Tailored-Designed Ligands for Enantioselective Gold(I)-Catalyzed Activation of Alkynes

Abstract

In this article, we describe the work performed at our laboratories over the years on the design and applications of novel chiral ligands for the enantioselective gold(I)-catalyzed activation of alkynes, with a focus on the cycloisomerization and cycloaddition reactions of 1,6-enynes. The rationale behind the development of each ligand and the mode of enantioinduction are discussed.

 

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Keywords

Chiral ligands - Enantioselective synthesis - Gold catalysis - Enynes - Alkynes

1

Introduction

Gold(I) complexes are excellent catalysts for the activation of π systems, in particular alkyne-containing substrates. Due to the exquisite alkynophilic character of gold(I) catalysts, the activation of alkynes is highly selective in the presence of other functional groups under very mild conditions.[1] The development of homogeneous gold(I) catalysis initiated with the pioneering work of Teles and Tanaka, who described the selective addition of alcohols and water to alkynes.[2] [3] Later, the discovery of the phenol synthesis by Hashmi contributed to the increasing interest and progress of homogeneous gold(I) catalysis.[4] In stark contrast to the impressive progress witnessed in gold(I) catalysis in the last two decades, the development of enantioselective gold(I)-catalyzed transformations evolved at a slower pace. This was mainly a result of the tendency of gold(I) complexes to adopt a bilinear coordination, which places the chiral information provided by ligands far away from the reaction center, resulting in an inefficient enantio-induction. Additionally, the relatively free rotation along the L*–Au and the Au–substrate axis raises the difficulty when fixating the substrate within the chiral environment ([Fig. 1]). The most common strategies to achieve good enantioselectivities in gold(I) catalysis rely on the use of atropoisomeric bisphosphines and phosphoramidites derived from chiral diols such as BINOL and TADDOL, while the use of chiral counterions allows delivering enantioselectivity via tight ion pairing.[5] This latter approach, however, is mainly limited to allenes, as silver phosphates form unreactive phosphine–Au(I) phosphate complexes that are catalytically inefficient in 1,n-enyne cyclizations.[6]

Fig. 1 Challenges associated with enantioselective gold(I) catalysis.

The mentioned strategies have been applied to several enantioselective gold(I)-catalyzed reactions; however, in some cases, the new chiral gold(I) catalysts are only effective for a narrow set of substrates.

Our group explored the use of chiral dinuclear complexes derived from commercially available bisphosphine ligands such as Tol-BINAP or JosiPhos in the alkoxycyclization of 1,6-enynes and in the intermolecular [2+2] cycloaddition between alkynes and alkenes.[5] [7] Due to the limitations discussed above, we decided to develop new chiral ligands customized to overcome the hurdles dictated by the geometry and particularities of gold(I) catalysis. Similarly, other groups have devoted efforts to implement new and original ligand scaffolds for the enantioselective gold(I)-catalyzed activation of alkynes ([Fig. 2]).[8]

Fig. 2 Representative ligand scaffolds for asymmetric gold(I) catalysis.

 

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2

Chiral Phosphite Complexes for Cycloisomerization of 1,6-Enynes

Our group described the synthesis of chiral phosphite gold(I) complexes for the enantioselective formal [4+2] cycloaddition of 1,6-arylenynes to form products that have the core structure of the pycnanthuquinone family of natural products ([Scheme 1]).[9] A screening involving dinuclear bisphosphines, chiral planar, and mononuclear complexes was first conducted, although the enantioselectivities were modest in most cases. A library of gold(I) phosphite complexes was then prepared from enantiopure BINOL using a simple and modular route. Phosphites were preferred over phosphines for their air stability and high reactivity of their gold(I) complexes in the activation of alkynes. Bulky triphenyl silyl groups were placed at the three position of the atropoisomeric backbone, while different substituted phenol moieties were explored to introduce the OR group. Phosphite gold complex with a para-alkyl substituted phenol 2 led to the highest enantioselectivity (82% ee) in the [4+2] cycloaddition of 1,6-aryl enyne 3. In combination with AgNTf₂ and performing the reaction −20 °C, it led to the corresponding cycloadduct 4 in 95% yield and 88% ee.

