Lewis acid-catalyzed asymmetric reactions of β,γ-unsaturated 2-acyl imidazoles

The investigation of diverse reactivity of β,γ-unsaturated carbonyl compounds is of great value in asymmetric catalytic synthesis. Numerous enantioselective transformations have been well developed with β,γ-unsaturated carbonyl compounds as nucleophiles, however, few example were realized by utilizing them as not only nucleophiles but also electrophiles under a same catalytic system. Here we report a regioselective catalytic asymmetric tandem isomerization/α-Michael addition of β,γ-unsaturated 2-acyl imidazoles in the presence of chiral N,N′-dioxide metal complexes, delivering a broad range of optically pure 1,5-dicarbonyl compounds with two vicinal tertiary carbon stereocenters in up to >99% ee under mild conditions. Meanwhile, stereodivergent synthesis is disclosed to yield all four stereoisomers of products. Control experiments suggest an isomerization process involved in the reaction and give an insight into the role of NEt3. In addition, Mannich reaction and sulfur-Michael addition of β,γ-unsaturated 2-acyl imidazoles proceed smoothly as well under the same catalytic system.


Results
Optimization of the reaction conditions. We began our study by employing β,γ-unsaturated 2-acyl imidazole E-1a as the model substrate to optimize the reaction conditions. Several metal salts coordinated with the N,Nʹ-dioxide ligand L 3 -RaPr 2 (Fig. 2) were evaluated, such as Sc(OTf) 3 , Ni(OTf) 2 , and Mg(OTf) 2 ; however, only trace amount of the self-α/β-addition product 2a was observed, which was generated from α-addition of E-1a with the corresponding α,β-unsaturated 2-acyl imidazole upon C=C isomerization (Table 1, entry 1). Pleasingly, the Y(OTf) 3 /L 3 -RaPr 2 complex was efficient to promote the tandem isomerization/α-Michael addition and provided the corresponding product 2a with 60% yield, 2.2:1 anti:syn ratio, and 96% ee in CH 2 ClCH 2 Cl (entry 2). Lanthanide metal salts La(OTf) 3 and Yb(OTf) 3 could also mediate the reaction but gave lower yields and ee values (entries 3 and 4). The screening of chiral backbones and steric hindrance of the amide moiety on the N,Nʹ-dioxide ligands afforded no better results (for details, see Supplementary Table 1). When toluene was used as solvent instead, the isolated yield of anti-2a was increased to 73% with 5.2:1 dr and 97% ee (entry 5). To our delight, the diastereoselectivity could be improved to 10:1 with addition of NEt 3 (entry 6). Other common chiral ligands such as Box, Pybox, and BINAP were also explored, and 32% yield, 5:1 dr with 60% ee were observed as the best results (for details, see Supplementary Table 3).
Substrate scope in isomerization/sulfur-Michael reaction. Inspired by the isomerization process of β,γ-unsaturated 2-acyl imidazoles into α,β-unsaturated 2-acyl imidazoles, we next enlarged the diverse reactivity of β,γ-unsaturated compounds as the electrophiles under the current catalytic system. However, only a trace amount of desired tandem isomerization/sulfur-Michael addition product 6a was achieved if E-1a reacted with thiophenol 5a. After examination of the reaction conditions (for details, see Supplementary Table 5), Z-1a was used instead, and 6a could be obtained in 89% yield with 90% ee (Fig. 5). The scope of isomerization/sulfur-Michael reaction was investigated next.  Thiolphenols and alkyl-substituted thiols could be converted into the final products (6a-6i) in 39-95% yields with 70-93% ee values. For the Michael acceptors, aryl-and alkyl-substituted β,γunsaturated 2-acyl imidazoles were also tolerated in this reaction, giving 6j-6p in 60-92% yields with 80-92% ee.
Gram-scale synthesis and derivatization of products. To evaluate the synthetic utility of this methodology, a gram-scale synthesis of 2a was conducted. The current reaction could be carried out at 7.0 mmol scale without loss of yield (70%), diastereoselectivity (10:1 dr), and ee value (98%) (Fig. 6a). Furthermore, hydrogenation of 2a in the presence of Pd/C and H 2 afforded derivative 7 in 98% yield with 98% ee (Fig. 6b). Chiral sulfone motif is found in numerous biological compounds 64-67 as well as drug candidates 68 . Upon treatment of 6a with m-CPBA, the oxidized sulfone product 8 was obtained in 85% yield with 90% ee. Moreover, 6a went through further transformations to afford sulfone 9 in 50% yield with 85% ee (Fig. 6c) 69 .
