Iridium-Catalyzed Asymmetric Synthesis of Functionally Rich

Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Iridium-Catalyzed Asymmetric Synthesis of Functionally Rich Molecules Enabled by (Phosphoramidite,Olefin) Ligands Simon L. Rössler,+ David A. Petrone,+ and Erick M. Carreira*

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ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland CONSPECTUS: The catalytic, asymmetric synthesis of complex molecules has been a core focus of our research program for some time because developments in the area can have an immediate impact on the identification of novel strategies for the synthesis of value-added molecules. In concert with this central interest, we have emphasized the design of ligand scaffolds as a tactic to discover and develop novel chemistry and overcome well-recognized synthetic challenges. Based on our group’s work on chiral pool-derived diolefin ligands, we designed and implemented a class of hybrid (phosphoramidite,olefin) ligands, which combines the properties of both phosphoramidite and olefin motifs to impact, fine-tune, and even override the inherent reactivity of the metal center. Specifically, we have utilized these unique modifying ligands to address several recognized limitations in the field of iridium-catalyzed, asymmetric allylic substitution. The methods we have documented typically employ branched, unprotected allylic alcohols as substrates and obviate the need for rigorous exclusion of air and moisture. Following Takeuchi’s seminal report demonstrating the high aptitude of Ir(I)-phosphite catalysts for branch-selective allylic substitution, concerted efforts from numerous research laboratories have led to a broadening of the synthetic utility of this reaction class. The first section of this Account outlines the process leading to our discovery of an unprecedented (phosphoramidite,olefin) ligand and its validation in the first iridium-catalyzed amination of branched, unprotected allylic alcohols. This section continues with our work involving heteroatom-based nucleophiles within inter- and intramolecular etherification, thioetherification and spiroketalization processes. The second section highlights the use of readily available carbon nucleophiles possessing sp, sp2, and sp3 hybridization in a series of enantioselective carbon−carbon bond-forming reactions. We describe how alkylzinc, allylsilane, and several classes of organotrifluoroborate nucleophiles can be coupled enantioselectively to enable construction of several key motifs including 1,5-dienes, 1,4-dienes, and 1,4-enynes. Since the unique electronic and steric properties of this class of ligands renders the (η3-allyl)-Ir(III) intermediate highly electrophilic, even weak nucleophiles such as alkyl olefins can be used. We also show that more nucleophilic alkene motifs such as enamines and in situ generated ketene acetals smoothly participate in substitution reactions with allylic alcohols to yield valuable piperidines and γ,δunsaturated esters, respectively. The concept of stereodivergent dual catalysis, which synergistically combines chiral amine catalysis with iridium catalysis to furnish α-allylated aldehydes containing two independently controllable stereocenters is then discussed. This process has enabled the independent, stereoselective synthesis of all four possible product stereoisomers from a single set of starting materials, and was highlighted in the stereodivergent synthesis of Δ9-tetrahydrocannabinol. This Account concludes with an overview of our organometallic mechanistic studies regarding relevant intermediates within the catalytic cycle of this class of allylic substitution. These studies have allowed us to better understand the origin of the unique characteristics exhibited by this catalyst in comparison to related systems.

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INTRODUCTION Stereoselective allylic substitution reactions are one of the most important transition-metal catalyzed processes in organic synthesis. At present, Pd-catalyzed variants have had the largest impact in organic chemistry as evidenced by the high number of applications in complex molecule synthesis.1 One of the limitations of these systems is their propensity to promote nucleophilic attack at the less substituted allylic terminus of a acyclic (η3-allyl)palladium(II) intermediates, thus, leading to a chiral, linear substitution products. Although a large number of other metal complexes prepared from metals including iron, © XXXX American Chemical Society

molybdenum, ruthenium, and tungsten promote branchselective allylic substitution, observed regioselectivities generally remain less than optimal.2 In contrast, rhodium has been shown to display excellent branch selectivity, but only until recently,3 these reactions have generally been limited to stereospecific transformations employing enantioenriched, protected allylic alcohol derivatives as substrates.2,4 Received: April 26, 2019

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DOI: 10.1021/acs.accounts.9b00209 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research Scheme 1. Overview of the Ir-(Phosphoramidite,Olefin)-Catalyzed Allylic Substitution