Scheme 1 Chiral phosphite gold(I) complexes for the enantioselective [4+2] cycloaddition of 1,6-aryl enynes.

More sterically demanding 1,6-aryl enynes 5–8 were also cyclized, but lower enantioselectivities were obtained. Thus, although our first foray into ligand design for enantioselective gold(I) catalysis was successful, in general, the achieved enantioselectivities were far from optimal.

 

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3

Chiral Pyrrolidinyl JohnPhos-Type Ligands

Gold(I) complexes with dialkyl biaryl phosphine ligands have become the catalysts of choice due to their improved reactivity across diverse transformations compared to PPh₃AuCl. Their cationic complexes are easily prepared from the gold chloride precursor using a halide abstractor (AgX or NaB_Ar ^F) in the presence of a weakly coordinating ligand such as a nitrile (usually MeCN).[10] These cationic complexes are bench-stable and do not require preactivation for catalysis. Hence, we disclosed a new phosphine ligand featuring a C ₂-symmetric diaryl pyrrolidine at the 4′ position of the bottom ring of the JohnPhos scaffold 9 ([Scheme 2]).[11]

Scheme 2 Chiral pyrrolidinyl JohnPhos-type ligands for enantioselective folding of 1,6-enynes.

These catalysts allow placing the chiral information next to the reaction center, circumventing the challenges posed by the linear geometry of gold(I). Key to the efficient enantioinduction was the C ₂-symmetric element, which prevents formation of rotamers and the use of a bulky di-adamantly phosphine, which blocks the C–P bond from rotation and forces the P–Au–Cl axis toward the chiral cavity. The new chiral JohnPhos-type gold(I) complexes were applied to three different enantioselective reactions, namely, the formal [4+2] cycloaddition of 1,6-aryl enynes 10, the cycloisomerization of N-tethered 1,6-arylenynes 12 that gives azabicyclo[4.1.0]hept-4-enes 13, and the (hydro)alkoxycyclization of benzene-tethered 1,6-aryl enynes 14 to afford 1,2-dihydronaphthalenes 15 in good yields and excellent enantioselectivities. Besides, the product of the hydroxycyclization 16 was used in the first enantioselective total synthesis of three members of the carexanes, a family of natural products ([Scheme 2]).

Surprisingly, while these seemingly related cyclizations of 1,6-enynes proceed with good-to-excellent enantiomeric ratios, the first two reactions take place with a facial preference for the Si face of the alkene, while the formation of products 15 takes place by reaction of the Re prochiral face of the alkene. Computational studies have identified noncovalent attractive π–π interactions in the chiral pocket of the catalysts, which are key to achieving good enantioselectivities ([Scheme 3]). Analysis of the non-covalent interaction (NCI) plots during the folding process revealed attractive interactions between the aromatic moieties of the substrates and those of the chiral diaryl pyrrolidine fragment. The key factor responsible for the enantioselectivity across the three reactions was found to be the π–π interactions between the aromatic moieties of the substrates and the remote C ₂-diaryl pyrrolidine, which induces the specific binding orientation inside the catalyst cavity and stabilizes the transition state.

Scheme 3 Enantioselective folding of enynes 10a and 14a and the two-most relevant binding orientations (A and B) with catalyst 9. Energy values given in kcal/mol relative to the most stable binding orientation in each case.

