Hydrogen-Bonded Matched Ion Pair Gold(I) Catalysis

Abstract

The enantioselective reaction of 1,6-enynes with O-, N-, and C-nucleophiles has been developed by matched ion pair gold(I) catalysis in which the chiral gold(I) cation and anion are H-bonded through a urea group. Very high levels of enantiocontrol are achieved (up to >99:1 er) for a broad scope of substrates. DFT studies demonstrate the importance of the H-bond donor group in anchoring the matched chiral cation- and anion-favoring additional noncovalent interactions.

Although the field of gold(I) catalysis has experienced an exponential growth in past decades,¹⁻⁹ the development of enantioselective transformations with broader scope has been more difficult.¹⁰⁻¹³ After the pioneering work by Toste et al. on gold asymmetric counterion-directed catalysis (ACDC) for the enantioselective cyclization of allenes using chiral phosphate salts in combination with achiral digold complexes (Figure 1),¹⁴⁻¹⁷ the use of that concept has been used for the activation of alkyne¹⁸⁻²² or allene-containing substrates²³⁻²⁷ to circumvent some of the limitations in enantioselective gold(I) catalysis.²⁸⁻³⁰

Figure 1.

Gold(I) in the ACDC and HCDC strategies.

Our group recently introduced H-bonded counterion-directed catalysis (HCDC) (Figure 1) using achiral gold catalysts containing urea or squaramide H-bond donor motifs.^31,32 In this approach, the H-bond donor facilitates the ligand-substrate exchange step and fixes the chiral information close to the reaction center, thereby allowing for an efficient transfer of the stereochemical information in cyclization reactions.³³⁻³⁶

Herein, we present the application of the HCDC approach with chiral binol-based phosphite gold(I) complexes³⁷ equipped with urea groups together with matched chiral counterions for the enantioselective gold(I)-catalyzed nucleophilic addition to 1,6-enynes, which takes place with excellent enantioselectivities.

A library of phosphite gold(I) complexes carrying a urea was easily prepared in a one-pot, two-step procedure starting from chiral (R)-binaphthols with the desired 3,3′-substitution pattern or from achiral resorcinol [4]arenes (Figure 2). Additionally, chiral silver salts were prepared from commercially available chiral BINOLs and related biphenols (Figure 2). Urea groups in the para-, meta-, or ortho-position with respect to the phosphite were introduced to test the directing effect of the H-bond donor. We envisioned that chiral phosphoramidate silver salts would form more reactive catalysts since they are less basic than their corresponding phosphoric acid counterparts and, therefore, more easily substituted by the unsaturated substrates from the gold(I) coordination sphere.³¹

Figure 2.

Library of chiral gold(I) complexes and Ag(I) salts. ^aCYLview representations are for X-ray crystallography structures of Au4 and Au11. Solvent molecules are omitted for clarity. Au4 forms dimers in the solid state. Color code: P, orange; Au, yellow; Cl, green; O, red; N, blue; C, gray; and H, white. anthr = anthracenyl, phenant = phenantracenyl.

Our system proved to be particularly efficient in the addition of nucleophiles to 1,6-enynes.³⁸⁻⁵² We first examined, using high-throughput experimentation (HTE), the addition of indole to 1a(40,41) with different chiral gold(I) complexes and silver(I) salts.⁵³ The best combinations were then scaled up to 0.05 mmol (Table 1). Gold(I) complexes with the urea in the para-position showed much higher reactivity than those with ureas at ortho or meta. Substituents in the 3,3′-position of the BINOL scaffolds in both the Au(I) catalyst and Ag salt also had an important impact. Through the use of toluene as solvent, a clear match-missmatch scenario was observed using (R)-Au4 with the (R)- or (S)-enantiomers of Ag6, which led to 1a with 95:5 er and 61.5:38.5 er, respectively (Table 1, entries 4 and 7). This observation was also present in other examples. For example, EtOH was used as a nucleophile with (R)-Au1 or (R)-Au4 in combination with the (R)- or (S)-enantiomers of the same Ag salt (Table 1, entries 8–11). Better yields and enantioselectivities were obtained in 1,4-dioxane. Thus, the combination of (R)-Au4 with the (R)-enantiomers of Ag1, Ag6, or Ag8 provided 1a in >99:1, 97.5:2.5, and 95:5 er, respectively (Table 1, entries 13–15). Control experiments showed that neither (R)-Au4 nor (R)-Ag1 was active on its own (Table 1, entries 17 and 18). Whereas cavitand Au9,⁵² equipped with para-urea groups, gives satisfactory results with (R)-Ag6 (Table 1, entry 16), achiral Au(I) complex Au12, which was found to be the optimal for the intramolecular formal [4 + 2] cycloaddition of arylalkynes with alkenes,³¹ together with (R)-Ag1, showed poor reactivity and low enantioinduction in the formation of 2a (Table 1, entry 19). Silver salt AgSbF₆ in combination with (R)-Au4 (Table 1, entry 20) gave lower yields and enantioselectivities than those observed with the dual-matched chiral system.⁵³

