Chiral Bicyclic Imidazole-Catalyzed Direct Enantioselective C -Acetylation of Indolones

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE11 Apr 2022Chiral Bicyclic Imidazole-Catalyzed Direct Enantioselective C-Acetylation of Indolones Muxing Zhou, Yashi Zou, Lu Zhang, Zhenfeng Zhang and Wanbin Zhang Muxing Zhou Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240 Google Scholar More articles by this author , Yashi Zou Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240 Google Scholar More articles by this author , Lu Zhang Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240 Google Scholar More articles by this author , Zhenfeng Zhang Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240 Google Scholar More articles by this author and Wanbin Zhang *Corresponding author: E-mail Address: [email protected] Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240 Frontier Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202201782 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail By adjusting the bond angle and stereocontrol substituent of the chiral bicyclic imidazole catalysts, direct enantioselective C-acetylation of indolones and their sequencial pattern have been successfully developed. Indolones bearing a quaternary stereocenter were synthesized with satisfactory yields and excellent enantioselectivities (up to 97% ee). The reaction can be realized with 410 turnover numbers, and the products can be transformed into several functional compounds via simple derivations of the acetyl group. Download figure Download PowerPoint Introduction Enantioselective acylation,1–15 mainly promoted by chiral Lewis base organocatalysts,16–33 is one of the most useful reactions and important tranformations in academic and industrial chemistry. Compared with O-, N-, and S-acylations, asymmetric C-acylation has received extensive attention due to its valuable applications in the construction of C–C bonds and tetrasubstituted stereocenters.34–69 In the pioneering work reported by Fu’s group in 1998,34O-acylated azlactones were rearranged to C-acylated azlactones by catalysis with a chiral 4-dimethylaminopyridine (DMAP) organocatalyst. From then on, this well-known reaction, called the Steglich rearrangement, was selected as a model reaction for testing new Lewis base organocatalysts.35–46 The substrate scope has since been extended to O-acylated benzofuranones (Black rearrangement),35,36,43,44,47–51 indolones,35,36,47–49,52–57 furanones,35,36,44,58 and pyrazolones59 (Scheme 1a). During this period, our group developed a series of chiral bicyclic imidazole organocatalysts based on the bond angle control strategy and achieved the highest reported enantioselectivity of the Steglich rearrangement reaction in that time (98% ee).38 This reaction stands out because it exhibits almost 100% atomic economy. However, the low activity of the prefabricated O-acylated material greatly limits the efficiency of this method. Another type of asymmetric C-acylation is the use of pre-prepared silyl ketene acetals/imines, which extend the initial substrates of this tranformation to simple ester/cyanide compounds (Scheme 1b).60–64 However, the low accessibility of silyl ketene acetals/imines and the formation of a large amount of silyl byproducts hindered this reaction from being widely employed. Therefore, a more efficient asymmetric C-acylation reaction is greatly desired. Scheme 1 | (a–c) The development of asymmetric C-acylation and examples of asymmetric C-acetylation. Download figure Download PowerPoint In 2017, our group proposed and realized the first direct enantioselective C-acylation (Scheme 1c) for the synthesis of the same products obtained using a Black rearrangement.65 Experimental and computational studies proved that the process does not proceed via the relatively inert O-acylated intermediates. Thus, the synthetic efficiency could be greatly improved, and the highest enantioselectivity of these products to date was obtained (97% ee). Later, this strategy was applied to modification of the Steglich rearrangement, achieving the highest enantioselectivity of Steglich rearrangement products to date (99% ee). Complex quaternary chiral amino acid derivatives from simple racemic amino acids via a four-step acylation catalyzed by