 

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4

Modifications to Chiral Pyrrolidinyl JohnPhos-type Ligands

Based on scaffold 9, our group prepared a library of gold(I) catalysts featuring a C ₂-symmetric 2,5-diaryl pyrrolidine with several variations including the removal of the bottom ring, enlargement of bottom ring, and the replacement of the phosphine by an N-heterocyclic carbene (NHC) and by diverse bis and tri-aryl phosphine ligands with remote chirality (22 new complexes) ([Scheme 4]).[12] Other modifications included the introduction of fluorine atoms at the bottom ring, the replacement of aromatic rings in the chiral pyrrolidine for alkyl groups, and the use of C ₂-chiral acyclic amines instead of the pyrrolidine.

Scheme 4 Novel variations of the chiral pyrrolidinyl gold(I) complexes and gold(I)-catalyzed atroposelective cyclization toward chiral 2-aryl indoles.

All the prepared complexes were tested in the intramolecular formal [4+2] cycloaddition of 1,6-aryl enynes 3 and 10 to benchmark their performance and in the atroposelective cyclization of 2-alkynyl sulfonamides 23, leading to 2-arylindoles 24.

Placing a CF₃ group at the meta-position in the aryl phosphine ring resulted in chiral catalyst 17, which showed increased reactivity compared to the parent gold complex 9. Among the second-generation gold(I) catalysts, bulky bis- and tris-biphenylphosphino ligands 22 gave poor enantioselectivities. Likewise, low enantiomeric ratios were determined with complexes 20-bearing ligands modified at the bottom ring due to reduced flexibility of the chiral diaryl pyrrolidine and ineffective orientation of the chiral cavities. On the other hand, complexes 19, in which the chiral element is directly attached to the ortho position of the phenyl phosphine ring, delivered good enantioselectivities in the [4+2] cycloaddition and the atroposelective cyclization for the formation of 2-aryl indoles. Interestingly, the enantio-divergent formation of 2-arylindoles took place despite the catalysts having the same absolute configuration at the C ₂-chiral pyrrolidine.

Recognition of substrate 23a by catalysts 17 and 19 was evaluated by DFT calculations to identify the importance of the stabilizing NCIs (between the sulfonamide and the chiral pocket of catalysts) in determining the preferred reaction pathway. Hence, when using catalyst 17, intermediate with R absolute configuration was preferentially formed through the proR face by at least 2.2 kcal/mol, in agreement with the experimental results. Meanwhile, when using the shorter catalyst 19, the reaction occurred preferentially through the opposite proS face, giving rise to the S arylindole 24a ([Scheme 5]).

Scheme 5 Computed pathways for the atroposelective cyclization of 23a with catalysts 17 and 19 and the two most relevant binding orientations (A and B). Energy values given in kcal/mol are relative to the most stable binding orientation in each case.

The diverse modifications made in the new ligands that were prepared allowed dissecting the most important elements within the ligand scaffold, realizing that subtle changes in the structures of these gold(I) catalysts, such as the introduction of an electron-withdrawing CF₃ group meta to the phosphine phenyl fragment or removal of the bottom ring, have a strong influence, leading to more active and selective catalysts. More abrupt changes, such as enlarging the aromatic bottom ring in complex 18, were unfortunately detrimental, indicating that those elements close to the chiral pyrrolidine can indeed force ineffective conformations in the catalysts when folding the substrates. In this line, highly bulky bis- and tri-aryl biphenyl complexes were excessively flexible, opening the chiral cavity to accommodate the substrate. Consequently, low enantioselectivities were obtained with these bulky chiral gold(I) complexes. The new family of chiral gold(I) complexes allowed us to identify the most relevant elements in the ligand scaffold bearing a C ₂-symmetric diaryl pyrrolidine. Among the catalysts that were synthesized, only gold complexes 17 and 19 showed comparable or better results than complex 9.

