiotics indanomycin (X-14547A) and stawamycin (Scheme 63). In 2007, You and co-workers reported an Ir-catalyzed regioand enantioselective decarboxylative allylic alkylation with excellent regio- and enantioselectivities.113 They also examined methyl sulfonylacetates as nucleophiles.114 Systematic evaluation of the reaction conditions revealed that, by utilizing [Ir(cod)Cl]2 and the Alexakis ligand as the catalyst, the reaction proceeded smoothly to give products 102. These were subjected to a one-pot reductive desulfonylation or a modified Julia olefination, leading to the formation of 103 or 104 in good yields and high enantioselectivity (Scheme 64). Fluoroorganic compounds often exhibit unique physical, chemical, and biological properties, and significant progress has been achieved in the development of their syntheses. Pioneering work by Shibata and Hu has demonstrated that monofluorobis(phenylsulfonyl)methane (FBSM) constitutes a synthetic equivalent of CH2F.115−118 Inspired by the elegant work of Shibata and Toru on the Pd-catalyzed highly enantioselective allylic fluorobis(phenylsulfonyl)methylation reaction,119 the groups of Zhao and You developed an enantioselective Ir-catalyzed allylic substitution of FBSM (105) with allylic carbonates. Using an Ir catalyst derived

linear products to the corresponding Brown σ+ substituent constants. A linear relationship was found that allowed them to quantitatively assess the experimental observations. Stoltz and co-workers further investigated reactions with enolates derived from α,β-unsaturated malonates and βketoesters. These underwent allylic substitution at the αposition to provide 1,5-dienes with a branched allylic moiety, which were demonstrated to readily undergo a Cope rearrangement to form linear γ-alkylated products (Scheme 57).108 Screening reaction conditions for α-alkylation showed once again that (S,Sa)-L12b (Me-THQphos) was an excellent ligand in conjunction with LiO-t-Bu as the base. The Cope rearrangement, with toluene as the solvent at 100 °C, proceeded with a high degree of chirality transfer via a chairlike transition state. This two-step procedure was then applied to a wide variety of substrates. Good to excellent yields and enantioselectivities were obtained for both substituted cinnamyl carbonates and exocyclic unsaturated malonates. In the case of endocyclic α,β-unsaturated β-ketoesters, (S,Sa)-L12e was used, but only moderate dr values were obtained for all the substrates that were investigated (Scheme 58). Pure diastereomers could be isolated and were individually tested in the Cope rearrangement. The major isomer, 89a, reacted via a chairlike transition state to produce the product 90a in 72% yield, while the minor one, 89b, reacted via a boatlike transition state and furnished the product in a lower yield (Scheme 59). Alkylallylic electrophiles are challenging substrates in Ircatalyzed allylic substitution reactions for the construction of vicinal tertiary and all-carbon quaternary stereogenic centers, yet they are useful for synthetic chemistry. Control of both regio- and diastereoselectivity is difficult to achieve. In 2016, this problem was solved for β-ketoesters to some extent by Stoltz and co-workers.109 For simple crotyl derivatives, almost all the reaction parameters were tuned. Crotyl chloride 92 showed better regioselectivity than crotyl carbonate, which might be due to a counterion effect. The use of proton sponge as the base improved the stereoselectivity further. In addition, the utilization of ligand L12e played a key role for high enantioselectivity. Finally, under the optimal reaction conditions, various β-ketoesters 91 were tested, providing allylic

Scheme 57. Sequential Ir-Catalyzed Allylic Alkylation/Cope Rearrangement

U

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Scheme 58. Allylic Alkylation of Endocyclic α,β-Unsaturated β-Ketoesters and Malonamides

philes in Ir-catalyzed asymmetric allylic alkylations (Scheme 67).121 Unfortunately, reactions of monofluorinated prochiral nucleophiles displayed low diastereoselectivity, while with 1substituted 1-fluoro-1-(arylsulfonyl)methylene derivatives somewhat higher diastereoselectivity was observed.122

Scheme 59. Cope Rearrangement of the Allylated Products

4.2. Aliphatic Nitro Compounds

The nitro group can be transformed into a variety of useful functional groups. Accordingly, the development of efficient reactions with nitro compounds is a very attractive objective. In 2006, Helmchen and co-workers established an Ir-catalyzed asymmetric allylic alkylation of aliphatic nitro compounds yielding valuable intermediates for organic synthesis.123 Using the Alexakis ligand L2 in conjunction with cesium carbonate as a base, the desired products were obtained in good yields and excellent enantioselectivity (Scheme 68). In addition, modified Krapcho deethoxycarbonylation conditions were developed that allowed ethyl nitroacetate to be used as an equivalent of nitromethane, giving primary nitro compounds 113 in good yields and excellent enantioselectivity (Scheme 69).

Scheme 60. Ir-Catalyzed Allylic Alkylation of β-Ketoesters with Crotyl Chloride

4.3. Glycine Equivalents

Enolates of imino glycinates 114 were first used as nucleophiles in Ir-catalyzed allylic alkylation reactions by Takemoto and co-workers in 2003 (Scheme 70).124,125 The authors developed conditions involving chiral phosphite ligand L9b, KOH as the base, and a biphasic solvent system, which were not compatible with allylic carbonates due to hydrolysis. With allylic phosphates 115 as substrates, the reactions proceeded smoothly to form the allylated glycine derivatives in good to excellent yields, with high enantioselectivity and moderate to good diastereoselectivity. Stereodivergence was accomplished to an acceptable degree by variation of the base and the cation of the enolate. It was postulated that the two optimal bases, KOH and LiN(SiMe3)2, induce the formation of nonchelated and chelated enolates, with an O/N-anticonfiguration and an O/N-syn-configuration, respectively (Scheme 70). In 2008, Eilbracht and co-workers also utilized an imino glycinate, 118, in an Ir-catalyzed allylic alkylation reaction with L2 as the ligand. Moderate diastereoselectivity with excellent regioselectivity and enantioselectivity was obtained (Scheme 71).126 A remarkable advance was achieved in 2018 by Wang and co-workers, who utilized the strategy of synergistic Cu/Ir catalysis for the enantio- and diastereodivergent synthesis of αamino acid derivatives using aldimine esters as nucleophiles.127 Cu(I)/(R,Rp)-Phosferrox (L28) was identified as an excellent catalyst for enantiofacial control of enolates derived from aldimines 119, while the standard in situ generated Ir catalyst derived from the Feringa ligand L1 was used for the control at the allylic moiety. α,α-Disubstituted as well as α-monosub-

Scheme 61. Synergistic Iridium and Copper Catalysis in Stereodivergent Allylic Alkylation Reactions

from [Ir(cod)Cl]2 and the Feringa ligand L1, they obtained the chiral fluorobis(sulfone)s 106 in excellent yields with high regio- and enantioselectivities (Scheme 65).120 Monofluorinated ibuprofen and naproxen were synthesized in high yields by utilizing this method (Scheme 66). Later, Zhao and co-workers reported that various kinds of fluorinated methylene derivatives 109 are excellent nucleoV

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Scheme 62. Stereodivergent Synthesis of the Four Stereoisomers of 95a

Scheme 63. Enantioselective Synthesis of the Hexahydroindene Cores of Indanomycin and Stawamycin

Scheme 64. Highly Enantioselective Synthesis of Allylated Methyl Acetates or Methyl Acrylates by an Ir-Catalyzed Allylic Alkylation and Subsequent Transformations

stituted α-amino acid derivatives were obtained with excellent enantio- and diastereoselectivities after reduction of the products with NaBH3CN (Scheme 72a). The four stereoisomers of product 120 could be generated by permutation of

the configurations of the ligands L1 and L28 (Scheme 72b). In addition, the α-monosubstituted α-amino acids 121 were obtained in a stereodivergent fashion; in this case, NEt3 was used as the base instead of Cs2CO3 (Scheme 72c). A simplified W

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substitution reactions.137−145 In 2007, You and co-workers first employed it in the Ir-catalyzed allylic substitution to open a convenient way to enantiomerically enriched γ,δ-unsaturated ketones 132 (Scheme 75).113 A crossover experiment with an equimolar amount of 131a and 131b under the standard conditions revealed that the four possible products were formed in almost equal amounts (Scheme 76). This result allowed reactions that proceeded via an intramolecular rearrangement or a cage ion pair mechanism to be excluded. 4.4.2. Silyl Enol Ethers and Related Compounds as Pronucleophiles. In 2005, Graening and Hartwig reported a highly regio- and enantioselective Ir-catalyzed allylic alkylation of silyl enol ethers.146 The authors employed an in situ Ir catalyst derived from L1 in combination with CsF and ZnF2 as additives, which were of critical importance for high reactivity and selectivity and the suppression of diallylation (Scheme 77). Good results were mostly obtained with acetophenones as substrates, while reactions of silyl enol ethers derived from alkyl methyl ketones proceeded with low yields, which might be caused by lack of site selectivity of the formation of enolates. Ir-catalyzed allylic substitutions with nonstabilized ester enolates were first reported by Chen and Hartwig in 2012.147 2-(Trimethylsiloxy)furan (136a), formally derived from a lactone, was used as the pronucleophile with ZnF2 as an additive to afford predominantly 3-allylated products. Tautomerization caused α,β-unsaturated lactones 137, containing a single stereogenic center, to be the main products, which were accompanied by side products formed via allylation at the 5-position and subsequent tautomarization and Claisen rearrangement (Scheme 78). With methyl-substituted (trimethylsiloxy)furans as pronucleophiles, fairly complex product mixtures were obtained. Subsequent rearrangement reactions allowed the composition of the products to be simplified. Thus, in the case of 3-methyl2-(trimethylsiloxy)furan (136b), a mixture of inseparable diastereomeric branched products, 140a/140a′, and a linear substitution product, 141, was obtained at rt. Heating a solution of the product mixture in CH2Cl2 at 40 °C led to depletion of 140a′ via Cope rearrangement to give 141, which could be separated from 140a (Scheme 79). In the case of 4- and 5-methyl-2-(trimethylsiloxy)furan, mixtures of double bond isomers and diastereoisomers of branched substitution products were formed. By addition of catalytic amounts of base, preferably O-desmethylquinine,

Scheme 65. Ir-Catalyzed Asymmetric Allylic Alkylation of Fluorobis(phenylsulfonyl)methane

procedure was realized by directly mixing the two metal sources and the two chiral ligands in one pot; the results were essentially identical to those obtained with separately prepared catalysts. Spectroscopic control showed that ligand scrambling did not occur. Finally, the practicality of the method was demonstrated by the formal synthesis of a bioactive pyrrolidine derivative, 122, and by a three-step total synthesis of a plant growth regulator, (2S,3S)-2-amino-3-cyclopropylbutanoic acid (124) (Scheme 73).128,129 Almost at the same time, Zhang and co-workers also developed a very similar procedure.130 In this case, either RuthePhox (L29) or FerroPhox (L30) was used for the formation of the chiral copper catalyst, while the same Feringa ligand L1 was applied in the Ir-catalyzed allylic alkylation of aldimine esters 125. With Cu/Ir dual catalysis, various α,αdisubstituted α-amino esters 126 were constructed in a stereodivergent fashion in excellent enantio- and diastereoselectivities after hydrolysis with citric acid (Scheme 74a). Additionally, stereodivergent α-allylation of cyclic ketimine Schiff bases 127 was also realized using the same reaction conditions (Scheme 74b). It is interesting that dipeptides 130 containing a non-natural α-amino acid could be easily accessed when substrates 129 were applied under these developed reaction conditions (Scheme 74c). 4.4. Unstabilized Ester and Ketone Enolates

Ketones are widely used as very important starting materials in organic synthesis. Unstabilized ketone enolates are challenging nucleophiles in Ir-catalyzed asymmetric allylic substitution for several reasons:131−135 First, diallylation of the ketone is commonly observed. Second, nonstabilized enolates are fairly basic; therefore, side reactions, such as elimination, may occur. Finally, aldol-type reactions must be minimized. 4.4.1. Decarboxylative Alkylation. The decarboxylative alkylation of allyl enol carbonates or allyl β-ketoesters (Tsuji reaction136) has been widely studied in Pd-catalyzed allylic

Scheme 66. Enantioselective Syntheses of Monofluorinated Ibuprofen and Monofluorinated Naproxen

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Scheme 67. Ir-Catalyzed Allylic Alkylation Reactions of Fluorinated Methylene Derivatives

reactions using these dienes with various substituted allylic carbonates (Scheme 81),151 under the reaction conditions described above.148 As an application, product 151a (R = Ph) was transformed into fesoterodine (Toviaz) over several steps.152 A mechanistic study was conducted, evaluating various additives to explore the function of KF and 18-crown-6. The stoichiometric reaction of iridium allyl complex K7c with the enol silane 148 did not proceed in the presence of KF and 18crown-6. This indicated that the fluoride anion does not activate silane 148 (Scheme 82). In addition, KF could be replaced by KOMe and Bu4NOAc, even in catalytic amounts (Scheme 83a,b). The preformed metallacyclic Ir complex K6e could catalyze this reaction without any additive (Scheme 83c). It was concluded from these studies that the silane is activated by the oxygen base, including carboxylate produced from the allylic substrate (see above), and KF functions as a base for the generation of the Ir catalyst by cyclometalation. Dianions of β-ketoesters are very strong bases and nucleophiles, which preferentially react at the γ-position with electrophiles, such as alkyl halides, producing products that are extended by a highly functionalized four-carbon chain. In 2014, Chen and Hartwig reported an Ir-catalyzed allylic substitution reaction of silyl dienolates 152a and 152b, which constitute synthetic equivalents of β-ketoester dianions (Scheme 84).153 Using the standard reaction conditions with in situ prepared Ir catalysts, two major problems were encountered for the development of this method. For both silyl ketene acetals 152a and 152b, the common allylic carbonates gave rise to low selectivity with respect to discrimination between the α- and γpositions of the dienolates. In the case of the α-methylated dienolate 152b, low b:l selectivity was found. By screening electrophiles, [(3,3,3-trichloroethyl)oxy]carbonyl (Troc) allylic carbonates were identified as suitable substrates. Under the optimal reaction conditions, γ-substituted products 153 and 154 were obtained with high regio- and enantioselectivities. Additional control experiments confirmed that an Ir catalyst is essential for the observed reactivity, and the phosphoramidite ligand significantly affects the regioselectivity. In addition, various transformations based on the reactivity of dioxinones were also conducted for the synthesis of esters, amides, and heterocycles.