Takeuchi and Kashio were the first to unlock the synthetic potential of iridium in catalytic allylic substitution.5 Their seminal study from 1997 showed that nucleophilic addition occurs with high levels of branch selectivity when using catalysts prepared in situ by combining [Ir(cod)Cl]2 and P(OPh)3. The authors commented on the use of P(OPh)3 as a ligand, stating “since it is a better π-acceptor, it promotes carbenium character at the more substituted allylic terminus in the π-allyl complex”.5 In the same year, Janssen and Helmchen reported the first enantioselective Ir-catalyzed substitution of allylic acetates with sodium malonate nucleophiles by employing a catalyst bearing a P,N ligand (PHOX).6 Together, these classic studies set the stage for the subsequent 20 years of research in the field of asymmetric iridium-catalyzed allylic substitution.2,7−10 Our efforts to develop a catalytic system that could enable the substitution of racemic, unprotected allylic alcohols led to the development of a novel class of phosphoramidite ligand (L), which incorporates a coordinating olefin. This Account details the use of iridium complexes with this ligand to vastly expand the scope of nucleophiles for asymmetric Ir-catalyzed allylic substitution and its establishment as a crucial component as one of the leading catalytic systems in this evolving field (Scheme 1).11

(−)-carvone and was shown to enable the highly selective kinetic resolution of (±)-1 using phenol nucleophiles (Scheme 2). This, as well as a concurrent report by Hayashi describing Scheme 2. Initial Studies on the Kinetic Resolution of Branched Allylic Carbonates Using Diolefin Ligands

chiral norbornadiene ligands in Rh-catalyzed asymmetric 1,4addition,14 represented the first successful applications of chiral dienes as ligands in asymmetric catalysis. This reaction ignited our interest in asymmetric allylic substitution reactions as we set out to further explore the use of a broad range of heteroatom nucleophiles in this process.15 In 2007, we evaluated the ability of sulfamic acid to serve as a convenient ammonia surrogate in allylic amination.16 Our initial optimization studies revealed that electron-poor ligands such as P(OPh) 3 enabled the direct substitution of unprotected, allylic alcohols (±)-3, albeit with a low level of conversion (Scheme 3). A similar level of conversion (30%) was obtained using phosphoramidite ligand L2. The high modularity and ease of preparation of phosphoramidite ligands makes them ideal for facile reaction optimization through variation of their steric and electronic properties.17 Our group’s interest in the use of alkenes as ligands in asymmetric catalysis, taken in combination with this encouraging result, led to our hypothesis that (phosphoramidite,olefin) hybrid ligand L3 could be useful in unmasking promising reactivity. In principle, the use of a phosphorus donor would ensure strong binding to the metal center, while the olefin component could as well coordinate,

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DEVELOPMENT OF A NOVEL CLASS OF PHOSPHORAMIDITE LIGANDS The importance of chiral ligands to the continuing development of asymmetric catalytic methods using metals has been the major driving force behind our group’s interest in the design of novel ligand scaffolds. In 2004, we found that [Ir(cod)Cl]2 was an active catalyst for the substitution reaction of branched allylic carbonates (±)-1, while the biscyclooctene analog, [Ir(coe)2Cl]2, failed to promote this transformation.12 This finding, compounded by work focused on the use of chiral dienes as stabilizing ligands for transition metals,13 led to our interest in developing chiral cyclooctadiene analogs as steering ligands for use in promoting a wide range of enantioselective allylic substitution reactions. Accordingly, chiral diene L1 was designed and synthesized in 4 steps from naturally occurring B


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Accounts of Chemical Research

amination process involving sulfamic acids. Ligand L3 was also found to be effective for the allylic amination of a series of branched allylic alcohols bearing both alkyl and aryl groups (Scheme 4). The ligand synthesis was extended to the

Scheme 3. Direct Substitution of Unprotected Allylic Alcohols with Sulfamic Acid

Scheme 4. Iridium-Catalyzed Synthesis of Allylic Amines

but in addition, act to modulate the electronic properties of the coordinated metal center through π-back donation.13 At that point in time, there had been only a limited number of reports concerning the preparation and use of olefin-containing phosphines as supporting ligands for transition metal complexes (Chart 1). In 2004, Grützmacher showed that Chart 1. Seminal Examples of Chiral Phosphine−Olefin Ligandsa

a

Conditions: [Ir(coe)2Cl]2 (3 mol %), (S)-L (6 mol %), DMF, rt, 24 h.

