Asymmetric Rhodium-Catalyzed Allylic Substitution Reactions

Perspective Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

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Asymmetric Rhodium-Catalyzed Allylic Substitution Reactions: Discovery, Development and Applications to Target-Directed Synthesis Ben W. H. Turnbull and P. Andrew Evans*

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Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston K7L 3N6, Canada ABSTRACT: The transition metal-catalyzed allylic substitution reaction is a particularly versatile method for the construction of carbon−carbon and carbon−heteroatom bonds. In this regard, the rhodium-catalyzed variant has emerged as a powerful method for the regioselective and stereospecific allylic substitution of chiral nonracemic secondary and tertiary allylic carbonates with a variety of carbonand heteroatom-based nucleophiles. In addition, recent developments have made the analogous enantioselective process possible using prochiral nucleophiles with achiral allylic electrophiles, which represents a significant advance in this area. In this Perspective, the discovery, development and applications of these conceptually orthogonal strategies to targetdirected synthesis are discussed, with a particular emphasis given to those methods developed in our laboratory.

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INTRODUCTION The ability to prepare carbon−carbon and carbon−heteroatom bonds in a stereoselective fashion is an ongoing challenge for modern synthetic organic chemistry. In this regard, the transition metal-catalyzed allylic substitution reaction has emerged as a powerful method for the construction of these types of bonds.1 This can largely be attributed to the unrivaled scope, with respect to the nucleophile, which permits the construction of C−C, C−N, C−O and C−S bonds in a regioand stereoselective manner. In addition, both stabilized and nonstabilized carbon- and heteroatom-based nucleophiles have been successfully employed in this process. Although the venerable palladium-catalyzed variant, the so-called Tsuji− Trost reaction, is by far the most studied,2,3 an array of other metals have now been shown to facilitate this reaction; for example, copper,4 iron,5,6 molybdenum,7 tungsten,8 nickel,9 rhodium, ruthenium10 and iridium.11 Furthermore, the successful and widespread application of the transition metalcatalyzed allylic substitution reaction to the total synthesis of bioactive natural products12 underscores its utility and drives further developments in this exciting area.

Scheme 1. General Mechanism for the Transition MetalCatalyzed Allylic Substitution Reaction

reductive elimination (hard nucleophiles, pKa >25) provides the substitution product 2 via the complex iv and regenerates the active catalyst.3 As a result of the challenges associated with controlling the regiochemistry in unsymmetrical intermediates, substrates that afford symmetrical π-allyl derivatives (R1 = R2) have historically been the most extensively studied. This can be ascribed to the fact that when the termini in the π-allyl are inequivalent (R1 ≠ R2) nucleophilic attack either occurs at the most stereoelectronically favorable position or more generally results in mixtures of regioisomers.

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TRANSITION METAL-CATALYZED ALLYLIC SUBSTITUTION REACTIONS A general mechanism for the transition metal-catalyzed allylic substitution reaction is outlined in Scheme 1.3 Initial coordination of a low-valent transition-metal complex i to the olefin of the allylic substrate 1 generates ii, which undergoes oxidative addition to furnish the π-allyl intermediate iii. Nucleophilic trapping of this intermediate either by direct attack of the π-allyl moiety (soft nucleophiles, pKa CF3CO > MeOCO > MeCO). Since these initial reports, relatively little progress has been made toward using hard nucleophiles in the rhodium-catalyzed allylic substitution reaction.39 Hence, there is significant room for further development in this area, particularly with regard to the use of unstabilized sp3-hybridized nucleophiles.40 Enolates and Enolate Equivalents. The functionalization of carbonyl derivatives is of paramount importance in organic synthesis because of the ubiquity of these motifs in bioactive natural products and their utility as synthetic intermediates. In this regard, the transition metal-catalyzed allylic substitution with enolates or enolate equivalents offers access to α- or βsubstituted carbonyl compounds in a regio- and stereoselective fashion, thus providing a valuable tool for target-directed synthesis.41 The aforementioned rhodium-catalyzed allylic substitution described by Tsuji demonstrated that the treatment of the allylic carbonate 43 with the silyl enol ether 44 in the presence of tri-n-butylphosphine modif ied RhH(PPh3)4, affords the cyclohexanone 45 in moderate yield (Scheme 11A).19 In 2000, Matsuda extended this approach to acyclic silyl enol ethers, such as 47.42 Hence, the γ,δ-unsaturated ketones 48 and

The stereospecific alkylation of enantiomerically enriched allylic carbonates also proved viable, which is exemplified by the synthesis of the dimethyl ether of the potent norlignan antifungal agent, (−)-sugiresinol (56) (Scheme 12). The chiral nonracemic allylic alcohol 52 was converted to the ketone 53, using an in situ activation/allylic alkylation protocol, in 80% yield and with excellent stereospecificity (100% cee). Subsequent Sharpless asymmetric dihydroxylation followed by a one-pot differential protection furnished 54/55 in good yield, albeit with moderate diastereocontrol. Finally, the desired diastereomer 54 was subjected to a bismuth-catalyzed reductive etherification,44 which upon removal of the acetyl group afforded (−)-sugiresinol dimethyl ether (56) in 45% overall yield for the four-step sequence. A particularly interesting feature of this work is that the nature of the copper(I) halide salt does not impact stereospecificity (I ∼ Br ∼ Cl), which is in stark contrast to previous studies with copper alkoxides (vide inf ra). However, additional studies indicate that the copper(I) halide does play an important role in a subsequent diastereospecific alkylation of the chiral nonracemic allylic alkylation adduct.45 For example, F

DOI: 10.1021/acs.joc.8b00583 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 12. Synthesis of (−)-Sugiresinol Dimethyl Ether via Rhodium-Catalyzed Allylic Alkylation

Acyl Anion Equivalents. Traditionally, the functionalization of carbonyl derivatives by transition metal-catalyzed allylic substitution has been accomplished via the alkylation of unstabilized enolates either directly (metal enolates) or with enolate equivalents such as enamines and silyl enol ethers (vide supra) (Scheme 15, left). However, problems associated with

treatment of the enantiomerically enriched allylic carbonate (S)-6a with acetophenone 50, under the standard conditions, furnished the β-substituted ketone 57 in 91% yield, with excellent regioselectivity and stereospecificity (Scheme 13). Scheme 13. Halide Ion Effects in the Rhodium-Catalyzed Allylic Substitution with Copper(I) Enolates

Scheme 15. Routes to α-Functionalized Carbonyl Compounds via the Transition Metal-Catalyzed Allylic Substitution Reaction

Interestingly, the allylic alkylation of the ketone 57 with (S)-6a affords the pseudo-C2-symmetrical linchpin 58 with only moderate diastereocontrol (dr = 5:1), which prompted reexamination of the role of the copper(I) halide. Hence, in an analogous fashion to our work with copper alkoxides, the chloride salt was found to give superior results, generating 58 with excellent diastereoselectivity (dr = 24:1). The asymmetric alkylation of α-heteroatom-substituted enolates is of significant interest because of its ability to generate two stereogenic centers. In this regard, we demonstrated that the enolates derived from the α-alkoxy ketones 59 are also competent nucleophiles for the regio- and diastereoselective allylic alkylation of a suite of branched allylic carbonates 6 (Scheme 14).46 The excellent diastereoselectivity

regioselective enolate formation from unsymmetrical ketones, polyalkylation and racemization via enolate equilibration have significantly hampered the development of asymmetric variants. 42 To this end, we have recently devised a fundamentally different approach that utilizes an acyl anion equivalent48 to directly install the acyl moiety into an allylic framework, thereby circumventing the formation of an enolate (Scheme 15, right).49,50 In 2012, we demonstrated the first highly regioselective and stereospecific rhodium-catalyzed allylic substitution reaction of tertiary allylic carbonates 14 using an acyl anion equivalent.51,52 A tert-butyldimethylsilyl-protected aryl cyanohydrin pronucleophile 64, which serves as a “masked” acyl anion equivalent, affords a range of α-quaternary aryl ketones 65 in 70−91% yield with excellent regioselectivity (eq 10). A key and striking

