Enantioselective Formation of Quaternary Centers by Allylic Alkylation with First Row Transition Metal Catalysts

Abstract

The asymmetric allylic alkylation mediated by transition metals provides an efficient strategy to form quaternary stereogenic centers. While this transformation is dominated by the use of second and third row transition metals (e.g., Pd, Rh and Ir), recent developments have revealed the potential of first row transition metals, which provide not only a less expensive and potentially equally efficient alternative, but also new mechanistic possibilities. This review summarizes examples for the assembly of quaternary stereocenters using prochiral allylic substrates and hard, achiral nucleophiles in the presence of copper complexes, and highlights the complementary approaches with soft, prochiral nucleophiles catalyzed by chiral cobalt and nickel complexes.

Graphical Abstract

1. Introduction

The asymmetric construction of quaternary stereogenic centers bearing four different carbon substituents is of great interest to synthetic chemists due to the prevalence of such structural arrangements in natural products and biologically active compounds (Figure 1).^1,2,3,4,5,6 Despite their importance, the assembly of these motifs via chemical syntheses is still challenging, and methods for their formation are limited.^7-10

Figure 1. Selected Natural Products and Biologically Active Compounds Containing Quaternary Carbon Stereocenters.

One of the most common strategies is the transition-metal-catalyzed allylic alkylation, which provides two approaches to generate the quaternary stereogenic center, depending upon the nature of the applied nucleophile.^11,12 In the case of achiral nucleophiles, quaternary stereocenters may be generated by the selective formation of the branched product, with a trisubstituted, prochiral electrophile (Scheme 1, A). Alternatively, in the case of prochiral nucleophiles, both the branched and linear products have the potential to form quaternary centers in a stereoselective fashion (Scheme 1, B).

Scheme 1. General Enantioselective Construction of Quaternary Centers by Allylic Alkylation.

TM = transition metal. LG = leaving group. EWG = electron-withdrawing group.

While this powerful transformation is dominated by the utilization of second and third row transition metals, in particular, by palladium,^13-17 rhodium,^18,19 and iridium,^13,20-22 which has been applied in several total syntheses of natural products,^10,11,23-25 the use of first row transition metals is much less common, despite the fact that these catalysts would be cheaper and more abundant alternatives to their second and third row counterparts. Additionally, these first row metals often afford alternative reactivity and distinct mechanistic possibilities relative to the second and third row counterparts. Recently, efficient new protocols that involve the utilization of less frequently used transition metal catalyst such as cobalt and nickel in combination with soft, prochiral nucleophiles have been developed. In addition, new chiral ligands for the well-established copper-catalyzed allylic alkylation with hard nucleophiles have been described, leading to highly regio- and enantioselective variants. This review will cover protocols employing first row transition metals and their application to construct quaternary stereogenic centers via enantioselective allylic alkylation by carbon nucleophiles that following allylic substitution are sp³ hybridized (Scheme 2, A). Approaches dealing with the enantioselective nucleophilic allylation (B)^8,26,27 or the Aldol-type alkylation (C)⁷ are not in the focus of this review and were only presented in exceptional cases.

Scheme 2. Different Approaches to Form Quaternary Stereocenters via Alkylation.

2. Allylic Alkylation with Copper

Over the last decades, the most explored first row transition metal for the allylic alkylation has been copper.^28-31 Typically hard, non-stabilized nucleophiles in the form of organometallic species, including organozinc, organomagnesium, organolithium, or organoaluminium, as well as the milder organoboron reagents, are used with an allylic system bearing a leaving group. Based on detailed investigations in the last decades, a general mechanism for the copper-catalyzed allylic alkylation with hard nucleophiles has been proposed (Scheme 3).^32,33 In the first step, the transmetalation between the ligated copper(I) salt I and the organometallic species II leads to the formation of the organocuprate species III. Upon coordination to the allyl substrate IV, the π-complex V is subsequently obtained. Oxidative addition on the copper, usually favoured at the γ-position to the leaving group, affords the [σ+π]-allyl copper(III) species VI. The newly formed [σ+π]-allyl complex VI could react under two competitive pathways. If the non-transferrable substituent X on the copper atom in VI is an electron-withdrawing group such as CN or Cl, the reductive elimination step will be favoured, which generates the branched product VII concomitant with the release of the copper(I) salt I. If X is an electron-donating group such as alkyl, isomerization from the [σ+π]-allyl complex VI via the π-allyl complex VIII to the [σ+π]-allyl complex IX is feasible and leads to the formation of the linear product X. However, not only the substituent X at copper dictates the regiochemical outcome of the reaction. Modern catalytic systems rely also on the influence of sterics and the presence of chelating groups on the ligand (L_n) to control the site selectivity of the bond formation.^34,35 Furthermore, parameters such as the structural and electronic properties of the electrophile, the leaving group, the nucleophile, solvents, and temperature also play an important role and require a fine tuning.^28-31

Scheme 3. Simplified Mechanism for the Copper-catalyzed Allylic Alkylation with Hard Nucleophiles.