Additionally, a new open-source tool called NEST App was developed to analyze the steric effect in ligands featuring the cylindrical shape and to predict the enantioselectivities of these complexes ([Scheme 6]).[12] NEST considers a volume of capsule shape and computes the percent volume occupied by atoms. Dividing the space between the central atom (gold) and the end of the capsule into quadrants, NEST also provides the occupied volumes of the different quadrants that are used as descriptors. Catalysts with experimentally known activity were used to perform single-variable regressions for each descriptor, and the best equation was selected to predict the enantiomeric ratio of systems with unknown reactivity, thereby enabling the development of reliable predictive models. Interestingly, our model was able to predict the stereodivergent formation of products 4a, 11a, and 24a.

Scheme 6 NEST Analysis design and occupied volume of selected gold(I) complexes. Selected predicted (pred) and experimental (exp) enantiomeric ratios for the formation of 4a, 11a, and 24a.

 

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5

1,3-Disubstituted Ferrocenyl Gold(I) Complexes

Inspired by the success of chiral pyrrolidinyl JohnPhos-type complexes, we later introduced a family of 1,3-disubstituted ferrocenyl gold(I) complexes 25 in which the chirality is provided by the chiral planarity of the ferrocene scaffold ([Scheme 7]).[13] These were the first planar chiral analogues of gold(I) catalysts with JohnPhos-type ligands.

Scheme 7 New 1,3-disubtituted ferrocenyl phosphines gold complexes and enantioselective [4+2] cycloaddition of 1,6-aryl enynes 10. Lowest energy transition states of enyne 10 coordinated to catalyst 25. Energy values are given in kcal/mol relative to the most stable binding orientation in each case.

In this design, bulky di-adamantyl phosphines were kept in the design to force the Au–Cl axis toward the biphenyl fragment. In a similar fashion to chiral pyrrolidinyl JohnPhos-type gold(I) catalysts, di-substitution at the 3,5-position with CF₃ groups on the top ring of the biphenyl fragment was preferred for higher enantioselectivities. These unprecedented chiral monodentate ligands featured exclusively chiral planarity and allowed performing the [4+2] cycloaddition of 1,6-arylenynes 10 with high enantioselectivity. Computational studies provided a working model showing very good agreement with the experimental results. Analysis of the NCI plots revealed that the biphenyl system engaged in T-shaped π–π interactions with the aryl ring present in the 1,6-aryl enyne. Furthermore, analysis of the steric profile of these ferrocenyl gold(I) complexes showed that the biphenyl substituent provides increased hindrance and higher buried volumes, which are also common in other chiral gold(I) complexes.[14] These novel gold(I) complexes 25 (in total 10 complexes synthesized) showed higher reactivity, allowing the reactions to be conducted at −25 °C using 2 mol% of the chiral catalyst ([Scheme 7]). However, this family of chiral gold(I) catalysts gave only good enantioselectivities in the formal [4+2] cycloaddition of substrates 10. In addition, the synthesis of the 1,3-disubstituted ferrocenyl ligands required eight steps from ferrocene.

 

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6

1,2-Disubstituted Ferrocenyl Indole Gold(I) Complexes

Following up with the previous work using chiral monodentate phosphine ligands and inspired by the work of Hu and Togni on the bidentate ferrocenyl ligand containing heterocycles,[15] we have recently developed a new ligand template based on a 1,2-disubstituted ferrocenyl scaffold ([Scheme 8]).[16] The ligands were prepared in a convergent manner from commercially available enantiopure Ugi’s amine and 2-aryl indoles via S_N ¹ reaction, reducing the synthetic route to four steps. A library of gold(I) complexes (17 examples) was prepared by varying substituents on the 2-aryl indole and the diaryl phosphine, which led to the identification of optimal gold(I) complex 26.

Scheme 8 Novel 1,2-disubstituted ferrocenyl phosphine gold(I) complexes and their applications in gold(I) catalysis.

