Catalytic asymmetric Nakamura reaction by gold(I)/chiral N,Nʹ-dioxide-indium(III) or nickel(II) synergistic catalysis

Intermolecular addition of enols and enolates to unactivated alkynes was proved to be a simple and powerful method for carbon-carbon bond formation. Up to date, a catalytic asymmetric version of alkyne with 1,3-dicarbonyl compound has not been realized. Herein, we achieve the catalytic asymmetric intermolecular addition of 1,3-dicarbonyl compounds to unactivated 1-alkynes attributing to the synergistic activation of chiral N,N′-dioxide-indium(III) or nickel(II) Lewis acid and achiral gold(I) π-acid. A range of β-ketoamides, β-ketoesters and 1,3-diketones transform to the corresponding products with a tetra-substituted chiral center in good yields with good e.r. values. Besides, a possible catalytic cycle and a transition state model are proposed to illustrate the reaction process and the origin of chiral induction based on the experimental investigations.

Therefore, developing an efficient catalytic system to realize the asymmetric version of the Nakamura reaction is challenging but highly desirable.
Bimetallic catalysis is also promising in asymmetric catalysis [44][45][46] . However, one of the perceived challenges is that two distinct metals might competitively coordinate with the ligand, as well as potentially affect each other's catalytic cycles. Recently, chiral N,Nʹ-dioxides/hard Lewis acid complexes developed by our group were found to be good partners with soft metals [47][48][49][50][51] in relay catalysis systems. We envisioned that N,Nʹ-dioxide/Lewis acid complex could also be applied to synergistic catalyst system.
In this work, we developed a gold(I)/chiral N,N'-dioxideindium(III) or nickel(II) synergistic catalyst system to realize the catalyic asymmetric Nakamura reaction of unactivated 1-alkynes with β-ketoamides, β-ketoesters, and 1,3-diketones in good reactivity and enantioselectivity. Mechanism study elucidates the process of the reaction and origin of chiral induction.