one bicyclic imidazole organocatalyst was also realized.66 Recently, we have also studied the direct enantioselective C-acylation of indolones using a chiral bicyclic imidazole organocatalyst.67 The substrates can be completely converted at 1 mol % catalyst loading, though the selectivity still requires improvement. It is important to note that in most of the above asymmetric C-acylation reactions, chloroformates act as the acylating reagent, and sporadic utilization of alkyl acyl chlorides gave positive reaction results (Schemes 1a and 1b, right)52,60,61 which greatly reduces the derivability of products and the applicability of the reactions. Among the alkyl acyl groups, the acetyl group stands out because of its simplicity and variability. However, enantioselective acetylation still remains a significant challenge due to the poor left-to-right differentiation between the small methyl group and carbonyl oxygen atom, which will ultimately affect the enantioselectivity of the reaction. (Bulky acylating reagents are always needed for high enantioselectivity in asymmetric O-acylation.)68–75 Here, by using a recently developed chiral bicyclic imidazole organocatalyst based on the bond angle control strategy, the first highly efficient direct enantioselctive C-acetylation of indolones was developed using readily available acetyl chloride as the acylating reagent (Scheme 1c, right). Experimental Methods General procedure for the direct enantioselective C -acetylation of indolones Under a N2 atmosphere, the substrate 2 or 5 (0.2 mmol), the catalyst (R)- OAc-TIP (0.36 mg, 0.002 mmol), and diisopropylethylamine (DIPEA) (84.0 μL, 0.48 mmol, 2.4 equiv) were dissolved in dry toluene (2 mL) and cooled to −10 °C. Acetyl chloride (28.3 μL, 0.4 mmol, 2.0 equiv) was added, and the vial was sealed with a septum. The reaction mixture was stirred at −10 °C for 8 h. After the reaction was completed, the reaction mixture was quenched with 0.1 M HCl (aq., 2 mL) and extracted with EtOAc (4 mL × 3). The combined organic phase was dried over Na2SO4. After filtration, the residue was purified by chromatography [petroleum ether/methyl tert-butyl ether (PE/MTBE)] to give the corresponding product 3 or 6. The ee value was determined by chiral high-performance liquid chromatography (HPLC) analysis. General procedure for the sequential enantioselective acetylation of indolones Under a N2 atmosphere, the substrate 1 (0.2 mmol), the catalyst (R)- AcO-TIP (0.36 mg, 0.002 mmol), and DIPEA (118.8 μL, 0.68 mmol, 3.4 equiv) were dissolved in dried toluene (2 mL) and cooled to −10 °C. Acetyl chloride (42.4 μL, 0.6 mmol, 3.0 equiv) was added, and the vial was sealed with a septum. The reaction mixture was stirred at −10 °C for 24 h. After the reaction was complete, the reaction mixture was quenched with 0.1 M HCl (aq., 2 mL) and extracted with EtOAc (4 mL × 3). The combined organic phase was dried over Na2SO4. After filtration, the residue was purified by chromatography (PE/MTBE) to give the corresponding product 6. The ee value was determined by chiral HPLC analysis. Results and Discussion The model substrate 1-(2,2-diphenylacetyl)-3-methylindolin-2-one ( 2a) can be synthesized easily from commercially available compound 1a. The acetylation of 2a to synthesize the desired product 3-acetyl-1-(2,2-diphenylacetyl)-3-methylindolin-2-one ( 3a) was conducted in order to optimize the reaction conditions (Scheme 2). Initially, we tested our previously developed chiral bicyclic imidaozle organocatalysts 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole ( DPI),38,76,77 which have recently been successfully applied in the enantioselective synthesis of ProTide drugs such as Remdesivir and chiral phthalidyl ester prodrugs.78,79 To our delight, OBn-DPI and OAc-DPI gave the desired product with good enantioselectivity of 82% and 88% ees while Cy-DPI, bearing more sterically hindered substituent, produced better enantioselectivity of 92% ee. In order to further improve the enantioselectivity, alternative catalysts with a narrow stereogenic enviroment were designed. Just as we noted during the design of chiral bicyclic imidazole catalysts, the bond angle (red-marked) is a key structural element to control the stereogenic environment: the smaller, the better.38 Therefore, we