Of particular interest is the selective formation of the branched product from disubstituted allylic substrates, allowing the assembly of quaternary centers at the γ-position. In the case of enantiospecific allylic substitutions of stereogenic starting materials, the quaternary centers can be generated stereospecifically through an S_N2’-like oxidative addition (Scheme 4, A).³⁶ As an alternative, two different approaches are known to achieve enantioselectivity (Scheme 4, B). The first involves the use of a chiral auxiliary as a leaving group in order to control the construction of the branched product in a diastereoselective fashion. The second method is based on the application of a chiral ligand on the copper catalyst. The following chapters will focus on both the auxiliary- as well as catalyst-controlled reactions.

Scheme 4. Types of Allylic Substitution Mediated by Cu with Hard Nucleophiles to Construct Quaternary Stereogenic Centers.

2.1. Allylic Alkylation with Chiral Auxiliaries

Pioneering work with chiral auxiliaries has been reported by Denmark and Marble, who employed carbamate-based directing groups on the allylic electrophile for the allylic alkylation.³⁷ Later, chiral oxazolin- and thiazolin-2-yl allyl thioethers were described by Caló and co-workers, which allowed the stereoselective construction of quaternary stereogenic centers.³⁸ The highest enantioinduction was obtained with oxazoline-substituted thioether 5, the alkylated product 6 was isolated with 98% ee (Scheme 5).

Scheme 5. Allylic Alkylation with a Chiral Oxazoline-Based Auxiliary.

^[a] The absolute configuration was not determined. Piv = pivalyl.

A ferrocene carboxylate ester, possessing planar chirality, was developed by Breit and Breuninger in 2005 (Scheme 6).³⁹ The copper-mediated allylic alkylation of geraniol- and nerol-based esters (E)-7 and (Z)-7 with Grignard reagents resulted in the regioselective formation of the branched product 8. Depending on the double bond geometry in 7, both enantiomers of 8 were accessible, albeit with modest enantioselectivity.

Scheme 6. Allylic Alkylation with a Planar-Chiral Ferrocene-Based Auxiliary.

^[a] The absolute configuration was not determined.

2.2. Catalytic Enantioselective Allylic Alkylation with Chiral Ligands

2.2.1. Organozinc Reagents as Nucleophiles

The first enantioselective copper-catalyzed allylic alkylation with a chiral ligand to form quaternary carbon centers was disclosed by Hoveyda and co-workers in 2001 (Scheme 7).⁶ For this purpose, the authors developed modular and non-C2-symmetric dipeptide-based ligands, which contained three different parts: (1) a ligation fragment, possessing a Schiff base and a pyridine moiety which enables a second point of coordination to the copper; (2) a chain of two amino acids forming the peptide unit needed for the asymmetric induction; (3) a N-butylamide terminus to obtain high selectivities. Through the use of dipeptide-based chiral ligands 9a–c, cinnamyl phosphates 10a–d were alkylated with Et₂Zn in the presence of CuCN with excellent regiocontrol (scheme 7). The branched products 11a–d were obtained with varying level of enantioselectivity, with the highest being for substrates containing electron-withdrawing aryl substituents.

Scheme 7. First Generation Dipeptide-Based Ligands with Alkylzinc Reagents.

The developed protocol was also applicable to longer-chain alkylzinc reagents such as 12, which was demonstrated in the concise synthesis of the natural product (−)-sporochnol (3, Equation 1).⁶ Interestingly, the use of these nucleophiles results in the opposite stereochemical outcome compared to Et₂Zn, leading to the preferred formation of the R enantiomer.

Equation 1. Enantioselective Synthesis of (−)-Sporochnol (3).

A few years later, Kacprzynski and Hoveyda presented a second generation of the dipeptide-based Schiff base ligand, resulting in a more general and effective catalytic system for the enantioselective alkylation of allylic phosphates (Scheme 8).⁴⁰ With (CuOTf)₂·C₆H₆ as the copper source and the new ligand 13, modified at the ligation and peptide parts, an improvement in enantioinduction was achieved with previously tested cinnamyl phosphates such as 10a and 10b (11a: 92% ee (R) with 13 vs. 11a: 78% ee (S) with 9a). In addition, the substrate scope was also expanded to allylic phosphates bearing aliphatic substituents; the alkenyl- and the challenging alkynyl-substituted allylic phosphate 10e and 10f were converted to the corresponding diene 11e and enyne 11f with an enantiomeric excess of 82% and 91%, respectively.

Scheme 8. Second Generation Dipeptide-Based Ligand with Alkylzinc Reagents.

Of particular interest are transformations that lead to the enantioselective formation of quaternary centers next to a carbonyl group, as the additional functional handle can provide a means for further functionalization of the enantioenriched building blocks generated from these reactions. Traditionally, transition metal-catalyzed allylic alkylation for the formation of such α-quaternary products involve the use of an enolate-derived nucleophile in combination with a second or third row transition metal.^13-17,20-22 An alternative approach has been described by Murphy and Hoveyda, which utilizes α,β-unsaturated esters bearing a phosphate leaving group at the γ-position as the electrophiles 14a–h, and alkylzinc reagents as nucleophiles (Scheme 9).⁴¹ Depending upon the identity of the substituent at the α-position of the carbonyl group (R²), two efficient dipeptide-based ligands were identified. While 16 provides the α,α’-dialkyl substituted β,γ-unsaturated esters (15a–d, R² = Me) in good yields and stereoselectivity, 17 gives similar results for aryl-substituted substrates (15e–h, R² = Ph). The authors also noted that this protocol is not limited to Et₂Zn, and a variety of different organozinc reagents, even those that have ester groups at the end of the alkyl chain, can be applied. However, the alkylation with the sterically hindered i-Pr₂Zn resulted in a significantly decreased enantioselectivity (15c: 46% ee). The utility of newly formed β,γ-unsaturated esters as interesting building blocks were illustrated on 15a and 15e, which can be formally converted to the biologically active compounds (+)-ethosuximide (18)⁴² and (−)-aminoglutethimide (19),⁴³ respectively (Scheme 10).

