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Asymmetric Spirocyclization Enabled by Iridium and Brønsted Acid-Catalyzed Formal Reductive Cycloaddition

2020; Chinese Chemical Society; Volume: 3; Issue: 7 Linguagem: Inglês

10.31635/ccschem.020.202000415

2096-5745

Nan-Fang Mo, Le Yu, Ying Zhang, Ya‐Hong Yao, Xun Kou, Zhi‐Hui Ren, Zheng‐Hui Guan,

Oxidative Organic Chemistry Reactions

Open AccessCCS ChemistryRESEARCH ARTICLE1 Jul 2021Asymmetric Spirocyclization Enabled by Iridium and Brønsted Acid-Catalyzed Formal Reductive Cycloaddition Nan-Fang Mo†, Le Yu†, Ying Zhang, Ya-Hong Yao, Xun Kou, Zhi-Hui Ren and Zheng-Hui Guan Nan-Fang Mo† Key Laboratory of Synthetic and Natural Functional Molecule of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi'an 710127 , Le Yu† Key Laboratory of Synthetic and Natural Functional Molecule of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi'an 710127 , Ying Zhang Key Laboratory of Synthetic and Natural Functional Molecule of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi'an 710127 , Ya-Hong Yao Key Laboratory of Synthetic and Natural Functional Molecule of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi'an 710127 , Xun Kou Key Laboratory of Synthetic and Natural Functional Molecule of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi'an 710127 , Zhi-Hui Ren Key Laboratory of Synthetic and Natural Functional Molecule of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi'an 710127 and Zheng-Hui Guan *Corresponding author: E-mail Address: [email protected] Key Laboratory of Synthetic and Natural Functional Molecule of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi'an 710127 https://doi.org/10.31635/ccschem.020.202000415 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail A catalytic, enantioselective spirocyclization of formanilides or formylindolines and enamides has been developed herein. The reaction proceeds through a sequential iridium-catalyzed hydrosilylation of tertiary formanilides and a chiral phosphoric acid-catalyzed formal cycloaddition of exocyclic enamides, thus providing straightforward access to a diverse array of enantioenriched azaspirocycles under mild conditions. A new bowl-shaped phosphoric acid bearing an o-CF3-aryl on the H8-BINOL-framework OCF-CPA (CPA18) has been developed as an effective, multipoint-controlled chiral catalyst for the reaction. And mechanistic investigations reveal the presence of crucial C–H⋯F hydrogen bonding in the enantiodetermining transition states. Download figure Download PowerPoint Introduction Spirocycles are not only important structural motifs in a wide array of natural products and bioactive compounds1,2 but also privileged scaffolds in modern drug discovery. Their rigid and unique three-dimensional structural diversity is used for efficiently designing pharmacophores to recognize target proteins.3–5 Among the different spirocyclic subclasses, 1-azaspirocycles are one of the most important scaffolds in drug discovery, in which their well-defined spatial arrangements are often beneficial for drug binding.2–6 The importance of this subclass of spirocycles can be gleaned by its appearance in the pentacyclic core of pyrroindomycins, NK1 tachykinin receptor antagonist, antimalarial cipargamin, and the U.S. Food and Drug Administration (FDA)-approved new drug rolapitant (Scheme 1a). However, due to the intrinsic complexity and challenge in stereocontrolled construction of the sterically congested nitrogen-constrained quaternary spirocenters,7–9 their enantioselective synthesis often involves multistep sequences,2,10–13 thus making them underrepresented in chemical libraries. Facile, enantioselective synthetic access to the core framework of this class of spirocycle remains an important challenge in organic chemistry.14–22 Scheme 1 | Selective examples of (a) 1-azaspirocycles, (b) reductive functionalization of amides, and (c) our work. Download figure Download PowerPoint The reductive functionalization of readily available amides has become a promising method for the synthesis of substituted amines.23,24 In this context, owing to the stability of the amide group, the two-step