NHC-catalyzed Enantioselective Hetero-[10+2] Annulation


 The higher-order cycloadditions are powerful strategies for construction of polycycles in one step, however an efficient and concise version for asymmetric induce is limited. N-heterocyclic carbenes are widely used organocatalysts for asymmetric synthesis and will be an ideal choice for enantioselective higher-order cycloadditions. Here we report an enantioselective [10+2] annulation between catalytically formed aza-benzofulvene intermediates and trifluoromethyl ketone derivatives. This protocol exhibits a wide scope, high yields and good ee values, reflecting a robust and efficient higher-order cycloaddition. Density functional theory (DFT) calculations provided an accurate prediction of the reaction enantioselectivity, and in-depth insight to the origins of stereocontrol.

In brief, NHC-catalyzed cycloadditions ranged from [2+2] to [8+2] have been extensively investigated over the past few years, but there is a remarkable lack of higher order cycloadditions (e.g.
Although the intricately competitive pathways make the reaction-control di cult, these higher-order cycloadditions can provide a direct way to e ciently build polycyclic scaffolds. Herein, we report a hetero- In addition, in medicinal chemistry, the incorporation of "F"-containing fragments normally provides an effective route to enhance the metabolic stability, as well as other chemical or physical properties, of target molecules [64][65][66] . Based on the importance of polycyclic structures and incorporated "F"-containing fragments, the potential of these synthesized molecules in drug discovery is worth our expectation.

Reaction Optimization.
We commenced our studies by investigating the reaction of indole-2-carbaldehyde 1a and 2,2,2tri uoroacetophenone 2a as the model substrates, K 2 CO 3 as the base, DQ as the oxidant, tetrahydrofuran (THF) as the solvent, and the results are brie y summarized in Table 1. When Lphenylalanine-derived triazolium NHC precatalyst A was exploited, the expected cycloadduct 3a was not observed. Replacing mesitylene group with penta uorophenyl group triazolium NHC precatalyst B gave desired product 3a in 40% yield and 0% ee, whereas the use of precatalyst C and D resulted in almost no reaction. To our delight, when indanol-derived triazolium catalyst E was tested, the [10+2] cycloadduct 3a was successfully formed in 61% yield with 35% ee and implies that this highly enantioselective [10+2] annulation can be achieved in the presence of ideal conditions. The catalytic performance could be further improved by changing the X group of precatalyst E from H to NO 2 (entry 6). After evaluating bases and solvents, we found that a combination of PhCO 2 Na as the base and hexane as the solvent gave the product 3a in 80% yield and 88% ee (entry 10). Improvements in yield and enantioselectivity were found when thiourea was used as the additive to form 3a (entry 12, 85% yield, 91% ee). Substrate Scope.
With the optimal catalytic system in hand, we moved our attention to explore the generality of this asymmetric higher order [10+2] annulation. As illustrated in Scheme 2, by reacting with indole-2carbaldehyde 1a, an array of aryl tri uoromethyl ketones 2 were examined rstly. In the reactions to generate the [10+2] cycloadducts 3, yields and enantioselectivities were found to be independent on the electronic properties of the substituents on aryl group in 2 (3b-i). When the heteroaryl tri uoromethyl ketones were reacted with indole-2-carbaldehyde 1a under optimal conditions, an [10+2] annulation was e ciently realized in all cases (3j-n). Reactions attempted using the alkyl tri uoromethyl ketones gave their corresponding [10+2] cycloadducts in good yields with high ee values (3o and 3p). Whereas the alkenyl tri uoromethyl ketone 2q was reacted with 1a, product 3q was also obtained in a good yield (73%) but with a slightly diminished enantioselectivity (72% ee). Switching the uorinated substituent from CF 3 to CF 2 H, ClCF 2 or C 2 F 5 in ketones, synthetic useful yields and high to excellent enantioselectivities were still obtained under current conditions (3r-t).
Next, we turned our focus to investigate the scope of substrate 1. Different substituents and substitution patterns on the indole skeleton were examined comprehensively. Electron-withdrawing substituents such as halo (4a and 4b) units on the phenyl ring of the aldehyde substrates were well tolerated. Electronreleasing groups such as methyl (4c, 4e, 4f and 4g) and methoxyl unit (4d) could also be installed on the indole scaffold of the aldehyde substrates. It is worth to noting that this [10+2] protocol could be extended to a higher order [14+2] cycloaddition, affording their corresponding cycloadducts (4h and 4i) in good enentioselectivities albeit with acceptable but dropped yields under the current standard conditions. The absolute con guration of 3e (CCDC 1961662) was determined by single-crystal X-ray analysis and other products were assigned by analogy.

Postulated Mechanism:
A postulated catalytic mechanism of [10+2] annulation is summarized in Fig. 4 To further reveal the enantioselectivity of this [10+2] annulation, density functional theory (DFT) calculation was performed to study the key step of nucleophilic attack of intermediate II onto tri uoroacetophenone. As shown in Figure 1, two transition states named TS(II-III)R and TS(II-III)S was located, where the reor si-face of tri uoroacetophenone was attacked respectively. The calculated relative free energy of transition state TS(III-IV)R is 5.0 kcal/mol lower than that of TS(II-III)S, which predicts that the generation of R-con guration product 4a is favorable. The calculated result is consistent with experimental observations. The geometry of those two transition states are also given in Figu. 5.
After the absorption of indole reactant onto NHC catalyst, a strong π-π stacking between indolyl moiety and the aryl in NHC catalyst can signi cantly stabilize the deprotonated indolyl moiety. The π-π attraction is clearly shown in calculated noncovalent interaction (NCI) maps (we also carried our kinetic experiment to prove it, please see SI). When the nucleophilic attack occurs, tri uoromethyl of tri uoroacetophenone appears at the more bulky inner side in transition state TS(II-III)R. It is more favorable than the case in transition state TS(II-III)S that phenyl group is set to inner side. The NCI map of transition state TS(II-III)R clearly reveals that the repulsion between phenyl group of tri uoroacetophenone and the NHC catalyst leads to instability of transition state TS(III-IV)S, while this repulsion is absent in transition state TS(II-III)R.

Synthetic transformations and applications:
Our protocol is amenable for large-scale preparation. For example, the use of standard conditions was su cient to produce 4d (1.29 g) in 92% yield and with 90% ee (Fig. 6a). A facile Pd-catalyzed Suzuki coupling of 3d with 4-methoxyphenylboronic acid 5 led to product 6 in a 72% yield and with a remained enantioselectivity (Fig. 6b).