In contrast to previous designs, an electron-rich arene is preferred in the 2-aryl indole fragment of the gold(I) complex instead of electron-poor aryl rings presented in the 1,3-disubstituted ferrocenyl complex 25 or the chiral pyrrolidinyl JohnPhos 9. A bulky dialkyl phosphine was not necessary, and an air-stable diphenyl phosphine gave the best results. The ligand geometry and the benzylic methyl group place the Au–Cl axis toward the chiral cavity. Additionally, NCIs between an axial phenyl phosphine and the indole arm provided robustness to the new chiral ligand. Gold(I) complex 26 gave high enantioselectivity in three gold(I)-catalyzed reactions, namely, the [4+2] cycloaddition of 1,6-arylenynes 3, the methoxycyclization of 1,6-arylenynes 27, and the alkoxycyclization of N-tethered 1,6-enynes 29 ([Scheme 8]). Although previously designed monodentate ligands performed well only with internal alkynes, however, these new chiral gold(I) catalysts circumvent this limitation by being capable of folding substrates with more challenging terminal alkynes.

The family of gold(I) complexes was evaluated in the [4+2] cycloaddition of 1,6-arylenynes 3 and alkoxycyclization of N-tethered 1,6-enyne 27. Modes of enantioinduction were unveiled by DFT calculations and analysis of the NCI plots, pointing out that the NCIs between the trimethoxy-substituted aryl ring of the indole of the catalyst and the aryl ring of the substrate are the key elements in the stabilization of the transition state ([Scheme 9]).

Scheme 9 Lowest energy intermediates and molecular structures and NCI plots of the transition states for the alkoxycyclization of N-tethered 1,6-enynes 27 with catalyst 26. Energy values are given in kcal/mol relative to the most stable binding orientation in each case.

The NEST analysis was applied to catalysts of type 26, which allowed for the reliable prediction of enantioselectivities, highlighting the importance of the size and position of the free space for the substrate coordination and the importance of attractive weak interactions ([Scheme 10]). The experimental data obtained, in combination with DFT-optimized catalyst structures, was used to develop a (multi)linear regression model to predict enantioselectivity. A single descriptor was found to be insufficient, while the combination of two descriptors led to more reliable models to validate and predict enantioselectivities in the two studied reactions. The newly developed NEST analysis and RDKit descriptors turned out to provide good correlation in the predictive models, demonstrating the suitability of this tool when analyzing elongated-shaped chiral catalysts.[11]

Scheme 10 NEST analysis, design, and occupied volume of selected gold(I) complexes. Selected predicted (pred) and experimental (exp) enantiomeric ratios for the formation of 4a and 28a for each catalyst.

 

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7

Chiral Resorcin[4]arene Phosphoramidite Ligands

The use of supramolecular systems that mimics the working mode of cyclases to improve the selectivity in metal catalysis has received considerable attention in the last years, with gold(I) cavitands supported by resorcin[4]arenes scaffolds finding use in diverse gold(I)-catalyzed reactions.[17] Based on the resorcin[4]arenes ligands developed by Iwasawa,[17a] ^-c our group reported chiral gold(I) complexes such as 31 ([Scheme 11]).[18] Chirality was introduced in the phosphoramidite binding site of the cavitand from commercially available chiral bis-(1-arylethyl)amines. Replacing the quinoxaline walls for 1,4-napthoquinones was explored as well as the formation of mono and dinuclear gold(I) cavitands, leading to a library of chiral gold(I) complexes. These chiral gold(I) catalysts were applied in the alkoxycyclization of benzene-tethered 1,6-enynes 32. While mononuclear gold(I) complexes gave low enantioselectivities, monocationic dinuclear cavitand 31 delivered the alkoxycyclization product 33 with high levels of enantioselectivity.

Scheme 11 Chiral gold(I) resorcene[4]arene cavitand 31 and its applications in gold(I) catalysis and total synthesis.

Different enynes and nucleophiles could be cyclized, leading to chiral 2,3-dihydro-1H-indene products 33 in excellent enantioselectivities.[18] The enantioselective alkoxycyclization with chiral gold(I) cavitands was applied in the first total synthesis of the carbazole alkaloid (+)-mafaicheenamine. The effects induced by the cavity and the presence of a non-activated secondary gold(I) center were found to be essential to achieve enantioinduction. NCI plot studies showed that attractive interactions between the cavitand and the aromatic ring of the enyne took place. Additionally, NCIs were observed within the gold complex during the transition state.