Table 1. Enantioselective Gold(I)-Catalyzed Addition of Indole to 1,6-Enyne 1a^a.

entry	[Au]	[Ag]	NuH	time (h)	yield (%)b	erc
1	Au1	(R)-Ag6	Indd	44	61	78:22
2	Au2	(R)-Ag6	Indd	44	69	54:46
3	Au3	(R)-Ag6	Indd	44	6	50:50
4	Au4	(R)-Ag6	Indd	44	82	95:5
5	Au5	(R)-Ag6	Indd	44	74	60:40
6	Au6	(R)-Ag6	Indd	44	39	54:46
7	Au4	(S)-Ag6	Indd	44	61	61.5:38.5
8	Au4	(R)-Ag6	EtOHd	14	87	98:2
9	Au4	(S)-Ag6	EtOHd	14	85	57:43
10	Au1	(R)-Ag6	EtOHd	14	67	91:9
11	Au1	(S)-Ag6	EtOHd	14	53	47:53
12	Au1	(R)-Ag1	Inde	14	82	91:9
13	Au4	(R)-Ag1	Inde	14	93	>99:1
14	Au4	(R)-Ag6	Inde	14	98	97.5:2.5
15	Au4	(R)-Ag8	Inde	14	90	95:5
16	Au9	(R)-Ag6	Inde	18	78	94:6
17	Au4		Inde	24	0
18		(R)-Ag1	Inde	24	0
19	Au12	(R)-Ag1	Inde	24	18	52:48
20	Au4	AgSbF6	Inde	24	76	92.5:7.5

^aReactions carried out under Ar or N₂ at a 0.05 mmol scale, at 27 °C with (R)-configured Au(I) complexes.

^bYields determined by ¹H NMR using dodecane as internal standard.

^cer determined by supercritical fluid chromatography (SFC) using a chiral stationary phase.

^dToluene (0.1 M) was used as solvent.

^e1,4-dioxane (0.1 M) was used as solvent. NuH = nucleophile. Ind = Indole.

It is interesting that, whereas in our system the matched pair is achieved with (R)-Au cation and (R)-phosphoramidate anion, in systems based on two BINOL-based cation/anion ion pairs, the matched catalyst resulted from the (R)/(S) ion combination.^17,24,26

We examined the scope of the reaction using the optimal combination (R)-Au4 and (R)-Ag1 (Scheme 1). The reactions of 1,6-enyne 1a were performed at 2 mol% catalyst loading in a 0.100 mmol scale, and two conditions were used depending on the nature of the nucleophile and the reactivity of the enyne: conditions A using 1,4-dioxane at 27 °C or conditions B using toluene at 27, 0, or −10 °C. Substituents in the 1, 2, and 5-positions of indole were well tolerated to give adducts 2b–e. Electron-rich arenes, such as 1,3,5-trimethoxybenzne, 1,3-dimethoxybenzene, and N,N-dimethylaniline, led to 2f–h in excellent yields and enantioselectivities. Similarly, excellent results were also obtained with heteroatom-centered nucleophiles, such as anilines; a carbamate; alcohols; and water to give 2i–r in excellent yields and enantioselectivities.

Scheme 1. Enantioselective Addition of O-, N-, and C-Nucleophiles to 1,6-Enynes.

Reaction performed under Ar or N₂ in anhydrous solvent (0.1 M). Yields given for isolated material after purification; er values were determined by HPLC or SFC on chiral stationary phase. Products were obtained as single diastereomers. Reaction times are in parentheses.

1,3-Cyclohexandione (2.0 equiv) was used as nucleophile.

Reaction carried out using (R)-Au7 and (R)-Ag5 at a 3 mol% catalyst loading.

Diphenylsulfoxide (1.5 equiv) was used as nucleophile.

1,6-Enynes with different substitutions at the alkene also gave the corresponding adducts 2t–ad in good to excellent yields and high enantioselectivities, except for those with a para- or ortho-anisyl group, which gave 2w and 2z in 87:13 and 93:7 er (Scheme 1). The absolute configurations of 2v and 2ai were determined to be the (S,S) and (R,S) by X-ray diffraction.⁵⁴ Changing the malonate to a dimethyl ether tether favored the formation of the cycloisomerization product, thereby leading to 2ae in moderate yield. However, increasing the size of the ester from methyl to isopropyl reduced the enantioselectivity to a 93:7 er in 2af, which suggests that the tether plays an important role in the folding of the 1,6-enyne in the chiral pocket of the catalyst.