Scheme 9. Preparation of α,α’-Dialkyl Substituted β,γ-Unsaturated Esters.

^[a] b:l 60:40. ^[b] b:l 80:20. Trt = trityl.

Scheme 10. β,γ-Unsaturated Ester 15a and 15e as Potential Building Blocks for the Synthesis of (+)-Ethosuximide (18) and (−)-Aminoglutethimide (19).

During the last decades, N-heterocyclic carbene (NHC) ligands have demonstrated tremendous applicability in metal-catalyzed protocols, due to their strong σ-donating ability and unique steric properties.^44,45 The first report utilizing chiral NHC ligands in a Cu-catalyzed enantioselective allylic alkylation reaction was described in 2004. Hoveyda and co-workers disclosed that an axially chiral copper NHC complex, generated in situ from a copper salt and bidentate silver NHC complex 20, is able to promote allylic alkylation of a wide range of allylic phosphates with alkylzinc reagents with high selectivity (Scheme 11).⁴⁶ One year later, the same group reported a new generation of chiral NHC ligands, in which the chirality is transferred to the diamine backbone (e.g. 21).⁴⁷ Compared to their previous systems involving the peptide-based ligands, this new class of ligands resulted in more efficient and selective copper catalysts, enabling the formation of products in higher enantiomeric excesses at reduced catalyst loading (11e: 82% ee with 13 vs. 11e: 96% ee with 20). In addition, with this new catalytic system, the formerly limited alkylating agent i-Pr₂Zn now allows the product formation with excellent enantioselectivity (up to 98% ee, not shown). After further modification of the NHC ligands, Hoveyda and co-workers disclosed an efficient catalytic method for the enantioselective synthesis of allylsilanes, including α-tertiary alkyl silanes (not shown).⁴⁸

Scheme 11. Chiral Hydroxyaryl NHC Ligands with Alkylzinc Reagents.

^[a] (CuOTf)₂·C₆H₆ (2.5 mol %) was used.

Recently, Crévisy, Baslé, Mauduit and co-workers reported a further class of bidentate NHC ligands in the Cu-catalyzed allylic alkylation.^49,50 These ligands contain a chelating hydroxyalkyl group derived from a chiral amino alcohol or amino acid. The copper NHC complexes, prepared in situ by deprotonation, for example, of the leucinol-based imidazolium salt 22 with n-BuLi in the presence of (CuOTf)₂·C₆H₆, mediated the alkylation of allyl phosphates with Et₂Zn (Scheme 12).⁵⁰ An important aspect of these new NHC ligands is also that their precursors are readily accessible through an efficient multi-component strategy, enabling rapid modifications of the substituents on the nitrogen atoms.

Scheme 12. Leucinol-Based NHC Ligand with Alkylzinc Reagents.

2.2.2. Grignard Reagents as Nucleophiles

Bidentate hydroxyalkyl NHC ligands have also been successfully applied in Cu-catalyzed allylic alkylation reactions with other organometallic nucleophiles.⁵¹ Inspired by their use in the copper-catalyzed asymmetric conjugate addition of Grignard reagents with β-substituted enones,^52-54 Mauduit and co-workers developed a protocol for the allylic alkylation of cinnamyl phosphates with Grignard reagents.⁵⁵ The saturated NHC ligand 23, derived from tert-leucinol, in the presence of Cu(OTf)₂, affords the alkylated products 11a,h,j with high regio- and enantioselectivity (Scheme 13). A practical advantage of Grignard reagents is their ability to deprotonate imidazolium salts, facilitating the formation of the desired complex in situ without requiring the preformation of a copper or silver carbene.

Scheme 13. tert-Leucinol-Based NHC Ligand with Grignard Reagents.

^[a] Cu(OTf)₂ (5 mol %) was used.

The hydroxyalkyl NHC ligands are not the only ones which were tested. The groups of Hong⁵⁶ and Woodward⁵⁷ also demonstrated NHC ligands, which were able to generate chiral quaternary products in a very limited set of cases, but with up to 76% ee and 58% ee, respectively (not shown). Another class of ligand applied by Alexakis were BINOL-based phosphoramidite ligands. After the achieved results in the Cu-catalyzed asymmetric allylic substitution on 1,4-bishalobut-2-ene (up to 94% ee, not shown),⁵⁸ the authors turned their attention to the challenging unsymmetrical 1,4-dibromo-2-methylbut-2-ene (24) as substrate (Scheme 14).^59,60 Alkylation of 24 with Grignard reagents in the presence of copper(I) thiophene-2-carboxylate (CuTC) and 27 resulted in the formation of isomeric products 26a–c and 25a–c, with a quaternary center on the latter. However, alkylation on the more sterically hindered position was disfavoured, and 25a–c were only obtained as minor products.

Scheme 14. Asymmetric Allylic Alkylation of an Unsymmetrical 1,4-Dibromomethylbutene.

