Recent Advances on the Catalytic Asymmetric Allylic α-Alkylation of Carbonyl Derivatives Using Free Allylic Alcohols

2.1. Using Transition Metal Catalysts through a π-Allyl Intermediate

The conventional Tsuji–Trost allylation typically demands a potent nucleophile and an allylic compound featuring an appropriate leaving group. However, numerous innovations have surfaced to tackle this challenge by combining organo- and transition metal catalysts. Expanding upon the established principle of asymmetric counteranion-directed catalysis, List’s group devised a three-component catalytic system comprising Pd(PPh₃)₄, the chiral Brønsted acid TRIP (L1), and benzhydryl amine (L2).¹⁵ The groundbreaking system exhibits exceptional catalytic activity and a notable degree of enantioselectivity, which enables the direct α-allylation of α-branched aldehydes with allylic alcohols. Central to this process is the crucial involvement of the E-enamine intermediate, which outperforms the activity of the nonselective E/Z-enol mixture (Scheme 1). The high enantioselectivity obtained in the process is proposed to arise from an asymmetric counteranion-directed catalysis (ACDC) complex that involves the amine, which engages in the formation of a configurationally defined E-enamine, the Pd(II) catalyst, and the chiral counteranion.

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Scheme 1

Pd-Chiral Phosphoric Acid/Racemic Amine-Catalyzed Asymmetric Counteranion-Directed α-Allylation of α-Branched Aldehydes

However, an alternative Pd/enamine catalyst for directly achieving counterion-enhanced asymmetric α-allylation of branched aldehydes has been recently reported employing chiral amines, such as (1R,2R)-cyclohexane-1,2-diamine (L4) and achiral phosphoric acids.¹⁶ This catalytic system has demonstrated high efficiency in the allylation of diverse α-branched aldehydes with a range of allylic alcohols. Interestingly, not only aromatic and cyclic aliphatic but also linear aliphatic aldehydes are efficiently allylated in moderate to high yield and enantioselectivity (Scheme 2). However, no reaction is observed for short-chained aliphatic aldehydes.

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Scheme 2

Pd-Phosphoric Acid/Chiral Amine-Catalyzed Asymmetric Counteranion-Directed α-Allylation of α-Branched and Linear Aldehydes

A stereodivergent dual-catalytic synthesis of γ,δ-unsaturated aldehydes was reported using chiral iridium and amine catalysts through the enantioselective allylation of α-substituted,^17,18 as well as linear,¹⁹ aldehydes. As depicted in Scheme 3, for the enantioselective allylation of 2-phenylpropanal with 1-phenylprop-2-en-1-ol, all four stereoisomers of the allylated aldehyde are obtained in good yields and excellent enantio- and diastereoselectivities when combining chiral phosphoramidite L5 and pseudoenantiomeric Cinchona-derived primary amines L6/L7. Under the optimized reaction conditions, this methodology shows good substrate scope with respect to the aldehyde component and the allylic alcohol (Scheme 3), and the competitive aldol process is not observed in any case.¹⁷

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Scheme 3

Iridium-Chiral Phosphoramidite/Chiral Primary Amine Catalyzed α-Allylation of α-Branched Aldehydes

From the mechanistic perspective, NMR and X-ray studies have effectively characterized the key Ir complexes A and B relevant to the catalytic cycle of the Ir-catalyzed allylic substitution involving (phosphoramidite, olefin) ligands L5 (Scheme 4).²⁰ The proposed mechanism involves coordination of the allylic alcohol to iridium to give the distorted trigonal bipyramidal (η²-allylicalcohol)Ir(I) complex A, which undergoes acid-promoted oxidative addition to furnish (η³-allyl)Ir(III) complex B, which suffers nucleophilic attack on the allyl fragment to afford complex C. Final displacement of the product by the allylic alcohol completes the catalytic cycle (Scheme 4). However, the reason behind the high selectivities in the reaction stems from detailed transition-state modeling using density functional theory (B3LYP-D3). This analysis uncovered how the stereodivergence occurs by flipping the configuration of the chiral catalysts engaged in activating the reacting components. Meanwhile, the control over enantioselectivity occurs during the formation of the chiral phosphoramidite–Ir−π-allyl intermediate, while diastereoselectivity arises due to differing stabilizations in the transition states governing C–C bond formation.²¹ Additionally, this investigation highlights the crucial role of the quinoline ring, thereby demonstrating its direct contribution to stabilizing the transition states that govern stereocontrol through weak π-stacking and C–H·π interactions.