Scheme 68. Enantioselective Ir-Catalyzed Allylic Alkylations with Nitroalkanes and Ethyl Nitroacetates

isomerization to the thermodynamically preferred butenolides 142b and 144 was accomplished (Scheme 79). Mechanistic investigations with (trimethylsiloxy)furan using the iridium allyl complex K8b·OTf (cf. Scheme 11) in catalytic or stoichiometric amounts gave interesting insights. In particular, the allylation proceeded without ZnF2 and could be promoted by NBu4OAc. This observation suggested that, not the fluoride anion, but the carboxylate anion, which was produced by reaction of the allylic substrate with the Ir catalyst, activates the (trimethylsiloxy)furan. α,β-Unsaturated ketones and their synthetic equivalents 145 are valuable building blocks in organic synthesis. In 2014, Chen and Hartwig reported Ir-catalyzed enantioselective allylic alkylation reactions with silyl enol ethers 145 (Scheme 80).148 The reaction conditions described above were not applicable to these fairly sensitive substrates. A new procedure involving a combination of KF and 18-crown-6 was developed. The substrate scope of the method is broad, including alkyl-, aryl-, and heteroaryl-substituted allylic carbonates. Diverse applications were carried out. The shortest formal synthesis of the putative anticancer agent TEI-9826 was accomplished starting with the readily available substrates 145a and 147 (Scheme 80). The practicality of the method was further demonstrated by diastereodivergent modifications of steroid side chains using ligands of opposite configurations, as well as by stereoselective syntheses of 4-methylpentan-2-ols, which are structural motifs in many bioactive natural products. Enol silanes of vinylogous esters 148 (Danishefsky’s dienes)149 and amides 150 (Rawal’s dienes)150 are widely used as dienes in Diels−Alder reactions. These reagents also constitute synthetic equivalents of unstabilized enolates derived from α,β-unsaturated ketones. Chen and Hartwig reported regio- and enantioselective allylic substitution

Scheme 69. Synthesis of Primary Nitro Compounds via a Modified Krapcho Deethoxycarbonylation

Y

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Scheme 70. Ir-Catalyzed Allylic Alkylations of Imino Glycinates and a Rationale for the Diastereodivergence Induced by Different Bases

Scheme 71. Ir-Catalyzed Allylic Alkylation of Glycine Derivatives

Scheme 72. Synergistic Cu/Ir Catalysis for the Stereodivergent Synthesis of α-Amino Acid Derivatives

Z

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Scheme 73. Synthetic Application of the Asymmetric Allylic Alkylation Reaction

Scheme 74. Cu/Ir Dual Catalysis for the Stereodivergent Synthesis of α-Amino Acids and Dipeptides

Chen and Hartwig have extended this work to include allylic substrates containing a substituent at the central carbon of the allylic moiety for the first time (Scheme 85).154 These substrates were previously not applicable in Ir-catalyzed enantioselective allylic substitution because of unfavorable oxidative addition to iridium. The problem was partially solved by the use of allylic phosphates 155, which contain a leaving group favoring the reversible oxidative addition step thermodynamically. The authors surmised that the enolates derived from 152a and 152b were sufficiently reactive to trap

Scheme 75. Ir-Catalyzed Highly Regio- and Enantioselective Decarboxylative Alkylation of Allyl β-Ketocarboxylates

AA

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4.4.3. Allylic Alkylations with Lithium, Barium, and Copper Enolates. Unstabilized prochiral ketone enolates were more challenging nucleophiles for Ir-catalyzed allylic substitution reactions because of their low reactivity as well as difficulty in control of diastereoselectivity. Under the guidance of previous work developed in their group,104,105 Chen and Hartwig continued to merge synergistic effects of additives and chiral ligands.157 By using Ir catalyst K7e and barium enolates derived from 163 and Ba(O-t-Bu)2, allylated products 164 with vicinal quaternary and tertiary stereogenic centers were obtained in good to excellent yields and diastereoselectivity and excellent enantioselectivity (Scheme 88). The aggregation state of the enolates was proposed to play an important role in the control of the diastereoselectivity. An example using benzofuran γ-lactones, i.e., unstabilized cyclic esters, as nucleophiles for Ir-catalyzed allylic substitution reactions was reported by Bos and Riguet in 2017.158 In this reaction, the strong base LiHMDS was used to generate the enolates. With the optimal ligand L13 (BHPphos), products with moderate dr and good to excellent ee values were obtained (Scheme 89a). The chiral products could be easily transformed via stereospecific heteroaromatic Cope rearrangement, in which dearomatized products 167 were observed, while rearomatized products 168 were produced when a catalytic amount of acid or base was applied (Scheme 89b). Unstabilized acyclic prochiral ketones are even more challenging substrates as nucleophiles for Ir-catalyzed allylic alkylation reactions; this is due to the lack of geometric control of the subsequently formed nonstabilized enolates. In 2016, Jiang and Hartwig developed a strategy based on the chelation of unstabilized enolates, derived from acyclic α-alkoxy ketones 169, with a copper(I) cation to dictate the geometry (Scheme 90).159 Under the optimal reaction conditions, products 170 containing vicinal tetrasubstituted and tertiary stereocenters were obtained in good to excellent yields and diastereo- and enantioselectivities (Scheme 90). By simple transformations of products 170, enantioenriched tertiary alcohols 171 and tetrahydrofuran derivatives 172 were readily accessed (Scheme 91). 4.4.4. Allylic Alkylations of Ketones via Dual, Synergistic, and Stereodivergent Catalysis. Ir-catalyzed allylic alkylation of unprotected α-hydroxy ketones is also challenging due to multiple nucleophilic sites and the undefined geometry of the corresponding enolates. In 2016, Huo, Zhang, and co-workers used a dual catalysis strategy (Ir and Zn) for the enantio- and diastereodivergent allylic alkylation of α-hydroxy ketones 173.160 Screening conditions led to identification of the Trost ligand ProPhenol (L31) as a suitable ligand for the Zn catalyst and the Feringa ligand L1 as a suitable ligand for the Ir catalyst (Scheme 92). All four stereoisomers of product 174a could be obtained in perfect stereocontrol via combination of ligands L31 and L1 with different configurations (Scheme 93). Further application of this method to different substrates revealed that various

Scheme 76. Crossover Experiment

the allyliridium intermediates despite their low concentration. Most examples possess the substitution pattern R1 = H or Ar and R2 = methyl. Overall, the branched products 156 were generated in high yields and with high regio- and enantioselectivities. Once more, control experiments showed that the Ir catalyst and the KF additive are both essential for reactivity and the ligand plays a significant role in controlling the regioselectivity. Enolates derived from aliphatic esters are rarely employed in asymmetric allylic substitution reactions because they are usually unstable. In addition, the low acidity of the α-proton requires stoichiometric amounts of a strong base for the in situ generation of the enolate without self-condensation. In 2017, Jiang and Hartwig applied silyl ketene acetals 157 as the equivalent of aliphatic ester enolates in Ir-catalyzed allylic substitution reactions (Scheme 86).155 The activation of substrate 157 could be realized through in situ generated carboxylates, while Bu4NOAc was required for the catalyst activation according to the previous study.151 The densely substituted acid derivatives obtained herein are difficult to access from other types of reactions. In addition, this reaction was successfully extended to the formation of α-allyl carboxylic acids 158a by using the silyl-protected enolate of isobutyric acid (Scheme 86). When unsymmetrical silyl ketene acetals were used as substrates, poor diastereoselectivity was observed (158b−158d) (Scheme 86). Lewis acids could also be applied as activators for silyl enol ethers in Ir-catalyzed allylic alkylation reactions. In 2015, Liang and Yang reported reactions of silyl enol ethers 159 and branched allylic alcohols 160 catalyzed by an Ir catalyst derived from the Carreira ligand L8.156 A catalytic amount of Sc(OTf)3 was employed to activate both substrates, while no fluoride additive was required (Scheme 87a). Under the optimal conditions, silyl enol ethers derived from either simple ketones or α,β-unsaturated ketones underwent allylic alkylation reactions smoothly, providing allylated ketones 161 in 38− 77% yields with 91% to > 99% ee and 6:1 to > 20:1 b:l. In addition, the resultant chiral homoallylic ketones could be transformed to calyxolanes A and B and their epimers via stereodivergent reduction and subsequent straightforward manipulation (Scheme 87b).

Scheme 77. Ir-Catalyzed Allylic Alkylations with Silyl Enol Ethers

AB

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Scheme 78. Ir-Catalyzed Allylic Alkylation with (Trimethylsiloxy)furan as the Pronucleophile

Scheme 79. Allylations of Methyl-Substituted (Trimethylsiloxy)furans

substituted allylic carbonates as well as α-hydroxy ketones were suitable substrates for stereodivergent synthesis of α-hydroxyl γ,δ-unsaturated ketones 174 in good to excellent yields and diastereo- and enantioselectivities (Scheme 92). In 2017, Zhang and co-workers also utilized unprotected αhydroxyindanones as nucleophiles, which are more challenging substrates relative to the previously used unprotected αhydroxy ketones. This is due to their weaker acidity and enhanced steric hindrance upon forming the corresponding enolates. Given these issues, the unprotected α-hydroxyindanones still underwent allylic alkylation under the previously established reaction conditions.160 By adjusting the ratio of Et2Zn and (S,S)-L31 to 2:1, they realized the stereodivergent α-allylic alkylation of α-hydroxyindanones 175 via Ir/Zn dual catalysis in good to excellent yields and enantioselectivity and moderate to good diastereoselectivity (Scheme 94).161 It is

proposed that the reactivity and selectivity are derived from a seven-membered ring intermediate consisting of the enolate chelated to two zinc atoms (Scheme 94), wherein stronger inductive effects are expected to enolize the substrates. A chiral Lewis base could also provide well-defined geometries of the enolates formed from aryl acetic acid esters to give high diastereoselectivity in Ir-catalyzed allylic alkylation reaction, as reported by Hartwig and co-workers.162 In this reaction, synergistic catalysis with a metallacyclic iridium complex, K7c, and benzotetramisole (BTM) was realized for stereodivergent access to all four stereoisomers of the products (Scheme 95). A possible mechanism for the synergistic process was proposed (Scheme 95). The geometry of the allyl moiety is finely controlled once the iridium allyl complex is formed. A “rebound” strategy163−165 in which the Lewis base catalyst can be regenerated by acyl transfer with the electron-deficient AC

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Scheme 80. Ir-Catalyzed Enantioselective Allylation Reactions with Silyl Enol Ethers Derived from α,β-Unsaturated Ketones and Formal Synthesis of (S)-TEI-9826

Scheme 81. Ir-Catalyzed Asymmetric Allylation of Enol Silanes of Vinylogous Esters and Amides

Scheme 82. Attempted Stoichiometric Reaction of π-Allyliridium Complex K7c

phenolate guarantees that a catalytic amount of chiral Lewis base is efficient for controlling the geometry of the nucleophile. 4.4.5. Allylic Alkylations with Trimethyl Orthoacetate and Ethylene Glycol Monovinyl Ether. Trimethyl orthoacetate is widely used in Johnson−Claisen rearrangement reactions under acidic conditions.166 However, there were no documents on the orthoesters as nucleophiles in metalcatalyzed allylic substitution reactions. Recently, the Carreira group disclosed that orthoacetate 179 could act as a commercially available surrogate for acetate enolates to participate in iridium-catalyzed allylic alkylation, providing the γ,δ-unsaturated esters 181 in good yields and excellent enantioselectivity (Scheme 96).167 In this reaction, allylic carbonates 180 were used instead of the frequently used allylic alcohols to avoid the formation of mixed ketene acetals. The Lewis acid additives had a dramatic influence on the outcomes. When a commonly used additive such as methanesulfonate was

employed, competitive methoxylation was observed as the major reaction pathway. Finally, ZnBr2 was identified as the optimal Lewis acid. The authors believed dimethyl ketene acetal (182) was generated under the acidic conditions and it would attack the electrophilic allyliridium species to form intermediate I, which could be trapped by methanol or deprotonated to form intermediate II. Upon workup procedures, both processes would give the desired product. The isolation of side products 183 and 184 supported the two proposed reaction pathways (Scheme 97). Commercially available ethylene glycol monovinyl ether (185) was also explored as a silyl enol ether surrogate, delivering the γ,δ-unsaturated dioxolane acetal protected aldehydes 186 in good yields and excellent enantiosleectivities (Scheme 98). AD

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Scheme 83. Reactions with Various Catalysts and Additive KOMe or Bu4NOAc

Scheme 84. Ir-Catalyzed γ-Selective Allylic Substitutions with Silyl Dienolates

Scheme 85. Ir-Catalyzed Asymmetric Allylic Substitution Reaction Using C2-Substituted Allylic Substrates as Electrophiles

4.5. Aldehydes and Enamines

reactions of methyl allylic carbonates were accompanied by competing formation of products from decarboxylative etherification of the allylic carbonate. This reaction could be suppressed by employing isopropyl carbonates along with ZnCl2 to trap the released 2-propanol. Finally, optimal results were obtained using iridium phosphoramidite complex K6a (cf. Scheme 9) as the catalyst, toluene as the solvent, ZnCl2 as an additive, and isopropyl allyl carbonates as substrates. Various substituted allylic carbonates and enamines were well tolerated to provide homoallylic ketones.