^[a] The absolute configuration was not determined.

In 2013, Feringa and co-workers described the asymmetric allylic alkylation of phosphonates and phosphine oxides with Grignard reagents.⁶¹ With the use of CuTC and phosphoramidite 28, the β,β’-dialkyl substituted phosphine oxides 30a–c were isolated in good yield and with modest enantioselectivity (Scheme 15). These products 30a–c represent interesting chiral phosphorus-containing intermediates, which are further utilized in Wittig-type reactions (not shown).

Scheme 15. Preparation of β,β’-Dialkyl-Substituted Phosphine Oxides.

Recently, another class of ligands were implemented in the copper-catalyzed allylic alkylation with Grignard reagents. The groups of Yu and Tang demonstrated that the P-chiral monophosphorus ligand 31 facilitates the alkylation of a broad series of trisubstituted allyl bromides 32a–k (Scheme 16).⁶² Moderate yields with good selectivities were achieved with p-, or m-substituted cinnamyl bromides, whereas a significantly diminished result was observed for the o-substituted substrate 32e (33e: 54% yield, 22% ee). In addition, the alkyl substituent at the γ-position (R) was limited to a methyl group, as n-propyl- or i-propyl group led to the generation of products in low regio- and enantioselectivity (33j and 33k).

Scheme 16. P-Chiral Monophosphorus Ligand with Grignard Reagents.

In 2019, an attractive strategy incorporating unactivated olefins as substrates was described by Tambar and co-workers.⁶³ Based on their previous work involving a selective C–H allylic functionalization with sulfur diimide reagent [(PhSO₂N)₂S] and a subsequent copper-catalyzed alkylation,⁶⁴ the authors developed a sequential and controllable conversion of a methyl group into a fully substituted allylic carbon center (Scheme 17).⁶³ The functionalization of the inexpensive propylene through three successive, branched-selective C–H allylic alkylations with different Grignard reagents yielded in a broad range of differentially substituted products. Besides, the synthesis of various racemic examples with phosphine 34, the authors also included an enantioselective variant employing chiral phosphepine 35 as ligand. The achieved low enantiomeric excess of 26% and 30% for 38a and 38b may be the result of the poor selectivity for the formation of the (E)- and (Z)-isomers of the corresponding allylic sulfinamides 37a and 37b in the allylic oxidation step.

Scheme 17. Sequential Allylic Alkylation of Propylene.

2.2.3. Organolithium and Organoboron Reagents as Nucleophiles

Another class of hard nucleophiles for the copper-catalyzed allylic alkylation are the cheap and readily available organolithium reagents. Employing these highly reactive nucleophiles, Feringa and co-workers reported the first efficient regio- and enantioselective synthesis of a wide range of quaternary center-containing products, while suppressing potential side reactions such as lithium-halogen exchange or homocoupling reactions.⁶⁵ This catalytic system, consisting of CuBr·SMe₂ and chiral phosphoramidite 28, was found to be very efficient for the alkylation of (E)-trisubstituted allyl bromides with primary alkyl organolithium reagents, such as n-BuLi and n-HexLi (Scheme 18). A few years later, the same group expanded their protocol to include (Z)-trisubstituted allyl bromides and investigated the crucial role of the electrophile olefin geometry on the reaction outcome.⁶⁶ It was found that the use of 28 in the alkylation of (Z)-32a lead to the same product enantiomer, however, with decreased enantioselectivity (w/ 28: (E)-32a → (R)-40a with 84% ee; (Z)-32a → (R)-40a with 34% ee). A higher enantioinduction for (Z)-trisubstituted allyl bromides was obtained with ligand 39, which promotes again the formation of the same enantiomer after the addition of n-BuLi to either the Z- or E- substituted allyl bromide (w/ 39: (Z)-32a → (S)-40a with 90% ee; (E)-32a → (S)-40a with 62% ee). The fact that the opposite enantiomer of 40a was received depending on the absolute configuration of the BINOL moiety regardless of the olefin geometry indicates that the BINOL configuration largely dictates the absolute configuration of the quaternary centers. This is in contrast to results by Hoveyda⁶⁷ and Sawamura,⁶⁸ in which they showed that the use of (Z)-trisubstituted allyl electrophiles led to preferential formation of the opposite enantiomer to that obtained with the (E)-isomer. A further interesting feature was observed with ortho-bromophenyl-substituted substrate 32e. While (E)-32e was converted to the corresponding product 40e in 93% yield with 84% ee with 28, the (Z)-allyl bromide 32e did not result in any conversion with 39. According to the authors, a hindered rotation between the aryl group and the double bond inhibits the coordination of the alkylcopper complex to this substrate.

Scheme 18. Phosphoramidite Ligands with Organolithium Reagents.

