Catalytic asymmetric Nakamura reaction by gold(I)/chiral N,N -dioxide-indium(III) 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 first catalytic asymmetric intermolecular addition of 1,3-dicarbonyl compounds to unactivated 1-alkynes. A range of β-ketoamides with a cyclic all-carbon quaternary center and acyclic quaternary center with a fluorine substituent were synthesized in excellent yields with good enantioselectivities attributing to the synergistic activation of chiral N,N′-dioxide-indium(III) Lewis acid and achiral gold(I) π-acid. Besides, a possible catalytic cycle and transition state models were proposed to illustrate the origin of process based on the experimental investigations.

Bimetallic catalysis is also promising in asymmetric catalysis [43][44][45] . 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,N -dioxides/hard Lewis acid complexes developed by our group were found to be good partners with soft metals [46][47][48][49][50] in relay catalysis systems.
We envisioned that N,N -dioxide/Lewis acid complex could also be applied to synergistic catalyst system. Herein, we report our efforts in developing a gold(I)/chiral N,N'-dioxide-indium(III) synergistic catalyst system to realize the catalyic asymmetric Nakamura reaction.

Results
Indanone-derived b-ketoamide 1a and phenylacetylene 2a were selected as the model substrates to conduct our research. Firstly, 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, 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,  Further exploration showed that the solvent had a great in uence on the reaction, when para-xylene was used as solvent, the desired product was isolated in 98% yield with 90:10 e.r. (entry 11). 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 12). 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 13). In comparison, other indium catalysts of the typical chiral ligands such as Pybox L3, Box L2, or CPA organocatalyst were used, the product 3aa was obtained in extremely low yield with poor enantioselectivity (entries [14][15][16]. With the optimized reaction conditions in hand (Table 1, entry 12), 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 transformed to the desired products in moderate to brilliant yields with good enantioselectivities (3am-3aq). 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-3hl), 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 was also tolerated, affording the product 3ja in moderate yield with good enantioselectivity. The absolute con guration of 3ae was determined to be R by X-ray crystallographic analysis and the absolute con gurations of 3aa-3ac and 3ag-3ah were determined to be R by comparison of the CD spectra with that of 3ae.
For acyclic b-ketoamide 3a, which without other substituent on α-position transformed to thermodynamically stable achiral α,β-conjugated carbonyl product 4aa through ole n isomerization (Fig.  3). When acyclic b-ketoamides 3b-3e which bearing methyl, phenyl, benzyl or chlorine group on the αposition were used as the nucleophiles, the corresponding products could not be observed due to steric hindrance of substituents. Therefore, α-uoro substituted 3f with smaller steric hindrance and stronger acidity of α-proton was evaluted (Fig 4). 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. Electrondonating 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 electron-withdrawing substituents. Compared with the phenylacetylene, the more electron-rich aromatic alkynes like 2l and 2s showed better reactivities (4 and 4fs). When aliphatic 1-alkynes 2m and 2n were applied to the reaction, the products were delivered in moderate yields with good e.r. values.
To evaluate the synthetic potential of the catalytic system, a gram-scale synthesis of the product 3aa was carried out (Fig. 5). Under the optimized conditions, 3.5 mmol of 1a and 7.0 mmol of 2a reacted smoothly, delivering 1.14 g (98% yield) of 3aa without any erosion of the enantioselectivity. The reduction of carbonyl group of 3aa using LiAlH 4 provided secondary alcohol product 5aa in 90% yield with 92:8 d.r. and 94.5:5.5 e.r.. The absolute con guration of the major isomer was con rmed to be (1S, 2R) by X-ray crystal analysis, and the stereo-arrangement at the quaternary carbon center is in consist with that of 3ae. Besides, the epoxidation of 3aa in the presence of m-CPBA afforded the epoxide derivative 6aa in 98% yield with 90:10 d.r. and 94.5:5.5 e.r. (Fig. 5).
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,N -dioxide/In(OTf) 3 crystal structure obtained in our previous study 48 showed that a OH-bridged dinuclear indium complex forms in the presence of H 2 O, in which N,N -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 coordinate to the catalyst in a 1:1 molecular ratio (Fig. 6c), which is consistent with our non-linear effect.
Based on above analysis and previous work, a catalytic cycle with a possible transition state is proposed.
As illustrated in Fig. 7, in In(OTf) 3 /L-PiEt 2 Me cycle, initially, the tetradentate L-PiEt 2 Me coordinates to In III to form a six-coordinate octahedral geometry complex A' and dimer A. When ketoamide 1a was added, the basic anion of the catalytic species accelerates the deprotonation process, and the enol ion of 1a cat 1 activated π-bond of 2a approaches preferably from the Re-face to undergo an energetically favorable C-C bond forming reaction, forming the complex D with R absolute con guration at the newly formed stereogenic center. Subsequent protonation of D gives the desired product 3 and releases the two catalysts.
In summary, we have successfully realized an e cient catalytic asymmetric Nakamura reaction of cyclic and acyclic 1,3-dicarbonyl compounds with unactivated 1-alkynes by developing a bimetallic synergistic catalysis. The combination of π-acid gold(I)/chiral N,N -doxide-indium(III) complex enabled the activation of alkyne and the e ciency and stereoselectivity of nucleophile. Various β-ketoamide derivatives with a cyclic all-carbon quaternary center and acyclic quaternary center with a uorine substituent were obtained in moderate to excellent yields with brilliant enantioselective ratios under mild conditions. 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
Full experimental details and the characterization of compounds can be found in the Supplementary Methods.

Data availability
The X-ray crystallographic coordinates for structures 3ae and 5aa reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 1964558 and 1989114. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. All other data is available from the corresponding author upon reasonable request.