4.5.1. Preformed Enamines from Methyl Ketones as Nucleophiles. Ketone enamines 187 as nucleophiles were first used in Ir-catalyzed allylic alkylation reactions by Weix and Hartwig in 2007 (Table 6).168 Enantioselectivity was markedly influenced by the polarity of the solvent: THF, EtOAc, toluene (95−96% ee) > NMP (84% ee) > CH2Cl2 (82% ee) > DMF, MeCN (77−80% ee). No competitive allylation of pyrrolidine was observed in toluene. Further studies revealed that the AE

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Scheme 86. Ir-Catalyzed Allylic Alkylation of Silyl Ketene Acetals

Scheme 87. Ir-Catalyzed Allylic Alkylation of Silyl Enol Ethers with Branched Allylic Alcohols and Stereodivergent Syntheses of Calyxolanes A and B

Scheme 88. Ir-Catalyzed Asymmetric Allylic Alkylation of Unstabilized Prochiral Ketone Enolates

AF

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Scheme 89. Benzofuran γ-Lactones as Nucleophiles for Ir-Catalyzed Asymmetric Allylic Substitution and Stereospecific Heteroaromatic Cope Rearrangement

Scheme 90. Ir-Catalyzed Allylation of Unstabilized Enolates of Acyclic α-Alkoxy Ketones

Scheme 92. Ir-Catalyzed Stereodivergent Allylic Alkylation of α-Hydroxy Ketones

4.5.2. Dual Catalysis and Stereodivergence in IrCatalyzed Allylic Substitutions via Enamines. It is feasible to obtain both enantiomers of a target compound by simply selecting a pair of enantiomeric catalysts. However, when it comes to diastereoisomers with multiple chiral centers, there are limited strategies to access the full set of stereoisomers. In 2013, the Carreira group reported a dual catalysis system involving a chiral Ir/(P,olefin) catalyst and a chiral amine catalyst, which furnished the four stereoisomers of γ,δ-unsaturated aldehydes 190 bearing vicinal quaternary/ tertiary stereogenic centers under identical conditions (Scheme

99).110 This was the first report on introducing another type of catalyst to control the stereogenic center derived from a prochiral nucleophile in Ir-catalyzed allylic substitution. The reactive prochiral faces of the reaction partners are controlled by the chiral amine and the chiral iridium catalyst, and an outer sphere transition-state mechanism operates, yielding the products with high diastereo- and enantioselectivities. Under the standard reaction conditions, various α-disubstituted aldehydes could be transformed to the desired stereoisomeric γ,δ-unsaturated aldehydes 190 smoothly in a single step. Notably, no aldol side products were observed in this process (Scheme 99). To gain a deeper understanding of this asymmetric cooperative catalysis for α-allylic alkylation of branched aldehydes, the Sunoj group carried out DFT calculations on the origin of stereodivergence for the example shown in

Scheme 91. Transformations of Allylation Products to Substituted Tetrahydrofuran Derivatives

AG

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Scheme 93. Synthesis of All Four Stereoisomers of 174a

Scheme 94. Ir-Catalyzed Stereodivergent α-Allylic Alkylation of α-Hydroxyindanones

Scheme 95. Synergistic Iridium and Lewis Base Catalysis for Stereodivergent Allylic Alkylation of Aryl Acetic Acid Esters and Mechanisms

Scheme 99.72 The authors concluded that, for this cooperative stereoselective catalysis, the control of diastereoselectivity is

due to differential weak interactions in the transition states of the C−C bond formation step. AH

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Scheme 96. Ir-Catalyzed Asymmetric Allylic Alkylation with Trimethyl Orthoacetate

Scheme 98. Ir-Catalyzed Asymmetric Allylic Alkylation with Ethylene Glycol Monovinyl Ether

Despite the inspiring results described above, some problems were encountered. For example, the substrate scope of the nucleophile was limited to branched aldehydes to avoid epimerization by forming a Cα quaternary stereocenter and self-aldol addition. To solve these problems, Carreira and co-workers further optimized the reaction conditions.169 Eventually, it was found that, with dimethyl hydrogen phosphate as the activator and secondary amine (S)A3 as the enamine catalyst, the allylic alkylation of linear aldehydes proceeded smoothly in good yields and with excellent diastereo- and enantioselectivities. No self-aldol addition and relatively slow epimerization were found under these conditions (Scheme 100). The procedure could be utilized as the key step in the enantioselective synthesis of (−)-paroxetine. The method was further expanded to include the α-allylic alkylation of protected α-amino- and α-hydroxyacetaldehydes 193. These useful aldehyde building blocks 194 could be prepared in good yields with good to excellent diastereo- and enantioselectivities.170 All stereoisomers could be accessed at will by choosing the proper combination of catalysts (Scheme 101). The resultant γ,δ-unsaturated aldehydes could be easily transformed into a set of protected amino alcohols with superb selectivity in a stereodivergent manner. Using this strategy, the Carreira group was able to synthesize the full set of stereoisomers in the case of the bioactive natural product Δ9-tetrahydrocannabinol.171 Notably, Zn(OTf)2 was used as the promoter instead of the previously used Brønsted acids to prevent the decomposition of highly electron-rich allylic alcohol in the presence of protic promoters. All the desired diastereoisomers could be obtained in good yields and excellent enantioselectivity. Further uniform synthetic sequences to the target molecules were successfully realized with no loss of the enantiomeric purity (Scheme 102). In 2015, Jørgensen and co-workers developed vinylogous aminocatalysis as a strategy to functionalize remote centers of polyunsaturated carbonyl compounds.172,173 In this strategy, enamines derived from α,β-unsaturated aldehydes 197 are

Table 6. Ir-Catalyzed Allylic Alkylation of Enamines

entry

R1

R2

t (h)

yield (%)

b:l

ee (%)

1 2 3 4 5 6 7 8 9 10

Ph Ph Ph Ph 4-anisyl 4-(CF3)C6H4 2-furyl 2-anisyl Me n-Pr

Ph i-Pr 2-anisyl i-Bu i-Bu i-Bu i-Bu i-Bu Ph i-Bu

6 5 3.5 4 2 11 2 7.5 4 39

91 86 86 91 91 75 90 86 68 64

>99:1 >99:1 96:4 98:2 97:3 85:15 98:2 98:2 95:5 89:11

94 95 96 96 96 94 97 77 94 83

combined with Ir-catalyzed allylic alkylation reactions to generate γ-allylated α,β-unsaturated aldehydes 198.174 This reaction posed many problems, including α:γ, branched:linear, E:Z, diastereo- and enantioselectivities. The Carreira ligand L8, in combination with (BuO)2PO2H as the promoter, gave optimal results with branched allylic alcohols as substrates and catalyst (R)-A4 as the aminocatalyst (Scheme 103). Various cyclic α,β-unsaturated aldehydes and allylic alcohols were investigated as substrates, leading to products 198 in good to excellent yields with very high selectivities. With the enantiomer (S)-A4 as the organocatalyst, the diastereoisomeric series of products were obtained with similar results. This diastereodivergent method was applicable to a wide range of substrates (Scheme 103).

Scheme 97. Proposed Mechanism for the Allylic Alkylation with Trimethyl Orthoacetate as the Nucleophile

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Scheme 99. Stereodivergent Dual Catalytic α-Allylic Alkylation of Branched Aldehydes

When the hemiacetal 200a was subjected to the standard reaction conditions, the enantioenriched N,O-acetal 202a was obtained. A spirocyclic product, 202b, was isolated in a moderate yield and good enantioselectivity when 4-chlorobutanal (200b) was employed (Scheme 105). These examples illustrate the electrophilic and nucleophilic reactivity of the proposed intermediates of the cyclization reaction. 4.6. Electron-Rich Arenes

The stereoselective Friedel−Crafts alkylation reaction is a practical method for the functionalization of arenes. In addition, catalytic asymmetric dearomatization (CADA) reactions were developed as a powerful method for the construction of complex chiral molecules from simple planar aromatic compounds.176−184 In recent years, various electronrich arenes have been successfully used as nucleophiles in Ircatalyzed asymmetric allylic alkylation reactions, via either the Friedel−Crafts-type process or the CADA process. 4.6.1. Indoles. Indoles are widely appearing and important structural cores of numerous biologically active natural products. Therefore, the synthesis of enantiomerically pure indole derivatives is highly desirable for organic chemists. In 1999, Kočovský and co-workers published the first Friedel− Crafts-type allylic substitution of indoles using Mo catalysis.185 Later the groups of Trost, Tamaru, Bandini, and Chan reported palladium-catalyzed allylic alkylations of indoles.186−190 In 2008, You and co-workers reported the first Ir-catalyzed Friedel−Crafts allylic alkylation of indoles, preparing enantiomerically pure indole derivatives 204 bearing a terminal alkene moiety.191 It was found that, in the presence of 2 mol % [Ir(cod)Cl]2, 4 mol % L1, and 1 equiv of Cs2CO3 in refluxed dioxane, various allylated indole derivatives could be prepared in up to 84% yield and 92% ee (Scheme 106). It should be noted that reactions of ortho-substituted cinnamyl carbonates require the use of the N-arylphosphoramidite ligand Me-THQphos (L12b) to achieve high enantioselectivity, while the Feringa ligand only gave poor ee and reactivity (Scheme 107).192 Spiroindolenines are privileged heterocyclic motifs frequently appearing as a structural core in a large family of alkaloids and bioactive pharmaceuticals, which could be easily accessed by dearomatization of indoles. The main challenge in the synthesis of spiroindolenines from indoles is the construction of a quaternary stereogenic center with high enantioselectivity while overcoming the loss of aromaticity.

4.5.3. Diastereoselective Intramolecular Allylic Alkylations via Enamines. Natural products and bioactive compounds in medicinal chemistry often contain substituted piperidines as substructures. In 2017, the Carreira group developed a one-pot cyclization/reduction strategy to prepare enantiomerically pure 3,4-disubstituted piperidines 202 from enantiomerically pure allylic alcohols 199 using the achiral ligand L32.175 The procedure involved trapping of a πallyliridium species, generated with an iridium/(P,olefin) complex under acidic conditions, by an in situ generated enamine. Subsequent reduction gave the desired piperidine 202 (Scheme 104). It was found that erosion of enantiomeric purity in the cyclization step could be avoided upon use of 3,5dichlorobenzoic acid (201) with LiI as an additive, while the subsequent reduction with NaBH4 was improved by addition of trifluoroacetic acid with respect to both overall conversion and diastereoselectivity. Diverse functional groups were tolerated in this reaction. Bulky substituents on the aldehyde gave rise to excellent diastereoselectivity in favor of the transisomer. The products could be prepared on a gram scale and were transformed into piperidine derivatives with higher complexity, demonstrating their value for synthetic organic chemistry.