Results
Optimization of the reaction conditions. Indanone-derived βketoamide 1a and phenylacetylene 2a were selected as the model substrates to conduct our research. First, several cooperative catalytic systems, which showed good ability in catalytic enantioselective Conia-ene reaction, including Pd(II)/Yb(III) dual catalyst system, Zn(II)/Yb(III) catalyst system, and amine-silver system, were investigated 13,16,19 . But all of them gave only trace amount of product without enantioselectivities even rising the reaction temperature to 70°C (Table 1, entries 1-3). Then chiral N,N'-dioxide ligand-metal complexes were chosen as the activators of ketoamides, in connection with AuCl•PPh 3 /AgOTf for the activation of 1-alkyne. First, Sc(OTf) 3 was used to coordinate with chiral N,N'-dioxide L-PiEt 2 to promote the reaction under air atmosphere, the byproduct 3bb was obtained as the main product along with the desired product 3aa in 11% yield with 60:40 e.r. (entry 4). Further research showed that the reaction could possess efficiency in an absolute anaerobic condition, delivering the product 3aa in 92% yield with 60:40 e.r. (entry 5). Then Ga(OTf) 3 that showed efficient catalytic activity in Shi's report 41 was used to coordinate with chiral N,N'-dioxide L-PiEt 2 to promote the reaction; however, only trace of product 3aa was obtained (entry 6). To our delight, In(OTf) 3 could improve the reaction activity greatly and deliver the desired product with 62:38 e.r. (entry 7). The ligand L-TQ-(S)-EPh derived from S-tetrahydroisoquinoline acid decreased the e.r. greatly (entry 8). To improve the enantioselectivity, other conditions were carefully studied. Changing the N,N'-dioxide ligand to L-PiEt 2 Me, which has ethyl groups at ortho-positions and methyl group at para-position of aniline, the yield could be improved to 99% (entry 9). Moreover, the addition of trace amount of H 2 O (entry 10) and increasing the amount of ligand L-PiEt 2 Me (entry 11) improved the enantioselectivity. The water might be beneficial for formation of the effective catalyst species, as well as beneficial for accelerating the enolization of 1,3dicarbonyl compounds 52 . Meanwhile, the increasement of ligand might be helpful for the complete coordination with In(OTf) 3 , avoiding the strong background reaction caused by free metal salt. Further exploration showed that the solvent had a great influence on the reaction, when para-xylene was used as the solvent, the desired product was isolated in 98% yield with 90:10 e.r. (entry 12). The enantioselectivity enhanced into 94.5:5.5 e.r. after the concentration of 1a reduced to 0.067 mol/L by enhancing the amount of solvent (entry 13). The steric hindrance of the ligands on [Au] catalyst was another key factor. Changing the AuCl·PPh 3 into more sterically hindered XPhosAu(TA)OTf, only trace product could be obtained (entry 14). The reason might be that the bulky X-Phos cause larger steric hindrance between the [Au]-activated 1-alkyne and the chiral Lewis acid-activated 1,3dicarboyl compound, making the reaction happen more difficultly. In comparison, other indium catalysts of the typical chiral Fig. 1 The catalytic asymmetric addition of 1,3-dicarbonyl compounds to alkynes. a Catalytic asymmetric Conia-ene reaction. b Development of Nakamura reaction. c Our strategies for the catalytic asymmetric Nakamura reaction. ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-23105-z ligands such as Pybox L3, Box L2, or CPA organocatalyst were used, the product 3aa was obtained in low yield with poor e.r. value (entries [15][16][17]. Substrate scope of the reaction about β-ketoamides. With the optimized reaction conditions in hand (Table 1, entry 13), the substrate scope was then evaluated (Fig. 2). A variety of ketoamides 1 derived from 1-indanones with different substituents were tested. Substrates with electron-donating groups exhibited excellent yields and enantioselectivities (3ba-3ea) at 50°C. Substrate 1f bearing an electron-withdrawing group transformed to the desired product 3fa in 98% yield with 85:15 e.r. at higher temperature (60°C). With respect to 1-alkynes 2, when the substituents at the aromatic ring of the phenylacetylenes varied, both steric hindrance and electronic properties had little effect on the reaction (3ab-3ai). However, substrate 1,4-diethynylbenzene 2j just delivered the product 3aj in moderate yield with excellent enantioselectivity. It might be caused by the competitive coordination of the alkyne-bearing product with AuOTf•PPh 3 . The thienyl-substituted alkynes (2k and 2l) were also suitable. Various aliphatic 1-alkynes (2m-2q) could also transform to the desired products in good enantioselectivities (3am-3aq); however, the yield was generally moderate. One reason is that an unidentified product generated that might be caused by In(III)-induced olefin isomerization 41 . Importantly, the methodology was applicable to the alkyl-alkyne derived from saccharide 2r. Next, ring structure of ketoamides was studied. The substrate 1h derived from 1-tetralone got good results (3ha-3hm), while 1i derived from 1-benzosuberone gave much lower yield and e.r.. It might be caused by steric hindrance between methylene of substrate 1i with AuOTf•PPh 3 -activated 2a. Meanwhile, aliphatic substrate 1j Table 1 Optimization of the reaction conditions.
Effect of N-protecting group. Other easily removable N-protecting groups such as N-benzyl or N-PMP were investigated by reacting with phenylacetylene ( Table 2). The desired products 3ka and 3la were obtained in excellent yields but with only 56.5:43.5 e. r. and 72.5:27.5 e.r. under standard conditions. After changing the ligand to L-TQ-(S)-EPh derived from (S)-tetrahydroisoquinoline-3-carbonyl acid and (S)-phenylethanamine, adjusting the reaction temperature and solvent, the enantioselectivities were improved sharply to 90:10 e.r. and 89:11 e.r., respectively. The possible reason might be that the N-protecting group, amide moiety and backbones of the catalyst are included in discrimination of Reand Si-face of the 1,3-dicarbonyl compounds. With L-PiEt 2 Me as ligand, the bulky N-tertbutylamide moiety could help to shield the Si-face of substrate 1a efficiently. On the contrary, the Nbenzyl or PMP with smaller steric hindrance showed poor ability to shield the Si-face of the 1,3-dicarbonyl compounds, causing the e.r. values of the products decreased sharply in the L-PiEt 2 Me/In (III) system. Changing to the L-TQ-(S)-EPh/In(III) system, the steric hindrance of amide moiety and backbones of the catalyst increased, and the Si-face of the 1,3-dicarbonyl compounds could also shield better; therefore, the e.r. values of products increased.  Fig. 2 Substrate scope of the reaction about β-ketoamides. Unless otherwise noted, all reactions were carried out, AuCl•PPh 3 /AgOTf (1:1, 5 mol%), In (OTf) 3 /L-PiEt 2 Me (1:1.2, 10 mol%), 1 (0.10 mmol) and 2 (2.0 equiv), H 2 O (2 μL) as additive in p-xylene (1.5 mL) at 50-70°C for 24-120 h. Isolated yields. The e.r. values were determined by HPLC analysis on chiral column. a L-PiEt 2 was used as ligand. b 3.0 equiv of 2 was used. c L-PiMe 3 was used as ligand.
system, the desired product was obtained in only 10% yield with 58.5:41.5 e.r.. After extensive investigation, including use of Ni (OTf) 2 /L-PiMe 2 as catalyst and prolonging the reaction time, the corresponding product 5aa could be obtained in 47% yield with 97.5:2.5 e.r.. The decomposition of substrate 4a is responsible for the moderate yield. More stable 4b with a smaller steric hindrance of ester protecting group could transform to the desired 5ba in 72% yield with 93.5:6.5 e.r.. Different ketoesters 4 derived from 1indanones bearing electron-donating group or withdrawing group tolerated well. Moreover, both aliphtic alkynes and aromatic alkynes were suitable in the reaction. The yields were generally good except product 5bc. The possible reason might be that the electron-withdrawing effect of the fluorine weakened the interaction between gold catalyst and alkyne (Fig. 3).
Substrate scope limitation. For acyclic β-ketoamide 8a, which without other substituent on α-position, transformed to thermodynamically stable achiral α,β-conjugated carbonyl product 9aa through olefin isomerization (Fig. 4). When acyclic βketoamides 8b-8i bearing methyl, phenyl, benzyl, or chlorine group on the α-position were used as the nucleophiles, the corresponding products could not be observed. The possible reason might be that the α-substitution on the 1,3-dicarbonyl compounds increased the steric hindrance when the two activated substrates participate in the reaction.
Substrate scope of α-fluoro substituted acyclic β-ketoamides. Therefore, α-fluoro substituted 8j with smaller steric hindrance and stronger acidity of α-proton was evaluated (Fig. 5). Moderate yields with good e.r. could be obtained after adjusting the ligand to L-PiEt 2 , increasing the reaction temperature and prolonging the reaction time. Electron-donating or electron-withdrawing substitutes on the para-position of phenyl ring were tolerated well. Generally, the 1-alkynes 2 with an electron-donating substituent led to better yields than the ones with electronwithdrawing substituents. Compared with the phenylacetylene, the more electron-rich aromatic alkynes like 2l and 2s showed better reactivities (9jl and 9js). When aliphatic 1-alkynes 2m and 2n were applied to the reaction, the products were delivered in moderate yields with good e.r. values.
Mechanism investigation. Next, the reaction mechanism was investigated ( Fig. 6). Some control experiments were carried out (Fig. 6a). In the absence of AuCl•PPh 3 /AgOTf or In(OTf) 3 /L-PiEt 2 Me, only trace amount of the product 3aa was detected, which indicates that the two catalysts work cooperatively. N,Nʹdioxide/In(OTf) 3 crystal structure obtained in our previous study 49 showed that a OH-bridged dinuclear indium complex forms in the presence of H 2 O, in which N,Nʹ-dioxide coordinates to In(III) in a tetradentate manner. Nevertheless, the investigation of relationship between the e.e. value of L-PiEt 2 Me and that of 3aa showed a clear linear effect (Fig. 6b), implying that the active catalytic species is likely to be the mixture of In(OTf) 3 and L-PiEt 2 Me in a 1:1 ratio. The OH anion generated from the water in situ preparation of the chiral indium catalyst might act as a base to accelerate the enolization of 1,3-dicarbonyl compounds. In addition, the M + peak (found: 561.1058), which corresponded to a 1:1 complex C of [Au·PPh 3 ] + and phenylacetylene 2a, was detected by ESI-TOF analysis in the positive-ion mode. The mixture of L-PiEt 2 Me, In(OTf) 3 , and 1a (1:1:1) in p-xylene displaying an ion at m/z 1114.4025 ([L-PiEt 2 Me+In 3+ +OTf − +1a-H + ] m/z calcd 1114.4036) suggested that enolized 1a coordinates to the catalyst in a 1:1 molecular ratio (Fig. 6c), which is consistent with our non-linear effect.
Proposed catalytic cycle and transition-state model. Based on the above analysis and previous work, a catalytic cycle with a  center. Subsequent protonation of D gives the desired product 3 and releases the two catalysts.