Further developments with organolithium reagents enable a means for the introduction of aryl- or heteroaryl groups in the asymmetric copper-catalyzed allylic substitutions.^69,70 In this context, also aluminium reagents were presented by Hoveyda and co-workers to provide aryl-, vinyl- and alkynyl-substituted quaternary centers.^67,71,72 After the development of catalytic systems employing highly reactive organometallic nucleophiles (e.g., Grignard and organoaluminum reagents), the focus shifted toward the use of milder species, such as organoboron nucleophiles. In 2011, Shintani, Hayashi and co-workers described a copper-catalyzed allylic arylation by using aryl-substituted boronic acid neopentylglycol esters as nucleophiles.^73,74 The first allylic alkylation was presented by Ohmiya, Sawamura and co-workers three years later (Scheme 19).^68,75 The authors used alkylboranes as nucleophiles, which were prepared in situ through a hydroboration of terminal alkenes with 9-borabicyclo[3.3.1]nonane (9-BBN). These were subjected to trisubstituted allyl chlorides 42a–g in the presence of KOEt and catalytic amounts of (CuOTf)₂·toluene and bisphosphine 36 favouring the branched products 43a–g with excellent regioselectivity. Furthermore, the quaternary centers thus generated bearing three sp³-alkyl groups and a vinyl group were obtained with high enantioselectivity. In the hydroboration step, various terminal olefins with different functional groups such as ester, silyl ether, chloro or acetal moieties on the aliphatic chain were compatible. Ethylene also served as a suitable substrate in this protocol and delivered the corresponding branched product in 63% yield with 71% ee (not shown). Replacing the methyl group (R²) at the γ-position in 42d with an ethyl (42e) or n-propyl (42f) group resulted in slightly decreased enantioselectivities (43d: 90% ee, 43e: 81% ee, 43f: 71% ee).

Scheme 19. Bisphosphine Ligand with Alkylborane Reagents.

In 2015, Hoveyda and co-workers reported a regio- and enantioselective synthesis of 1,5-enynes using propargylboron reagents as nucleophiles (Scheme 20).³⁵ The addition of a silicon-containing propargyl group to alkyl- and aryl-substituted allylic phosphates is catalyzed by a sulfonate-based copper NHC complex, which is generated from the dimeric Ag ligand 44 and CuCl. During the exploration of the substrate scope, only the ortho-methoxyphenyl-substituted product 46d was isolated with a significant lower enantiomeric excess as compared to the other products. It turned out that the copper complex derived from the less hindered ligand 45 was more effective in this case, while with 44, a 60:40 branched to linear ratio of 46d was generated. Through the course of their investigations, the authors did note that a competitive isomerization event between the propargylboron species and the copper complex could occur, leading to the competitive formation of allenyl addition products 47 and 48. While the branched sideproduct 47 was not detected during the reaction, the linear 48 was always obtained in small amounts.

Scheme 20. NHC Ligands with Propargylborone Reagents.

2.2.4. β-Ketoester as Soft Nucleophiles

In addition to the large body of research concerning the copper-catalyzed allylic alkylation with hard nucleophiles, a few selected examples of the use of soft nucleophiles have been reported in this context. In contrast to the prevailing mechanistic understanding of copper-catalyzed allylic alkylation of hard nucleophiles, when soft nucleophiles are employed, the copper catalyst is not involved in the formation of a σ-allyl complex (cf. Scheme 3). Instead, in these cases the copper catalyst likely acts as a Lewis acid and activates the soft nucleophiles. After the formation of a copper enolate by deprotonation, alkylation with the corresponding electrophile takes place and generates the corresponding alkylated product. In combination with substituted allyl iodides, Gade and co-workers developed an elegant alkylation procedure to enantioselectively construct quaternary centers in the α-position to the carbonyl groups (Scheme 21).⁷⁶

Scheme 21. Cu-catalyzed Allylic Alkylation of β-Ketoesters with Ally Iodide and Subsequent Cyclization.

Cu(OTf)₂, in combination with the pincer ligand 49, acts as a highly efficient catalyst, delivering the indanone- and cyclopentanone-derived alkylated products in good yield and enantioselectivity. Furthermore, through the subsequent treatment of the chiral alkylated products with BF₃·OEt₂ in the presence of the copper complex, a cyclization takes place, affording the spirolactones 52a–e.

This methodology was further extended to substituted allylic alcohols, which were converted in situ to the corresponding allylic iodides by treatment with CsI and BF₃·OEt₂ in MeCN (Scheme 22). Application of the aforementioned reaction condition afterwards, consisting of the copper-catalyzed alkylation and subsequently BF₃-mediated cylization, provided the bisspirolactones of various ring sizes. In contrast to the previous copper-catalyzed examples with hard nucleophiles, this approach enables the direct use of ubiquitous allylic alcohols and does not require the preparation of electrophiles with more activated leaving groups.

Scheme 22. Cu-catalyzed Allylic Alkylation of β-Ketoesters with Allylic Alcohols and Subsequent Cyclization.

^[a] Isolated product after the second step.

A further approach with β-ketoesters and allylic alcohols were recently reported by Trillo and Baeza.⁷⁷ This time, the bisoxazoline ligand 60 was identified as suitable ligand, promoting the Cu-catalyzed allylic alkylation of acyclic α-methyl-substituted ketoester 61a with allylic alcohol 62 in moderate diastereo- and enantioselectivity (Scheme 23). Although an improved yield and stereoselectivity were observed with the cyclic ketoester 61b, the substrate scope of this protocol was generally limited for the construction of quaternary stereogenic centers. Additional cyclic substrates examined, such as tetralone or indanone derivatives, resulted in sluggish reactions and the corresponding products were obtained as racemic mixtures (not shown).

Scheme 23. Cu-catalyzed Allylic Alkylation of β-Ketoesters with Allylic Alcohols.