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Scheme 4

Iridium–(Phosphoramidite, Olefin)-Catalyzed Enantioselective Allylic Substitution Mechanism

The robustness of the Ir catalytic system has been demonstrated from an off-cycle pathway involving reversible binding of molecular oxygen to Ir, which contributes to the air tolerance of the catalyst.²⁰ This aspect, along with the demonstrated compatibility of organocatalytic methods with aqueous media, has been used to expand the nucleophile scope of the Ir-catalyzed enantioselective allylic substitution of allyl alcohols to unstable and volatile nucleophiles usually available as aqueous solutions, such as hydrazines, methylamine, t-butyl hydroperoxide, N-hydroxylamine, α-chloroacetaldehyde, and glutaraldehyde.²²

One challenge often encountered in the stereoselective α-functionalization of linear aldehydes is the emergence of products featuring an enolizable stereogenic center, which makes them susceptible to epimerization. Secondary amine prolinol-type Jorgensen–Hayashi organocatalyst L8 has been successfully used as chiral enamine promoter for the Ir-catalyzed asymmetric allylation of the less sterically hindered linear aldehydes, substrates prone to participate in side reactions, such as self-condensation.¹⁹ As depicted in Scheme 5a, in the presence of dimethylhydrogen phosphate or trichloroacetic acid as cocatalyst, a stereodivergent dual-catalyzed allylation of unfunctionalized linear aldehydes with aryl-substituted allylic alcohols has been achieved by using chiral phosphoramidite (S)-L5 and Jorgensen–Hayashi chiral organocatalysts (R)-L8.

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Scheme 5

Iridium–chiral Phosphoramidite/Chiral Secondary Amine-Catalyzed α-Allylation of Linear and α-Functionalized Aldehydes

In a similar manner, phosphoramidite (R)-L5 and organocatalyst (S)-L8, using dichloro- or trichloroacetic acid as cocatalysts, have been used for the allylation of protected α-amino- and α-hydroxyacetaldehydes 4, which are substrates of special synthetic relevance since they are precursors of β,β′-disubstituted α-amino and α-hydroxy acid derivatives (Scheme 5b).

The asymmetric allylation of carbonyl derivatives is an interesting synthetic technique for the preparation of naturally occurring and other bioactive compounds. In this way, the allylation of aldehydes with a dual asymmetric catalysis has been reported in the generation of two consecutive stereocenters of an intermediate in the preparation of tetrahydrocannabinol derivatives (Scheme 6). The choice of catalysts has allowed the stereodivergent synthesis of the four possible stereoisomers with high levels of enantio- and diastereoselectivity from the same starting reagents under similar conditions. Thus, the reaction between 6 and 7 (1:3 ratio) in the presence of iridium(I), zinc(II), and chiral ligands L5 and L8 constitutes the key step to control the stereochemistry of compound 8, which has been transformed into the corresponding tetrahydrocannabinol 9 after four additional steps (Scheme 6).²³ Following the same strategy, photoswitchable azo-tetrahydrocannabinol derivatives 13 have been synthesized from tetrahydrocannabinol 12 following the same protocol. Thus, the allylic alcohol 10 has been transformed into the stereoisomer 11 with high selectivity, which is cyclized to 12 (Scheme 7).²⁴

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Scheme 6

Stereodivergent Synthesis of the Four Tetrahydrocannabinol 9

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Scheme 7

Stereoselective Preparation of Compound 11 in the Synthesis of Photoswitchable azo-Tetrahydrocannabinol Derivatives 13

The combination of catalysts described by Carreira’s group has been successfully employed in the total asymmetric synthesis of other natural compounds with bioactivity. The only difference introduced in the following cases is the use of other acidic promoters instead of Zn(II) salts, which may have an influence on the diastereoselectivity of the process. Thus, (−)-paroxetine (17), a selective serotonin reuptake inhibitor, has been prepared from intermediate 16, which is stereoselectively obtained from allylic alcohol 14 and aldehyde 15 using L5 and L8 in the presence of an iridium complex and trichloroacetic acid as promoter (Scheme 8).²⁵

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Scheme 8

Stereoselective Preparation of Compound 16 in the Total Synthesis of Paroxetine 17