preparation of chiral analog (S)-L from commercially available (S)-BINOL. This chiral phosphoramidite−olefin ligand was used to obtain proof-of-concept for the asymmetric variant of the allylic amination with sulfamic acid from which enantioenriched allylic amine could be obtained in 70% ee in reactions employing Ir(I) and (S)-L in a 1:1 ratio. The active catalyst complex based on this novel hybrid ligand was presumed to be reliant on a phosphorus−olefin chelate, which structurally contrasts the acid-labile iridacyclic system based on Feringa−de Vries-type phosphoramidites and popularized by Hartwig (vide infra).7 This key difference was though to manifest itsself in an increased tolerance toward acidic media, such as that employed for the allylic substitution of free allylic alcohol substrates by sulfamic acid as nucleophile (vide infra). More generally, it suggested to us that the Ir-(P,olefin) complexes were quite robust, and could likely lead to the tolerationof a wide variety of reaction conditions. A stereospecific variant of the allylic amination reaction was later developed that employs enantiomerically enriched allylic alcohol substrates (Scheme 5).23 Using this method, a range of optically active allylic amines 4 were obtained in good yields with up to >98% enantiospecificity. The combination of toluene as solvent and DMF as a stoichiometric additive (5 equiv) was shown to effectively replace earlier procedures prescribing only DMF as solvent. The addition of DMF to the reaction media is crucial as it is thought to condense with sulfamic acid to form ammonia and a key Vilsmeier-type adduct (i.e., Int-1). The allylic alcohol substrate can add to this species to generate an dimethyloxomethylene ammonium intermediate (i.e., Int-2) that is primed to undergo oxidative addition to the Ir(I) catalyst. Furthermore, the addition of molecular sieves and a catalytic amount of lithium iodide (10 mol %) was found to be important. Experimental evidence suggests the formation of an iridium iodide complex which renders the transformation more enantiospecific than the corresponding iridium chloride complex.24

a

Note: step counts do not include preparative HPLC resolutions using chiral stationary phases.

phosphine−olefin ligands L4 and L5 were effective in asymmetric Ir-catalyzed hydrogenation of imines,18 and Rhcatalyzed 1,4-conjugate addition of boronic acids to α,βunsaturated carbonyl compounds, respectively.19 Shortly thereafter, Hayashi reported that bridged [2.2.1]bicyclic phosphine−olefin L6 was an effective ligand for asymmetric Rh-catalyzed 1,4-addition20 and Pd-catalyzed allylic substitution.21 Widhalm had also shown that asymmetric Rh-catalyzed 1,4-addition could be accomplished when dinaphthophosphepine-derived L7 was used as a ligand.22 However, access to these ligands generally require multistep synthetic sequences and, in certain cases, resolution by preparative HPLC using chiral stationary phases. Hybrid (phosphoramidite,olefin) ligand L3 could be prepared from commercially available PCl3, 2,2′-biphenol, and iminostilbene in a simple protocol (Scheme 3). Gratifyingly, full conversion of the racemic allylic alcohol (±)-3 was observed when this novel hybrid ligand was used in the allylic C


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Accounts of Chemical Research Scheme 5. Stereospecific Ir-Catalyzed Allylic Amination

Reaction run at 50 °C.

a

In 2012, the catalytic system consisting of [Ir(cod)Cl]2 and (S)-L was used to achieve the first enantioconvergent allylic amination (i.e., both substrate enantiomers are converted to the same product enantiomer) of racemic secondary allylic alcohols (±)-3. This reaction provides access to a diverse array of protected allylic amines 4 with excellent enantioselectivities (Scheme 6). It was during these studies that we determined

Scheme 7. Enantioselective Etherification of Racemic Allylic Alcohols

Scheme 6. Enantioconvergent Amination of Racemic Allylic Alcohols

that 1:2 was the optimal Ir:(S)-L ratio for obtaining excellent levels of enantioselectivity. This observation, made in the early stages of this study, has proven to be an important rule-ofthumb in the successful development of subsequent asymmetric allylic substitution methods.