Discussion
An efficient catalytic asymmetric Nakamura reaction of βketoamides, β-ketoesters, and 1,3-diketones with unactivated 1-alkynes is realized by developing a bimetallic synergistic catalysis. The combination of π-acid gold(I)/chiral N,Nʹ-doxide-indium (III) or nickel(II) complex enables the activation of alkyne and the efficiency and stereoselectivity of nucleophile. The steric hindrance of α-substituent on 1,3-dicarbonyl compounds and hard Lewis acid are found crucial factors for the reactivity of the reaction. In addition, the substituent of 1,3-dicarbonyl compounds, the amide moiety, and backbones of the catalyst are found to affect the enantioselectivity of the reaction greatly. A possible catalytic cycle with a transition-state model was proposed to elucidate the process of the reaction and origin of chiral induction. Further studies on hetero bimetallic synergistic or relay catalysis are underway in our laboratory.

Methods
Typical procedure for cyclic β-ketoamides involved in catalytic asymmetric reaction.     Fig. 7 Proposed catalytic cycle and transition-state model. The in situ formed chiral N,N′-dioxide-indium(III) Lewis acid actives the 1,3-dicarbonyl compounds (intermediate B) and achiral gold(I) π-acid actives the alkyne (intermediate C) synergistically; the two intermediates reacts following subsequent protonation, giving the desired product 3 and releases the two catalysts.