Changing the malonate tether in the 1,6-enyne to a N-tosyl led to a decrease in the enantioselectivity, which provided 2ag in 78:22 er. (Scheme 1) However, using (R)-Au7 together with (R)-Ag5 gave adducts 2ag and 2ah, as well as aldehyde 2ai, which resulted from the oxidation of the gold(I) carbene intermediate with diphenylsulfoxide,⁵⁵ in 98:2 to >99:1 er.

To further demonstrate the utility of this enantioselective addition of nucleophiles to 1,6-enynes, selected transformations into more complex products were performed (Scheme 2). Thus, the ring-closing metathesis of 2r with the second generation Grubbs catalyst⁵⁶ gave bicyclic derivative 3a with no erosion on the enantioselectivity. The ortho-iodoaniline addition product 2k underwent an intramolecular Heck reaction with the concomitant formation of a new stereocenter to afford 2,3,3a,9b-tetrahydro-1H-cyclopenta[c]quinoline 3b.⁵⁰ Finally, the allylic position in pyrrolidine 2ah was oxidized with NaClO₂ and N-hydroxyphthalimide to give lactam 3c with 98.5:1.5 er.

Scheme 2. Product Derivatization.

DFT studies were conducted [B3LYP-D3/6-31G(d) (C, H, P, O, F, N, S)//B3LYP-D3/6-311G(d,p) and SDD (Au), PCM = toluene]⁵⁷ to gain insight into the role of the urea and the possible secondary interactions involved in the enantioselective cyclization step using chiral (R)-Au4 and chiral counterion from (R)-Ag6, which provided 2a in 95:5 er.

Our computations predicted a Curtin–Hammett scenario (Scheme 3a), where the two orientations of the alkenes (int1a and int3a) are in equilibrium. Although int3a is 4.9 kcal/mol more stable than int1a, the major product arises from the latter via TS_int1a-2a, which is lower in energy than TS_int3a-4a, thereby giving rise to product 2a with an S configuration by reaction through the Re face of the alkene, which agrees with the experimental results.

Scheme 3. DFT Calculations for the Enantiodetermining Step.

Two most relevant pathways for the enantiodetermining cyclization step of 1a with (R)-Au4 and (R)-Ag6. NCI plots and CYLview representations for TS_int1a-2a and TS_int3a-4a. Hydrogens are omitted for clarity, except relevant ones. Strong attractive interactions are blue, weak attractive interactions are green, and strong repulsive interactions are red. Color code: P, orange; Au, yellow; F, cyan; O, red; N, blue; S, purple; C, gray; and H, white. Energy values are in kcal/mol. HB = hydrogen bond.

Noncovalent interaction (NCI) plots were performed to visualize the noncovalent interactions in the two possible transition states (Scheme 3b,c) which revealed that the H-bond interactions from the urea and phosphoramidate group act as anchors of the two parts and favor the additional interactions that stabilize the transition state TS_int1a-2a. Apart from the strong H-bonding interactions, T-shaped-π interactions between the ortho-C–H of the N-phenyl urea and the π-system of the BINOL counterion were observed. A strong extended attractive sandwich π–π interaction between the π-system of the cinnamyl alkene of the substrate and one anthracenyl group of the chiral counterion were observed in TS_int1a-2a. However, for TS_int3a-4a, a T-shaped π-attractive interaction was found between the C–H in para position to the alkene in the aryl ring of the substrate and the anthracene of the counterion, which helped to stabilize the transition state.

Finally, other reactions were tested by combining BINOL-derived gold(I) catalysts and different silver(I) salts as chloride scavengers, but the optimal ion pair combination could not be found. We discovered that 1,6-enynes bearing internal aryl-substituted alkynes led to formal products of [4 + 2] cycloaddition³¹ with poor yields and moderate enantioselectivities, most likely because of the small pocket generated by the ion pair. However, when using chiral gold(I) complexes and small achiral counterions, such as AgSbF₆, promising enantioselectivities were found (95:5 er). We also tested the [2 + 2] cycloaddition of phenylacetylene with alkenes,⁵⁸ but no promising combination was observed.

In summary, we have developed the enantioselective nucleophilic addition of hetero- and carbonucleophiles that proceeds with the broadest scope and highest enantioselectivity using a chiral catalyst with a chirally matched gold(I) phosphitourea and phosphoramidate, which can be readily prepared from commercially available BINOLs. A model for the enantioinduction has been proposed on the basis of DFT calculations and NCI plots where the urea in the chiral gold(I) cation anchors the chiral counterion in close proximity creating a chiral pocket to fold the unsaturated substrate.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscatal.3c02638.

• Optimization tables, procedures, characterization, NMR spectra, SFC and HPLC traces, DFT computations, and crystallographic data (PDF)

Accession Codes

CCDC 2266405–2266408 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.

The authors declare no competing financial interest.