process of amide reduction–activation and nucleophilic substitution or nucleophilic addition are generally involved. Therefore, stoichiometric activating agents or reductants, including triflic anhydride (Tf2O),25–27 DIBAL-H,28,29 Schwartz's reagent (Cp2ZrHCl),30,31 and NaH32 have been used to successfully motivate the reaction (Scheme 1b). And Tf2O-mediated formal reductive cycloadditions of amides with alkynes or alkenes in a one-pot manner to give azaheterocycles have been reported.33–35 Particularly, an interesting l-proline-catalyzed reductive bis-functionalization of secondary amides for one-pot construction of chiral 2,2-disubstituted 3-iminoindoline has been developed recently.36 Alternatively, the seminal catalytic reductive functionalization of amides with silane reagents has emerged. IrCl(CO)(PPh3)237–44 and Mo(CO)645–47 have been developed as effective catalysts for the hydrosilylation of amides, thus diversifying the reaction of reductive functionalization of amides significantly. Despite these notable achievements, an amide reduction-initiated enantioselective transformation has rarely been explored. The development of an asymmetric reductive transformation of amide to access enantiomerically pure products remains highly desirable. Since an O-silylated hemiaminal is the proposed intermediate of hydrosilylation of amides,37–44 we hypothesized that the desilanolation of hemiaminal silyl ether I in the presence of a chiral phosphoric acid would initiate a formal cycloaddition reaction with exocyclic enamides (Scheme 1c). As such, a 1-azaspirocycle framework would be constructed accordingly. In this case, the chiral phosphate counterion of the resulting iminium phosphate II might impart chirality on the formal cycloaddition reaction through an ion-pairing interaction.48–50 Simultaneously, a hydrogen-bonding interaction between the Lewis basic site on the phosphate and a proton on the enamide might enhance the enantioinduction of the reaction.51,52 Therefore, we present herein the development of a highly effective amide reduction-initiated enantioselective transformation: an asymmetric formal reductive cycloaddition of formanilide or formylindolines and enamides for the synthesis of spirocycles (Scheme 1c). Experimental Methods General procedure for spirocyclization of formanilides: to a 10 mL tube (tube A), which was charged with formanilide (0.12 mmol, 1.2 equiv), IrCl(CO)(PPh3)2 (0.9 mg, 1.0 mol %), and dry o-xylene (1.0 mL), 1,1,3,3-tetramethyldisiloxane (TMDS) (26.8 mg, 2.0 equiv) was added and stirred for 0.5 h. Another 10 mL tube (tube B) was charged with enamide (0.1 mmol, 1.0 equiv), CPA18 (OCF-CPA) (10 mol %), and o-xylene (2.0 mL). The solution in tube A was transferred into tube B, and then, the mixture in tube B was stirred at –25 °C. After reaction completion, the mixture was warmed to room temperature. The crude reaction mixture was directly purified by flash column chromatography on silica gel (CH2Cl2/ethyl acetate = 8∶1 to 3∶1 as the eluent) to afford the corresponding pure product. More experimental details and characterization are available in the Supporting Information. Computational Methods All calculations were performed with the Gaussian 09 package. All the stable structures and the transition states were fully optimized unrestrainedly by the dispersion-corrected density functional theory (DFT) using the B3LYP functional (B3LYP-D3) and the 6-31G(d) basis set. Normal vibrational mode analysis at the same level of theory confirmed that the optimized structures are minima (zero imaginary frequency) or saddle points (one imaginary frequency). Furthermore, the intrinsic reaction coordinate (IRC) theory was applied to identify the transition states connecting reactants and products. Corrected single-point energies in o-xylene solvent were computed by using the B3LYP-D3 method and the 6-311G(d,p) basis set with the solvation model based on density. The relative energies with zero-point energy (ZPE) correction and free energies (at 298.15 K) are in kcal/mol. Results and Discussion Reaction conditions and the outcome We began with the identification of optimized reaction conditions for