The dual Ir/amine catalysis has been also employed in the reaction between a benzyl-protected 4-hydroxybutanal and two different (indolyl)allylic alcohols to yield chiral aldehydes, such as compounds 20 and 23, with good enantio- and diastereoselectivity using trifluoroacetic acid and maleic acid, respectively, as promoters (Scheme 9).^26,27 Compound 20 has been used as a key intermediate for the synthesis of (−)-actinophyllic acid (21), which has potential uses for the treatment of cardiovascular diseases.²⁶ Similarly, the construction of the two stereogenic centers of intermediate 23 has been crucial in the total synthesis of (−)-alstoscholarine (24).²⁷

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Scheme 9

Stereoselective Synthesis of Compounds 20 and 23 for the Total Synthesis of Actinophyllic Acid (21) and Alstoscholarine (24), Respectively

The total synthesis of lycorane stereoisomers has been achieved employing the Carreira group’s dual Ir/amine-catalyzed allylation using maleic acid as promoter. The use of 2-phthalimidoacetaldehyde (26) allows the introduction of a nitrogen-containing fragment in the structure with high stereocontrol, which results in the synthesis of these alkaloid derivatives. Thus, the reaction of 26 with allylic alcohol 25, under the standard conditions, provides stereoisomers 27a and 27b depending on the combination of Ir/L5 and L8 employed and the use of maleic acid or bismuth(III) triflate as promoter (Scheme 10).²⁸ Then, compound 27a has been employed as an intermediate in the preparation of α-lycorane (28) and β-lycorane (29), while 27b has been used in the synthesis of γ-lycorane (30) and δ-lycorane (31).

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Scheme 10

Selective Synthesis of Stereoisomers 27 for the Synthesis of Four Isomers of Lycorane

The total synthesis of the marine benzoxazole alkaloids 35 and 36, which have shown significant antimicrobial activity for tuberculosis disease, has been achieved starting from aldehyde 34. The chiral compound 34 has two contiguous stereocenters, which have been selectively obtained by the allylation reaction of propanal (33) with alcohol 32 by means of the dual-catalytic protocol employing Ir/L5 and L8 with difluoroacetic acid as promoter (Scheme 11).²⁹ The obtained isomers are the naturally occurring alkaloids, but the asymmetric dual-catalytic allylation would allow the synthesis of the other stereoisomers of intermediate 34 giving access to structural analogues of the natural product.

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Scheme 11

Selective Preparation of Chiral Compound 34 in the Total Synthesis of the Marine Benzoxazole Alkaloids 35 and 36

Stemona alkaloids, which have interesting biological activities, present polycyclic systems with different stereocenters. The tetracyclic structure 39, which has been obtained from the pyrrole derivative 38, has been employed in the total synthesis of bisdehydrotuberostemonine D. Compound 38 has been prepared by allylation of butanal with allylic alcohol 37 employing the Carreira group’s methodology (Scheme 12).³⁰ Because of the possibility of generating the different stereoisomers of 38 by selecting the appropriate combinations of L5 and L8, bisdehydrotuberostemonine E was selectively prepared. Other Stemona alkaloids, such as parvistemonine and parvistemoline, can be prepared from intermediate 43. Chiral aldehyde 42, which is a precursor of tryciclic compound 43, has been successfully prepared by reacting furyl vinyl carbinol 40 with the O-protected 6-hydroxyhexanal 41 under asymmetric dual-catalyzed allylation (Scheme 13).³¹

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Scheme 12

Stereoselective Synthesis of Pyrrole Derivative 38 in the Preparation of Compound 39 as an Intermediate in the Synthesis of Stemona Alkaloids

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Scheme 13

Stereoselective Synthesis of Compound 42 as Precursor of Tricyclic Compound 43 in the Synthesis of Stemona Alkaloids

The iridium/amine-catalyzed strategy has resulted in an effective protocol for the allylation of aqueous solutions of acetaldehyde under biphasic conditions. The enantioenriched 3-substituted pent-4-enal 44, formed by this methodology, can be employed in the total asymmetric synthesis of natural products. Thus, compound 44 has been transformed into compound 45, which is an intermediate in the total synthesis of (−)-heliannuol C. Alternatively, 44 has been converted into 46, which is a compound leading to the total synthesis of (+)-heliespirone A, (−)-heliespirone C, and (+)-heliannuol E (Figure ​Figure33).³²

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Figure 3

Intermediates lead to the total synthesis of (−)-heliannuol C, (+)-heliannuol E, (+)-heliespirone A, and (−)-heliespirone C.