proposed reducing the bond angle of the catalyst by changing the 5-membered pyrroridine ring to a 6-membered piperidine ring. Before the experiment, the energy difference ΔG between the two acetylimidazolium rotamers was calculated to evaluate the left-to-right differentiation (Scheme 2). It can be seen that the DPI catalysts show a similar bond angle of approxomately 137°, and the obtained enantioselectivity increased from 82% to 92% ee as the calculated ΔG increased from 0.6 to 2.1 kcal/mol. The newly designed 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine ( TIP) catalysts possess a smaller bond angle of 127°, which resulted in higher ΔG values, indicating better stereocontrol. As expected, OBn-TIP, OAc-TIP,80 and Cy-TIP showed improved enantioselectivities of 94%, 95%, and 94% ee respectively, and only a small amount of O-acetylated by-product 1-(2,2-diphenylacetyl)-3-methyl-1H-indol-2-yl acetate ( 4a) was generated (Scheme 2). Scheme 2 | Catalyst evaluation (B3LYP-D3(BJ)/def-TZVP, toluene, 298.15 K). aMTBE was used as solvent due to the low solubility of toluene for Cy-TIP. Download figure Download PowerPoint After further optimization (see Supporting Information Table S1 for details), the substrate scope was investigated under the conditions as shown in Scheme 3. When the substituent of N-DPA (DPA = diphenyl acetyl) was changed to N-Ac, slightly reduced yield and enantioselectivity were detected for product 6a. Substrates bearing other substituents at the 3-position gave the corresponding products 3b– 3e with excellent enantioselectivities ranging from 92% to 96% ee. Other substrates bearing Me, Et, Pr, i-Pr, Bu, and t-Bu substituents at the 5-position of the phenyl ring were also tested and afforded the desired products 3f– 3k with satisfactory yields and enantioselectivities (93%–97% ee). Substrates possessing F, Cl, Br, and OMe groups at the 4-position of the phenyl ring gave the corresponding products 3l–3o with reduced yields and enantioselectivities (64%–86% ee). Scheme 3 | Substrate scope for direct C-acetylation. Conditions: 0.2 mmol substrate 2 or 5, 2.5 mol % OAc-TIP, AcCl (2.0 equiv), DIPEA (2.4 equiv), toluene (2 mL), −10 °C, 8 h. Isolated yields were recorded. The ee values were determined by HPLC using chiral columns. Download figure Download PowerPoint Using the same catalytic system, sequential N-acetylation and direct C-acetylation were realized. Compared with the reported method to synthesize the target compounds over three steps,52 this newly developed method was able to achieve the desired products 6 in two steps and in one pot, which greatly enhanced the synthetic efficiency. The substrate scope was also explored and is listed in Scheme 4. Substrates bearing different substituents at the 3-position gave the corresponding products 6a, 6b, 6d, and 6e with moderate yields and enantioselectivities (86%–92% ee). Other substrates bearing Me, Et, and i-Pr substituents at the 5-position of the phenyl ring gave the corresponding products 6f, 6g, and 6l with better enantioselectivities (91%–93% ee) while the 5-t-Bu-substituted 6k was obtained with reduced enantioselectivity of 87% ee. By control experiments the reaction process was confirmed to occur via N-acetylation followed by direct C-acetylation (see Supporting Information Scheme S1 for details). Scheme 4 | Substrate scope for sequential acetylation. Conditions: 0.2 mmol substrate 1, 2.5 mol % OAc-TIP, AcCl (3.0 equiv), DIPEA (3.4 equiv), toluene (2 mL), −10 °C, 8 h. Isolated yields were recorded. The ee values were determined by HPLC using chiral columns. Download figure Download PowerPoint To fully explore the potential of this methodology, the direct C-acetylation of 2a was conducted under low catalyst loading, and the chiral product 3a was transformed to several functional compounds (Scheme 5). With the catalyst loading of OAc-TIP reduced to 1 mol %, the gram-scale reaction proceeded smoothly in 12 h to give the product in 87% yield and 97% ee. Further decreasing the catalyst loading to 0.2 mol % using another catalyst, Cy-DPI also provided the desired product in a satisfactory yield of 82% [with a calculated turnover numbers (TON) of 410] and enantioselectivity of 91% ee after 24 h reaction time. Such a low catalyst loading is difficult to