^[a] Yield was estimated by ¹H NMR of the crude reaction mixture. The preferred configuration of the major diastereomers was not reported.

3. Allylic Alkylation with Zinc

During investigations of the copper–NHC catalyzed allylic alkylation with Grignard reagents, Lee and Hoveyda noted that the transformation still takes place in the absence of a copper salt. In this case, a magnesium–NHC complex promotes the C-C bond forming reaction between allyl chlorides and Grignard reagents, facilitating the construction of quaternary stereogenic centers.⁷⁸ In 2009, a similar observation was made involving the utilization of dialkylzinc reagents and the imidazolium sulfonate 64.⁷⁹ Hoveyda and co-workers found that when Et₂Zn and 64 are combined at room temperature, a monomeric bidentate zinc–NHC complex 65 is formed (Scheme 24, top). Subjection of one equivalent of this species 65 to an allylic phosphate under typical reaction conditions resulted in the complete recovery of the starting material. In contrast, when 30 equivalents of Et₂Zn were added to this mixture, the allylic phosphate was completely consumed, affording the desired, alkylated product in high regio- and enantioselectivity (not shown).

Scheme 24. Synthesis of the Zinc–NHC Complex 65 and Its Proposed Role in the Allylic Alkylation of Allyl Phosphates.

On the basis of the aforementioned experiments, the authors suggested that the chiral complex 65 is unlikely to be the operative nucleophile in this reaction, and instead may be acting as a bifunctional catalyst that activates both coupling partners and organizes the transition state (Scheme 24, bottom).⁷⁹ A Lewis acidic zinc center can coordinate the phosphate and generates a catalyst·substrate complex XI, in which the allylic leaving group is activated. At the same time, coordination of the dialkylzinc reagent through the Lewis basic oxygen of the sulfonate unit occurs, enabling the highly S_N2’-selective alkylation. Effective substrates for the developed zinc-NHC-mediated transformation were aryl-, alkyl- or carboxylate ester-substituted allyl phosphates (Scheme 25). Other nucleophiles besides Et₂Zn, such as n-Bu₂Zn and sterically demanding i-Pr₂Zn were applicable, however, for the latter a slightly increased reaction temperature was necessary. Notable, all of the corresponding terminal olefins 11a,b,g,m–o and 15i were formed with high enantioselectivities and in a similar range to those obtained with copper–NHC complexes as catalysts (cf. Scheme 11, chapter 2).

Scheme 25. Zinc-NHC-Mediated Allylic Alkylation of Disubstituted Allylic Phosphates.

4. Allylic Alkylation with Chromium

The allylic alkylation was scarcely studied with chromium-based catalysts. In 2005, Doyle and Jacobsen accomplished the Cr-catalyzed enantioselective alkylation of cyclic, tetrasubstituted tin enolates with a wide range of commonly utilized electrophiles like allyl bromide (Scheme 26, top).⁸⁰ The chiral chromium–salen complex 66 as catalyst provides an access to enantioenriched α-carbonyl quaternary stereocenters. Two years later, the method was extended to acyclic tin enolates, which required a slight modification of the catalyst.⁸¹ Although the acyclic tin enolates were used as a mixture of E- and Z-isomers, the corresponding α-alkylated ketones were isolated in high yield and enantioselectivity (Scheme 26, bottom). Whereas the mechanism of this transformation is still unclear, preliminary investigations by the authors suggested that the catalysis likely proceeds by generation of a tin ate species from the [Cr(salen)X] catalyst (66 or 67), perhaps with simultaneous activation of the alkyl halide by the in situ-generated cationic chromium complex.

Scheme 26. Cr-catalyzed Alkylation of Tributyltin Enolates 68 and 70.

Th = thexyl.

5. Allylic Alkylation with Cobalt

Compared to other typically used first row transition metals, cobalt-catalyzed allylic alkylation has been much less explored.^18,19,82 Although protocols with both hard nucleophiles, such as organozinc reagents, and soft nucleophiles such as β-ketoesters, have been reported, highly regio- and enantioselective variants have only recently been described, and are limited to the use of soft, prochiral nucleophiles.^83-85 In the context of enantioselective construction of quaternary stereocenters, the first example was published by Li and co-workers in 2019.⁸³ A cobalt(I)-bisphosphine complex, generated in situ via an zinc reduction, mediates the addition of cyclic β-ketoesters 72a–j to α,α-dimethyl allyl methyl carbonate 73a in good yields and high enantioselectivities (Scheme 27). Exploration of the substrate scope showed that, in particular, t-butyl ester substrates were converted to the corresponding products with high enantioinduction (74a (R² = Et): 85% ee vs. 74d (R² = t-Bu): 92% ee). In addition, different substituents such as chloro, methoxy, phenyl, and even a phenylethynyl group on the tetralone moiety were tolerated. Slightly diminished results were observed by changing the ring size of the β-ketoester: 74i, possessing a five-membered ring, was formed in lower enantioselectivity compared to six-membered 74d (74i: 75% ee vs. 74d: 92% ee). Although the high level of enantiomeric excess was retained in seven-membered analogue 74j (86% ee), a double catalyst loading was required, as this larger nucleophile led to a more sluggish reaction.

Scheme 27. Co-Catalyzed Allylic Alkylation of β-Ketoesters with α,α-Dimethyl Allyl Methyl Carbonate 73a.