Scheme 14. Rhodium-Catalyzed Allylic Substitution Reactions with α-Alkoxy Ketone Enolates

feature of this methodology is the ability to reveal the ketone functionality in situ from the cyanohydrin adduct 66 through exposure to fluoride ion, which generally requires multiple steps in related transformations. Importantly, this approach was also extended to a stereospecific variant; hence, this method represents a convenient method for the asymmetric construction of α-quaternary aryl ketones, which are highly challenging substrates for conventional enolate alkylation.53 In 2015, we described an extension of this approach to prepare α-quaternary α,β-unsaturated ketones, which are more versatile synthetic intermediates compared to the corresponding aryl derivatives.54 For example, the stereospecific allylic alkylation of the chiral nonracemic tertiary allylic carbonate

was attributed to the impact of the chelated (Z)-copper(I) enolate with the enyl organorhodium complex (61), in which the size of the ether impacts the level of stereoselectivity (e.g., R′ = Bn > Me ≫ H). Importantly, this process is highly stereospecific, wherein the enantioenriched allylic carbonate (S)-6a (R = Me) affords the anti-ketone product 60a (R′ = Bn) in 94% yield with excellent enantiospecificity (≥99% cee). Kazmaier and Stolz later extended this approach to zincchelated α-amino ester enolates, thus providing access to α-allyl amino acid derivatives with high levels of stereospecificity.47 G


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The Journal of Organic Chemistry Scheme 16. Stereospecific Rhodium-Catalyzed Allylic Substitution with Alkenyl Cyanohydrin Pronucleophiles

(R)-14b with the alkenyl cyanohydrin 67 furnished the enone 68 in 82% yield and with excellent conservation of enantiomeric excess (Scheme 16). The chemoselective 1,4reduction of the enone with Stryker’s reagent provides access to the acyclic α,α′-dialkylallyl ketone 69, which is a very challenging motif to prepare using conventional enolate alkylation. Notwithstanding the importance of generating quaternary carbon centers, we envisioned that the ability to employ secondary allylic carbonates to prepare the corresponding αternary ketones, would significantly expand the scope of this process. In this regard, we recently reported the highly regioselective and stereospecific allylic substitution of chiral nonracemic secondary allylic carbonates with an acyl anion equivalent (eq 11).55 A key feature of this method is the ability

As is typical of the trimethyl phosphite modified Wilkinson’s catalyst system, the transformation was also highly stereospecific (100% cee) and the stereochemical outcome was confirmed via conversion of the nosyl-protected amine 75 to (R)-homophenylalanine (76), which is a component of a number of biologically active agents (Scheme 17). Interestingly, Scheme 17. Synthesis of (R)-Homophenylalanine (76)

to suppress competing isomerization of the β,γ-unsaturated ketone 71 to the thermodynamically more stable α,βunsaturated derivative 72 by employing an electron-rich aryl cyanohydrin 64 (Ar = 4-Me2NC6H4) to modulate the pKa of the α-proton in the ketone product. Importantly, further functionalization of the dimethylamino substituent was readily enabled via Kumada coupling of the trimethylammonium salt, which provides considerable flexibility with this approach compared to other variants. Nitrogen Nucleophiles. The asymmetric construction of allylic amines using the transition metal-catalyzed allylic substitution reaction has received considerable attention owing to the prevalence of this structural motif in numerous natural products and unnatural bioactive agents.56 Hence, it is no surprise that the use of amine pronucleophiles in the rhodium-catalyzed allylic substitution represents one of the most developed areas within this reaction manifold. As with many related amination strategies, the sulfonamide derivatives were the first to be studied. To this end, we reported the very first highly regioselective allylic amination of unsymmetrical allylic carbonates 6 with the lithium salt of Ntosyl benzyl amine for the construction of N-allyl amines 73 (eq 12).57 A critical observation in this approach was that the sodium and potassium salts of the sulfonamide pronucleophile furnished the amine products with significantly lower efficiency and regioselectivity, which was attributed, at least in part, to the higher basicity of these adducts. Prior to these studies, the allylic amination was restricted to electronically biased allylic alcohol derivatives and epoxides.

in addition to providing a more labile protecting group, the nosyl-protected benzyl amine furnished the product with substantially improved regioselectivity (rs = 55:1 vs 20:1). In a related study, we developed a sequential rhodiumcatalyzed allylic substitution/ring-closing metathesis strategy for the diastereospecif ic construction of both cis- and trans-2,5disubstituted pyrrolines.58 The enantioenriched amine 77 was prepared in two steps via the stereospecific rhodium-catalyzed allylic substitution with N-tosyl-p-methoxybenzyl amine, followed by deprotection of the PMB group (Scheme 18). The subsequent diastereospecific allylic alkylation of the phenyl carbonates (S)-6d and (R)-6d then furnished the bis-allyl amines 78 and 79, respectively, which upon treatment with Grubbs’ first-generation catalyst afforded the cis- and transpyrrolines 80 and 81 in excellent yields. Notably, although the alkylation has the propensity for matched/mismatched pairings, excellent levels of stereospecificity are obtained in both cases, which represents one of the first examples of preparing both stereoisomers of a pyrroline using a single strategy. Anilines are another common class of nitrogen nucleophiles that have proven effective in the rhodium-catalyzed allylic substitution reaction. For example, N-arylsulfonyl anilines also undergo a highly regioselective coupling with allylic carbonates to afford the aryl amines in excellent yield.59 Curiously, branching at the α-position of the allylic carbonate is not tolerated in this particular case (R = iPr), wherein the linear allylic amine is formed as the major isomer (rs = 1:2). Nevertheless, the stereospecific allylic amination of carbonate (R)-6a with the o-vinyl-substituted aniline proceeded in 91% H


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The Journal of Organic Chemistry

Scheme 18. Construction of Cis- and Trans-2,5-Disubstituted Pyrrolines 80 and 81 via Diastereospecific Rhodium-Catalyzed Allylic Amination/Ring-Closing Metathesis

reaction.60 The enantiomerically enriched allylic carbonate (S)-6e undergoes a highly stereospecific amination, in the presence of trimethyl phosphite modif ied Wilkinson’s catalyst, to afford the N1-substituted thymine 88 in 80% yield with excellent regioselectivity (Scheme 20). Furthermore, the synthesis of a novel, conformationally rigid nucleoside 90 in seven additional steps highlighted the utility of this method for the preparation of such motifs, which are related to important antiviral and antitumor agents. A similar strategy was later employed as a key step in the asymmetric synthesis of the polycyclic guanidine-containing marine alkaloid (−)-batzelladine D.61 The 3,4-dihydropyrimidin-2(1H)-one 92 was efficiently coupled with the cyclic allylic carbonate 91 in a highly diastereospecific fashion, furnishing the alcohol 93 in 84% yield (Scheme 21). The intermediate 93

yield with excellent regioselectivity and stereospecificity, en route to dihydroquinoline 83, which represents a common motif for applications in total synthesis (Scheme 19). Scheme 19. Stereospecific Synthesis of Dihydroquinoline 83 from o-Vinyl Aniline 82

In 2007, Martin and co-workers demonstrated that [Rh(CO)2Cl]2 provides a suitable catalyst for the allylic amination with a number of common nitrogen pronucleophiles.39a As is common with this method, both branched and linear allylic carbonates exhibit high levels of regioselectivity in the reaction with benzyl amine and aniline-based nucleophiles. Interestingly, cyclic alkyl amines, such as pyrrolidine (85) were also effective, which currently represents the only example of a rhodiumcatalyzed allylic amination with this class of pronucleophile (eq 13). Furthermore, catalytic tetrabutylammonium iodide is

Scheme 21. Total Synthesis of (−)-Batzelladine D Using a Stereospecific Rhodium-Catalyzed Allylic Amination as a Key Step

essential for attaining high turnover with neutral pronucleophiles, namely 85, which was attributed to exchange of the bridging chloride ion in [Rh(CO)2Cl]2 with iodide, thus generating a complex that is less susceptible to forming an unreactive rhodium amine complex. In 2006, we described the use of N3-benzoyl-protected thymine 87 in the rhodium-catalyzed allylic amination

was then converted to (−)-batzelladine D (94) in an additional 10 steps, which featured a diastereoselective free-radical cyclization and reductive guanidine construction.