Scheme 100. Stereodivergent Dual Catalytic Allylation of Linear Aldehydes with Iridium and Amine Catalysis

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Scheme 101. Stereodivergent Dual Catalytic α-Allylic Alkylation of Protected α-Amino- and α-Hydroxyacetaldehydes

Scheme 102. Stereodivergent Synthesis of All Stereoisomers of Δ9-Tetrahydrocannabinols

Scheme 103. Combined Organocatalysis and Ir Catalysis for the Synthesis of γ-Allylated Cyclic α,β-Unsaturated Aldehydes

Notably, Tamaru187 and Trost189 reported elegant work on Pd-catalyzed allylic dearomatization of indoles in a racemic and enantioselective manner, respectively. In 2006, Bandini and coworkers reported a Pd-catalyzed intramolecular allylic substitution of indole derivatives, which allows tetrahydrocarbolines to be prepared with high enantioselectivity.188 Following this pioneering work, an intramolecular asymmetric allylic dearomatization reaction of indoles by forming six-membered spiroindolenines was realized by You and coworkers (Scheme 108).193 With the iridium complex derived from the ligand L12b, the asymmetric allylic dearomatization

of indoles proceeded smoothly, affording spiroindolenines 206 containing a quaternary stereogenic center in excellent yields with high dr and ee values. In addition, this reaction featured a broad substrate scope and ready availability of the starting materials. Moreover, the spiroindolenine products could undergo versatile transformations with no loss of enantiomeric purity, yielding the spiroindoline 209, which constitutes the core structure of the growth hormone secretagogue receptor MK-0677 (Scheme 108).194 To access the spiro[cyclopentane-1,3′-indole]s, the substrate 210 was synthesized and subjected to Ir catalysis (Scheme AK

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Scheme 104. Modular Synthesis of Piperidines by IridiumCatalyzed Enantioconservative and Diastereoselective Cyclocondensation

Scheme 106. Ir-Catalyzed Regio- and Enantioselective Intermolecular Friedel−Crafts Allylic Alkylation of Indoles

Subsequently, You and co-workers developed a tandem dearomatization/migration sequence for the enantioselective construction of polycyclic indoles and pyrroles by tuning the electronic nature of the tether in the pyrrol-2-yl or indol-3-yl allylic carbonate substrates.196 After a series of attempts, it was found that, with an iridium catalyst system consisting of the commercially available iridium precursor [Ir(cod)Cl]2 and the readily accessible BHPphos ligand (L13; cf. Figure 1), developed in the You group, the planned reaction proceeded efficiently to afford a novel type of polycyclic indole, 215, with up to 99% ee. This reaction could also be carried out with pyrroles 216 to furnish polycyclic pyrroles 217 with high efficiency (Scheme 110). A mechanistic study based on in situ IR supported the proposed reaction pathway involving a dearomatized spiro intermediate followed by an in situ migration of the methylene group (path a). Experimentally, the spiroindolenine could be trapped by in situ NaBH4 reduction to afford an isolable spirocyclic amine.197 By this work, a previously reported misassignment of the structures of the products was corrected.188 The spiroindolenine intermediates constitute useful structural motifs. To prevent the migration process, a substituent was installed at the 2-position of the indole.198 With an Ir catalyst generated from [Ir(cod)Cl]2 and the Feringa ligand L1, the spiroindolenines were formed in high yields and with excellent diastereo- and enantioselectivities. As the products partially decomposed during silica gel column chromatography, they were reduced with LiAlH4 in situ to form stable spiroindolines 219, containing three contiguous stereogenic centers, with excellent diastereo- and enantioselectivities (Scheme 111). During the study of this iridium-catalyzed asymmetric allylic dearomatization reaction, the chiral tryptamine derivative 220a was obtained in high enantiomeric purity (93% ee), albeit in low yield (8%), when the indolenine product was subjected to

109).195 Systematic screening of solvents, bases, and ligands revealed that use of dioxane, Cs2CO3, and the Feringa ligand furnished the five-membered spiroindolenines with excellent enantioselectivity. As some substituted spiroindolenines were not sufficiently stable to be isolated, the reaction mixture was treated with NaBH3CN upon completion of the dearomatization reaction, affording the corresponding indolines 212. Good tolerance with steric and electronic demands of substituents in the indole substrates was observed. In all cases, good to excellent yields and diastereo- and enantioselectivities were obtained except for the substrate with R2 = H. The fivemembered spiroindolenines 211 could be smoothly converted to their corresponding tetrahydrocarbazoles 213 with a catalytic amount of TsOH, while the ee was conserved in this one-pot procedure. DFT calculations revealed that the dearomatization reaction was the favored process compared with a direct indole C2alkylation pathway. The “three-center two-electron” carbocation intermediate III may account for the preference of the stereospecific migration (Scheme 109).

Scheme 105. Iridium-Catalyzed Stereoselective Synthesis of Bicyclic Piperidines

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Scheme 107. Comparison of Feringa Ligand L1 with Me-THQphos L12b in Reaction of ortho-Substituted Cinnamyl Carbonates

Scheme 108. First Iridium-Catalyzed Asymmetric Allylic Dearomatization of Indole Derivatives and Transformations

unambiguously by X-ray crystallographic analysis (Scheme 113). Various indole substrates bearing different substituents on the indole core or the phenyl group were smoothly transformed to the corresponding spiroindolenine products. In addition, enantiomerically pure indoles (R)-221 and(S)221 were subjected to the standard reaction conditions to gain insights into the origin of the three diastereoisomers 222. (R)221 underwent the reaction smoothly to give the major diastereoisomer 222a in excellent yield and enantioselectivity. On the other hand, two diastereoisomers were obtained with (S)-221. These results revealed that the formation of the three diastereoisomers is determined by the catalyst and the relative configuration of the starting materials (Scheme 114). It was further found that the relative configuration of the spiroindolenines 222a−222c has a great influence on the reaction pattern of the migration step. To this end, the three diastereoisomers were subjected to the previously established migration conditions (10 mol % TsOH·H2O in THF at room

silica gel column chromatography. It was reasoned that this product might be formed by a retro-Mannich reaction via intermediate IV (Scheme 112). To further promote this process, an aryl group was installed at the benzylic position of the indole core to stabilize the iminium cation of the intermediate V and facilitate the retro-Mannich process (Scheme 112). Finally, the chiral tryptamine derivative 220c could be easily accessed in good yield and with excellent ee through this unprecedented dearomatization/retro-Mannich/ hydrolysis cascade. The stability of spiroindolenines could be fine-tuned by varying their electronic properties. You and co-workers could isolate spiroindolenines by adding an electron-withdrawing group (EWG) at the N-linker to stabilize the five-membered azaspiroindolenines.199 In this case, three diastereoisomers were obtained with excellent enantioselectivity starting from racemic substrate 221. The structures and absolute configurations of the three diastereoisomers were determined AM

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Scheme 109. Ir-Catalyzed Asymmetric Allylic Dearomatization Reaction and Stereospecific Migration of Spiroindolenine Derivatives

Scheme 110. Enantioselective Synthesis of Polycyclic Indoles and Pyrroles via an Ir-Catalyzed Allylic Dearomatization/in Situ Migration Reaction Sequence

Scheme 111. Ir-Catalyzed Enantioselective Syntheses of the Spiroindolines with Three Contiguous Stereogenic Centers

dearomatization/migration procedure (Scheme 116). This reaction required strongly acidic conditions (saturated HCl in THF) to transform all three indolenine diastereoisomers into 223. Medium-sized rings, especially indole-annulated mediumsized rings, are prevalent in the core structure of natural products and pharmaceutical agents. However, because of the unfavorable transannular interaction and entropic factors, approaches toward the synthesis of medium-sized rings are limited. Taking advantage of the unprecedented dearomatization/retro-Mannich/hydrolysis cascade reaction of indole

temperature, Scheme 115). 222c was converted to the tetrahydro-β-carboline cis-223 in excellent yield and with preserved ee within 1 min, while the diastereoisomer 222b required 12 h. In contrast, the other major diastereoisomer, 222a, hardly reacted even at 50 °C. However, inspired by DFT calculations on the mechanism of stereoselective aryliminium migration process, You and coworkers were able to obtain the enantioenriched Pictet− Spengler-type tetrahydro-1H-pyrido[3,4-b]indoles, bearing an additional allylic stereogenic center adjacent to the C3 position of the indole core, in a one-pot asymmetric allylic AN

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Scheme 112. Allylic Dearomatization/Retro-Mannich/Hydrolysis Cascade for the Formation of Chiral Tryptamine Derivatives

Scheme 113. Ir-Catalyzed Stereoselective Synthesis of Five-Membered Chiral Azaspiroindolenines

Scheme 114. Study on the Origin of the Diastereoisomeric Spiroindolenines with Enantiomerically Pure Substrates

derivatives,198 an enantioselective synthesis of medium-sizedring compounds was devised. This process started from readily available indoles 224 and occurred via an Ir-catalyzed allylic dearomatization/retro-Mannich/hydrolysis cascade reaction (Scheme 117).200 After a series of attempts, it was found that the phenyl group at the α-position of the tether was crucial to the success of this reaction, which was believed to stabilize the intermediate VII and promote the retro-Mannich/

hydrolysis step. The desired product 225 could be obtained in high yield and excellent enantioselectivity with an iridium catalyst derived from [Ir(cod)Cl]2 and the Alexakis ligand L2. By adding methylene groups in the linker or the ring, various seven-, eight-, or nine-membered rings could be obtained smoothly in good to excellent yields and with excellent enantioselectivity (Scheme 117). AO

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catalyzed allylic substitution of 4-indolyl allylic carbonates.202 Under the conditions of an in situ generated catalyst, derived from [Ir(cod)Cl]2 and the Feringa ligand L1, and Cs2CO3 as the base, 4-indolyl allylic carbonates 231 underwent Friedel− Crafts alkylation reactions at the C3-position smoothly, affording the seven-membered ring products 232 in 40−78% yields with 91−97% ee (Scheme 120a). However, fused sixmembered ring compounds 234 were obtained when substrates bearing a substituent at the C3-position of the indole moiety were utilized. No dearomatized product was observed (Scheme 120b). These results indicated that the generation of two adjacent stereogenic centers, including one quaternary carbon center, is unfavorable compared with the C5-alkylation process. In contrast, an asymmetric allylic dearomatization of indoles was realized with a palladium catalyst derived from a chiral ferrocene-based PHOX ligand, affording the nine-membered ring products 236 in 48−78% yields and 35−78% ee (Scheme 120c). In 2013, the You group reported a facile pathway to access a chiral tetrahydrocarboline framework via a dearomatization/ migration process.196 In the same year, they also presented an Ir-catalyzed intramolecular Friedel−Crafts-type allylic alkylation reaction of 2-indolyl allylic carbonates 237 to construct these privileged products 215, as an alternative method to access the same products from different substrates.203 In all cases, tetrahydrocarboline derivatives were obtained in moderate to good yields as well as excellent chemo- and enantioselectivities, using BHPphos as the ligand in the presence of K3PO4 as the base (Scheme 121). No N-allylic alkylation products were observed. The control of enantioselectivity with prochiral nucleophiles was less explored in iridium-catalyzed asymmetric allylic substitution reactions before You and co-workers developed an Ir-catalyzed intermolecular asymmetric allylic dearomatization reaction of substituted indoles in 2014. Using the Carreira ligand in the presence of Fe(OTf) 2 as an additive, enantioenriched indolines 240 bearing an all-carbon quaternary chiral center at the prochiral nucleophiles were furnished in good yields with up to 98% ee (Scheme 122).204 It was surprising that, for the first time, the reaction with linear allylic alcohols gave linear allylic substitution products exclusively rather than the branched products. The formation of the linear allylic alkylation products is likely due to a high steric hindrance of the nucleophiles. Preliminary mechanistic studies revealed that the allylic dearomatization/cyclization/ allylic amination cascade was the dominant pathway compared with the allylic amination/dearomatization/cyclization process. The asymmetric synthesis of (−)-debromoflustramine B was accomplished in a highly concise manner by employing this method (Scheme 123).

Scheme 115. Stereoselective Aryliminium Migration of the Five-Membered Azaspiroindolenines

The proposed mechanism was corroborated by trapping the intermediate VI by in situ reduction with 6 equiv of NaBH4 to give product 226 (Scheme 118). With the substrate 227, the reaction did not proceed (Scheme 118). These experiments strengthen the view that the success of the cascade process is due to the preorganization of the six- or seven-membered rings, which reduces energetically unfavorable transannular and torsional strain. Desymmetrization sometimes allows multiple stereogenic centers to be constructed in a single step. Merging this strategy with the CADA reaction is of interest in order to generate useful building blocks. In 2017, this idea was realized by the You group with the iridium catalyst derived from [Ir(dbcot)Cl]2 and the phosphoramidite ligand L12e.201 From the symmetric bis(indol-3-yl) substituted allylic carbonates 228, the spiroindolenines 229 containing three contiguous stereogenic centers were obtained in high yields as a single diastereoisomer with high enantiomeric purity (Scheme 119). A remarkable six- to seven-membered ring expansion of the dearomatized products 229 was achieved in an acidic medium, yielding the hexahydroazepino[4,5-b]indoles 230 with high enantio- and diastereoselectivities. Notably, an inversion of the configuration of the migrating carbon was observed, indicating a possible stepwise migration involving a free vinyliminium intermediate. Compared to the previously presented five- to six-membered ring expansion of spiroindolenines, this six- to seven-membered ring expansion required much harsher reaction conditions (Scheme 119). Recently, diversity-oriented synthesis has received considerable attention from organic synthesis, agrochemical chemistry, and pharmaceutical chemistry because of its ability to provide compound libraries from similar starting materials. In 2013, You and co-workers reported a diversity-oriented synthesis of indole-based peri-annulated compounds via Ir-

Scheme 116. One-Pot Asymmetric Allylic Dearomatization/Migration Procedure To Give Tetrahydro-β-carbolines

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Scheme 117. Iridium-Catalyzed Allylic Dearomatization/Retro-Mannich/Hydrolysis Cascade Reaction for the Synthesis of Indole-Annulated Medium-Sized-Ring Compounds

Scheme 118. Mechanistic Studies and Comparison with Substrate 227

Scheme 119. Ir-Catalyzed Allylic Dearomatization Reaction of Indoles and Six- to Seven-Membered Ring Expansion of the Products

from Me-THQphos (L12b) in the presence of TBD, introduced by the Helmchen group,81 delivered optimal results in both diastereoselectivity and yield. The utility potential of this newly developed method has been further enhanced by diverse transformations allowing facile access to various heterocycles.