3.1. Using Transition Metal Catalysts through a π-Allyl Intermediate

An enantioselective C-allylation between allylic alcohols 2 and Meldrum’s and tetronic acids (52 and 53, respectively, including their 5- and 3-methyl-substituted analogues) was developed by Kitamura et al. in 2011 (Scheme 19).³⁶ The reaction, which involves the use of the chiral bidentate sp²-N ligand [(S)-L12] in combination with [RuCp(CH₃CN)₃]PF₆ and p-TsOH, proceeds with high reactivity and selectivity. Various allylic alcohols 2 having an sp²- or sp-hybridized carbon at C(3) can be used both in inter- (Scheme 19) and intramolecular (Scheme 20) allylation reactions. It is worth noting that saturated R substituents or 3,3-disubstituted alcohols 2 lead to no detectable intermolecular C-allylation and that the reaction does not occur when dimethyl malonate is used as nucleophile instead of the Meldrum’s (52) or tetronic (53) acids.

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Scheme 19

Intermolecular C-Allylation Reaction Developed by Kitamura et al.

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Scheme 20

Intramolecular C-, O- and N-Allylations Reaction Developed by Kitamura et al.

The predominant formation of the (S)-branched product from both E and Z-2a (R″ = Ph) implies that π–σ–π interconversion should be faster than the intermolecular nucleophilic attack on a π-allyl intermediate. This hypothesis is also supported by the high level of asymmetric induction in the dynamic kinetic resolution (DKR) of racemic 1-phenylprop-2-en-1-ol.

The scope of the reaction includes intramolecular C-, O-, and N-allylations (Scheme 20), thereby allowing the highly enantioselective construction of five- and six-membered cycloalkanes and N- and O-heterocycles, all of which are versatile key intermediates for a wide range of biologically active natural products.

In 2012, Shibasaki developed the first example of a direct asymmetric α-allylation of cyclic ketones with simple allylic alcohols using a novel tethered complex that provides cooperative Pd/phosphine activation and enamine activation (Scheme 21).³⁷ The reaction proceeds with moderate yields (14–66%) and enantioselectivities (36–56% ee), and high loading of Pd and ligand L13 are required. The scope of the reaction is limited to para-substituted aromatic alcohols 55 and cyclohexanone and dihydro-2H-pyran-4(3H)-one as cyclic ketones (56). Three equivalents of ligand (S)-L13 to Pd are required for efficient conversion, which the authors attribute to the fact that the active Pd complex is a Pd/(S)-L13 complex in a ratio of 1:2 or 1:3 and/or attribute to the reluctant hydrolysis of the proposed iminium intermediate B.

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Scheme 21

Asymmetric α-Allylation of Cyclic Ketones with Simple Allylic Alcohols Developed by Shibasaki et al.

In 2013, Gong et al. reported the combined use of a palladium complex with the chiral phosphoramidite ligand (R)-L14 and the chiral phosphoric acid (R)-L15 that enables a highly enantioselective allylic alkylation of pyrazol-5-ones with allylic alcohols (Scheme 22).³⁸ The methodology is compatible with a diverse scope of functional groups in both the allylic alcohol and the pyrazol-5-one 58, which furnishes multiple functionalized heterocyclic products in high yields with excellent enantioselectivities (see examples in Scheme 22). Chiral pyrazol-5-one-derived compounds appear prevalently in several nonsteroidal anti-inflammatory drugs, such as Analgin, nifenazone, and Feprazone.

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Scheme 22

AAA of Pyrazol-5-ones with Allylic Alcohols Developed by Gong et al.

High-resolution mass spectrometry (HRMS) analysis of a reaction mixture of the palladium complex with 2-l and (S)-L15 shows that two molecules of (S)-L14 are favorably coordinated to palladium. Authors propose that the chiral phosphoric acid facilitates the formation of a π-allyl–Pd complex by activation of the C–O bond and that the AAA reaction proceeds via intermediate I (Figure ​Figure44) in which the chiral phosphate counteranion has a hydrogen-bonding interaction with the nucleophile 58. In intermediate I, the chiral palladium complex and chiral phosphate counteranion work cooperatively to activate the substrates and control the stereochemistry, thereby affording the products with high enantioselectivity.

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Figure 4

Intermediate proposed in the AAA of pyrazol-5-ones with allylic alcohols developed by Gong et al.