Scheme 20. Preparation of a Conformationally Rigid Nucleoside 90 via the Stereospecific Rhodium-Catalyzed Allylic Amination

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The Journal of Organic Chemistry In 2009, we reported the first example of a metal-catalyzed allylic substitution reaction with a charge-separated nucleophile.62 The aza-ylide derived from 1-aminopyridinium iodide provided a competent nucleophile to prepare the allylic amino pyridinium salt 95 in 88% yield with excellent regioselectivity and stereospecificity (Scheme 22). Reductive cleavage of the

[b]furan 98 with excellent diastereocontrol and thus provided a novel route to this important class of heterocycles. Martin and co-workers later extended this approach to copper phenoxides, although the stereospecificity was not examined in this case.39a The ability to use the rhodium-catalyzed allylic etherification reaction for the coupling of hindered alcohols was further demonstrated with primary, secondary and tertiary copper(I) alkoxides.64 For example, a range of allylic carbonates 70 were efficiently coupled with the bulky, secondary alcohol 99 to afford the allylic ethers 100 in 46−73% yield with excellent regioselectivity, although α- and β-branching in the allylic carbonate were not tolerated with this particularly hindered pronucleophile (eq 14). Interestingly, the copper(I) salt plays

Scheme 22. Rhodium-Catalyzed Allylic Amination with a Charge-Separated Pronucleophile

an important role in the regioselectivity of the process, which is in sharp contrast to our work with copper enolates (vide supra).45 The aforementioned difference in reactivity was tentatively ascribed to an in situ salt metathesis of the rhodium-complex and the formation of the lithium halide/ cyanide salt, which may be responsible for regenerating the catalyst and thus maintaining turnover. A key and striking feature of this methodology is that the stereospecificity of the reaction follows an inverse trend as compared to regioselectivity with respect to the copper(I) salt (Cl > Br > I). Nevertheless, treatment of the enantiomerically enriched allylic carbonate (R)-70a with the copper alkoxide derived from benzyl alcohol (101) and copper(I) chloride affords the benzyl ether 102 with 88% cee, which could be further improved to 96% cee at lower temperature (eq 15). In

N−N bond in the pyridinium salt furnished the enantiomerically enriched primary amine 96, which demonstrated the utility of the aza-ylide as a novel ammonia equivalent. Interestingly, both phosphonium and sulfonium aza-ylides were completely unreactive under the optimal reaction conditions. This was attributed to their lower nucleophilicity as a result of being both field and resonance stabilized, which is in sharp contrast to the ammonium or pyridinium derivatives that are only field stabilized. Oxygen Nucleophiles. The rhodium-catalyzed allylic substitution reaction has also been applied to the asymmetric synthesis of allyl ethers, which are key structural motifs in a plethora of bioactive natural products. Hence, despite this area being noticeably less studied than the alkylation with stabilized carbon and nitrogen pronucleophiles, there has been significant progress. In 2000, we reported the first example of a rhodiumcatalyzed allylic etherification reaction using sodium phenoxides as the nucleophilic component.63 Moreover, this protocol permits the construction of 2,6-disubstituted allyl phenyl ethers, which would have been difficult to access via conventional cross-coupling strategies. For example, the use of a sterically demanding, ortho-disubstituted phenol afforded access to the allyl ether 97 in 87% yield with excellent stereospecificity (92% cee) (Scheme 23). Subsequent treatment of the aryl iodide 97 with tris(trimethylsilyl)silane and triethylborane in the presence of oxygen at room temperature furnished the dihydrobenzo-

contrast, copper(I) iodide results in significantly lower stereospecificity (41% cee), which was initially attributed to the greater trans-effect of the iodide ligand, thus increasing the rate of σ−π−σ isomerization.45 However, recent studies point to the fact that the nature of the copper salt is more likely to impact the rate of alkylation and thus the level of stereospecificity (vide supra). In 2004, we described a two-step, stereodivergent synthesis of 5-, 6-, 7- and 8-membered cyclic ethers via the diastereospecif ic rhodium-catalyzed allylic etherification accompanied by ring-closing metathesis.65 A particularly attractive feature of this methodology is the ability to construct both cisand trans-disubstituted cyclic ethers with excellent diastereospecificity using a minimal conformational bias for the ringclosing metathesis to prepare the 8-membered rings. Hence, treatment of the allylic carbonate (S)-70a with the copper alkoxide of the enantiomeric alcohols (R)- and (S)-103, in the presence of trimethyl phosphite modif ied Wilkinson’s catalyst, followed by ring-closing metathesis with Grubbs’ II catalyst furnished the trans- and cis-cyclic ethers 104 and ent-105,

Scheme 23. Rhodium-Catalyzed Allylic Etherification with Ortho-Substituted Phenols

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The Journal of Organic Chemistry respectively, in good yield and with excellent diastereospecificity (Scheme 24). Notably, the modif ication of the copper(I) Scheme 24. Rhodium-Catalyzed Allylic Etherification/RingClosing Metathesis Approach to Cis- and TransDisubstituted Cyclic Ethers

rhodium complex [Rh(NBD)Cl]2 performed better than the corresponding palladium- (11.6% optical yield) or iridiumcatalyzed (8.5% optical yield) variants, which are generally regarded as stalwart in asymmetric metal-catalyzed allylic substitution reactions. Despite this relatively early report, there was very little in the way of significant advancements in this approach over the following decade. However, a number of examples have begun to emerge, which serve to demonstrate where the future advances in this field of study are likely to appear. Hence, the following discussion is divided in to two distinct areas, based upon the mechanism of asymmetric induction. First, the reaction of achiral nucleophiles with branched racemic allyl electrophiles, which constitutes an enantioconvergent or dynamic kinetic asymmetric transformation (DYKAT), is discussed. Second, the use of prochiral nucleophiles with unsubstituted allyl electrophiles is covered, in which the asymmetry is induced via π-facial discrimination of the pronucleophile. Currently, no additional examples of the enantioselective rhodium-catalyzed allylic substitution of achiral nucleophiles with prochiral allylic substrates have been reported, which is most likely due to the high “memory effect” afforded in these types of rhodium-catalyzed systems (vide supra). Achiral Nucleophiles with Substituted Allyl Electrophiles. The enantioconvergent rhodium-catalyzed allylic substitution reaction of achiral nucleophiles with branched allyl electrophiles has been by far the most studied. In this regard, the alkylation of stabilized carbon nucleophiles was the first to be developed,67 in which Pregosin and co-workers demonstrated the asymmetric allylic alkylation of the sodium salt of dimethylmalonate with the racemic acetate 111.68 Although high enantioselectivity could be obtained for the minor regioisomer 113 using the phosphito-thioether ligand 112, significantly lower selectivity was obtained for the major isomer 114 (Scheme 26A). In 2003, Hayashi and co-workers reported the first highly regioselective and enantioconvergent rhodiumcatalyzed allylic substitution reaction.69 Treatment of a range of racemic, branched allyl acetates 115 with dimethyl malonate, in the presence of the chiral complex derived from Rh(dpm)(C2H4)2 and the phosphino-oxazoline ligand 116, furnished the enantiomerically enriched allyl malonate derivatives ent-12 in excellent yield and enantioselectivity (Scheme 26B). A critical observation in the development of this process was the ability to extend the lifetime of the rhodium allyl to permit the

alkoxide with additional trimethyl phosphite is critical for achieving high levels of stereospecificity, which presumably promotes the rapid nucleophilic attack of the rhodium allyl intermediate. This strategy was successfully applied to the first total synthesis of the mosquito deterrent gaur acid (108), which enabled the determination of the absolute configuration of this biologically important agent. The key step involved the diastereospecif ic union of the allylic carbonate (R)-70b with the allylic alcohol 106 to furnish the bis-allyl ether 107 in 69% yield with excellent regioselectivity and diastereospecificity (Scheme 25), which could then be converted to ent-gaur acid (108) in three additional steps.