 

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Hydrogen-bonded Counterion-directed Enantioselective Catalysis

Our group developed a new strategy for enantioselective gold(I) catalysis by combining metal catalysis, H-bond organocatalysis, and counterion-directed catalysis ([Scheme 12]).[19] A cationic gold(I) complex containing a H-bond donor in its structure is bound to a chiral BINOL-based phosphoramidite anion via hydrogen bonding, thus creating a chiral supramolecular system 36 for the folding of unsaturated substrates that are held together by NCIs ([Scheme 12]). The new strategy introduced for the first time the use of chiral anions for the gold(I)-catalyzed activation of alkyne substrates. Our group had previously shown that mixing phosphine gold(I) complexes with BINOL-derived phosphates leads to the formation of neutral gold(I) complexes bearing an anionic phosphate ligand, which are not catalytically active.[6] A JohnPhos-type phosphine was selected to support the gold(I) center, and the meta- and para-positions of the distal ring were functionalized with(thio)ureas and squaramides as “anchor” for the chiral anion. The H-bond donor was envisioned to perform two roles: abstract the halide from the P–Au–Cl, thus allowing substrate coordination, and to anchor the chiral anion close to the substrate to deliver the stereochemical information during the folding process.

Scheme 12 Concept of hydrogen-bonded counterion-directed enantioselective gold(I) catalysis 36 and achiral phosphinourea gold(I) complex 37, chiral silver salt 38, and applications of H-bonded asymmetric-counteranion directed catalysis (ACDC) in gold(I) catalysis.

The use of a two-component catalytic system was as well advantageous because of the flexibility to quickly tune these two components via high-throughput screening methods. The H-bonded asymmetric-counteranion directed catalysis (ACDC) approach was first validated in the cycloisomerization of 1,6-arylenynes 10, a well-established gold(I)-catalyzed reaction to benchmark enantioinduction. Different silver salts were tested in combination with phosphinourea gold(I) complexes, resulting in the identification of N-triflyl phosphoramidate salts as the best performer in terms of reactivity and enantioselectivity and 37 as the optimal phosphino urea gold(I) complex ([Scheme 12]). The enantioselectivities obtained were also highly dependent on the substitution at the 3,3′-position of the BINOL skeleton, whereas substitution at phosphorus regulated the coordinating ability and reactivity. After solvent evaluation and fine-tuning of the catalytic system, the substrate scope of the formal [4+2] cycloaddition of 1,6-enynes was explored using 37 and 38, which delivered the highest yield and enantioselectivities. 1,6-Enynes with different tethers and substitutions were cyclized to give the tricyclic products 11 with high enantioselectivities and yields, demonstrating a broad scope across the substrate set. Furthermore, the standard [4+2] cycloaddition reaction with enynes 10 could be conducted on a 2-mmol scale using only 1 mol% of 37/38 ([Scheme 12]).

The enantioselective 6-endo-dig cyclization/nucleophilic addition of 14 and the cycloisomerization of 39 could also be performed in good yields and high enantioselectivities ([Scheme 12]). Similarly, the tandem cyclization of 41 and addition indoles 42 gave adducts 41 in moderate-to-good enantioselectivities.[19] Mechanistic investigations involving ¹H NMR experiments, structure–activity studies of both components, and kinetic analysis supported the relevant role of H-bonding interactions and the need of precise positioning of the chiral anion to achieve high enantioselectivity in this new approach. The breadth of the scope across different 1,6-enynes and consistent high enantiomeric ratios of this supramolecular chiral ligand system provide a new platform to develop challenging enantioselective metal-catalyzed transformations.