In 2014, while reporting the direct use of allylic alcohols³⁹ or allylic alkyl ethers⁴⁰ in the nonenantioselective Pd-catalyzed allylic alkylations of simple ketones/aldehydes (Scheme 23), Zhang et al. also showed that the Pd-catalyzed asymmetric allylic alkylation of acetone and cyclohexanone can be carried out with high yield and excellent enantioselectivity in the presence of the chiral ferrocene-based phosphinooxazoline ligand L16 (Scheme 24). Both enantioselective and nonenantioselective reactions take place under mild conditions by using pyrrolidine as cocatalyst and methanol as a hydrogen-bonding solvent. Computational studies suggest that methanol plays a crucial role in the formation of the π-allylpalladium complex by lowering the activation barrier and stabilizing the hydroxide leaving group.

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Scheme 23

Nonenantioselective Pd-Catalyzed Allylic Alkylation of Simple Ketones/Aldehydes Developed by Zhang et al.

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Scheme 24

Enantioselective Pd-Catalyzed Allylic Alkylation of Simple Ketones Developed by Zhang et al.

Xia and Jiang et al. also reported in 2014 a Brønsted acid-accelerated Pd-catalyzed asymmetric allylic alkylation of azlactones with simple allylic alcohols under mild reaction conditions using a commercially available ligand L17 and benzoic acid (Scheme 25).⁴¹ The benzoic acid accelerates the reaction by activating the alcohol by hydrogen bonding to expel the hydroxy group, followed by insertion of a Pd(0) catalyst for the generation of the key π-allyl-Pd intermediate.^15,38 The reaction is compatible with a wide range of azlactones (63) and functionalized linear and branched allylic alcohols. The fact that branched allylic alcohols afford exclusively linear allylated products in similar yields and enantioselectivities compared with the liner analogues reveals that the reaction might require a cationic π-allylpalladium(II) intermediate to facilitate acquiring a linear product regioselectively.⁴² The method provides a direct and readily scalable approach for the synthesis of all-carbon quaternary allylic amino acid derivatives in excellent yields with good enantioselectivities.

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Scheme 25

Enantioselective Brønsted Acid-Accelerated Pd-Catalyzed Asymmetric Allylic Alkylation of Azlactones with Allylic Alcohols Developed by Xia and Jiang et al.

In 2015, Luo et al. reported an efficient synergistic dual-catalytic system composed of the chiral primary–tertiary diamine L18a and allylpalladium(II) chloride dimer to promote the direct asymmetric allylic alkylation (AAA) of β-ketocarbonyl compounds 65 with simple allylic alcohols (Scheme 26).⁴³ The reaction features the enantioselective construction of quaternary stereocenters with challenging acyclic aliphatic ketones, such as β-ketocarbonyl compounds and 1,3-diketones, where the transition-metal-catalyzed AAA reaction is often hampered because of the steric and electronic similarities of the two keto moieties. Both diamines L18a and L18b provide comparable results in most cases with, in general, slightly higher enantioselectivities for L18b. Diamine L18a often allows higher yields at the expense of a small drop in enantioselectivity and it also provides better results for bulky α-substituted 1,3-dicarbonyl compounds and for allylic alcohols, such as (E)-3-(thiophen-2-yl)prop-2-en-1-ol and the aliphatic prop-2-en-1-ol. Secondary allylic alcohols, such as 2-cyclohexen-1-ol and 4-phenyl-2-butenol, show very low reactivity, probably as a result of their inertness toward the formation of an π-allyl intermediate.

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Scheme 26

AAA under Synergistic Dual Catalysis Developed by Luo et al.

The authors propose a Si-facial attack of the π-allylpalladium complex on the enamine intermediate, on the basis of the observed (S)-stereoinduction of the products (Figure ​Figure55). Thus, steric effects play a key role in channeling the attack of the π-allylpalladium species for which a notable H-bonding site is lacking. The observed effect of bulky substituents on the tertiary amino moiety is clearly in support of this steric model (Scheme 26). Besides serving as a steric directing group, the protonated tertiary amine also participates in intramolecular H-bonding, as previously verified,⁴⁴ and results in a restricted conformation, which is also beneficial for stereoselectivity.

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Figure 5

(S)-Selective sterically favored transition state proposed by Luo et al.