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ENANTIOSELECTIVE RHODIUM-CATALYZED ALLYLIC SUBSTITUTION REACTIONS The enantioconvergent and the enantioselective rhodiumcatalyzed allylic substitution reactions have been far less studied than the analogous process with other transition metals, which is presumably due to the relatively slow π−σ−π isomerization with the racemic secondary alcohol derivatives and the poor regiochemistry afforded by the achiral linear derivatives (vide supra). Nevertheless, Scalone and Rama described the first enantioselective rhodium-catalyzed allylic substitution reaction via the decarboxylative etherification of the allyl phenyl carbonate 109 to give the allyl phenyl ether 110 with excellent regioselectivity, albeit with moderate levels of asymmetric induction (eq 16).66 Interestingly, in this case the

Scheme 25. Total Synthesis of ent-Gaur Acid (108) Featuring a Diastereospecific Rhodium-Catalyzed Allylic Etherification as a Key Step

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excellent regio- and enantioselectivity (eq 18). The presence of a β-oxygen substituent that is capable of ligating the metal

Scheme 26. Enantioconvergent Rhodium-Catalyzed Allylic Substitution Reactions with Stabilized Carbon Nucleophiles

center is essential (R1 = alkyl, aryl), since substrates that are devoid of this motif or have an oxygen substituent that reduces chelation (e.g. R1 = Bz, TBS) results in substantially lower selectivity. This approach was later extended to secondary allylic trichloroacetimidates, which proved more general and could be applied to the synthesis of 7-membered nitrogen heterocycles.73 In 2016, Li and Breit described the first highly regio- and enantioconvergent rhodium-catalyzed allylic etherification of phenols via a dynamic kinetic asymmetric transformation.74 Hence, the chiral catalyst derived from [RhCl(COD)]2 and (R,R)-QuinoxP* permits the etherification of chiral racemic allylic carbonates 6 with phenols under neutral conditions to furnish the allyl ethers 121 with exquisite levels of enantioselectivity (eq 19). Interestingly, this method was also equilibration of the diastereomeric complexes and thereby improve the level of enantioselectivity. Nitrogen pronucleophiles have also featured in the enantioconvergent rhodium-catalyzed allylic amination, although only benzyl amines and aniline derivatives have been studied. In 2009, Vrieze and co-workers described the rhodium-catalyzed kinetic resolution of allylic carbonates with benzylamine pronucleophiles.70 Although this process only resolves the enantiomers (max. yield = 50%), it affords exquisite selectivity for a variety of alkyl-substituted allylic carbonates 6, furnishing the enantioenriched carbonates ent-6 (≥99% ee) and allylic amines 117 with excellent enantioselectivity (eq 17).

amenable to the ortho-C-allylation of naphthols and other electron-rich phenols in addition to the N-allylation of 2hydroxypyridines, which provides significant versatility to this approach. Prochiral Nucleophiles with Unsubstituted Allyl Electrophiles. The enantioselective rhodium-catalyzed allylic substitution of prochiral nucleophiles with unsubstituted allyl electrophiles, in which the asymmetry is induced via π-facial discrimination of enantiotopic olefin faces, has been far less studied. In 2012, we described the first enantioselective rhodium-catalyzed allylic alkylation of prochiral ketone enolates with allyl benzoate.75 In a similar vein to our work with copper enolates,46 the Z-enolate formed from α-alkoxy-substituted ketones was critical to achieving high levels of enantioselectivity. Treatment of allyl benzoate (122) with the enolates derived from aryl ketones 59 with LiHMDS, in the presence of the complex derived from Wilkinson’s catalyst modif ied with the chiral, monodentate phosphite (S)-BINOL-POMe, afforded the α-alkoxy ketones 123 in excellent yield and with 78−98% enantiomeric excess (eq 20). Interestingly, chiral phosphites

Interestingly, the aryl-substituted allylic carbonate 6d (R = Ph) was poorly resolved under the optimum conditions (16% ee), despite the amine being formed with high selectivity (89% ee). Additional studies demonstrated that this substrate was amenable to a DYKAT, which afforded the benzyl amine in 88% yield and with 89% enantiomeric excess. The most significant advances in the enantioconvergent rhodium-catalyzed allylic amination reaction have been achieved with anilines. Following on from their work on the regioselective allylic amination of trichloroacetimidates,71 in which enantiomerically enriched substrates were shown to undergo significant racemization, Arnold and Nguyen demonstrated the enantioconvergent amination of β-oxygen-substituted tertiary trichloroacetimidates 118 via a DYKAT.72 The chiral complex derived from [RhCl(C2H4)2]2 and the diene 119 proved optimal, providing the allylic amines 120 with L


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The Journal of Organic Chemistry Scheme 27. Enantioselective Rhodium-Catalyzed Allylic Substitution with a Nitrile Anion

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CONCLUSIONS This Perspective outlines some of the unique features of the rhodium-catalyzed allylic substitution reaction, which represents a powerful method for the regioselective and stereospecific construction of carbon−carbon and carbon−heteroatom bonds. Moreover, asymmetric variants, although challenging, have recently come to the fore, with a number of examples now able to furnish highly enantiomerically enriched products. Nevertheless, a number of areas still remain underdeveloped, which will undoubtedly be the focus of future discoveries. For example, there are just a handful of reports describing the use of unstabilized carbon nucleophiles in the rhodium-catalyzed allylic substitution reaction, although these nucleophiles are known to be problematic in related processes. Moreover, much of the work has focused on the use of secondary allylic alcohol derivatives whereas reactions involving tertiary derivatives, which permit the formation of valuable acyclic quaternary stereocenters, are less common. Finally, although there has been significant progress in the development of the asymmetric rhodium-catalyzed allylic substitution reaction, the scope is still limited in comparison to palladium- and iridium-catalyzed variants. Hence, we anticipate that our studies will continue to inspire many new exciting discoveries in the coming years, which should provide new opportunities to apply the rhodiumcatalyzed allylic substitution reaction to target-directed synthesis.

bearing an isopropyl or phenyl substituent, as opposed to methyl, furnished the product in lower yield and significantly reduced selectivity, favoring the opposite enantiomer, which suggested the formation of intrinsically different active catalysts. This was tentatively ascribed to the ability of (S)-BINOLPOMe to undergo a metal-Arbuzov rearrangement to give a phosphonate ligand in contrast to the isopropyl and phenyl derivatives. Further studies also indicated that the relative basicity of the enolate plays an important role in suppressing racemization and polyalkylation. In 2015, we described the first enantioselective allylic alkylation of α-metalated benzyl nitrile anions for the construction of acyclic quaternary centers.76,77 Despite the prevalence of nitriles in natural products and pharmaceuticals, the direct asymmetric alkylation of a nitrile anion had not been forthcoming, which is likely due to the fluxional nature of the intermediate carbanion that can exist as both C- and Nmetalated forms. Hence, treatment of the lithium salt of α-alkyl benzyl nitriles 124 with allyl benzoate (122), in the presence of the chiral complex derived from Rh(COD)2OTf and the chiral monodentate phosphite BINOL-POMe, furnished the quaternary-substituted nitriles 125 in excellent yield and enantioselectivity (Scheme 27). Interestingly, the addition of 15-crown-5 to the intermediate lithium keteniminate was critical to achieving high levels of asymmetric induction, which most likely arises from increased stabilization of the N-metalated resonance form of the anion.78 The synthetic utility of the homoallylic nitriles 125 was demonstrated through the preparation of a bioactive aryl piperazine 128, which represents the most efficient synthesis of this target reported to date.79 Recently, we also described the asymmetric allylic alkylation of aldehyde enolates for the construction of quaternary carbon centers via an analogous process.80 Interestingly, slow addition of the lithium silyl amide base to the aldehyde 129 was important for achieving high yields of 130, which presumably minimizes the side-reactions associated with aldehyde enolates (eq 21). Finally, mechanistic studies indicated that both the

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

P. Andrew Evans: 0000-0001-6609-5282 Notes

The authors declare no competing financial interest. Biographies

(E)- and (Z)-enolate isomers produce the same enantiomer of the product, which obviates the necessity to control enolate geometry. This requirement is invariably a necessity in related methods, thereby rendering the current protocol particularly attractive in this regard. M


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for a Camille Dreyf us Teacher−Scholar Award (PAE), the Royal Society for a Wolfson Research Merit Award (PAE) and the National Sciences and Engineering Research Council for a Tier 1 Canada Research Chair (PAE). Finally, we are grateful to several pharmaceutical companies for unrestricted grants and student fellowships over the years, namely, AstraZeneca, GlaxoSmithKline and Pfizer.

Ben W. H. Turnbull obtained an M.Chem (Hons) degree in Applied Chemistry from Northumbria University (UK) in 2012, where he conducted undergraduate research with Professor Stephen Stanforth. In 2016, he received a Ph.D. in organic chemistry from Queen’s University (Canada) under the mentorship of Professor P. Andrew Evans where he worked on rhodium-catalyzed allylic alkylation reactions using nitrile-stabilized carbanions. In 2017, he joined the laboratory of Professor Michael J. Krische at the University of Texas at Austin as a postdoctoral fellow. He is presently a Senior Scientist in process research and development at Merck in Rayway, New Jersey.

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DEDICATION Dedicated to Professor Stephen P. Stanforth for his inspiration, mentorship and friendship.