This approach was later expanded to the enantioselective gold(I) tandem cycloisomerization/nucleophile addition to 2-alkynyl enones 41 using H-bonded counterion-directed catalysis with a simpler gold(I) complex 44 bearing a squaramide ([Scheme 13]).[20] Other gold(I) complexes equipped with different H-donor donors were also studied. In comparison with the use of JohnPhos-type phosphino urea ligand, the scaffold of 44 presents higher flexibility to accommodate chiral anions. Initial studies gave bicyclic furans 45 in moderate yields when using the phosphino squaramide gold(I) complexes. High-throughput experimentation (HTE) was performed to evaluate combinations of seven chiral anions with seven achiral gold(I) complexes. The best results were obtained with a combination of 44 and (R)-38 in toluene at low temperature. The scope of the tandem cycloisomerization/nucleophile addition was assessed using 1 mol% loading of 44/(R)-38. Different variations on the indole, the enone substituents, as well as the use of diverse C-, N-, and O-based nucleophiles could be used to form corresponding tetrahydrobenzofurans 45 in excellent yields and enantiomeric ratios. Distinct modes of action were identified in the combinatorial screening, pointing at the versatility of H-bonded, counterion-directed catalysis to switch enantiofacial selectivity.

Scheme 13 Expansion of H-bonded counterion directed catalysis to tandem cyclization/nucleophile addition reaction.

An evolution of the H-bonded ACDC concept combined chiral gold(I) complexes and chiral counterions, which allowed us to examine a match/mismatch situation.[21] A new library of gold(I) complexes inspired by chiral BINOL-based phosphites 2 (see [Scheme 1]) was prepared with diverse urea units at the para-, meta-, and ortho-positions with respect to the phenol fragment. In parallel, achiral phosphite cavitands with urea groups at the aryl of the phosphonite were prepared. Then, combinations of gold(I) complexes 46 and 47 with different chiral silver salts were tested using HTE in different cyclizations. The most promising results were obtained for the cyclization/nucleophile addition of 1,6-enynes 49 ([Scheme 14]). As expected, a match/mismatch scenario was observed when using the (R) and (S) enantiomers of the chiral silver salts. For the BINOL-based phosphite gold complexes, the best results were achieved with the match pair (R)-46 and (R)-48, while in the case of phosphonite-based cavitands, 47 and (R)-48 afforded the best results ([Scheme 14]). The scope of the tandem cycloisomerization/nucleophile addition was examined with (R)-46 and (R)-48 at 2 mol% in either 1,4-dioxane at 27 °C or toluene (−10, 0 and 27 °C). It is interesting to note that chiral silver salt (R)-48 provided the best counterion for both phosphitourea 46 and cavitand gold(I) 47 complexes.

Scheme 14 Hydrogen-bonded matched ion pair gold(i) catalysis and enantioselective cyclization/nucleophile addition to 1,6-enynes.

Products 50 were consistently obtained with high levels of enantioselectivity across a broad set of 1,6-enynes and C-, N-, and O- nucleophiles, highlighting the robustness of this catalytic system.[21] NCI plots of the two possible transition states allowed the visualization of H-bond interactions between the H-bond donor and the phosphoramidate group, holding the two components together. Similarly, diverse attractive π–π stacking interactions between the aryl alkene of the substrate and the anthracenyl group of the chiral counterion were observed, which helped stabilizing the transition state. The catalytic system was also investigated in the formal [4+2] cycloaddition of 1,6-enynes 10 bearing internal alkynes and resulted in poor yields and moderate enantioselectivities. The small size of the chiral pocket generated by the ion pair may be behind the ineffectiveness of this approach with internal alkynes.