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at significantly different rates. This observed effect was exploited in utilizing the allylic etherification for a highly selective kinetic resolution of by conducting the reaction at room temperature (Scheme 7b). Subsequently, we developed the analogous allylic thioetherifaction of (±)-3 which operated well using benzyl mercaptan derivatives as nucleophiles in the presence of a phosphoric acid activator (Scheme 7c).26 Mechanistic investigations revealed that a rare enantioconvergent process was operative wherein each starting material enantiomer proceeds to form the same product enantiomer via a unique mechanism.27 The phosphoric acid promoter proved

ALLYLIC SUBSTITUTION WITH OTHER HETEROATOM NUCLEOPHILES Based on the success of the allylic amination reaction, the analogous enantioconvergent etherification was investigated (Scheme 7a). Racemic branched allylic alcohols were found to react with a variety of alcohol nucleophiles when mchlorobenzoic acid was used as a promoter.25 Although this process is enantioconvergent, NMR-based reaction progress studies revealed that the two enantiomers of the racemate react D


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Accounts of Chemical Research critical for high enantioselectivity, and experimental evidence suggested that initial conversion of the R enantiomer into an allyl phosphoric ester was required before it could undergo ionization by the active Ir(I) catalyst. In 2017, we extended the scope of the allylic substitution to intramolecular processes using substrates 9 containing heteroatom- or carbon-based nucleophiles (Scheme 8).28

Scheme 9. Enantio- and Diastereoselective Spiroketalization

Scheme 8. Cyclization via Intramolecular Allylic Substitution

Scheme 10. Cascade Spiroketalization Processes

Under a single set of conditions, an array of heterocyclic building blocks 10, which included 7- and 8-membered rings, could be obtained in a streamlined fashion. This method was highlighted in the key step of the syntheses of erythrococcamides A and B. The high aptitude of the heteroleptic Ir catalyst incorporating the P,olefin ligand to form allylic ethers led to the development of a stereoselective spiroketalization of allylic carbonates bearing pendant hydroxyketone motifs 11 (Scheme 9).29 The reaction is thought to proceed via several equilibria, and following a ring−chain tautomerization/mutarotation sequence, the fully anomeric spiroketal can be selectively obtained. This mode of cyclization facilitated highly stereoselective formation of spiroketals 12 containing various ring sizes, and could be embedded within tandem hemiacetalization and bis-spiroketalization processes (Scheme 10). Furthermore, the enantio- and diastereoselective nature of this process enables streamlined access to functionalized spiroketals, which renders the method useful when considering target-oriented synthesis. Given the distinct ability of this spiroketalization to afford either product enantiomer, we envisioned its application within a total synthesis of (+)-broussonetine H, a polyhydroxylated alkaloid containing multiple stereocenters with unassigned configuration. In conjunction with a stereoselective Brown allylation, this spiroketalization allowed rapid access to all four possible stereoisomers, and ultimate structural assignment of the secondary metabolite (Scheme 11).30

Scheme 11. End Game of the Total Synthesis of (+)-Broussonetine H

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Accounts of Chemical Research Scheme 12. Asymmetric Synthesis of 1,4-Dienes (left) and 1,4-Enynes (right)

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NONSTABILIZED CARBON NUCLEOPHILES Despite significant focus on stabilized carbon nucleophiles (i.e. malonates) in metal-catalyzed allylic substitution, there has been a paucity of methods which utilized the corresponding nonstabilized carbon nucleophiles. We sought to leverage the generality and robustness of the Ir-(phosphoramidite,olefin) system to develop methods that were compatible with the diverse range of carbon nucleophiles commonly employed in synthesis. For example, potassium organotrifluoroborates constitute a popular class of such compounds which can be easily accessed, and in 2013, we reported both the vinylation and alkynylation of racemic allylic alcohols (±)-3 using vinyl trifluoroborates 19 and alkynyl trifluoroborates 21, respectively (Scheme 12).31,32 These methods enabled the synthesis of a range of 1,4-dienes 20 and 1,4-enynes 22 with excellent regioand enantioselectivity. Addition of a phase transfer catalyst (nBu4NHSO4 or nBu4NBr) led to a marked increase in yield, which presumably helped to mitigate the sparing solubility of the organotrifluoroborate salts. In addition to the asymmetric allylation of sp2 and sp hybridized carbon nucleophiles, the corresponding sp 3 hybridized nucleophiles were also evaluated. Readily available, functionalized, alkyl organozinc reagents 24 were identified as suitable nucleophiles for the enantioselective allylation with racemic allylic carbonates (±)-23 (Scheme 13).33 Due to the unique reactivity of these nucleophiles, the C(sp3)−C(sp3) coupling reactions tolerate substrates bearing functional groups that include alkyl chlorides, esters, and nitriles. Interestingly, the optimal reaction conditions obviated the need for an additional promotor, which suggests that the Lewis-acidic Zn reagents may play a supporting role in oxidative addition by promoting the ionization of the allylic carbonate motif. The toolbox of carbon nucleophiles was further expanded to include neutral formyl anion surrogates. In this respect, the use of formaldehyde hydrazone 26 enabled the synthesis of enantioenriched α-allyl aldehyde derivatives (Scheme 14).34 Both racemic and optically active allylic carbonates 23 could be