iridium-catalyzed hydrosilylation of N-methyl formanilide 1. It was found that the hemiaminal silyl ether 1′ was quantitatively generated at ambient temperature by using Vaska's complex, IrCl(CO)(PPh3)2, as a catalyst in the presence of (Me2HSi)2O (TMDS). Having obtained this N-phenyl iminium precursor, we next examined whether a chiral phosphoric acid-catalyzed cycloaddition reaction of hemiaminal silyl ether 1′ with enamide 2 could be engineered (Table 1). Many commonly used chiral phosphoric acid catalysts with different steric and electronic properties were screened; we found that most catalysts tested promoted the desired reaction to give the desired product 3 in high yield, but generally in low-to-moderate enantiomeric excess (ee) under different conditions (Table 1, CPA1– CPA16). These preliminary results revealed the challenge associated with accomplishing this spirocyclization reaction. Table 1 | Optimization of the Reaction Conditionsa aConditions: formanilide (0.12 mmol), IrCl(CO)(PPh3)2 (1.0 mol %), and TMDS (0.2 mmol) in o-xylene (1.0 mL) were stirred at room temperature for 0.5 h. Then, the mixture was transferred into a solution of enamide (0.1 mmol, 1.0 equiv) and CPA (10 mol %) in o-xylene (2.0 mL) and stirred at 0 °C for 1 h. Isolated yields andee were determined by high-performance liquid chromatography (HPLC). bToluene as the solvent. cCH2Cl2 as the solvent. dThe reaction was carried out at –25 °C. The weaker and less directional nature of the electrostatic ion-pairing interaction between the chiral counteranion and the substrate might be a key factor for the effectiveness of the catalyst in enantiocontrol.53 Inspired by the state-of-the-art multipoint-controlled chiral catalyst design incorporating fluorine effects,54–58 we speculated that enantiocontrol of the catalyst might be enhanced through an additional electrostatic attraction or hydrogen-bonding interaction between the counteranion and the substrate.59,60 Therefore, catalysts CPA17 and CPA18 bearing either o-F-aryl substitutions or o-CF3-aryl substitutions on the 3,3′-positions of the H8-BINOL-framework were first synthesized and subsequently tested in our reaction. We were delighted to observe that the enantioselectivity of the reaction indeed gave rise to a notable improvement, achieving 72% ee of 3 in the presence of CPA17 and 80% ee of 3 in the presence of CPA18. Moreover, the enantioselectivity of the reaction in the presence of CPA18 increased to 83% ee by lowering the reaction temperature to −25 °C. Despite achieving 83% ee with CPA18, no further improvement was obtained by modifying the catalyst ( CPA19– CPA25) and reaction parameters. Because the substituent on the N-aryl iminium ion may alter the ion-pairing or hydrogen-bonding interaction between the cationic N-aryl iminium and the counteranion, we then tuned the substituents on the formanilides to further improve the enantioselectivity of the reaction (Figure 1a). In this respect, the 2,4,6-trimethylbenzyl protected 1-G8 provided the corresponding 4,4′-spiro-tetrahydroquinoline 3-G8 with 97% ee in 94% yield. Furthermore, the 2,4,6-trimethylbenzyl group on the product 3-G8 was conveniently removed to give N–H product 8 in 90% yield without loss of enantiomeric purity via a Pd/C-catalyzed hydrogenation reaction (Figure 1b), thus demonstrating the synthetic utility of this reaction. In addition, formylindoline 4 displayed high reactivity and enantioselectivity in the reaction. This result revealed that the valuable indoline-fused chiral spirocycles can be readily constructed through our method. However, only 4% ee was observed when 1 and acyclic enamide 5 were employed in the reaction, albeit 90% yield of the desired product was obtained. Figure 1 | (a) Asymmetric spirocyclization reaction of N-alkyl formanilides with different alkyl groups from optimization studies; *reaction run in o-xylene/toluene (v/v = 1/2) at −78 °C. (b) Removal of the 2,4,6-trimethylbenzyl group from the product. Download figure Download PowerPoint Scope of the reaction Having established the optimal reaction conditions, we investigated the formanilides scope (Table 2a). Formanilides with