 

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Concluding Remarks

The challenges imposed by the linear coordination that gold(I) complexes tend to adopt have given rise to creative ligand designs specifically tailored to achieve high enantioselectivity levels in reactions involving alkynes. Since our very first work on the enantioselective alkoxycyclization with di-nuclear complexes,[7] our laboratory has introduced chiral gold(I) catalysts with novel ligands based on one-point binding P-ligands, phosphines, and phosphites in most cases, to which various chiral elements such as atropoisomeric backbones, chiral 2,5-diaryl pyrrolidines, and chiral planar ferrocenes were introduced or used as templates. The variety of ligand scaffolds evolved from well-known BINOL-based phosphites and JohnPhos-type phosphines to unprecedented ferrocenyl ligands and bifunctional ligands. Likewise, our group has pioneered supramolecular approaches toward enantioselective gold(I) catalysis consisting of chiral phosphoramidites within resorcene[4]arene cavitands and H-bonded counterion-directed catalysis. This latter approach, in principle, seemed challenging because of the two-component nature of the systems and the delicate balance required among H-bonding, reactivity, and NCIs; however, it represents our most successful strategy toward enantioselective gold(I) catalysis. Lastly, the use of the recently introduced NEST analysis to evaluate the steric properties of linearly coordinated gold(I) complexes, along with well-established DFT methods, has greatly contributed to the design and development of novel electrophilic catalysts for the chiral folding of unsaturated substrates.

 

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Pablo Mora

Pablo Mora was born in Yecla (Murcia, Spain). After a one-year stay as an Erasmus student at The Robert Gordon University (Aberdeen, UK) and one semester at the University of North Carolina at Greensboro (USA), he obtained his degree in Pharmacy at Universidad de Granada (Spain) in 2020. After 6 months as intern at Syngenta (Switzerland), he joined the research group of Prof. Echavarren at the Institute of Chemical Research of Catalonia (Tarragona, Spain) where he obtained his PhD (2025) working on the design of new chiral gold(I) complexes and their application in catalysis.

Imma Escofet

Imma Escofet was born in La Granada, in the Alt Penedès region of Catalonia (Barcelona, Spain). She studied chemistry at the University of Barcelona (UB) and did her bachelor’s thesis at the University of Aberdeen (Scotland, UK) under the supervision of Prof. Laurent Trembleau (2010). Then, she joined the research group of Prof. Antonio M. Echavarren at the Institute of Chemical Research of Catalonia (ICIQ) in Tarragona, as a laboratory engineer where she also completed her PhD studies (2020) working on computational mechanistic studies of gold(I) catalysis and design of new chiral ligands. In 2022, she was promoted as Scientific Group Coordinator in Prof. Echavarren’s research group at ICIQ.

Prof. Dr Antonio M. Echavarren

Prof. Dr Antonio M. Echavarren was born in Bilbao (Spain). He received his PhD at the Universidad Autónoma de Madrid (UAM, 1982). After a postdoctoral stay in Boston College and Colorado State University, he joined the Institute of Organic Chemistry of the CSIC in Madrid. In 1992, he returned to the UAM as a Professor of Organic Chemistry and, in 2004, he moved to Tarragona as a Group Leader at the Institute of Chemical Research of Catalonia (ICIQ). In 2013, he got an ERC adv. grant to develop gold catalysis and, in 2019, a second ERC adv. grant to develop new catalysts for the biomimetic cyclization of unsaturated substrates. He received the 2004 Janssen-Cylag Award in organic chemistry and the 2010 Medal of the Royal Spanish Chemical Society and an Arthur C. Cope Scholar Award from the ACS. He is the President of the Spanish Royal Society of Chemistry (RSEQ).

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgment

We would like to thank all group members who contributed to the design of ligands and worked on their application in asymmetric gold(I) catalysis. We are also grateful to those who carried out early work on the discovery of new gold(I)-catalyzed cyclizations of 1,n-enynes for enlightening us of their mechanisms.

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Publikationsverlauf

Eingereicht: 11. Mai 2025

Angenommen nach Revision: 03. Juli 2025

Accepted Manuscript online:
07. Juli 2025

Artikel online veröffentlicht:
20. August 2025