^[a] The reaction was performed with 10 mol % of cobalt salt, ligand, and zinc.

In addition to α,α-dimethyl allyl methyl carbonate 73a, other electrophiles such as cyclic allylic methyl carbonates 73b and 73c were also tested. These bulkier electrophiles resulted in the formation of hindered products 76 and 77 in only moderate enantiomeric excesses of 48% and 51% (Scheme 28). When electrophiles possessing two different substituents (R¹ ≠ R²) are used, there is the additional challenge of controlling the formation of the second, adjacent stereocenter. Notably, with racemic 4-vinyl-1,3-dioxolan-2-one (73d) as the electrophile, the product 78 is obtained as a diastereomeric mixture (83:17 d.r.) in a combined 96% yield after the allylic alkylation and subsequent intramolecular transesterification. Although the major diastereomer was isolated with excellent 94% ee, the enantioenrichment of the minor diastereomer was much lower, at only 70% ee. A similar result was obtained when n-pentyl-substituted allylic carbonate 73e was used to form 79 with the vicinal quaternary and tertiary carbon centers.

Scheme 28. Co-Catalyzed Allylic Alkylation of β-Ketoesters with Various Methyl Carbonates.

^[a] The reaction was performed at 60°C. ^[b] Combined yield.

6. Allylic Alkylation with Nickel

Unlike the aforementioned cobalt-catalyzed systems, nickel catalysis can enable the reaction of soft, prochiral nucleophiles with allyl electrophiles in a linear selective fashion. Thus, nickel catalysis presents a complimentary strategy for the formation of all-carbon quaternary centers via asymmetric allylic alkylation.^18,19,86,87 In 2016, Mashima and co-workers reported the first asymmetric example using cyclic β-ketoesters and allylic alcohols (Scheme 29).⁸⁸ Catalytic amounts of Ni(COD)₂, together with the H₈-BINAP ligand (80) affords α,α-disubstituted β-ketoesters 81–83 and 84a–g in good yields and enantioselectivities. Examination of the substrate scope demonstrated that the use of prochiral nucleophiles with less-hindered substituents on the ester groups (e.g., R² = Me) led to greater enantioinduction (89a (R² = Me): 86% ee vs. 89d (R² = t-Bu): 14% ee). In addition, while five- and six-membered cyclic β-ketoesters such as 84a and 84f were converted to corresponding products 89a and 89f with a high enantiomeric excess, diminished selectivity was observed when seven-membered substrate 84g was applied. Acyclic substrates were also tested under this catalytic system, however, the corresponding alkylated products were obtained with low enantioselectivity (not shown).

Scheme 29. Ni-Catalyzed Allylic Alkylation of Cyclic β-Ketoesters.

^[a] The absolute configuration of the alkylated products 86–88, and 89a–g was not given. COD = cycloocta-1,5-diene.

Another benefit of these catalytic systems is that it allows the use of ubiquitous allylic alcohols, obviating the need for the synthesis of electrophiles with more activated leaving groups. As these electrophiles are often synthesized from the corresponding alcohol, this serves to remove a step in the electrophilic components of these reactions. A variety of functionalized secondary allylic alcohols bearing electron-donating as well as electron-withdrawing substituents were tolerated, providing the linear, alkylated products in high enantioselectivity (Scheme 30). Interestingly, when the analogous primary allylic alcohols 90a,d,e were employed in this reaction, a nearly identical reaction outcome was observed (87a (w/ 85a): 98%, 95% ee vs. 87a (w/ 90a): 88%, 94% ee).

Scheme 30. Ni-Catalyzed Allylic Alkylation with Various Allylic Alcohols.

^[a] The absolute configuration of the alkylated products 86a–i was not given.

These results indicate that a nickel π-allyl complex is likely an intermediate in the catalytic cycle.^89-92 Based on this observation and previous reports, the authors proposed a mechanism that involves a π-allyl complex (Scheme 31). Initially, coordination of the ligated nickel to the allylic substrate XII resulted in the formation of the nickel(0) π-complex XIII, which is poised to undergo an oxidative addition to generate a hydroxy π-allyl nickel(II) complex XIV. The hydroxy ligand may then abstract a proton from the β-ketoester XV, generating the corresponding enolate nucleophile.⁹³ The C–C bond forming process may proceed through nucleophilic attack by the enolate in XVI on the allyl moiety, resulting in nickel(0) π-complex XVII.^88,91,92 Finally, ligand exchange releases the product XVIII concomitant with the regeneration of the nickel(0) complex XIII. It should be noted that it is not clear whether the enolate ligates the nickel(II) as in complex XVI, representative for an inner-sphere mechanism, or if alternate an outer-sphere pathway via intermediate XIX is operative.⁹²

Scheme 31. Proposed Mechanism of Ni-Catalyzed Allylic Alkylation with Allylic Alcohols.

In 2018, Stoltz and co-workers accomplished the first application of cyclic α-acyl lactones and lactams as prochiral nucleophiles in the nickel-catalyzed asymmetric allylic alkylation (Scheme 32).⁹⁴ These soft nucleophiles reacted with various allylic alcohols in the presence of Ni(COD)₂ and bisphosphine ligand 91. The corresponding alkylated products 94a–k and 95a,b were isolated in good yields and enantioselectivities. In addition, the utility of this method was demonstrated through a number of synthetically useful product transformations, allowing access to chiral building blocks such as spirocyclic enones or 3,3-disubstituted piperidine derivatives with all-carbon quaternary centers (not shown).