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REFERENCES

(1) Crawley, M. L. In Science of Synthesis: Stereoselective Synthesis 3; Evans, P. A., Ed.; Thieme: Stuttgart, 2011; p 403. (2) Frost, C. G.; Howarth, J.; Williams, J. M. J. Selectivity in Palladium Catalysed Allylic Substitution. Tetrahedron: Asymmetry 1992, 3, 1089. (3) Trost, B. M.; Van Vranken, D. L. Asymmetric Transition MetalCatalyzed Allylic Alkylations. Chem. Rev. 1996, 96, 395. (4) Fouquet, G.; Schlosser, M. Improved Carbon-Carbon Linking by Controlled Copper Catalysis. Angew. Chem., Int. Ed. Engl. 1974, 13, 82. (5) Roustan, J. L.; Mérour, J. Y.; Houlihan, F. Reactions D’alkylation de Chlorures, Formate et Acetates Allyliques Catalysees par des Complexes du fer et du Cobalt. Tetrahedron Lett. 1979, 20, 3721. (6) Xu, Y.; Zhou, B. The Regio- and Stereoselectivity of Bu4N[Fe(CO)3NO]-Catalyzed Allylic Alkylation. J. Org. Chem. 1987, 52, 974. (7) Trost, B. M.; Lautens, M. Molybdenum Catalysts for Allylic Alkylation. J. Am. Chem. Soc. 1982, 104, 5543. (8) Trost, B. M.; Hung, M.-H. Tungsten-Catalyzed Allylic Alkylations. New Avenues for Selectivity. J. Am. Chem. Soc. 1983, 105, 7757. (9) Cuvigny, T.; Julia, M. Alkylations Allyliques Catalysees au Nickel. J. Organomet. Chem. 1983, 250, C21. (10) Zhang, S.-W.; Mitsudo, T.; Kondo, T.; Watanabe, Y. Ruthenium Complex-Catalyzed Allylic Alkylation of Carbonucleophiles with Allylic Carbonates. J. Organomet. Chem. 1993, 450, 197. (11) For seminal contributions, see: (a) Takeuchi, R.; Kashio, M. Highly Selective Allylic Alkylation with a Carbon Nucleophile at the More Substituted Allylic Terminus Catalyzed by an Iridium Complex: An Efficient Method for Constructing Quaternary Carbon Centers. Angew. Chem., Int. Ed. Engl. 1997, 36, 263. (b) Janssen, J. P.; Helmchen, G. First Enantioselective Alkylations of Monosubstituted Allylic Acetates Catalyzed by Chiral Iridium Complexes. Tetrahedron Lett. 1997, 38, 8025. (c) Ohmura, T.; Hartwig, J. F. Regio- and Enantioselective Allylic Amination of Achiral Allylic Esters Catalyzed by an Iridium-Phosphoramidite Complex. J. Am. Chem. Soc. 2002, 124, 15164. (d) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Iridium-Catalyzed Synthesis of Primary Allylic Amines from Allylic Alcohols: Sulfamic Acid as Ammonia Equivalent. Angew. Chem., Int. Ed. 2007, 46, 3139. (12) Trost, B. M.; Crawley, M. L. Asymmetric Transition-MetalCatalyzed Allylic Alkylations: Applications in Total Synthesis. Chem. Rev. 2003, 103, 2921. (13) For seminal contributions, see: (a) Lumbroso, A.; Koschker, P.; Vautravers, N. R.; Breit, B. Redox-Neutral Atom-Economic RhodiumCatalyzed Coupling of Terminal Alkynes with Carboxylic Acids Toward Branched Allylic Esters. J. Am. Chem. Soc. 2011, 133, 2386. (b) Gellrich, U.; Meißner, A.; Steffani, A.; Kähny, M.; Drexler, H.-J.; Heller, D.; Plattner, D. A.; Breit, B. Mechanistic Investigations of the Rhodium-Catalyzed Propargylic CH Activation. J. Am. Chem. Soc. 2014, 136, 1097. (c) Koschker, P.; Käh ny, M.; Breit, B. Enantioselective Redox-Neutral Rh-Catalyzed Coupling of Terminal Alkynes with Carboxylic Acids Toward Branched Allylic Esters. J. Am. Chem. Soc. 2015, 137, 3131 and pertinent references cited therein.

P. Andrew Evans gained a B.Sc. (Hons) in Applied Chemistry at Newcastle Polytechnic (UK) in 1987 and a Ph.D. in organic chemistry at the University of Cambridge (UK) in 1991 under the supervision of Professor Andrew B. Holmes, FRS. He then completed postdoctoral studies with Professor Philip D. Magnus, FRS, at the University of Texas at Austin as a NATO Postdoctoral Fellow. In 1993, he joined the faculty at the University of Delaware as an Assistant Professor and was rapidly promoted through the ranks to Professor in 2000. He subsequently moved to Indiana University in 2001, followed by the University of Liverpool (UK) in 2006, where he was the Heath Harrison Chair of Organic Chemistry. In 2012, he moved to his current position as the Alf red R. Bader Chair in Organic Chemistry at Queen’s University in Kingston, Ontario (Canada). He has been recognized with numerous honors and awards, including most recently, the Cope Scholar Award from the American Chemical Society and the Pedler Award from the Royal Society of Chemistry. In addition, he was elected as a Fellow of the American Chemical Society, and he currently holds a Tier 1 Canada Research Chair in Organic and Organometallic Chemistry. His research interests focus on the development of new synthetic transformations that permit the expeditious total synthesis of complex natural products.

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ACKNOWLEDGMENTS We are extremely grateful for the many intellectual and experimental contributions of our talented co-workers that have driven this program over the years, namely, W. J. Andrews, B. Bazin, J. Chae, E. A. Clizbe, L. J. Kennedy, K. W. Lai, M. J. Lawler, D. K. Leahy, K. K. Moffett, J. D. Nelson, S. Oliver, J. Qin, J. E. Robinson, L. M. Slieker, D. Uraguchi, T. B. Wright and H.-R. Zhang. Additionally, many of these co-workers have gone on to have outstanding careers in academia and industry, which is a testament to the training this program provided for their professional development. We thank the National Institutes of Health (NIGMS), the National Science Foundation (NSF), the Petroleum Research Fund (PRF), and the National Sciences and Engineering Research Council (NSERC) for generous financial support. In addition, the Camille and Henry Dreyfus Foundation is also acknowledged N