achieve in organocatalysis. The DPA substituent could be easily removed by treatment with diethylamine to give the product 7a with good yield and almost unaltered ee. The obtained C-acetylated products 3a and 7a could provide several derivatives based on the reactivity of the acetyl group. Compound 3a could be oxidized to ester 8a via Baeyer–Villiger oxidation, and compound 7a could be transformed to alcohol 9a via reduction or to oxime 10a via simple dehydration whilst retaining ee. The absolute configuration of the compound 10a was confirmed by single-crystal X-ray diffraction (see Supporting Information for details).a Scheme 5 | Scale-up and applications. Download figure Download PowerPoint Density Functional Theory Studies In order to better understand this reaction, we used density functional theory (DFT) calculations to study the catalytic mechanism (Figure 1). Starting with the initial state ( sub-DIPEA) including the base-activated oxindole anion and catalyst-activated acetylimidazolium cation, the reactants form complexes with different configurations ( IM1), which result in the formation of the product-catalyst complexes ( IM2) via the corresponding transition states ( TS). Thereinto, the S-pathway via TS S has the lowest energy barrier and is the main pathway of the reaction. According to the calculation, the energy of TS R is 4.7 kcal/mol higher than that of TS S, which partially explains the experimental results that the S-products is obtained with 95% ee. Additionally, we found that the energy of TS O is between those of TS S and TS R. This result rationalizes why the reaction produces a certain number of O-acetylated byproducts. In addition, the high energy barrier of 22.1 kcal/mol between pro- O and TS O prevents the O- to C-acetyl rearrangement from occurring at low temperatures. After careful analysis of the optimized structures of these transition states, a number of noncovalent interactions were found, as shown in Figure 2. The reason why TS S is more stable than TS R lies in the extra CH-π interaction between the H on the chiral C of the catalyst and the benzo part of the oxindole (the interaction distance is 2.53 Å). Finally, the corresponding transition states generated by the DPI catalyst have also been calculated and show a smaller TS R/ TS S energy difference of 3.0 kcal/mol (see Supporting Information Figures S1–S4 for details), indicating why DPI with a bond angle of 137° shows lower enantioselectivity than TIP, which has a bond angle of 127°. Figure 1 | Free energy profile (ΔG298) of catalytic mechanism calculated at B3LYP-D3(BJ)/def-TZVP level of theory. Download figure Download PowerPoint Conclusion In summary, based on the bond angle control strategy, a challenging direct enantioselective C-acetylation of indolones was realized by the use of chiral bicyclic imidazole catalysts bearing a small bond angle. Excellent enantioselectivities (up to 97% ee) and high efficiency (up to 410 TON) were achieved for indolones possessing a quanterary stereocenter, which could be further elaborated to several functional compounds. Figure 2 | Optimized structures of the transition states stabilized by CH-π interaction (red) and Van der Waals force (blue). [The noncovalentinteractions up to 3 Å are dotted based on atoms in molecules topology analysis.] Download figure Download PowerPoint Footnote a CCDC 2129950. Supporting Information Supporting Information is available and contains general information, optimization details, synthetic procedures and characterization data of all new compounds, and computational details. Supplementary characterization data includes copies of NMR spectra and HPLC charts. X-ray crystallographic data of compound 10a has been deposited in the Cambridge Structural Database (CCDC: 2129950). Conflict of Interest There is no conflict of interest to report. Acknowledgments This work was supported by the National Key R&D Program of China (grant no. 2018YFE0126800), the National Natural Science Foundation of China (grant nos. 21831005, 91856106, 21991112, and 22071 150), the Shanghai Municipal Education Commission (grant no. 201701070002E00030), and the China Postdoctoral Science Foundation (grant no. 2021M692058). We also thank the Instrumental Analysis Center of Shanghai Jiao Tong University.