Scheme 13. Enantioselective Allyl−Alkyl Coupling

a

Conditions: 4 mol% [Ir] and 8 mol% (S)-L in EtOAc as solvent.

used as substrates in either kinetic resolutions or enantiospecific displacements, respectively. In the former process, the combination of citric acid (30 mol %) and Sc(OTf)3 (0.5 mol %) as promoters proved optimal. In initial developments, the reaction proceeded best only when freshly distilled nucleophile was used; however, it was subsequently determined that trace amounts of Sc(OTf)3 (20:1 dr) and absolute stereocontrol (>99% ee). In the study, we demonstrated the first example of stereodivergent dual-catalytic process by independently synthesizing all four stereoisomers of 61a by implementating all four possible chiral catalyst combinations (Scheme 27a). A range of α-substituted alkyl aldehydes (±)-60a and aryl vinyl carbinols (±)-3 efficiently underwent the desired transformation to afford products containing quaternary stereocenters in a vicinal relationship to tertiary stereocenters with excellent levels of diastereo- (10:1 to >20:1) and enantioselectivity (>99% ee in all cases) (Scheme 27b). This process, which involving the use of α-branched aldehydes, generates products that are not prone to epimerization under the reaction conditions. The scope of this stereodivergent reaction was later expanded to include the more challanging class of linear aldehydes 49, which are prone to organocatalyst mediated self-condensation reactions. Nonetheless, products 62 were formed in a stereodivergent fashion with high stereocontrol, despite the presence of a potentially epimerizable stereocenter (Scheme 28).50 The replacement of A2/A3 with the proline-derived Hayashi−Jørgensen catalyst A4, and trichloroacetic acid (pKa = 0.65 in H2O) with dimethylhydrogen phosphate (pKa = 1.29 in H2O) were necessary modifications to the reaction conditions to ensure useful rates and stereocontrol. Variation of the acidic promoter to dichloroacetic acid also enabled the use of protected αamino and α-hydroxyaldehydes 63 in an analogous process (Scheme 29).51 The corresponding α-N/O-substituted γ,δunsaturated aldehyde products 64 were obtained with good to excellent yields and diastereoselectivities with >99% ee in all cases. Furthermore, the synthetic potential of the products

catalysis is an approach in reaction design involving the concurrent activation of both nucleophile and electrophile using two distinct catalysts (Scheme 25a).47 We envisioned Scheme 25. Dual Catalysis

that if two chiral catalysts were to be employed (*Cat1 and *Cat2), the result would be a dual-catalytic system that enables stereodivergency. In principle, by simply interchanging among all four possible catalyst combinations, the full series of stereoisomeric products in a molecule containing two stereocenters could be accessed (Scheme 25b). We hypothesized that the Ir-(phosphoramidite,olefin) catalyst system would be ideal for the exploration of stereodivergent dual catalysis because both ligand enantiomers are readily available, and excellent levels of product enantiomeric excess (>99% ee) are achieved across a wide array of nucleophiles. Furthermore, the tolerance of this system to air and moisture as well as myriad reaction conditions increases the odds of the iridium catalyst operating efficiently under the conditions required by an additional catalyst system. The combination of a chiral cinchona alkaloid-based organocatalyst for the activation of aldehydes with the Ir(phosphoramidite,olefin) system for the generation of chiral

Scheme 26. Control Experiments Highlighting Independent Stereocontrol

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Accounts of Chemical Research Scheme 27. Stereodivergent α-Allylation of Branched Aldehydes

Scheme 28. Stereodivergent α-Allylation of Linear Aldehydesa

Scheme 29. Stereodivergent α-Allylation of Protected αHetero Aldehydes

desirable. The stereodivergent synthesis of all stereoisomers of THC have enabled a comprehensive study of their bioactivity in functional and cell-based assays. This stereodivergent route has more recently been extended to the efficient preparation of other phytocannabinoids found in Radula liverworts for the purposes of natural product profiling,53 as well as photoswitchable Δ9-tetrahydrocannabinol derivatives, which enable the optical control of CB1 signaling.54

a

50 mol % of trichloroacetic acid instead of dimethyl hydrogen phosphate.