electron-donating substituents, such as alkyl and methoxy, underwent reduction and asymmetric cycloaddition reaction smoothly to afford the desired products with excellent enantioselectivities in high yields ( 9– 19, 95–98% ee, 87–97% yield). Specifically, the 3,4-dimethoxy formanilide gave rise to a single regioselective product 17 with 97% ee in 89% yield. Formanilides with halide substituents, such as F, Cl, and Br, were compatible with both iridium-catalyzed hydrosilylation and chiral phosphoric acid-catalyzed cycloaddition conditions ( 20– 22, 92–94% ee, 80–91% yield). Notably, formyl-2-naphthylamine also produced exclusively 23 with 95% ee in 93% yield. Table 2 | Scope for Asymmetric Spirocyclization Reaction of Formanilides and Enamidesa aConditions: formanilide (0.12 mmol), IrCl(CO)(PPh3)2 (1.0 mol %), and TMDS (0.2 mmol) in o-xylene (1.0 mL) were stirred at room temperature for 0.5 h. Then, the mixture was transferred into a solution of enamide (0.1 mmol, 1.0 equiv) and CPA18 (10 mol %) in o-xylene (2.0 mL) and stirred at –25 °C for 12 h. We investigated the scope of enamides (Table 2b) and found the ability of the reaction to tolerate functional groups in the enamide component is remarkable. Enamides with electron-neutral or electron-donating groups on aryl rings, such as methyl and methoxy, all gave the corresponding tetrahydroquinolines with excellent enantioselectivities in high yields ( 24– 28, 93–98% ee, 88–95% yield). 1,3-Benzodioxole-containing enamide participated in the reaction smoothly to produce the tetrahydroquinoline 29 with 93% ee in 82% yield. Enamide with the strong electron-withdrawing nitro group was efficiently converted into the corresponding product 30 with 96% ee in 75% yield. Enamides bearing the chloro group at 1 to 4 position all produced the desired products with excellent yields and enantioselectivities ( 31– 34, 96–98% ee, 93–97% yield). Moreover, enamides containing fluoro or trifluromethyl were also well tolerated in our reaction to form the desired products in excellent yields and enantioselectivities ( 35– 37, 97–98% ee, 90–92% yield). These results indicate that the electronic property of enamides has little influence on the reaction. Furthermore, we demonstrated the utility of this enantioselective spirocyclization reaction through late-stage functionalizations (Table 2c). To our satisfaction, a family of steroid and vitamin E-containing substrates were compatible with the reaction conditions, generating cholesterol, β-sitosterol, estrone, trans-dehydroandrosterone, and tocopherol-containing tetrahydroquinolines with high diastereoselectivities in good yields ( 38– 42, >20∶1 dr, 62–73% yield). Specifically, the alkenyl and electrophilic ketone groups on these substrates were compatible under the conditions, thus demonstrating the chemoselectivity of iridium-catalyzed hydrosilylation and the spirocyclization reaction. Since the indoline nucleus is a ubiquitous motif in natural products and pharmaceutical targets, functionalization of readily accessible indolines is particularly attractive in organic synthesis. The installation of a quaternary stereocenter on the C7-position of indolines especially remains an important challenge. An advantage of our catalytic system is its ability to construct chiral indoline-fused spirocycles with C7 bound to the nitrogen substituted quaternary spirocenters, which was not easily achieved by an alternative protocol (Table 3). We were delighted to observe that formylindolines with a substituent at the 4-, 5-, or 6-position were all compatible with the reaction conditions. In particular, the sterically hindered 6-methyl-substituted formylindoline underwent the reaction to produce the corresponding indoline-fused spirocycle 45 with 99% ee in 94% yield. Like the functional group tolerance noted earlier, functional groups including methyl, methoxy, fluro, chloro, and bromo, on the formylindolines, were well tolerated in our enantioselective spirocyclization. In addition, the absolute configuration of product 56 was unambiguously determined by X-ray crystallographic diffraction. Table 3 | Scope for Asymmetric Spirocyclization Reaction of