Later, the You group also realized an Ir-catalyzed intermolecular allylic dearomatization of substituted indoles, providing the polycyclic indolines 242 bearing contiguous vicinal tertiary and all-carbon quaternary stereocenters with high chemo-, regio-, diastereo-, and enantioselectivities (Scheme 124).205 In addition, the catalyst generated in situ AQ

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Scheme 120. Enantioselective Friedel−Crafts-Type Allylic Alkylation and Dearomatization of Indoles

diastereo- and enantioselectivities (Scheme 125).206 This method provides an efficient and straightforward route to the construction of highly enantioenriched spiro-2H-pyrroles. Having established that the migration pathway in the tandem dearomatization/migration sequence could be altered by tuning the electronic nature of the tether in the indol-3-yl allylic carbonate substrates, it could be envisioned that the fivemembered spiro-2H-pyrroles could be similarly obtained by changing the migratory aptitude of the linker. Accordingly, You and co-workers designed substrates 245 bearing an all-carbon tethered allylic carbonate to test the hypothesis under iridium catalysis.207 With BHPphos (L13) as the ligand, the fivemembered spiro-2H-pyrroles 246 were obtained in good yields and excellent enantioselectivity. The dearomatized products could also be transformed to their corresponding polycyclic pyrroles 247 with preserved ee via a [1,2]-allyl migration reaction upon treatment with a catalytic amount of 4toluenesulfonic acid (Scheme 126). Preparation of K16 revealed that the active catalyst was formed via C(sp2)−H activation (Scheme 127).69 The dearomatization/retro-Mannich/hydrolysis cascade reaction developed by You and co-workers could also be applied in highly efficient and enantioselective syntheses of pyrroleannulated medium-sized-ring compounds 249 (Scheme 128).208 These occur as structural cores in many natural products and bioactive pharmaceutical agents. 4.6.3. Phenols and Naphthols. Phenols have been frequently used as O-nucleophiles in transition-metal-catalyzed allylic substitutions in recent years. However, there are only a few examples of C-allylations, i.e., Friedel−Crafts-type reactions, with phenols. Furthermore, dearomatization of phenols is an attractive method for the construction of highly functionalized chiral cyclic enones from readily available

Scheme 121. Ir-Catalyzed Enantioselective Synthesis of Tetrahydrocarbolines

Scheme 122. Ir-Catalyzed Intermolecular Asymmetric Allylic Dearomatization Reaction of Indole Derivatives

4.6.2. Pyrroles. The main challenges in the stereoselective allylic substitution of pyrroles are similar nucleophilicities of the 2- and 3-positions and the typically increased reactivity of alkylated pyrroles compared to their parent compounds. In 2012, with an iridium catalyst derived from [Ir(cod)Cl]2 and Me-THQphos (L12b), You and co-workers reported the first Ir-catalyzed intramolecular asymmetric allylic dearomatization of pyrroles to afford spiro-2H-pyrrole derivatives 244 with a quaternary stereogenic center in excellent yields and with high AR

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Scheme 123. Enantioselective Synthesis of (−)-Debromoflustramine B

Scheme 124. Ir-Catalyzed Intermolecular Diastereo- and Enantioselective Allylic Dearomatization of Indole Derivatives

yields and regio- and enantioselectivities (25−88% yields, 4.0:1 to 6.0:1 rr, 86−95% ee).212 The reaction proceeded particularly smoothly to give a single isomer of 253 when there was a substituent at the 4- or 5-position of the phenol ring. Pure isomers 254 were obtained when a substituent was present at the 2-position of the phenol ring (Scheme 130). It appears more challenging when the allylic tether is anchored next to the hydroxyl group on the naphthol or phenol ring, as allylic etherification might proceed easily. In 2016, You and co-workers described an intramolecular stereoselective allylic dearomatization reaction of β-naphthols using a novel iridium catalyst generated from [Ir(cod)Cl]2 and diPh-THQphos (L12e). Spironaphthalenones 256 bearing an all-carbon quaternary stereogenic center and a contiguous tertiary stereogenic center were prepared with good to excellent chemo-, diastereo-, and enantioselectivities (Scheme 131).213 It was found that an electron-deficient and sterically hindered protecting group on the nitrogen gave better results in terms of chemo-, diastereo-, and enantioselectivities. All the allylations of phenols reviewed above are intramolecular reactions. Intermolecular reactions were accomplished with allylic alcohols instead of allylic carbonates in 2017. Utilizing the Carreira ligand, an Ir-catalyzed intermolecular stereoselective dearomatization of β-naphthols was achieved by You and co-workers (Scheme 132). βNaphthalenones 260 bearing an all-carbon quaternary stereogenic center were generated in good yields (up to 92% yield)

Scheme 125. Ir-Catalyzed Intramolecular Asymmetric Allylic Dearomatization of Pyrroles

starting materials. However, transition-metal-catalyzed asymmetric allylic dearomatization reactions of phenols have to overcome a number of problems that are listed in Scheme 129. In 2011, You and co-workers designed an intramolecular reaction of allylic carbonates 250 tethered with a parasubstituted phenol moiety.209 In this way the competing allylic etherification reaction and Friedel−Crafts-type reaction could be avoided. This strategy was successful, and highly enantioenriched spirocyclohexadienones 251 were obtained in good to excellent yields (Scheme 129). Almost at the same time, the Hamada group reported a Pd-catalyzed asymmetric allylic dearomatization reaction of phenols.210,211 In 2012, You and co-workers reported an iridium-catalyzed asymmetric intramolecular Friedel−Crafts-type allylic alkylation of substituted allylic carbonates 252, offering a facile access to tetrahydroisoquinolines with moderate to excellent

Scheme 126. Ir-Catalyzed Asymmetric Allylic Dearomatization of Pyrroles and Controllable Migration Reactions

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Scheme 127. Preparation of the Iridium Catalyst K16

Scheme 128. Ir-Catalyzed Asymmetric Allylic Dearomatization of Pyrroles/Retro-Mannich/Hydrolysis Cascade

enantioselective allylic substitutions under Ir catalysis for the first time, although a longer reaction time or increased catalyst loading was necessary. These results not only added new methods to the intermolecular asymmetric dearomatization reactions of phenols, but also expanded the scope for Ircatalyzed asymmetric allylic substitution reactions. At the same time, the Zhong group also reported an asymmetric allylic dearomatization of naphthol derivatives by cooperative iridium and Brønsted acid catalysis (Scheme 133).215 They found that the Brønsted acid TRIP and the concentration of the reaction mixture played an important role in improving the yields and chemo- and enantioselectivities. However, control experiments involving changing the configuration of the ligand and the Brønsted acid implied that the Brønsted acid TRIP has no notable effect on the control of the absolute configuration of the dearomatized products. Anthrones and their derivatives 261 serve as important building blocks in organic synthesis. In 2016, You and coworkers realized a highly enantioselective synthesis of anthrone derivatives 262 by allylic alkylations of anthrones 261 with an iridium catalyst generated from [Ir(cod)Cl]2 and BHPphos (Scheme 134).216 4.6.4. Anilines. Anilines can function as carbon nucleophiles if the amino group is fully protected. An application in the Ir-catalyzed allylic substitution reaction with anilines has not been realized until recently. Fu and co-workers reported an intermolecular allylic alkylation of anilines at the para-position with newly developed ligands (L17a−L17c) derived from the Carreira ligand L8.217 They found that these ligands performed

Scheme 129. Ir-Catalyzed Intramolecular Asymmetric Allylic Dearomatization Reaction of Phenols

Scheme 130. Ir-Catalyzed Intramolecular Friedel−CraftsType Asymmetric Allylic Alkylation of Phenols

and with excellent enantioselectivity (up to 98% ee).214 Moreover, allylic ethers 259 were found to undergo

Scheme 131. Synthesis of Spironaphthalenones via an Iridium-Catalyzed Intramolecular Enantio- and Diastereoselective Allylic Dearomatization of Naphthols

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Scheme 132. Ir-Catalyzed Enantioenselective Dearomatization of β-Naphthols with Allyl Alcohols or Allyl Ethers

Scheme 133. Enantioselective Dearomatization of β-Naphthols by Cooperative Iridium and Brønsted Acid Catalysis

Scheme 134. Ir-Catalyzed Enantioselective Synthesis of Allylated Anthrone Derivatives

Scheme 135. Ir-Catalyzed Asymmetric Allylic Arylation with Anilines

Scheme 136. Ir-Catalyzed Intramolecular Friedel−Crafts-Type Asymmetric Allylic Alkylation of Anilines

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was applied in a stereoselective formal synthesis of sertraline (Scheme 138). In 2015, the Carreira group reported allylic alkylations with functionalized alkyl organozinc bromides. This work considerably expanded the substrate scope of Ir-catalyzed asymmetric allylic alkylation reactions and opened routes to previously inaccessible products.221 Using an iridium catalyst generated in situ from (S)-L8 and [Ir(cod)Cl]2, various functionalized organozinc bromides 273 underwent the reaction smoothly (Scheme 139). Branched O-(tert-butoxycarbonyl)allylic alco-

well with much better efficiency and selectivity in this reaction than L8. The enantioselectivity increased with the polarity of the solvent. This reaction was applied to various substituted branched allylic alcohols 160 as well as anilines 263. Under optimized conditions, allylated products were obtained in good to excellent yields and with very high enantioselectivity (Scheme 135). In addition, the vinylbenzoxazinanone 265 underwent this reaction efficiently with concomitant arylation (88% yield, >99% ee) (Scheme 135). An intramolecular Ir-catalyzed Friedel−Crafts-type enantioselective allylic alkylation of N-monoalkylanilines was achieved recently. In the competition between an intermolecular amination and an intramolecular C-alkylation, it was the latter that proceeded faster (Scheme 136).218 The N-substituent R controlled the 268/269 ratio of this reaction, which ranged from 4:1 to >19:1 with increasing bulk of R. No reaction occurred with the N-[(benzyloxy)carbonyl]anilines, likely because of insufficient NH acidity. With methyl-protected anilines containing various substituents on the phenyl ring, the products were obtained with high regio- and enantioselectivities.

Scheme 139. Ir-Catalyzed Asymmetric Allylic Alkylation with Functionalized Alkylzinc Bromides

4.7. Organometallic Reagents

Organometallic compounds, usually considered as hard nucleophiles, are rarely used in Ir-catalyzed allylic alkylation reactions. In 2007, Alexakis and co-workers reported that the reaction with arylzinc reagents proceeds directly to give arylsubstituted branched allylic products.219,220 The arylzinc reagents were generated in situ via reaction of aryllithium compounds or Grignard reagents with zinc bromide, the latter of which furnished higher enantioselectivity (Scheme 137).

hols 180 rather than alcohols were used to furnish alkylation products 274 with excellent enantioselectivity and in satisfactory yields. Notably, no additive was required for this highly enantioselective process. A concise enantioselective synthesis of the drug candidate (−)-preclamol was realized with this method as the key step, showcasing the utility of the method (Scheme 140). Allenes are a class of compounds with intriguing structures and a potential for diverse transformations.222,223 Under Pd catalysis, soft nucleophiles give rise to allenylic substitution reactions. However, with hard nucleophiles, 1,3-dienes are produced as E/Z mixtures via inner sphere pathways. In 2004, the Takeuchi group reported that Ir catalysts are capable of catalyzing allenylic substitution reactions yielding the branched allenylic products.224 In 2018, the Carreira group published results on the first Ircatalyzed highly enantioselective allenylic substitution reaction (Scheme 141).225 With the catalyst derived from (P,olefin)ligand L8, alkyl organozinc bromides 273 and branched O(tert-butoxycarbonyl)allenylic alcohols 276 gave branched allenylic products 277 under mild conditions with excellent regio- and enantioselectivities (Scheme 141). However, 1,1disubstituted allenes and alkyl-, alkenyl-, and pyridyl-

Scheme 137. Ir-Catalyzed Asymmetric Allylic Arylation with Organozinc Compounds

Allylic carbonates were superior to acetates. Ligand L2 proved optimal, and with LiBr as an additive, improved b:l ratios were obtained. Numerous allylic carbonates were tested, leading to products in good to excellent yields and moderate to good regio- and enantioselectivities. The substitution product 270a Scheme 138. Formal Synthesis of Sertraline

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Scheme 140. Enantioselective Synthesis of (−)-Preclamol

Scheme 141. Ir-Catalyzed Enantioselective Allenylic Alkylations

containing allenylic carbonates were not tolerated under the reported conditions. Control experiments revealed that replacement of L8 by L1 and a Pd or Rh catalyst only furnished 1,3-dienes 278 as the product. In previous studies with their Ir/(P,olefin) catalyst, the Carreira group had often encountered kinetic resolution. A series of control experiments were conducted to gain insight into this aspect of the enantioselective allenylic alkylation reaction (Scheme 142). First, it was found that, at a conversion of 60%, the recovered allenylic carbonate 276a was almost racemic. Second, both enantiopure (S)-276a and (R)-276a were transformed into the same product (S)-277a with identical results. Finally, erosion of the enantiomeric purity of the substrate was found with a racemic ligand. These results excluded a kinetic resolution pathway and indicated that the newly formed chiral center is entirely formed under catalyst control. In addition, they were able to obtain an X-ray crystal structure of the complex K19, in which the allene 276a binds at iridium via the terminal double bond. It was demonstrated that the complex K19 was capable of catalyzing the enantioselective allenylic alkylation (Scheme 143). On the basis of DFT studies, an unusual Ir(I) intermediate, wherein an arylbutadienylium π-system is coordinated in an η2-fashion at Ir, was proposed for the enantiodiscriminating addition of the nucleophile. Pyridines and their derivatives are abundant in nature and widely applied in many fields. The Trost group introduced Pdcatalyzed asymmetric allylic alkylation with 2-methylpyridines. The acidity of the CH3 group was increased by addition of BF3·OEt2.226,227 In 2017, You and co-workers reported the use of this strategy in Ir-catalyzed allylic alkylation.228 With iridium