obtained was highlighted through the preparation of amino acids and alcohols possessing various diastereomeric arrangements of the 1,2,3-stereotriad motif. The aforementioned stereodivergent α-allylation of linear aldehydes was implemented as a key tactical step in the total synthesis of all four stereoisomers of Δ9-tetrahydrocannabinol (Δ9-THC) 65.52 Through the stereodivergent dual catalytic αallylation of aldehyde 49a with allyl alcohol (±)-3d, we achieved the synthesis of all four diastereomers of γ,δunsaturated aldehyde 62a in good yields (55−62%) with excellent levels of stereocontrol (≥15:1 dr and 99% ee). These isomeric aldehydes were transformed into all four diastereomers of the Δ9-THC target via a unified sequence (Scheme 30). The potential therapeutic properties of Δ9-THC make the development of novel, modular syntheses of this scaffold highly

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MECHANISTIC STUDIES Throughout the discovery and applied synthesis work described in this Account, the catalyst system generated from an Ir(I) precursor and 2 equiv of (phosphoramidite,olefin) L has distinguished itself by imparting high enantioselectivity across a wide array of reactions with a broad range of nucleophiles, while displaying excellent tolerance toward acid, air, and moisture. Most notably, this combination has enabled the use of unprotected racemic substrates, which complements contemporary systems dealing almost exclusively with protected linear analogs. To better understand the intricacies K


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Accounts of Chemical Research Scheme 30. Stereodivergent Synthesis Δ9-Tetrahydrocannabinol

Scheme 31. Putative Mechanism for the Ir-(Phosphoramidite,Olefin)-Catalyzed Allylic Substitution

of this catalyst system, we undertook a mechanistic investigation wherein several key intermediates of the catalytic cycle were isolated and characterized. These studies led to the proposal of a general catalytic cycle which has assisted us in

understanding the various observations noted throughout this Account (Scheme 31).55 As a means to probe the substrate binding step, [Ir(cod)Cl]2 and (R)-L were combined in the presence of either (R)- or L


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involves an Ir−olefin coordination, which, unlike the Ir−C bond, is not susceptible to the same decomposition pathway. As a result, this complementary system displays uniquely high tolerance for wet solvents, protic substrates, and acidic additives. Furthermore, the coordination of two π-acidic phosphoramidite ligands renders the metal center more electrophilic than the Helmchen/Hartwig system, which bears only a single phosphoramidite as well as a σ-donating sp3-carbon ligand. This increase in electrophilicity has clearly manifested itself in a proclivity for the catalyst system to efficiently promote substitution reactions using even weak nucleophiles such as alkenes. More recently, the neutral πallyliridium C,O-benzoate catalysts initially developed by Krische (i.e., Ir-3) for nucleophilic allylation reactions have been shown to also efficiently catalyze asymmetric allylic substitutions of various amine nucleophiles.56 This expansion in the scope of catalysts available to the end users is sure to increase the ability to implement this class of substituion reaction in synthetic planning.

(S)-aryl vinyl carbinol. This facilitated the isolation of the two corresponding diastereomerically pure Ir(I) complexes (R,R,R)-Ir(I) and (R,R,S)-Ir(I), which could be characterized by X-ray crystallography. In the solid state, one (phosphoramidite,olefin) ligand is shown to bind in a bidentate fashion with the second binding solely through phosphorus, while the substrate coordinates in an η2-fashion via the olefin motif. In line with the ionization step, which follows substrate binding, treatment of these Ir(I) complexes with triflic acid yielded an η3-allyl-Ir(III) species as a mixture of endo and exo products. The ratio of these isomers was found to be strongly dependent on the substitution pattern found on the substrate's arene moiety. Notably, the ortho-NO2 substituted analog was found to be present exclusively as the exo isomer. Initial efforts to obtain single crystals of the enantiopure complex were unsuccessful; however, X-ray quality crystals could be obtained from the corresponding racemate, which led to unambiguous structural assignment. In order for the observed major product enantiomer to be formed from this intermediate, we hypothesize that outer-sphere nucleophilic attack must occur on the endo-η3-allyl-Ir(III) species following π−σ−π interconversion. Importantly, all isolated complexes were found to be catalytically and kinetically competent. During these studies, we found that in the presence of oxygen we could observe complex η2-O2-Ir(I) resuling from side-on binding by dioxygen to the parent Ir-complex. This complex could also be independetly synthesized by stirring a solution of [Ir(cod)Cl]2iridium precursor and ligand (R)L under an atmosphere of oxygen. Interestingly, the complexation of oxygen was found to be reversible, which enables this η2-oxygen complex to behave as a precatalyst. We propose that it is this reversible interaction with oxygen that accounts for the observed tolerance of this catalyst system to air. For other allylation catalysts that have been reported based on Feringa− de Vries-type phosphoramidite ligands, the active species has been shown to be present as an iridacyclic P,C-chelate (i.e., Ir1), involving an covalent Ir−C(sp3) bond. However, this Ir−C bond is known to be susceptible to protodemetallation under acidic conditions, and is this propensity to Ir−C cleavage that sets a limit to the reaction conditions that are compatible with its use. By contrast, the (phosphoramidite,olefin) ligand we have developed forms a chelate (i.e., Ir-2, Figure 1) that