The same year, Mashima et al. reported the asymmetric allylic alkylation of β-ketoesters with allylic alcohols catalyzed by [Ni(cod)₂]/(S)-H₈–BINAP (L19) as an excellent synthetic protocol for constructing quaternary chiral centers at the α-position of cyclic β-ketoesters (Scheme 27).⁴⁵ The reaction proceeds in high yield and with high enantioselectivity using a wide range of functionalized β-ketoesters 67 and branched (2-b) and linear (2-l) allylic alcohols without any additional activators. The fact that branched alcohols provide linear products suggests that the reaction proceeds via a π-allyl nickel intermediate.⁴⁶ A drop in enantioselectivity is observed when increasing the bulkiness of the R¹ group in the β-ketoesters 67; the methyl and ethyl ester derivatives are the ones that provide better results. Noncyclic β-ketoesters undergo allylic allylation but in low enantioselectivity. The scope for aromatic allylic alcohols is wide and it includes heteroaromatic systems; only when the R group in the allylic alcohol is an alkyl group is the enantiomeric excess moderate.

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Scheme 27

AAA of β-Ketoesters with Allylic Alcohols Catalyzed by [Ni(cod)₂]/(S)-H₈–BINAP Developed by Mashima et al.

The authors propose that the mechanism of this reaction involves a π-allylcation intermediate (Scheme 28). Initially, allylic alcohol is oxidatively added to a Ni⁰/diphosphine complex derived from [Ni(cod)₂] and L19 to generate hydroxo π-allyl Ni^II complex B. The hydroxo ligand abstracts the α proton of the β-ketoester,⁴⁶ thus generating complex C. It is not clear whether the resulting enolate ligates to Ni^II or not. Finally, the nucleophilic attack of the enolate affords the product and regenerates the Ni⁰/diphosphine intermediate. The lack of a requirement for an activator of β-ketoesters could be attributed to the generation of the hydroxo π-allyl Ni^II complex abstracting the α proton of β-ketoesters because other transition metal systems normally generate cationic π-allyl metal complexes with the concomitant formation of water by oxidative addition of allyl alcohols.

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Scheme 28

Proposed Mechanism for the Ni-Catalyzed AAA Reaction of Allylic Alcohols Developed by Mashima et al.

In 2018, Stoltz et al. reported the first nickel-catalyzed enantioselective allylic alkylation of α-ester lactones 69 and lactams 71 with free unactivated allylic alcohols to deliver products bearing an all-carbon quaternary stereocenter (Schemes 29 and 30).⁴⁷ The reaction utilizes the commercially available chiral bisphosphine ligand L20 and proceeds in moderate to good yields with high levels of enantioselectivity (up to 90% ee) on lactone and lactam nucleophiles under slightly different reaction conditions. The corresponding α-ethyl esters (for both lactones and lactams) provide higher yield and enantioselectivity in the reaction than the α-methyl esters; so, only these examples have been compiled here. The alcohol scope for lactone nucleophiles 69 (Scheme 29) consists mainly of (hetero)aromatic allylic alcohols, with one example of an aliphatic and another example of an alkenyl derivative. In general, electrophiles containing electron-rich aryl substituents provide the corresponding products in higher yields than their electron-deficient counterparts, and para- and meta-substituted aryl rings exhibit higher reactivity compared with the ortho-substituted aryl ring.

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Scheme 29

Nickel-Catalyzed Enantioselective Allylic Alkylation of α-Ester Lactones with Free Unactivated Allylic Alcohols Developed by Stoltz et al.

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Scheme 30

Nickel-Catalyzed Enantioselective Allylic Alkylation of α-Ester Lactams with Free Unactivated Allylic Alcohols Developed by Stoltz et al.

While only branched allylic alcohols 2-b were explored for the AAA of lactones, a linear allylic alcohol 2-l was also included in the electrophiles scope with the benzyl-protected α-ester lactam 71, which provided an almost identical result compared with the corresponding branched alcohol 2-b, thereby indicating that a nickel π-allyl is likely an intermediate in the catalytic cycle (Scheme 30).⁴⁵ The utility of this method is further highlighted via a number of synthetically useful product transformations/derivatizations for the construction of small chiral building blocks with multiple functional handles.