Scheme 142. Control Experiments for Ir-Catalyzed Enantioselective Allenylic Alkylations

complex K7g derived from [Ir(cod)Cl]2 and the Alexakis ligand L2, various 2-methylpyridines and allyl carbonates were well suited, furnishing 2-homoallylpyridine derivatives 280 with high enantioselectivity (Scheme 144). This method was employed in the first total synthesis of (−)-lycopladine A (Scheme 145). In 2014, the Carreira group reported an Ir-catalyzed direct allyl−alkene coupling, furnishing chiral 1,5-dienes in good AW

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Scheme 143. Synthesis of an Allene-Coordinated Iridium Complex and Catalytic Allenylic Alkylation

Scheme 144. Ir-Catalyzed Asymmetric Allylic Substitution with 2-Methylpyridines

Scheme 145. Enantioselective Synthesis of (−)-Lycopladine A

yields and excellent enantioselectivity.229 However, mono-, 1,2di-, or trisubstituted alkenes were unreactive under the described reaction conditions, limiting the substrate scope. Moreover, mixtures of regioisomeric products were obtained for some olefin nucleophiles. These disadvantages were incentive to search for alternative nucleophilic alkenes to construct the valuable enantioenriched 1,5-dienes. Finally, it was found that, with Sc(OTf)3 as the promoter, allylsilanes could couple with an allyliridium intermediate to afford highly enantioenriched 1,5-dienes 287 in good to excellent yields (Scheme 146).230 Various substituted allylsilanes were well tolerated and gave the corresponding products, which were difficult to obtain by previous Ir-catalyzed allyl−alkene

coupling. The procedure is robust and can be scaled up. It was applied as the first step in an enantioselective synthesis of the pyrethroid protrifenbute. Subsequent hydroboration, Suzuki−Miyaura coupling, and cyclopropanation furnished the target in good yield with very high enantioselectivity (Scheme 146). Chiral organoboron compounds are useful intermediates for the synthesis of complex molecules. Bis(pinacolatoboryl)methane (290) is a commercially available reagent. Niu and co-workers incorporated this simple compound as a nucleophile in Ir-catalyzed allylic alkylation reactions, furnishing enantioenriched homoallylic organoboronic esters.231 A silver salt additive was crucial for the reactivity and selectivity AX

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Scheme 146. Ir-Catalyzed Asymmetric Allylic Alkylation of Allylsilanes

Scheme 147. Ir-Catalyzed Asymmetric Allylic Alkylation of Bis[(pinacolato)boryl]methane

Cu-catalyzed enantioselective vinylation reactions with vinylaluminum or boronic acid esters as nucleophiles have been reported by the Hoveyda and Hayashi groups.234−236 An enantioselective vinylation with another transition-metal catalyst was only reported in 2013, when Carreira et al. described a simple protocol to construct a variety of dienes and polyenes 295 with control of olefin geometry.237 By employing their Ir/(P,olefin) complex L8 as the catalyst, a highly enantioselective allylic substitution of unactivated allylic alcohols with potassium alkenyltrifluoroborates was realized (Scheme 149). In this case, n-Bu4NHSO4 functions both as a phase transfer catalyst and as the Brønsted acid activator for the allylic alcohols. The reaction was stereoconservative with respect to the alkenyltrifluoroborates. The utility of this reaction was showcased by total syntheses of (−)-hinokiresinol and (−)-nyasol on a gram scale (Scheme 149). Subsequently, Carreira and co-workers extended the method to alkynyltrifluoroborates.238 With their catalyst derived from [Ir(cod)Cl]2 and the (P,olefin)-ligand L8, various alkynyltrifluoroborates underwent the reaction smoothly, yielding 1,4enynes 297 as products in good to excellent yields and with high enantioselectivity (Scheme 150). Notably, KHF2 in combination with trifluoroacetic acid was used rather than the hazardous and corrosive HF. A concise enantioselective synthesis of the medicinal agent AMG 837 was achieved, which demonstrates the potential of this method.

of this reaction. Ligands L1 and L8 were applicable to this reaction. With aryl allyl carbonates, the chiral monoboronic esters were obtained in good to excellent yields and enantioselectivity (Scheme 147). This reaction was proposed to proceed through deboration with the assistance of the silver additive to form the actual nucleophile. In recent years, much more attention has been paid to the preparation of multiorganometallics as they can be transformed to versatile compounds by chemoselective bond-forming reactions.232 In 2018, Cho and co-workers developed a convenient way to generate (gem-diborylalkyl)zinc(II) species by reaction of (diborylmethyl)lithium 292 with ZnBr2 or ZnCl2. This new multiorganometallic species could be applied in the Ir-catalyzed asymmetric allylic alkylation reactions, delivering homoallylic gem-diboronate 293 in good to excellent yields and enantioselectivity (Scheme 148).233 Diverse valuable chiral building blocks could be obtained by further elaboration of the enantioenriched products 293, demonstrating the synthetic practicality of this methodology. Scheme 148. Generation of (Diborylmethyl)zinc(II) Species and Its Application in Ir-Catalyzed Asymmetric Synthesis of gem-Diborylalkanes

5. IR-CATALYZED ASYMMETRIC ALLYLIC SUBSTITUTIONS WITH OLEFINS AS NUCLEOPHILES 5.1. Olefins via C−H Activation

Tetrahydroquinolines with a chiral center at the 2-position constitute a common class of biologically active natural products, for example, augustureine. You and co-workers AY

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Scheme 149. Ir-Catalyzed Asymmetric Allylic Vinylation Reaction

Scheme 150. Ir-Catalyzed Asymmetric Alkynylation with Allylic Alcohols and Synthetic Application

planned to synthesize this compound via an Ir-catalyzed asymmetric allylic amination of 2-vinylaniline and a subsequent ring closing metathesis reaction. However, a Heck-type product, 299a, a skipped (Z,E)-diene with exclusively cisgeometry, was obtained from an attempted Ir-catalyzed allylic substitution using [Ir(cod)Cl]2 and Feringa ligand L1 as the catalyst (Scheme 151).239 This result induced further investigation into this Ir-catalyzed allylic vinylation reaction, which had been unknown. Under optimized conditions, the reaction could be carried out with a variety of substituted vinylanilines and allylic carbonates to furnish dienes 299 with good to excellent stereoselectivities and yields (Scheme 152). A mechanistic investigation led to the following proposal.240 First, coordination of 2-vinylaniline to the Ir catalyst generates

Scheme 152. First Ir-Catalyzed Vinylation of Allylic Carbonates with 2-Vinylaniline Derivatives

complex B. Next, reversible deprotonation of complex B yields the unstable complex C, which was postulated to account for H/D exchange observed for the olefinic hydrogens in deuteration experiments. Aromatization of complex C gives complex D with a Z-double bond, and subsequent oxidative addition of the allylic methyl carbonate gives intermediate E. Finally, reductive elimination affords the product and regenerates the catalyst (Scheme 153). Furthermore, an efficient method for the synthesis of 1benzazepine derivatives, an important pharmacophore, via a tandem allylic vinylation/intramolecular allylic amination reaction from 2-vinylaniline and (E)-but-2-ene-1,4-diyl dimethyl dicarbonate [(E)-301] was developed.241 The catalyst derived from [Ir(cod)Cl]2 and Feringa ligand L1 promoted formation of the desired product 302 in excellent yield with high enantioselectivity (Scheme 154). Notably, 2.6 equiv of DABCO were essential for the full conversion of the reaction.

Scheme 151. Retrosynthetic Route for a Synthesis of Augustureine and an Unexpected Finding

AZ

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standard reaction conditions, amination product was obtained instead of vinylation product. These results suggested that the designed amination reaction could be accessed with 2aminostyrenes by choosing a more reactive allylic precursor that facilitated the formation of the π-allyliridium intermediates. After careful examination of the allylic precursor’s leaving groups, ligands, iridium precursors, bases, and solvents, it was found that, with the catalyst generated from [Ir(dbcot)Cl]2 and ligand L2, the desired amination products could be obtained from allylic phosphates. Various 2-vinylanilines or cinnamyl phosphates all led to the corresponding amination products 304 with excellent yields (80−95%) and enantioselectivities (84−93% ee) except in the case of dibromidebearing vinylaniline. The amination products 304 could be easily transformed into the corresponding enantiopure 1,2dihydroquinolines 306 via a two-step process without notable loss of enantiomeric purity (Scheme 156). Subsequently, a chemo- and regioselective iridium-catalyzed dienylation of o-aminostyrene derivatives with dienyl carbonates was realized by the same group, delivering (1Z,4E,6E)trienes 308 in moderate to good yields with high selectivity of a cis double bond.242 A simplified racemic phosphoramidite ligand was used instead of the Feringa ligand in the dienylation with comparable efficiency (Scheme 157).

Scheme 153. Proposed Mechanism of the Ir-Catalyzed Allylic Vinylation Reaction

Scheme 154. Ir-Catalyzed Tandem Allylic Vinylation/ Enantioselective Amination Reaction with (E)-301 and Double Vinylation with (Z)-301

5.2. Alkenes in Polyene Cyclization

Polycyclic frameworks are among the most common structures in organic synthesis. Control of the configuration is a significant challenge in many cases. Recently, great progress has been made in the field of catalytic polyene cyclizations, particularly with various types of organocatalysis such as Brønsted acid catalysis.243−248 However, few procedures making use of enantioselective transition-metal catalysis have been developed.249,250 The Carreira group reported an entirely new approach based on Ir catalysis: polyene cyclization with a π-allyliridium species as an initiator of the reaction.251 An aryl group was used as the concluding nucleophile in their first examples. With an iridium catalyst generated from [Ir(cod)Cl]2 and their standard ligand L8, various branched alcohols 310 underwent the reaction smoothly, furnishing polycyclic compounds 311 in good to excellent yields with excellent diastereo- and enantioselectivities (Scheme 158). The reaction is robust and can be scaled up, rendering this methodology particularly attractive. In 2013, Carreira and co-workers realized the first enantioselective total synthesis of asperolide C, a labdane diterpene isolated from Aspergillus wentii EN-48 (Scheme 159).252 An Ir-catalyzed asymmetric polycyclization cascade concluding with an allylsilane nucleophile was employed as the key step to construct the core carbobicyclic scaffold 313. The linear polyene precursor 312 was prepared via a series of efficient cross-coupling reactions.

A series of 2-vinylaniline substrates bearing different substituents could be transformed to their corresponding enantiopure 1-benzazepine derivatives. Interestingly, when (Z)-but-2-ene-1,4-diyl dimethyl dicarbonate [(Z)-301] was subjected to the standard reaction conditions, the double vinylation product 303 was obtained (Scheme 154). Moreover, the skipped (Z,E)-diene 299b could be isolated in the reaction and furnished the 1-benzazepine product 302b with identical enantioselectivity when subjected to the reaction conditions (Scheme 155). This finding supports the proposal of a tandem allylic vinylation/intramolecular allylic amination reaction pathway. When the π-allyliridium complex generated from an allylic phosphate and a cyclometalated Ir catalyst was used under the

5.3. Intermolecular Allylic Substitution with Alkenes as Nucleophiles

1,5-Dienes are structural motifs with particular synthetic value, and a variety of transition-metal-catalyzed allyl−allyl crosscoupling reactions have been reported for their synthesis. Catalytic enantioselective transformations include Pd-catalyzed regio- and enantioselective cross-coupling of allylboronic acid esters with allylic carbonates, developed by the Morken group,253−255 and Cu-catalyzed enantioselective reactions of allyl bromides with allyl Grignard reagents, reported by Feringa and co-workers.256

Scheme 155. Isolation and Intramolecular Amination of the Intermediate 299b

BA

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Scheme 156. Ir-Catalyzed Asymmetric Allylic Amination Reaction with o-Aminostyrene Derivatives

Scheme 157. Ir-Catalyzed Allylic Vinylation for the Synthesis of (1Z,4E,6E)-Triene Derivatives

amounts of side products. The reaction is atom economical and displays good functional group tolerance. Carbocations are proposed to be the primary reaction products. Accordingly, double bond isomers of the products are formed in the case of unsymmetrically substituted terminal alkene substrates. The synthetic utility of this method was demonstrated by a gramscale reaction with isobutene gas and a concise preparation of γ-secretase modulator JNJ-40418677 in excellent enantioselectivity.