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SUMMARY The (phosphoramidite,olefin) ligand class has allowed many challenges in the area of asymmetric iridium-catalyzed allylic substitution to be overcome. In 2011, a review of this field by Hartwig and Pouy highlighted several of such unsolved challenges.57 Of particular concern was the ability to use branched, unprotected allylic alcohols and prochiral nucleophiles as means to streamline substrate synthesis and allow for additional stereocenters to be set, respectively. Furthermore, the development of catalyst systems that do not necessitate the use of dry solvents or inert atmosphere increases the potential for widespread implementation of this method. By helping to overcome these issues, the catalyst system comprised of the (phosphoramidite,olefin) ligand has allowed for vastly increased scope of allylic substitution reactions, involving free racemic allylic alcohols. This catalyst system has enabled the incorporation a diverse array of nucleophiles, which include weakly nucleophilic olefins or chiral enamines within a stereodivergent dual catalytic setting. We hope that this Account will provide a useful perspective as the catalytic system continues to be applied by the broader synthetic community in the synthesis of complex molecules58 and the development of novel methods,59 which are not restricted to the use of iridium.60

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Simon L. Rössler: 0000-0002-5057-0576 David A. Petrone: 0000-0001-9867-9178 Erick M. Carreira: 0000-0003-1472-490X Author Contributions +

S.L.R. and D.A.P. contributed equally.

Notes

The authors declare no competing financial interest. Biographies Simon L. Rössler obtained a B.Sc. and M.Sc. in chemistry from the ETH Zürich, during which time he conducted his master’s thesis under the supervision of Tobias Ritter at Harvard University. He is

Figure 1. Comparison of the three prevalent classes of cationic Irbased catalysts for allylic substitution. M