Also, in 2018, You et al. reported a highly regio- and enantioselective rhodium-catalyzed allylic alkylation of 1,3-diketones with secondary racemic allylic alcohols (Scheme 31).⁴⁸ In the presence of Rh, phosphoramidite ligand L5 and catalytic TFA to activate the alcohol, chiral-branched α-allylated 1,3-diketones 66 can be obtained in good to excellent yields and enantioselectivities with excellent regioselectivities (b/l > 19/1) in all cases. Both aryl- and aliphatic-substituted allyl alcohols with a wide range of functional groups are suitable substrates with excellent reaction outcomes. In general, aromatic substrates with electron-withdrawing groups require prolonged reaction times compared with those with electrodonating substituents. It is worth noting the good tolerance with Cl, Br, and I groups, which are known to undergo diverse Pd-mediated transformations, under this Rh catalytic system. 1,3-Diketones 65 with both aliphatic and aromatic R¹ substituents are tolerated, although the enantioselectivity of the reaction drops for bulky substrates (R¹ = ^tBu). α-Branched 1,3-diketones (with a methyl, ethyl, or chlorine substituent) also provide good results with longer reaction times (48 h). Aliphatic allylic alcohols, known as challenging substrates in allylic substitution reactions catalyzed by other metals,⁴⁹⁻⁵¹ provide their corresponding alkylation products in high to excellent selectivities and good yields under slightly modified reaction conditions. The scope of aliphatic alcohols includes generally labile functional groups, such as Br, N₃, benzoyl, and ether.

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Scheme 31

Rhodium-Catalyzed Allylic Alkylation of 1,3-Diketones with Secondary Racemic Allylic Alcohols Developed by You et al.

In addition to 1,3-diketones 65, β-ketoesters are also suitable substrates for this methodology, although acyclic β-ketoesters only react when 1 equiv of Yb(OTf)₃ is used instead of TFA and provide the corresponding product in opposite configuration as the standard conditions (Scheme 32).

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Scheme 32

Rhodium-Catalyzed Allylic Alkylation of β-Ketoester with Secondary Racemic Allylic Alcohols Developed by You et al.

Mechanistic studies prove that for the product formation, an overall dynamic kinetic resolution process of the racemic allylic alcohols takes place. On the basis of the experimental observations, the authors propose a plausible mechanism (Scheme 33) involving (η³-allyl)rhodium(III) species B produced by oxidative addition of the allylic alcohol into the rhodium(I) initial species A.

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Scheme 33

Mechanism Proposed for the Rh-Catalyzed Allylic Alkylation of 1,3-Diketones Developed by You et al.

In 2019, Yang et al. reported the Ir-catalyzed enantioselective allylic alkylation of branched racemic allylic alcohols with malonates by using the phosphoramidite ligand (R)-5.⁵² The scope of the reaction includes methyl, ethyl, and benzyl malonates and a wide range of aromatic and heteroaromatic alcohols (Scheme 34), and all of them provide moderate to good yields and excellent enantioselectivities. Aliphatic allylic alcohols provide, however, very low yield in the reaction.

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Scheme 34

Ir-Catalyzed Enantioselective Allylic Alkylation of Branched Racemic Allylic Alcohols with Malonates Developed by Yang et al.

Ethyl nitroacetate is also a suitable nucleophile for this Ir-phosphoramidite catalytic system. The corresponding AAA reaction takes place in good yields and excellent enantioselectivities, albeit with poor diastereocontrol (dr 1.3:1, Figure ​Figure66). In the case of using acetylacetone as nucleophile, lower enantioselectivity is observed, especially compared with the previous Rh-catalyzed system reported by You et al.⁴⁸

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Figure 6

Products of AAA of ethyl nitroacetate and acetylacetone under the reaction conditions are shown in Scheme 33.

In 2021, Yang, Tian, and Deng et al. reported the asymmetric allylation/ring expansion reaction of 2-(1-hydroxyallyl)phenols 73 and cyclobutanone carboxamides 74, enabled by sequential iridium/zinc/bifunctional squaramide catalysis, to furnish 8-membered benzo[b]oxocines 77 in high diastereoselectivities and excellent enantioselectivities (Scheme 35).⁵³ First, the cascade allylation/hemiketalization reactions occur to deliver key hemiketals 76 via dual Ir/Zn catalysis in the presence of phosphoramidite (S)-L5. Then, this highly strained intermediate 76, after filtration over Celite to remove the metals that poison (S,S)-L21 and lower the diastereoselectivity of the reaction, is activated by the chiral bifunctional squaramide (S,S)-L21 catalyst to produce benzo[b]oxocine products 77 through a fragmentation process. Mechanistic investigations supported by density functional theory calculations reveal that the enantioselectivity is controlled by the chiral iridium catalyst, while the diastereoselectivity is controlled by the chiral bifunctional squaramide catalyst.