Scheme 158. Ir-Catalyzed Enantioselective Polyene Cyclization

6. IR-CATALYZED ASYMMETRIC ALLYLIC SUBSTITUTIONS WITH HYDRAZONES AND IMINES

In 2014, the Carreira group reported an Ir-catalyzed direct allyl−alkene coupling, which afforded chiral 1,5-dienes 315 in good yields with excellent enantioselectivity (Scheme 160).229 Simple alkenes were used as the nucleophiles instead of allylmetals. The nature of the acid necessary for activation of the alcohol was critical; the unsymmetric sulfonimide 316 was identified as an excellent promoter giving rise to minimal

6.1. Hydrazones

In 2015, the Carreira group described an Ir-catalyzed enantioselective kinetic resolution of branched allylic carbonates and stereospecific substitution of enantiomerically pure carbonates with formaldehyde N,N-dialkylhydrazones 317,

Scheme 159. Ir-Catalyzed Enantioselective Synthesis of (+)-Asperolide C

BB

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Scheme 160. Ir-Catalyzed Asymmetric Allylic Alkylation of Alkenes

corresponding enantioenriched hydrazone adducts (Scheme 161). This strategy was further used in divergent diastereoselective syntheses of chiral homoallylic amines using Enders’ chiral hydrazone derivatives as nucleophiles (Scheme 162).

affording formylated products 318 in high yields and enantioselectivity.257 This strategy features umpolung of formaldehyde to C1-formyl anion nucleophiles. Interestingly, in this kinetic resolution process, Sc(OTf)3 was crucial to increase the reaction rate and yields of starting materials together with citric acid as the Brønsted acid promoter. The reaction is highly effective as most of the calculated selectivity factors (s) exceed 600 and the catalyst loading can be reduced to 1 mol % for a gram-scale reaction (Scheme 161). The

6.2. Umpolung of Imines

In 2016, Niu and co-workers reported an Ir-catalyzed enantioselective allylic alkylation of imines 322, proceeding via an intermediary 2-azaallyl anion, an allylic substitution, and a 2-aza-Cope rearrangement. In a formal sense, this constitutes an umpolung of the imine. The products are valuable chiral homoallylic amines 323 (Scheme 163).258 Ligand L1 proved optimal in conjunction with tert-butyl allylic carbonate substrates. The aromatic stabilization of the fluorenyl anion allowed deprotonation of the starting imines with DBU. Bases weaker than DBU led to no product. The reaction tolerated a broad range of substrates, leading directly to homoallylic amines as products after hydrolytic workup. The isolation of intermediates 324 was possible. Subsequent heating induced rearrangement to give the N-(tert-butoxycarbonyl)homoallylamines. This finding supports the proposed mechanism (Scheme 163). Umpolung of allylic substitutions with α-imino esters catalyzed by Ir complexes has rarely been reported. In 2017, Han and co-workers provided a strategy implementing Ir/PTC cooperative catalysis for diastereo- and enantioselective allylic alkylation of α-imino esters 325.259 Notably, ligand L9b,

Scheme 161. Ir-Catalyzed Allylic Alkylation of N,NDialkylhydrazones via a Kinetic Resolution and Stereospecific Allylic Substitution Process

recovered starting materials could be used to take part in a stereospecific substitution using ligand L32, affording the

Scheme 162. Catalyst-Controlled Diastereodivergent Synthesis of Chiral Homoallylic Amines

BC

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Scheme 163. Ir-Catalyzed Umpolung Asymmetric Allylic Substitution of Imines

Scheme 164. Asymmetric Umpolung Allylic Substitution with α-Imino Esters

developed from the Takemoto group, was found to be optimal, while TBAB (tetrabutylammonium bromide) was the optimal PTC. With this method, various α-quaternary amino acid derivatives 326 could be readily accessed in good to excellent yields and diastereo- and enantioselectivities (Scheme 164).

the branched allylic amines to the thermodynamically more stable linear isomers only took place when the reactions were allowed to proceed for a prolonged period of time. Further investigation revealed that catalysts activated by pretreatment with n-propylamine, DABCO,260 or (in situ) TBD261,262 furnished even better results in terms of yield and ee. Ir-catalyzed asymmetric allylic aminations with arylamines 329 were also realized by the Hartwig group (Scheme 166).263 Since arylamines are not sufficiently basic to induce in situ generation of the active catalytic species, prepreparation of the catalyst using n-propylamine or DABCO was necessary. The procedure was applicable to a variety of substituted arylamines 330. Furthermore, the catalyst loading could be reduced to as low as 0.1 mol %. In 2004, Helmchen and co-workers reported highly enantioselective Ir-catalyzed amination reactions of dienyl carbonates using Feringa ligand L1 (Scheme167).261 For both aryl- and alkyl-substituted dienyl carbonates, branched products 331 were obtained with good to excellent regioand enantioselectivities. A Pb(II) salt was found to improve the reaction rate and regioselectivity of the Ir-catalyzed intermolecular asymmetric amination reactions, especially under the conditions of very low catalyst loading (0.4 mol %) (Scheme 168).264 In 2004, Alexakis and co-workers introduced phosphoramidite ligand L2 into Ir-catalyzed allylic substitution reactions.265 When compared with results from a study by Ohmura and Hartwig,55 it was found that amination reactions promoted by L2 displayed higher enantioselectivity (Table 7). Henceforth, this ligand was widely used as an excellent ligand in Ir-catalyzed allylic substitution reactions.

7. IR-CATALYZED ASYMMETRIC ALLYLIC AMINATIONS 7.1. Aliphatic Amines and Arylamines

7.1.1. Intermolecular Allylic Aminations with Alkyland Arylamines. The first Ir-catalyzed enantioselective allylic amination was reported by the Hartwig group in 2002,55 where the Feringa ligand L152 was introduced in this reaction. Primary and secondary aliphatic amines 327 were identified as suitable nucleophiles (Scheme 165) and furnished chiral allylic amines 328 in uniformly high yields (up to 95%) and with excellent regio- and enantioselectivities (up to 97% ee). It was established that the solvent had a strong influence on the reaction. THF was found to be optimal due to the balance of reaction rate and enantioselectivity. Notably, isomerization of Scheme 165. Ir-Catalyzed Asymmetric Allylic Amination with Alkylamines

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Scheme 166. Ir-Catalyzed Asymmetric Allylic Amination with Arylamines

Table 7. Ir-Catalyzed Asymmetric Allylic Amination with the Alexakis Ligand L2

Scheme 167. Ir-Catalyzed Asymmetric Allylic Amination Reaction of Dienyl Carbonates

Several other ligands have also been developed for use in Ircatalyzed asymmetric allylic substitution reactions with alkylamines. Nemoto, Hamada, and their co-workers introduced Pstereogenic diaminophosphine oxides (DIAPHOXs), which were activated in situ by O-silylation with BSA to form active phosphine L33, which could be used in the Ir-catalyzed allylic amination reactions (Scheme 169).88 In addition, NaPF6 as additive was crucial for both reactivity and selectivity. Allylic amination reactions with alkylamines were also realized with a catalyst derived from [Ir(cod)Cl]2 and helicene-based phosphite L34.266 The helically chiral ligand was derived from the enantiomerically pure alcohol 333 (Scheme 170).267 Reactions with primary and cyclic secondary amines proceeded with high regio- and enantioselectivities (Table 8). Ir-catalyzed asymmetric allylic substitution reactions generally provide branched products with high enantioselectivity, in particular with a base-activated catalyst generated from [Ir(cod)Cl]2 and Feringa-type ligands. However, this catalytic system is not very stable upon heating and is also sensitive to oxygen. In addition, regioselectivity with some alkylsubstituted allylic substrates can be unsatisfactory. To solve these problems, the Helmchen group developed a new series of catalysts generated from [Ir(dbcot)Cl]2 and phosphoramidite ligands.268 These were based on the fact that dbcot, in comparison with cod, is more strongly bound to Ir and a better electron acceptor. The results were indeed promising, as the asymmetric allylic alkylation reactions could be conducted under air using a catalyst generated from [Ir(dbcot)Cl]2 and Alexakis ligand L2. Various nucleophiles, such as primary amines and NaCH(CO 2 Me) 2 , underwent substitutions smoothly to furnish products in good to excellent yields and regioselectivity. It should be noted that a slightly elevated

a

entry

R

liganda

b:la

eea (%)

1 2 3

Bn allyl n-hexyl

L2 [L1] L2 [L1] L2 [L1]

98:2 [99:1] 99:1 [−] 98:2 [98:2]

97 [95] 97 [97] 98 [96]

The values in brackets were reported by Ohmura and Hartwig.55

Scheme 169. Ir-Catalyzed Asymmetric Allylic Amination Using Chiral Diaminophosphine Oxides

reaction temperature was required to shorten the reaction times. It was demonstrated by a mechanistic study that reversible C−H activation occurred in the case of a catalyst derived from [Ir(cod)Cl]2, while Ir complexes based on [Ir(dbcot)Cl]2 did not undergo reversible C−H activation under standard reaction conditions. In 2013, You and co-workers reported another air-stable Ir catalyst, derived from [Ir(dncot)Cl]2 and a phosphoramidite ligand.269 This catalytic system displayed high efficiency and excellent control of regioselectivity with BnNH2 and NaCH(CO2Me)2 as nucleophiles. It was shown that the regiose-

Scheme 168. Ir-Catalyzed Intermolecular Asymmetric Allylic Amination with Lead Salt Additive

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Scheme 170. Synthesis of Helicene-Based Phosphite L34

Table 9. Ir-Catalyzed Allylic Amination of O-Protected Hydroxyalkyl-Substituted Carbonates

Table 8. Ligand L34 for Asymmetric Allylic Amination Reactions

entry

substrate

b:l

total yield (%)

ee(335) (%)

1a 2b 3b 4b

334c 334c 334a 334b

2.5:1 >99:1 99% ee) after various reaction parameters were screened.399 Product 570 was transformed into aldehyde 571, from which a Horner−Wadsworth−Emmons olefination could be performed

furnished excellent results. Attempts to introduce the isobutenyl group by cross-metathesis were not successful. Instead, a stepwise oxidative double bond cleavage followed by a Julia−Kocienski olefination afforded the desired product in good yield. The synthesis was completed by N-Boc deprotection. CU

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Scheme 305. Ir-Catalyzed Diastereodivergent Reverse Prenylation of Tryptophan Derivatives

followed by deprotection and N-alkylation to furnish iodide 572. Cyclization by a Ni-catalyzed reductive Heck reaction and subsequent deprotection and reduction produced the final product. Yang and co-workers also reported the first enantioselective total synthesis of the indole alkaloid (−)-alstoscholarisine A (Scheme 302).400 An intramolecular Ir-catalyzed allylic alkylation at the 2-position of 3-methylindole was utilized to establish the first stereogenic center. The terminal double bond of 575 was then dihydroxylated, and the diol was subsequently protected as an acetal. A selenenylation−elimination protocol led to enone 577, which was treated with a vinyl cuprate and then acetaldehyde to give 578 via a highly stereoselective 1,4addition/aldol cascade. Removal of the acetal protecting group, followed by oxidation with NaIO4, afforded hemiacetal 579. Further reduction and hydroborationoxidation gave aldehyde 581, which was subjected to a one-pot reductive amination/ cyclization procedure to furnish the targeted alkaloid (−)-alstoscholarisine A. This total synthesis was accomplished in only 10 steps. Taking advantage of the dual catalytic α-allylic alkylation strategy developed by the Carreira group,110 Yang reported a catalytic asymmetric total synthesis of (−)-actinophyllic acid in 2018 (Scheme 303).401 Under the optimized reaction conditions for the Ir/amine dual catalytic allylation of indolebased vinyl carbinol derivatives, 582 could be prepared on a gram scale in good yield and excellent enantioselectivity. An aldol reaction was then carried out to deliver 583 in good yield and diastereoselectivity. Key intermediate 585 was obtained by inverting the configuration at C19 of 584 in high yield. This was followed by oxidation and methylation to give product 586, which could be transformed to the seven-membered ring product 587 by a Mannich-like cyclization. (−)-Actinophyllic

acid hydrochloride was eventually obtained following nine further linear manipulations. In 2014, the Carreira group developed an Ir-catalyzed reverse prenylation of 3-substituted indoles to access dearomatized products bearing two contiguous quaternary carbon centers. The use of ligand L8 and their standard procedure failed to give useful results. However, after considerable experimentation, they found the reaction could be achieved using an achiral ligand, L38, with t-BuOK and Et3B as additives (Scheme 304a).402 The latter has previously been employed by others to activate 1H-indoles.403 Further exploration of conditions was required to perform this reverse prenylation on tryptophan derivatives; following optimization, excellent results were achieved using LiHMDS/9-BBN-nC6H13 as activators (Scheme 304b). The reverse prenylated tryptophans exo-589 were then transformed into several prenylated indole alkaloids, as showcased by the total syntheses of (+)-aszonalenin and (−)-brevicompanine B (Scheme 304c,d). Intrigued by the unique structures of the reverse prenylated indole alkaloids, Müller and Stark developed a direct Ircatalyzed chemo-, regio-, and stereoselective reverse prenylation of indole and tryptophan derivatives.404 They were able to identify conditions (Scheme 305a) which not only allowed the Carreira procedure to be performed using chiral ligand L8 but could also be applied to various protected tryptophans. Interestingly, when 9-BBN-octyl and DBU were used as additives together with ligand (R)-L8, the newly formed quaternary stereogenic center had the same absolute configuration irrespective of whether L- or D-tryptophan was used as the starting material; i.e., catalyst control was operative. However, when BPh3 and TBD were used as additives with ligand (R)-L8, the product with the opposite configuration of CV