Mechanistic studies. To gain insight into the mechanism of tandem isomerization/α-Michael addition, some control experiments were carried out. Firstly, we wondered why the addition of NEt 3 led to an increase in diastereoselectivity (  (Fig. 7a).  Moreover, when Z-α,β-unsaturated 2-acyl imidazole Z-10 was used to react with E-1a, the product 2a was obtained in 1:5.2 anti: syn after 2 h, and decreased to 1:2.8 anti:syn after 5 h (Fig. 7b). These experiments confirmed the isomerization of β,γ-unsaturated C=C bond into α,β-unsaturated C=C bond in the presence of N,N′-dioxide-metal complexes, and this process was likely to be the rate-determining step. It also suggests the diastereoselectivity was mainly controlled by the E/Z-configuration of the α, β-unsaturated 2-acyl imidazole intermediate, and the addition of NEt 3 might improve the E/Z ratio during the isomerization process. As a result of equilibrium between E-1a, E-10, and Z-10 (Fig. 7c), the use of E-10 as the starting substrate alone, albeit unstable yielded the corresponding anti-2a as the major product in 98% ee after 3 h (Fig. 7d), while the reaction from only Z-10 gave the syn-2a product in 60% isolated yield and 92% ee (Fig. 7e). In addition, operando IR experiments were also performed to interpret the reaction process (for details, see Supplementary Note 7). Furthermore, we set out to establish the Dy(OTf) 3 /L 3 -PePr 2 (1:1, 5 mol%)  availability of stereodivergent access to 2a. All four stereoisomers of 2a could be readily obtained in good yields (67-85%) and diastereoselectivities (8:1->19:1) with excellent ee values by matching the E/Z-configurated 10 and the chiral ligand (Fig. 7f).
Proposed catalytic cycle. Based on the absolute configuration of the product 2j, control experiments and our previous studies 56-59 , a possible catalytic cycle with a transition-state model was proposed (Fig. 8). First, the coordination of chiral N,N′-dioxide L 3 -RaPr 2 and metal salt in situ to form chiral metal complex (Y*). Then, the β,γ-unsaturated ketone E-1a attaches to Y* as a dienolate in the presence of NEt 3 to give the intermediate T1, and which partly transforms into the α,β-unsaturated ketone E/Z-10 upon 1,5-proton shift. Next, the catalyst-bonded dienolate will react with the newly formed Michael acceptors. The α-Re-face of β,γ-unsaturated 2-acyl imidazole E-1a is strongly shielded by the nearby aryl ring of the ligand. Therefore, the dienolate prefers to attack E/Z-10 from its α-Si-face (T2). Finally, the desired product 2a dissociates after a protonation of the intermediate T3, and the catalyst is regenerated to accomplish one catalytic cycle.

Discussion
In summary, we have disclosed the diverse transformation of β,γunsaturated 2-acyl imidazoles in the presence of chiral Lewis acid catalysts, involving catalytic asymmetric tandem isomerization/α-Michael addition, sulfur-Michael addition, and direct Mannich reaction. A wide range of chiral 1,5-dicarbonyl and functionalized carbonyl compounds was afforded with good to excellent levels yields, diastereoselectivities, and enantioselectivities. The β,γunsaturated 2-acyl imidazoles features various reactivities, acting as both α-nucleophile and β-electrophile upon isomerization, which provides a route for conjugate addition of unstable α,βunsaturated carbonyl compounds. Meanwhile, all four stereoisomers with two vicinal tertiary stereocenters could be prepared by matching the configuration between substrates and chiral ligand. Besides, the desired products could be easily transformed

Data availability
The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 1972987 (2j), 2001513 (4r), and 1972937 (11). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via https:// www.ccdc.cam.ac.uk/data_request/cif. All other data are available from the corresponding author upon reasonable request.