Scheme 32. Ni-Catalyzed Allylic Alkylation of Cyclic α-Acyl Lactones and Lactams.

^[a] Reaction was at −10°C. ^[b] Reaction was performed with toluene:MTBE (2:3) as solvent mixture.

Very recently, Zhang, Carpentier, Mashima, and co-workers reported the use of allylic amines instead of allylic alcohols in the asymmetric alkylation of cyclic β-ketoesters (Scheme 33).⁹⁵ A C–N bond cleavage in the N-allyl-N-methylaniline derivatives 96a–e provides the allyl fragment for alkylation reaction mediated by a nickel–diphosphine system. The axially chiral 97 served as an efficient ligand for the conversion of various cyclic six- and seven-membered β-ketoesters to the corresponding allylated products. In the case of cyclic five-membered nucleophiles, the authors noted that benzo-fused systems possessing a bulky 3-ethylpenta-3-yl ester (99) resulted in improved enantioselectivities when H₈-BINAP (80) ligand was used (104 (w/ 97): 99%, 21% ee vs. 104 (w/ 80): 99%, 88% ee). Examination of the other soft, cyclic nucleophiles revealed that both β-ketoamides and β-diketones are rather unsuitable substrates. However, an excellent result was obtained when a β-ketonitrile 102 was applied; the corresponding product 107 was isolated in 94% yield and >99% ee (gray box). Based on DFT calculations, the authors propose an outer-sphere mechanism for the nickelmediated allylic alkylation with allylamine, in which a non-ligated enolate attacks the nickel(II) π-allyl complex.

Scheme 33. Ni-Catalyzed Allylic Alkylation of Cyclic β-Ketoester, β-Diketone, and β-Ketonitrile with Allylamines.

^[a] The absolute configuration of the alkylated products was not given. ^[b] Reaction was performed with 80 (6 mol %) at −20°C.

7. Summary and Future Outlook

Over the last two decades, a number of protocols for the construction of all-carbon quaternary stereocenters via allylic alkylation using first row transition metals have been developed. In particular, copper catalysts play a dominant role in these transformations with prochiral allylic electrophiles and hard, achiral nucleophiles providing the branched products in excellent yield and enantioselectivity (cf. Scheme 1). Complementary asymmetric approaches applying soft, prochiral nucleophiles, have recently been described with cobalt and nickel complexes. While the use of cobalt enables the formation of branched products with a quaternary center, the corresponding linear products are exclusively generated with nickel complexes. However, both methods still have shortcomings. Namely, with respect to the soft nucleophiles, the scope is almost exclusively limited to β-ketoesters, with the exception of Stoltz’s protocol using cyclic α-acyl lactones and lactams.⁹⁴ The development of approaches that extend the scope of these systems and solve the challenges in stereocontrol associated with acyclic nucleophiles could be considered a worthy future goal. Moreover, transition metal-catalyzed allylic alkylation with prochiral nucleophiles provides an opportunity to simultaneously generate two adjacent stereogenic centers in the branched products. Further investigations of the asymmetric formation of vicinal quaternary and tertiary centers, as briefly described by Li,⁸³ could be an efficient and inexpensive alternative to the well-established iridium-catalyzed methods in this field.^13,20-22 In this context, the construction of two vicinal quaternary centers, which to date has not yet been reported, could be achieved in the near future through further developments in this field. Meeting these challenges will require continuous efforts in ligand and catalyst improvements, which ideally are based on a deep mechanistic understanding of the allylic alkylation.

ABBREVIATIONS

BSA

bis(trimethylsilyl)acetamide

COD

cycloocta-1,5-diene

EWG

electron-withdrawing group

LG

leaving group

MTBE

methyl tert-butyl ether

NHC

N-heterocyclic carbene

Piv

pivalyl

TC

thiophene-2-carboxylate

Th

thexyl

TM

transition metal

Trt

trityl

Biography

Lars Süsse (born in 1990 in Berlin, Germany) studied chemistry at the Technische Universität Berlin (2010–2015), including a three-month research internship at Syngenta (Stein, Switzerland). He obtained both his bachelor’s degree (2013) and master’s degree (2015) with Martin Oestreich. He then stayed on for a Dr.rer.nat. in Organic Chemistry with Martin Oestreich (2015–2019), developing syntheses of chiral boron and phosphorus Lewis acids and investigating their application in hydrosilylation reaction and Nazarov cyclization. Currently, he holds a Feodor Lynen Research Fellowship (Alexander von Humboldt Foundation) to support postdoctoral studies in the group of Brian M. Stoltz at the California Institute of Technology, where he is working on enantioselective iridium-catalyzed allylic alkylation and its implementation in natural product synthesis.

Brian M. Stoltz was born in Philadelphia, PA in 1970 and obtained his B.S. degree from the Indiana University of Pennsylvania in Indiana, PA. After graduate work at Yale University in the laboratories of John L. Wood and an NIH postdoctoral fellowship at Harvard in the Corey laboratories, he took a position at the California Institute of Technology. A member of the Caltech faculty since 2000, he currently is a Professor of Chemistry. His research interests lie in the development of new methodology for general applications in synthetic chemistry.