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methoxycarbonylation. Subsequent steps involved azidation, reduction, and N-alkylation to incorporate an iodoalkene group. Finally, a Ni-catalyzed cyclization reaction, using reductive Heck conditions followed by deprotection, furnished (−)-aspidophylline A. In 2017, Yang and co-workers reported an impressive enantioselective total synthesis of (−)-communesin F (cf Scheme 309), a complex heptacyclic indole alkaloid with interesting biological activity. This challenging target contained five stereogenic centers, including two vicinal quaternary carbons.406 The key reaction of this total synthesis was an Ir-catalyzed intermolecular enantioselective allylic dearomatization reaction of indole derivatives 597 to construct the CDEF tetracyclic core in a single step (Scheme 308). Initially, an allylic alcohol

the newly formed stereogenic center was formed instead; i.e., the borane was acting as a configurational switch. It should be noted that when imidazolium salt 591 (a carbene precursor in the presence of base) was added to the latter catalyst system (Ir:L:591 = 1:1:1), the conversion was significantly improved. Homodimerization of diastereomers exo-589 and endo-589 was achieved using standard peptide synthesis, furnishing the alkaloids amauromine or novoamauromine, respectively (Scheme 305b). Remarkably, heterodimerization could also be realized from a 1:1 mixture of the diastereomers; only trace amounts of the homodimerized isomers were observed in this case (Scheme 305c). It was postulated that the heterodimerization reaction occurred due to the different nucleophilicities and electrophilicities of reacting sites within each diastereomer. Ir-catalyzed enantioselective intramolecular allylic dearomatization of indoles 592 followed by cyclization has been shown to generate tricyclic ring systems 593 (Scheme 306), which are

Scheme 308. Ir-Catalyzed Intermolecular Stereoselective Dearomative Cascade Cyclization of Indole Derivatives

Scheme 306. Ir-Catalyzed Asymmetric Intramolecular Allylic Dearomatization of Indoles

was used as the electrophile with palladium catalyst; however, only the linear allylation product was formed. Therefore, conditions that had been successful in revered prenylations were employed instead. This involved changing the allylic alcohol to the Boc-protected allylic carbonate 598 and using 9BBN-n-C6H13 as the Lewis acid promoter. Under these conditions, the desired reaction proceeded smoothly with excellent enantioselectivity, up to the 5 mmol scale. With the crucial intermediate 599 in hand, protecting group manipulation, including N-methylation and TBS removal, were carried out, followed by a Mitsunobu reaction to generate 600 in 80% yield. Next, transformation of the vinyl moiety to a methoxycarbonyl group and subsequent lactam formation gave 601, which was accomplished via a Lemieux−Johnson

core structural elements of a variety of indole alkaloids. In 2016, Yang and co-workers realized this concept by application of the Carreira Ir catalyst system.405 After identification of a suitable Lewis acid promoter, reactions proceeded in good yields and with high enantioselectivity, albeit with moderate diastereoselectivity. This process was also used in the total synthesis of (−)-aspidophylline A (Scheme 307). The key allylic substitution/cyclization cascade furnished tricyclic products 593 with high enantioselectivity and tolerable diastereoselectivity. The mixture of isomers was degraded to ketone 594, from which 595 was prepared by triflation and a Pd-catalyzed Scheme 307. Total Synthesis of (−)-Aspidophylline A

CW

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Scheme 309. Stereoselective Total Synthesis of (−)-Communesin F

oxidation/Pinnick oxidation/methylation/deprotection/N-acylation sequence, where only one chromatographic purification was needed. Alkylation of lactam 601 with allyl iodide/KO-tBu furnished a 1:1 mixture of C- and O-allylation products 602a and 602b, which could be transformed to 603 under basic hydrolysis conditions at 80 °C via Boc deprotection and a Claisen rearrangement. Standard functional group manipulations furnished the secondary amide 604. The end game involved an O-mesylation/N-deprotection sequence to afford (−)-communesin F in good yield (Scheme 309).

It has been shown in this review that there are three main highly efficient reaction modes in this field, which are in accordance with three different robust phosphoramidite ligand systems. The first one is the system making use of the Feringa and Alexakis ligands and their analogues, in which an active iridacycle catalyst is generated by C(sp3)−H bond activation of the methyl group in the ligands. The second system contains ligands derived from THQphos and BHPphos as well as their derivatives, where C(sp2)−H bond activation of an aryl group in the ligands should be responsible for the activity and selectivity of the promoted reactions. Notably, the C(sp2)−H bond activation could also be applied to NHC ligands, leading to efficient catalytic systems. The third catalyst type was mainly developed by the Carreira group; these highly efficient catalysts are based on a (P,olefin)-binding mode, and an acidic promoter is usually required for high reactivity and selectivity. The high electrophilicity of allylic complexes generated from the Carreira catalyst allows reactions with olefins to be accomplished. The first two catalytic systems generally require basic conditions as the active iridacycles undergo reversible C− H bond activation. The Carreira system, however, tolerates both acidic and basic conditions. Though significant advances have been achieved, unsolved problems are still encountered:

11. CONCLUSIONS AND PERSPECTIVES Since the early seminal work by Takeuchi, Helmchen, and Hartwig, there has been rapid progress in the development of chiral ligands and scope of nucleophiles in Ir-catalyzed allylic substitution reactions over the past 20 years. Detailed mechanistic investigations into reactivity, regioselectivity, and enantioselectivity have greatly accelerated recognition and application of these reactions. In addition, Ir-catalyzed asymmetric allylic substitution reactions have been applied in stereoselective total syntheses of a variety of complex chiral molecules, providing solid evidence of the efficiency of this methodology in controlling both regio- and enantioselectivities and good functional group tolerance.407 CX

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(1) To date, there is still no general method for the efficient control of prochiral nucleophiles to obtain highly diastereoselective allylated products. (2) Though several organometallic reagents have been shown to be applicable in this reaction, the scope is still quite limited. Hard nucleophiles are still challenging. (3) Reactions of alkyl-substituted allylic substrates sometimes proceed with moderate regio- and enantioselectivities. (4) Generally, allylic substrates with tri- or tetrasubstituted alkenes are poor substrates with low reactivity and selectivity. (5) The lowest catalyst loading in Ir-catalyzed allylic substitution reactions is 0.1 mol %, limiting the industrial application of this reaction. Thus, to overcome these challenges, more efforts in this research area are required. It is foreseeable that future extensive efforts in this field will likely provide solutions to the above problems and furnish more unforeseen aspects for Ir-catalyzed asymmetric allylic substitution reactions.

Helmchen at the University of Heidelberg in Germany, she joined the Nanjing Tech University in 2017. Günter Helmchen obtained a Dr. sc. techn. degree in 1971 for work under the guidance of Prof. V. Prelog at the ETH Zürich. He then carried out a “Habilitation” at the Technical University of Stuttgart (1980). In 1981, he was appointed as an associate professor at the University of Wurzburg, and in 1981, he joined the chemistry faculty of the University of Heidelberg as a Full Professor. After his retirement in 2010, he became a Senior-Professor at this institution. His research interests include natural products chemistry, general stereochemistry, and asymmetric catalysis. Shu-Li You received his B.Sc. in chemistry from Nankai University (1996). He then obtained his Ph.D. from the Shanghai Institute of Organic Chemistry (SIOC) in 2001 under the supervision of Prof. Lixin Dai before doing postdoctoral studies with Prof. Jeffery Kelly at The Scripps Research Institute. From 2004, he worked at the Genomics Institute of the Novartis Research Foundation as a Principal Investigator before returning to SIOC as a Professor in 2006. He is currently the director of the State Key Laboratory of Organometallic Chemistry of the SIOC. His research interests mainly focus on asymmetric C−H functionalization and catalytic asymmetric dearomatization (CADA) reactions. He has published over 250 research papers in internationally peer-reviewed journals and edited 2 books.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Chao Zheng: 0000-0002-7349-262X Jian-Ping Qu: 0000-0002-5002-5594 Günter Helmchen: 0000-0003-3125-4313 Shu-Li You: 0000-0003-4586-8359

ACKNOWLEDGMENTS We thank the National Key R&D Program of China (Grant 2016YFA0202900), National Natural Science Foundation of China (Grants 21332009, 21572252, and 21821002), Strategic Priority Research Program (Grant XDB20000000) and Key Research Program of Frontier Sciences (Grant QYZDYSSWSLH012) of the Chinese Academy of Sciences, and Science and Technology Commission of Shanghai Municipality (Grant 16XD1404300) for their generous financial support. We thank Mr. James Alexander Rossi Ashton (University of York) for helpful discussions.

Author Contributions ∥

Q.C. and H.-F.T. contributed equally to this work.

Notes

The authors declare no competing financial interest. Biographies Qiang Cheng received his B.Sc. (2013) from the College of Chemistry at Sichuan University. Then he moved to the Shanghai Institute of Organic Chemistry (SIOC) to pursue his Ph.D. degree (2013−2018) under the supervision of Prof. Shu-Li You, where he performed research on Ir/Pd-catalyzed asymmetric allylic dearomatization reactions. Recently, he joined Professor Tobias Ritter’s laboratory at the Max-Planck-Institut für Kohlenforschung, focusing his research on the late-stage functionalization reactions.

ABBREVIATIONS Ac acyl 9-BBN 9-borabicyclo[3.3.1]nonane BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl BINOL 1,1′-binaphthalene-2,2′-diol Bn benzyl Boc tert-butoxycarbonyl BSA N,O-bis(trimethylsilyl)acetamide BTM benzotetramisole Bz benzoyl Cbz (benzyloxy)carbonyl cod cyclooctadiene coe cycloheptene CPME cyclopentyl methyl ether CSA camphorsulfonic acid DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone dbcot dibenzocyclooctatetraene DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC dicyclohexylcarbodiimide DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DIAD diisopropyl azodicarboxylate DIBAL-H diisobutylaluminum hydride

Hang-Fei Tu was born in Anhui, China, in 1991. He received his B.Sc. degree from Zhejiang University in 2014, and then he joined Professor Shu-Li You’s group at the Shanghai Institute of Organic Chemistry (SIOC) as a Ph.D. student. His current research interest focuses on transition-metal-catalyzed allylic dearomatization reactions. Chao Zheng was born in Hubei Province, China, in 1985. He studied chemistry and received his B.Sc. degree at Shanghai Jiao Tong University in 2007. He obtained his Ph.D. degree at the Shanghai Institute of Organic Chemistry (SIOC) under the supervision of Prof. Shu-Li You and Prof. Yu-Xue Li in 2012. Then he joined Prof. Shu-Li You’s group at SIOC and was promoted to Associate Professor in 2015. His current work is focused on the mechanistic understanding of homogeneous organic reactions by employing computational chemistry, and developing new catalytic asymmetric reactions. He has published over 30 journal papers and 4 book chapters. Jianping Qu received Ph.D. at the Shanghai Institute of Organic Chemistry (SIOC) with Professor Yong Tang in 2011. After an Alexander von Humboldt Fellowship with Professor Gü nter CY

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DIPEA DMAP DMP dncot DPPA dppb dppf EWG FBSM FG Fmoc HATU

diisopropylethylamine 4-(N,N-dimethylamino)pyridine Dess−Martin periodinane dinaphthocyclooctatetraene diphenylphosphoryl azide 1,4-bis(diphenylphosphino)butane 1,1′-bis(diphenylphosphino)ferrocene electron-withdrawing group monofluorobis(phenylsulfonyl)methane functional group (9-fluorenylmethoxy)carbonyl O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate IMDA intramolecular Diels−Alder reaction KHMDS potassium bis(trimethylsilyl)amide LAH lithium aluminum hydride LDA lithium diisopropylamide LiHMDS lithium bis(trimethylsilyl)amide m-CPBA m-chloroperbenzoic acid Mes mesityl MOM methoxymethyl MsCl mesyl chloride NMO N-methylmorpholine oxide PCC pyridinium chlorochromate PG protecting group PHOX phosphinooxazoline Phth phthaloyl PMB p-methoxybenzyl PMHS poly(methylhydrosiloxane) PMP 4-methoxyphenyl p-NS (4-nitrobenzyl)sulfonyl PS proton sponge PTSA (or TsOH) p-toluenesulfonic acid TBAB tert-butylammonium bromide TBAT tert-butylammonium difluorotriphenylsilicate TBAF tert-butylammonium fluoride TBAI tert-butylammonium iodide TBD 1,5,7-triazabicylo[4.4.0]dec-5-ene TBDMS (TBS) tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TEA trimethylamine TES triethylsilyl Teoc [2-(trimethylsilyl)ethoxy]carbonyl Tf (trifluoromethyl)sulfonyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THT tetrahydrothiophene TIPS triisopropylsilyl TM transition metal TMS trimethylsilyl Troc (2,2,2-trichloroethoxy)carbonyl Ts p-tolylsulfonyl

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DOI: 10.1021/acs.chemrev.8b00506 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

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DOI: 10.1021/acs.chemrev.8b00506 Chem. Rev. XXXX, XXX, XXX−XXX