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Catalytic, Kinetic Resolution of Allyl Carbonates. J. Am. Chem. Soc. 2004, 126, 1628. (13) Defieber, C.; Grützmacher, H.; Carreira, E. M. Chiral Olefins as Steering Ligands in Asymmetric Catalysis. Angew. Chem., Int. Ed. 2008, 47, 4482. (14) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. A Chiral Chelating Diene as a New Type of Chiral Ligand for Transition Metal Catalysts: Its Preparation and Use for the Rhodium-Catalyzed Asymmetric 1,4-Addition. J. Am. Chem. Soc. 2003, 125, 11508. (15) Lyothier, I.; Defieber, C.; Carreira, E. M. Iridium-Catalyzed Enantioselective Synthesis of Allylic Alcohols: Silanolates as Hydroxide Equivalents. Angew. Chem., Int. Ed. 2006, 45, 6204. (16) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. IridiumCatalyzed Synthesis of Primary Allylic Amines from Allylic Alcohols: Sulfamic Acid as Ammonia Equivalent. Angew. Chem., Int. Ed. 2007, 46, 3139. (17) Teichert, J. F.; Feringa, B. L. Phosphoramidites: Privileged Ligands in Asymmetric Catalysis. Angew. Chem., Int. Ed. 2010, 49, 2486. (18) Maire, P.; Deblon, S.; Breher, F.; Geier, J.; Böhler, C.; Rüegger, H.; Schönberg, H.; Grützmacher, H. Olefins as Steering Ligands for Homogeneously Catalyzed Hydrogenations. Chem. - Eur. J. 2004, 10, 4198. (19) Piras, E.; Läng, F.; Rüegger, H.; Stein, D.; Wörle, M.; Grützmacher, H. Chem. - Eur. J. 2006, 12, 5849. (20) Shintani, R.; Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi, T. Chiral Phosphine−Olefin Bidentate Ligands in Asymmetric Catalysis: Rhodium-Catalyzed Asymmetric 1,4-Addition of Aryl Boronic Acids to Maleimides. Angew. Chem., Int. Ed. 2005, 44, 4611. (21) Shintani, R.; Duan, W.-L.; Okamoto, K.; Hayashi, T. Palladium/Chiral Phosphine−Olefin Complexes: X-Ray Crystallographic Analysis and the Use in Catalytic Asymmetric Allylic Alkylation. Tetrahedron: Asymmetry 2005, 16, 3400. (22) Kasák, P.; Arion, V. B.; Widhalm, M. Tetrahedron: Asymmetry 2006, 17, 3084. (23) Roggen, M.; Carreira, E. M. Stereospecific Substitution of Allylic Alcohols to Give Optically Active Primary Allylic Amines: Unique Reactivity of a (P,alkene)Ir Complex Modulated by Iodide. J. Am. Chem. Soc. 2010, 132, 11917. (24) Fagnou, K.; Lautens, M. Halide Effects in Transition Metal Catalysis. Angew. Chem., Int. Ed. 2002, 41, 26. (25) Roggen, M.; Carreira, E. M. Enantioselective Allylic Etherification: Selective Coupling of Two Unactivated Alcohols. Angew. Chem., Int. Ed. 2011, 50, 5568. (26) Roggen, M.; Carreira, E. M. Enantioselective Allylic Thioetherification: The Effect of Phosphoric Acid Diester on Iridium-Catalyzed Enantioconvergent Transformations. Angew. Chem., Int. Ed. 2012, 51, 8652−8655. (27) For seminal examples showing enantioconvergence, see: (a) Ito, H.; Sawamura, M.; Kunii, S. Direct Enantio-Convergent Transformation of Racemic Substrates Without Racemization or Symmetrization. Nat. Chem. 2010, 2, 972−976. (28) Schafroth, M. A.; Rummelt, S. M.; Sarlah, D.; Carreira, E. M. Enantioselective Iridium-Catalyzed Allylic Cyclizations. Org. Lett. 2017, 19, 3235. (29) Hamilton, J. Y.; Rössler, S. L.; Carreira, E. M. Enantio- and Diastereoselective Spiroketalization Catalyzed by Chiral Iridium Complex. J. Am. Chem. Soc. 2017, 139, 8082. (30) Rössler, S. L.; Schreib, B. S.; Ginterseder, M.; Hamilton, J. Y.; Carreira, E. M. Total Synthesis and Stereochemical Assignment of (+)-Broussonetine H. Org. Lett. 2017, 19, 5533. (31) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. Iridium-Catalyzed Enantioselective Allylic Vinylation. J. Am. Chem. Soc. 2013, 135, 994. (32) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. Iridium-Catalyzed Enantioselective Allylic Alkynylation. Angew. Chem., Int. Ed. 2013, 52, 7532. (33) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. Iridium-Catalyzed Enantioselective Allylic Alkylation with Functionalized Organozinc Bromides. Angew. Chem., Int. Ed. 2015, 54, 7644.

currently a Ph.D. student in the group of Erick M. Carreira at the ETH Zürich. David A. Petrone obtained a B.Sc. with honors in chemistry in 2011 from the University of Guelph under the supervision of William Tam and a Ph.D. in 2016 from the University of Toronto under the supervision of Mark Lautens. In 2016, he joined the group of Erick M. Carreira at the ETH Zürich as an NSERC postdoctoral fellow. Erick M. Carreira obtained a B.S. in 1984 from the University of Illinois at Urbana−Champaign under the supervision of Scott E. Denmark and a Ph.D. in 1990 from Harvard University under the supervision of David A. Evans. After carrying out postdoctoral work with Peter Dervan at the California Institute of Technology through late 1992, he joined the faculty at the same institution as an assistant professor of chemistry and subsequently was promoted to the rank of associate professor of chemistry in spring 1996 and full professor in spring 1997. Since September 1998, he has been professor of chemistry at ETH Zürich in the Laboratory of Organic Chemistry.

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ACKNOWLEDGMENTS This work has been supported over the years by the Swiss National Science Foundation (200020 152898 and 200020 172516) and ETH Zürich. We wish to acknowledge past and present co-workers for their valuable contributions to this chemistry throughout the years.

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REFERENCES

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