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Scheme 35

Asymmetric Allylation/Ring Expansion Reaction of Phenols 73 and Cyclobutanone Carboxamides 74, Enabled by Sequential Iridium/Zinc/Bifunctional Squaramide Catalysis Developed by Yang, Tian, and Deng et al.

The ester- or tertiary-amide-substituted cyclobutanone performs poorly in this transformation, thereby indicating that the secondary amide activating group is indispensable. The phenolic hydroxyl group on the allylic alcohol partner 77 also plays a key role for excellent diastereocontrol in the allylation step. The plausible mechanism proposed for this transformation involves, at first, the coordination of the in situ generated iridium catalyst to the allylic alcohol 77, which undergoes oxidative addition to produce the π-allyliridium intermediate AA (Figure ​Figure77) with the assistance of the Lewis acid Zn(OTf)₂. The acidity of the α-proton for the cyclobutanone carboxamide 74 is believed to be enhanced via the intramolecular hydrogen bond between the acidic N–H proton and the ketone carbonyl group, so the corresponding enolate is believed to participate in the proposed intermediate AA.

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Figure 7

AA intermediated proposed by Yang, Tian, and Deng et al. in their AAA/ring expansion reaction of 2-(1-hydroxyallyl)phenols and cyclobutanone carboxamides to explain the formation of 77.

The methodology can also be applied to hydroxyallylanilines 78 (Scheme 36) for the construction of cyclobuta[b]quinolines 80 and 82 and benzo[b]azocines 81. These aniline allylic alcohols 78 require higher amounts of Zn(OT)₂ (1 equiv) during the AAA step and higher catalyst loading [(S,S)-L21, 20 mol %] and temperature (50 °C) during the fragmentation step compared with the hydroxyallylphenol counterparts (73) but a wide range of products with potential biologically activity and bearing different substituents that can be accessed in good yields (35–76%) and excellent enantioselectivities (>99% ee) with high diastereoselectivities (9:1–10:1 dr) in the case of the benzo[b]azocines 75.

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Scheme 36

Asymmetric Allylation/Ring Expansion Reaction of Hydroxyallylanilines 78 and Cyclobutanone Carboxamides 74 Enabled by Sequential Iridium/Zinc/Bifunctional Squaramide Catalysis Developed by Yang, Tian, and Deng et al.

In 2023, Mukherjee et al. reported a highly enantioselective α-allylic alkylation of 4-cyano-3-oxotetrahydrothiophene (83, a safe and easy-to-handle surrogate of acrylonitrile) and 4-carbomethoxy-3-oxotetrahydrothiophene (84, a surrogate of methyl acrylate) using branched racemic allylic alcohols in the presence of Ir(I) and the phosphoramidite (S)-L5 with camphor sulfonic acid (CSA) as promoter (Scheme 37).⁵⁴ The AAA reaction is followed by a retro-Dieckmann/retro-Michael fragmentation to produce α-allylic acrylates 87 and acroleins 88 (Scheme 37) in moderate yields and good enantioselectivities.

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Scheme 37

Enantioselective α-Allylic Alkylation of 4-Cyano-3-oxotetrahydrothiophene and 4-Carbomethoxy-3-oxotetrahydrothiophene Developed by Mukherjee et al.

In the same year, Sun et al. reported the iridium-catalyzed diastereo- and enantioselective [4 + 1] cycloaddition reaction of a wide range of substituted hydroxyallyl anilines with aromatic and aliphatic sulfoxonium ylides 89 (Scheme 38).⁵⁵ The reaction is a straightforward way to synthesize highly substituted 3-vinyl indolines 91 containing two stereogenic centers in moderate to good yields with good diastereoselectivities (>19:1 dr in all cases) and excellent enantioselectivities. On the basis of experimental results, the reaction is believed to proceed via an AAA process that furnishes intermediate C from the π-allyliridium species B, followed by an intramolecular N-nucleophilic substitution that provides intermediate D and dimethyl sulfoxide. (Scheme 39).

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Scheme 38

Iridium-Catalyzed Diastereo- and Enantioselective [4 + 1] Cycloaddition Reaction of Substituted Hydroxyallyl Anilines with Aromatic and Aliphatic Sulfoxonium Ylides Developed by Sun et al.

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Scheme 39

Mechanism Proposed for the Iridium-Catalyzed Diastereo- and Enantioselective [4 + 1] Cycloaddition Reaction of Substituted Hydroxyallyl Anilines with Aromatic and Aliphatic Sulfoxonium Ylides Developed by Sun et al.