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(28) Evans, P. A.; Leahy, D. K. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; Chapter 10, pp 191−214. (29) Evans, P. A.; Kennedy, L. J. Regioselective Rhodium-Catalyzed Allylic Alkylation/Ring-Closing Metathesis Approach to Carbocycles. Tetrahedron Lett. 2001, 42, 7015. (30) For an example of a rhodium complex coordinating the nitrile group of an α-substituted cyanoacetate, see: Sawamura, M.; Sudoh, M.; Ito, Y. An Enantioselective Two-Component Catalyzed System: Rh− Pd-Catalyzed Allylic Alkylation of Activated Nitriles. J. Am. Chem. Soc. 1996, 118, 3309. (31) Evans, P. A.; Kennedy, L. J. Enantiospecific and Regioselective Rhodium-Catalyzed Allylic Alkylation: Diastereoselective Approach to Quaternary Carbon Stereogenic Centers. Org. Lett. 2000, 2, 2213. (32) Evans, P. A.; Kennedy, L. J. Regioselective Rhodium-Catalyzed Allylic Linchpin Cross-Coupling Reactions: Diastereospecific Construction of Anti-1,3-Carbon Stereogenic Centers and C2-Symmetrical Fragments. J. Am. Chem. Soc. 2001, 123, 1234. (33) Evans, P. A.; Robinson, J. E. Regio- and Diastereoselective Tandem Rhodium-Catalyzed Allylic Alkylation/Pauson−Khand Annulation Reactions. J. Am. Chem. Soc. 2001, 123, 4609. (34) For related rhodium-catalyzed allylic alkylation reactions with stabilized carbon nucleophiles, see: (a) Ashfeld, B. L.; Miller, K. A.; Martin, S. F. Direct, Stereoselective Substitution in [Rh(CO)2Cl]2Catalyzed Allylic Alkylations of Unsymmetrical Substrates. Org. Lett. 2004, 6, 1321. (b) Ashfeld, B. L.; Miller, K. A.; Smith, A. J.; Tran, K.; Martin, S. F. [Rh(CO)2Cl]2-Catalyzed Domino Reactions Involving Allylic Substitution and Subsequent Carbocyclization Reactions. Org. Lett. 2005, 7, 1661. (35) Keinan, E.; Roth, Z. Regioselectivity in Organo-TransitionMetal Chemistry. A New Indicator Substrate for Classification of Nucleophiles. J. Org. Chem. 1983, 48, 1769 and pertinent references cited therein. (36) (a) Alexakis, A.; Hajjaji, S. E.; Polet, D.; Rathgeb, X. IridiumCatalyzed Allylic Substitution with Aryl Zinc Reagents. Org. Lett. 2007, 9, 3393. (b) Polet, D.; Rathgeb, X.; Falciola, C. A.; Langlois, J.-B.; Hajjaji, S. E.; Alexakis, A. Enantioselective Iridium-Catalyzed Allylic Arylation. Chem. - Eur. J. 2009, 15, 1205. (37) Kabalka, G. W.; Dong, G.; Venkataiah, B. Rhodium-Catalyzed Cross-Coupling of Allyl Alcohols with Aryl- and Vinylboronic Acids in Ionic Liquids. Org. Lett. 2003, 5, 893. (38) Evans, P. A.; Uraguchi, D. Regio- and Enantiospecific RhodiumCatalyzed Arylation of Unsymmetrical Fluorinated Acyclic Allylic Carbonates: Inversion of Absolute Configuration. J. Am. Chem. Soc. 2003, 125, 7158. (39) For other examples of rhodium-catalyzed allylic arylation reactions, see: (a) Ashfeld, B. L.; Miller, K. A.; Smith, A. J.; Tran, K.; Martin, S. F. Features and Applications of [Rh(CO)2Cl]2-Catalyzed Alkylations of Unsymmetrical Allylic Substrates. J. Org. Chem. 2007, 72, 9018. (b) Riveiros, R.; Tato, R.; Sestelo, J. P.; Sarandeses, L. A. Rhodium-Catalyzed Allylic Substitution Reactions with Indium(III) Organometallics. Eur. J. Org. Chem. 2012, 3018. (40) For an example of using an sp3-hybridized unstablized carbon nucleophile in the rhodium-catalyzed substitution reaction, see: Yasui, H.; Mizutani, K.; Yorimitsu, H.; Oshima, K. Cobalt- and RhodiumCatalyzed Cross-Coupling Reaction of Allylic Ethers and Halides with Organometallic Reagents. Tetrahedron 2006, 62, 1410. (41) For recent reviews on the transition-metal-catalyzed allylic alkylation of enolates and enolate equivalents, see: (a) Braun, M.; Meier, T. New Developments in Stereoselective Palladium-Catalyzed Allylic Alkylations of Preformed Enolates. Synlett 2006, 661. (b) Mohr, J. T.; Stoltz, B. M. Enantioselective Tsuji Allylations. Chem. - Asian J. 2007, 2, 1476. (c) Oliver, S.; Evans, P. A. Transition-Metal-Catalyzed Allylic Substitution Reactions: Construction of α- and β-Substituted Carbonyl Compounds. Synthesis 2013, 45, 3179. (42) Muraoka, T.; Matsuda, I.; Itoh, K. Rhodium-Catalyzed Substitution of Allylic Carbonates with Enoxysilanes. Tetrahedron Lett. 2000, 41, 8807.

(14) For seminal contributions, see: (a) Koschker, P.; Lumbroso, A.; Breit, B. Enantioselective Synthesis of Branched Allylic Esters via Rhodium-Catalyzed Coupling of Allenes with Carboxylic Acids. J. Am. Chem. Soc. 2011, 133, 20746. (b) Cooke, M. L.; Xu, K.; Breit, B. Enantioselective Rhodium-Catalyzed Synthesis of Branched Allylic Amines by Intermolecular Hydroamination of Terminal Allenes. Angew. Chem., Int. Ed. 2012, 51, 10876. (c) Li, C.; Breit, B. RhodiumCatalyzed Chemo- and Regioselective Decarboxylative Addition of βKetoacids to Allenes: Efficient Construction of Tertiary and Quaternary Carbon Centers. J. Am. Chem. Soc. 2014, 136, 862 and pertinent references cited therein. (15) Onoue, H.; Moritani, I.; Murahashi, S.-I. Reaction of Cycloalkanone Enamines with Allylic Compounds in the Presence of Palladium Complexes. Tetrahedron Lett. 1973, 14, 121. (16) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. Facile Generation of a Reactive Palladium(II) Enolate Intermediate by the Decarboxylation of Palladium(II) β-Ketocarboxylate and its Utilization in Allylic Acylation. J. Am. Chem. Soc. 1980, 102, 6381. (17) Hayashi, Y.; Komiya, S.; Yamamoto, T.; Yamamoto, A. Regioselective C-O Bond Cleavage of Allylic Phenyl Carbonates Promoted by Group 8 Transition Metal Hydrido Complexes. Chem. Lett. 1984, 13, 977. (18) Tsuji, J.; Minami, I.; Shimizu, I. Synthesis of γ,δ-Unsaturated Ketones by the Intramolecular Decarboxylative Allylation of Allyl βKeto Carboxylates and Alkenyl Allyl Carbonates Catalyzed by Molybdenum, Nickel, and Rhodium Complexes. Chem. Lett. 1984, 13, 1721. (19) Tsuji, J.; Minami, I.; Shimizu, I. Allylation of Carbonucleophiles with Allylic Carbonates under Neutral Conditions Catalyzed by Rhodium Complexes. Tetrahedron Lett. 1984, 25, 5157. (20) Minami, I.; Shimizu, I.; Tsuji, J. Reactions of Allylic Carbonates Catalyzed by Palladium, Rhodium, Ruthenium, Molybdenum, and Nickel Complexes; Allylation of Carbonucleophiles and Decarboxylation-Dehydrogenation. J. Organomet. Chem. 1985, 296, 269. (21) Evans, P. A.; Nelson, J. D. Regioselective Rhodium-Catalyzed Allylic Alkylation with a Modif ied Wilkinson’s Catalyst. Tetrahedron Lett. 1998, 39, 1725. (22) Takeuchi, R.; Kitamura, N. Rhodium Complex-Catalysed Allylic Alkylation of Allylic Acetates. New J. Chem. 1998, 22, 659. (23) Evans, P. A.; Nelson, J. D. Conservation of Absolute Configuration in the Acyclic Rhodium-Catalyzed Allylic Alkylation Reaction: Evidence for an Enyl (σ + π) Organorhodium Intermediate. J. Am. Chem. Soc. 1998, 120, 5581. (24) Although possible, direct insertion of the rhodium into the C− O bond followed by substitution of the secondary σ-organorhodium intermediate via an SN2 mechanism is unlikely because increasing alkene substitution on the allylic carbonate leads to significantly decreased reactions rates (25) The term conservation of enantiomeric excess (cee) = (ee of product/ee of starting material) × 100. (26) For an alternative explanation that invokes an SN2′ metaltransfer of a σ-bound organorhodium intermediate, see: Wucher, B.; Moser, M.; Schumacher, S. A.; Rominger, F.; Kunz, D. First X-Ray Structure Analyses of Rhodium(III) η1-Allyl Complexes and a Mechanism for Allylic Isomerization Reactions. Angew. Chem., Int. Ed. 2009, 48, 4417. (27) For examples of Rh(III)−allyl complexes proposed to demonstrate enyl binding, see: (a) Lawson, D. N.; Osborn, J. A.; Wilkinson, G. Interaction of Tris(triphenylphosphine)chlororhodium(I) with Iodomethane, Methylallyl, and Allyl Chloride. J. Chem. Soc. A 1966, 1733. (b) Tanaka, I.; Jin-no, N.; Kushida, T.; Tsutsui, N.; Ashida, T.; Suzuki, H.; Sakurai, H.; Moro-oka, Y.; Ikawa, T. Crystal Structures of (1,5-Cyclooctadiene)di-μ-methoxo-dirhodium(I) and Tetrakis(η3-allyl)di-μ-hydroxo-dirhodium(III). Bull. Chem. Soc. Jpn. 1983, 56, 657. (c) Pasternak, H.; Glowiak, T.; Pruchnik, F. Structure of Rh2Br2(allyl)4 and (RhBr2allyl)n and their Application in Homogenous Hydrogenation. Inorg. Chim. Acta 1976, 19, 11. (d) McPartlin, M.; Mason, R. Bis-π-allylrhodium Chloride. Chem. Commun. 1967, 0, 16. O


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The Journal of Organic Chemistry (43) Evans, P. A.; Leahy, D. K. Regioselective and Enantiospecific Rhodium-Catalyzed Allylic Alkylation Reactions Using Copper(I) Enolates: Synthesis of (−)-Sugiresinol Dimethyl Ether. J. Am. Chem. Soc. 2003, 125, 8974. (44) (a) Evans, P. A.; Cui, J.; Gharpure, S. J.; Hinkle, R. J. Stereoselective Construction of Cyclic Ethers Using a Tandem TwoComponent Etherification: Elucidation of the Role of Bismuth Tribromide. J. Am. Chem. Soc. 2003, 125, 11456. (b) Evans, P. A.; Cui, J.; Gharpure, S. J. Stereoselective Construction of cis-2,6Disubstituted Tetrahydropyrans via the Reductive Etherification of δ-Trialkylsilyloxy Substituted Ketones: Total Synthesis of (−)-Centrolobine. Org. Lett. 2003, 5, 3883. (c) Evans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H.-R. Enantioselective Total Synthesis of the Potent Antitumor Agent (−)-Mucocin Using a Temporary SiliconTethered Ring-Closing Metathesis Cross-Coupling Reaction. J. Am. Chem. Soc. 2003, 125, 14702. (45) Evans, P. A.; Leahy, D. K.; Slieker, L. M. Halide Ion Effects in the Rhodium-Catalyzed Allylic Substitution Reaction Using Copper(I) Alkoxides and Enolates. Tetrahedron: Asymmetry 2003, 14, 3613. (46) Evans, P. A.; Lawler, M. J. Regio- and Diastereoselective Rhodium-Catalyzed Allylic Substitution with Acyclic α-AlkoxySubstituted Copper(I) Enolates: Stereodivergent Approach to 2,3,6Trisubstituted Dihydropyrans. J. Am. Chem. Soc. 2004, 126, 8642. (47) Kazmaier, U.; Stolz, D. Regio- and Stereoselective RhodiumCatalyzed Allylic Alkylations of Chelated Enolates. Angew. Chem., Int. Ed. 2006, 45, 3072. (b) Stolz, D.; Kazmaier, U. Rhodium-Catalyzed Allylic Alkylations as Key Steps in the Synthesis of Cyclic α-Alkylated Amino Acids. Synthesis 2008, 2288. (48) Seebach, D. Methods of Reactivity Umpolung. Angew. Chem., Int. Ed. Engl. 1979, 18, 239. (49) For related palladium-catalyzed allylic substitution reactions with acyl silanes and stannanes, see: (a) Obora, Y.; Ogawa, Y.; Imai, Y.; Kawamura, T.; Tsuji, Y. Palladium Complex Catalyzed Acylation of Allylic Esters with Acylsilanes. J. Am. Chem. Soc. 2001, 123, 10489. (b) Obora, Y.; Nakanishi, M.; Tokunaga, M.; Tsuji, Y. Palladium Complex Catalyzed Acylation of Allylic Esters with Acylstannanes: Complementary Method to the Acylation with Acylsilanes. J. Org. Chem. 2002, 67, 5835. (50) For related metal-catalyzed allylic substitution reactions with acyl anion equivalents, see: (a) Trost, B. M.; Kuo, G.-H.; Benneche, T. A Transition-Metal-Controlled Synthesis of (±)-Aristeromycin and (±)-2′,3′-diepi-Aristeromycin. An Unusual Directive Effect in Hydroxyations. J. Am. Chem. Soc. 1988, 110, 621. (b) Trost, B. M.; Dirat, O.; Dudash, J., Jr.; Hembre, E. J. An Asymmetric Synthesis of C-2-epiHygromycin A. Angew. Chem., Int. Ed. 2001, 40, 3658. (c) Gnamm, C.; Förster, S.; Miller, N.; Brödner, K.; Helmchen, G. Enantioselective Iridium-Catalyzed Allylic Alkylations − Improvements and Applications Based on Salt-Free Reaction Conditions. Synlett 2007, 790. (d) Förster, S.; Tverskoy, O.; Helmchen, G. Malononitrile as Acyl Anion Equivalent. Synlett 2008, 2803. (e) Trost, B. M.; Osipov, M.; Kaib, P. S. J.; Sorum, M. T. Acetoxy Meldrum’s Acid: A Versatile Acyl Anion Equivalent in the Pd-Catalyzed Asymmetric Allylic Alkylation. Org. Lett. 2011, 13, 3222. (f) Breitler, S.; Carreira, E. M. Formaldehyde N,N-Dialkylhydrazones as Neutral Formyl Anion Equivalents in Iridium-Catalyzed Asymmetric Allylic Substitution. J. Am. Chem. Soc. 2015, 137, 5296. (51) The palladium-catalyzed allylic substitution with protected cyanohydrins has previously been described; however, the products were not deprotected to afford the ketone; see: Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K. Allylic Carbonates. Efficient Alkylating Agents of Carbonucleophiles in PalladiumCatalyzed Reactions under Neutral Conditions. J. Org. Chem. 1985, 50, 1523. (52) Evans, P. A.; Oliver, S.; Chae, J. Rhodium-Catalyzed Allylic Substitution with an Acyl Anion Equivalent: Stereospecific Construction of Acyclic Quaternary Carbon Stereogenic Centers. J. Am. Chem. Soc. 2012, 134, 19314.

(53) Evans, P. A.; Oliver, S. Regio- and Enantiospecific RhodiumCatalyzed Allylic Substitution with an Acyl Anion Equivalent. Org. Lett. 2013, 15, 5626. (54) Turnbull, B. W. H.; Oliver, S.; Evans, P. A. Stereospecific Rhodium-Catalyzed Allylic Substitution with Alkenyl Cyanohydrin Pronucleophiles: Construction of Acyclic Quaternary Substituted α,βUnsaturated Ketones. J. Am. Chem. Soc. 2015, 137, 15374. (55) Turnbull, B. W. H.; Chae, J.; Oliver, S.; Evans, P. A. Regio- and Stereospecific Rhodium-Catalyzed Allylic Alkylation with an Acyl Anion Equivalent: An Approach to Acyclic α-Ternary β,γ-Unsaturated Aryl Ketones. Chem. Sci. 2017, 8, 4001. (56) For a recent review on asymmetric allylic amination reactions, see: Grange, R. L.; Clizbe, E. A.; Evans, P. A. Recent Developments in Asymmetric Allylic Amination Reactions. Synthesis 2016, 48, 2911. (57) Evans, P. A.; Robinson, J. E.; Nelson, J. D. Enantiospecific Synthesis of Allylamines via the Regioselective Rhodium-Catalyzed Allylic Amination Reaction. J. Am. Chem. Soc. 1999, 121, 6761. (58) Evans, P. A.; Robinson, J. E. Regioselective Rh-Catalyzed Allylic Amination/Ring-Closing Metathesis Approach to Monocyclic Azacycles: Diastereospecific Construction of 2,5-Disubstituted Pyrrolines. Org. Lett. 1999, 1, 1929. (59) Evans, P. A.; Robinson, J. E.; Moffett, K. K. Regioselective and Enantiospecific Rhodium-Catalyzed Allylic Amination with N(Arylsulfonyl)anilines. Org. Lett. 2001, 3, 3269. (60) Evans, P. A.; Lai, K. W.; Zhang, H.-R.; Huffman, J. C. Regioselective and Enantiospecific Rhodium-Catalyzed Allylic Amination with Thymine: Synthesis of a New Conformationally Rigid Nucleoside. Chem. Commun. 2006, 844. (61) Evans, P. A.; Qin, J.; Robinson, J. E.; Bazin, B. Enantioselective Total Synthesis of the Polycyclic Guanidine-Containing Marine Alkaloid (−)-Batzelladine D. Angew. Chem., Int. Ed. 2007, 46, 7417. (62) Evans, P. A.; Clizbe, E. A. Unlocking Ylide Reactivity in the Metal-Catalyzed Allylic Substitution Reaction: Stereospecific Construction of Primary Allylic Amines with Aza-Ylides. J. Am. Chem. Soc. 2009, 131, 8722. (63) Evans, P. A.; Leahy, D. K. Regioselective and Enantiospecific Rhodium-Catalyzed Intermolecular Allylic Etherification with OrthoSubstituted Phenols. J. Am. Chem. Soc. 2000, 122, 5012. (64) Evans, P. A.; Leahy, D. K. Regio- and Enantiospecific RhodiumCatalyzed Allylic Etherification Reactions Using Copper(I) Alkoxides: Influence of the Copper Halide Salt on Selectivity. J. Am. Chem. Soc. 2002, 124, 7882. (65) Evans, P. A.; Leahy, D. K.; Andrews, W. J.; Uraguchi, D. Stereodivergent Construction of Cyclic Ethers by a Regioselective and Enantiospecific Rhodium-Catalyzed Allylic Etherification: Total Synthesis of Guar Acid. Angew. Chem., Int. Ed. 2004, 43, 4788. (66) Consiglio, G.; Scalone, M.; Rama, F. Enantioselective Carbon Dioxide Extrusion from Allyl Phenyl Carbonates Catalyzed by Nickel, Palladium and Rhodium Catalysts. J. Mol. Catal. 1989, 50, L11. (67) The use of unstabilized carbon nucleophiles in the enantioselective rhodium-catalyzed allylic substitution is currently limited to cyclic derivatives and will not be discussed here. For leading references, see: (a) Dong, L.; Xu, Y.-J.; Yuan, W.-C.; Cui, X.; Cun, L.F.; Gong, L.-Z. Rhodium-Catalyzed Asymmetric Nitroallylation of Arylmetallics with Cyclic Nitroallyl Acetates and Applications in Organic Synthesis. Eur. J. Org. Chem. 2006, 4093. (b) Menard, F.; Chapman, T. M.; Dockendorff, C.; Lautens, M. Rhodium-Catalyzed Asymmetric Allylic Substitution with Boronic Acid Nucleophiles. Org. Lett. 2006, 8, 4569. (c) Sidera, M.; Fletcher, S. P. Rhodium-Catalysed Asymmetric Allylic Arylation of Racemic Halides with Arylboronic Acids. Nat. Chem. 2015, 7, 935. (68) Selvakumar, K.; Valentini, M.; Pregosin, P. S.; Albinati, A. Chiral Phosphito-Thioether Complexes of Palladium(0). Comments on the Pd, Rh, and Ir Regio- and Enantioselective Allylic Alkylations of PhCH=CHCH(OAc)R, R = H, Me, Et. Organometallics 1999, 18, 4591. (69) Hayashi, T.; Okada, A.; Suzuka, T.; Kawatsura, M. High Enantioselectivity in Rhodium-Catalyzed Allylic Alkylation of 1Substituted 2-Propenyl Acetates. Org. Lett. 2003, 5, 1713. P


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The Journal of Organic Chemistry (70) (a) Vrieze, D. C.; Hoge, G. S.; Hoerter, P. Z.; Van Haitsma, J. T.; Samas, B. M. A Highly Enantioselective Allylic Amination Reaction Using a Commercially Available Chiral Rhodium Catalyst: Resolution of Racemic Allylic Carbonates. Org. Lett. 2009, 11, 3140. (b) Atallah, T.; Blankespoor, R. L.; Homan, P.; Hulderman, C.; Samas, B. M.; Van Allsburg, K.; Vrieze, D. C. Substituent Effects on the Amination of Racemic Allyl Carbonates Using Commercially Available Chiral Rhodium Catalysts. Tetrahedron Lett. 2013, 54, 5795. (71) (a) Arnold, J. S.; Stone, R. F.; Nguyen, H. M. RhodiumCatalyzed Regioselective Amination of Secondary Allylic Trichloroacetimidates with Unactivated Aromatic Amines. Org. Lett. 2010, 12, 4580. (b) Arnold, J. S.; Cizio, G. T.; Nguyen, H. M. Synthesis of α,αDisubstituted Aryl Amines by Rhodium-Catalyzed Amination of Tertiary Allylic Trichloroacetimidates. Org. Lett. 2011, 13, 5576. (72) Arnold, J. S.; Nguyen, H. M. Rhodium-Catalyzed Dynamic Kinetic Asymmetric Transformations of Racemic Tertiary Allylic Trichloroacetimidates with Anilines. J. Am. Chem. Soc. 2012, 134, 8380. (73) (a) Arnold, J. S.; Cizio, G. T.; Heitz, D. R.; Nguyen, H. M. Rhodium-Catalyzed Regio- and Enantioselective Amination of Racemic Secondary Allylic Trichloroacetimidates with N-Methyl Anilines. Chem. Commun. 2012, 48, 11531. (b) Arnold, J. S.; Nguyen, H. M. Rhodium-Catalyzed Asymmetric Amination of Allylic Trichloroacetimidates. Synthesis 2013, 45, 2101. (c) Arnold, J. S.; Mwenda, E. T.; Nguyen, H. M. Rhodium-Catalyzed Sequential Allylic Amination and Olefin Hydroacylation Reactions: Enantioselective Synthesis of Seven-Membered Nitrogen Heterocycles. Angew. Chem., Int. Ed. 2014, 53, 3688. (74) Li, C.; Breit, B. Rhodium-Catalyzed Dynamic Kinetic Asymmetric Allylation of Phenols and 2-Hydroxypyridines. Chem. Eur. J. 2016, 22, 14655. (75) Evans, P. A.; Clizbe, E. A.; Lawler, M. J.; Oliver, S. Enantioselective Rhodium-Catalyzed Allylic Alkylation of Acyclic αAlkoxy Substituted Ketones Using a Chiral Monodentate Phosphite Ligand. Chem. Sci. 2012, 3, 1835. (76) For recent reviews on the enantioselective construction of quaternary carbon stereogenic centers, see: (a) Corey, E. J.; GuzmanPerez, A. The Catalytic Enantioselective Construction of Molecules with Quaternary Carbon Stereocenters. Angew. Chem., Int. Ed. 1998, 37, 388. (b) Christoffers, J.; Mann, A. Enantioselective Construction of Quaternary Stereocenters. Angew. Chem., Int. Ed. 2001, 40, 4591. (c) Denissova, I.; Barriault, L. Stereoselective Formation of Quaternary Carbon Centers and Related Functions. Tetrahedron 2003, 59, 10105. (d) Trost, B. M.; Jiang, C. Catalytic Enantioselective Construction of All-Carbon Quaternary Stereocenters. Synthesis 2006, 369. (e) Quasdorf, K. W.; Overman, L. E. Catalytic Enantioselective Synthesis of Quaternary Carbon Stereocenters. Nature 2014, 516, 181. For reviews on the construction of acyclic quaternary carbon stereogenic centers, see: (f) Das, J. P.; Marek, I. Enantioselective Synthesis of All-Carbon Quaternary Stereogenic Centers in Acyclic Systems. Chem. Commun. 2011, 47, 4593. (g) Feng, J.; Holmes, M.; Krische, M. J. Acyclic Quaternary Carbon Stereocenters via Enantioselective Transition Metal Catalysis. Chem. Rev. 2017, 117, 12564. (77) Turnbull, B. W. H.; Evans, P. A. Enantioselective RhodiumCatalyzed Allylic Substitution with a Nitrile Anion: Construction of Acyclic Quaternary Carbon Stereogenic Centers. J. Am. Chem. Soc. 2015, 137, 6156. (78) Carlier, P. R.; Madura, J. D. Effective Computational Modeling of Constitutional Isomerism and Aggregation States of Explicit Solvates of Lithiated Phenylacetonitrile. J. Org. Chem. 2002, 67, 3832. (79) For previous syntheses, see: (a) Denmark, S. E.; Fu, J. Asymmetric Construction of Quaternary Centers by Enantioselective Allylation: Application to the Synthesis of the Serotonin Antagonist LY426965. Org. Lett. 2002, 4, 1951. (b) Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-Gauthier, R.; Scott, H. K.; Aggarwal, V. K. Enantioselective Construction of Quaternary Stereogenic Centers from Tertiary Boronic Esters: Methodology and Applications. Angew. Chem., Int. Ed. 2011, 50, 3760.

(80) Wright, T. B.; Evans, P. A. Enantioselective Rhodium-Catalyzed Allylic Alkylation of Prochiral α,α-Disubstituted Aldehyde Enolates for the Construction of Acyclic Quaternary Stereogenic Centers. J. Am. Chem. Soc. 2016, 138, 15303.

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Asymmetric Rhodium-Catalyzed Allylic Substitution Reactions

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