Formylindolines and Enamidesa aReaction conditions: Formylindoline (0.12 mmol, 1.2 equiv), [IrCl(CO)(PPh3)2] (1.0 mol %), and TMDS (0.2 mmol, 2.0 equiv) in o-xylene (1.0 mL) were stirred at room temperature for 0.5 h. The mixture was transferred into a solution of enamide (0.1 mmol, 1.0 equiv) and CPA18 (10 mol %) in toluene (2.0 mL) and stirred at –78 °C for 12 h. Mechanistic investigation To gain mechanistic insight into the catalytic cycle, we conducted control experiments. The reaction of hemiaminal silyl ether 1′ with enamide 2 did not proceed in the absence of phosphoric acid, but the formal cycloaddition reaction occurred in the presence of p-toluene sulfonic acid (Figure 2). These experiments suggest that the phosphoric acid plays a vital role in the desilanolation of hemiaminal silyl ether 1′ to generate the active iminium phosphate for the formal cycloaddition. Figure 2 | Mechanistic investigation: control experiments with and without acid catalysis. Download figure Download PowerPoint Since the enantioselectivity of the reaction was obviously determined by the intramolecular electrophilic cyclization of the key intermediate III, which could not be isolated or trapped, we carried out DFT calculations to better understand the origin of the enantiocontrol of this reaction and to uncover the special role of the CF3 group on our catalyst CPA18 during the chiral induction (simple N-methyl iminium phosphate was used a model). The free-energy profile for the intramolecular electrophilic cyclization of the key complex III with R chirality and the structures of transition states are given in Figure 3a. The calculated activation free energy of intramolecular nucleophilic addition of the reactive aryl site onto isoindolone-ium to form intermediate im1 via transition state TS-1 is 6.8 kcal/mol. Subsequently, the deprotonative rearomatization reaction of im1 is exothermic and occurred easily via the transition state TS-2 barrier of only 0.1 kcal/mol to generate complex im2. Release of the final product 3 and reactive CPA18 requires an activation free energy of 5.6 kcal/mol. Figure 3 | Mechanistic investigation with DFT. (a) Calculated Gibbs free energy profiles for the intramolecular electrophilic cyclization of the key intermediate III at the PCM(o-xylene)B3LYP-D3/6-311G(d,p)//B3LYP-D3/6-31G(d) level of theory. (b) Calculated lowest-energy structures of enantiodetermining transition states of substrates 1 with catalyst CPA7 and CPA18. (c) The same as in (b) for substrate 1-G8 and CPA18. The selected distances for hydrogen bonds and π-stacking interaction are shown in (b) and (c). Download figure Download PowerPoint Enantiodetermining TS-1 structures were explored with catalyst CPA7 and CPA18. The lowest-energy TS-1 for two different catalysts are shown in Figure 3b (the comparative transition state structures are depicted in the Supporting Information). The reactant docked on the CPA7 mainly via the N–H⋯O and C–H⋯O hydrogen bonds. In TS1-R-CPA7, there is sigma–π interaction between the methylene H of reactant and β-benzene group of CPA7,61,62 while in TS1-S-CPA7, a weak C–H⋯O hydrogen bond exits between the β-benzene H and carbonyl O of reactant. As a result, the ΔG values for TS1-R-CPA7 (8.5 kcal/mol) and TS1-S-CPA7 (8.6 kcal/mol) are almost identical, which agrees with the low enantioselectivity in the experiment (16% ee). In contrast, CPA18 shows a bowl-shaped geometry in the enantiodetermining transition state TS-1, and important C–H⋯F hydrogen bonds are formed between the reactant and the o-CF3 on CPA18. In both TS1-R-CPA18 and TS1-S-CPA18, the C–H⋯F hydrogen bonds play important roles in holding the reactant on the catalyst from the back side to make the reactant–catalyst interaction much stronger,56,59–60 thus lowering the free energy of transition state TS-1 in comparison with CPA7. The force of the multiple C–H⋯F hydrogen bonds also allows generation of a parallel-displaced π-stacking interaction either between the isoindolone-ium moiety and the o-CF3-benzene group of the catalyst in TS1-R-CPA18 or between the aniline moiety and the o-CF3-benzene group of the catalyst in TS1-S-CPA18.61,62 In TS1-S-CPA18, the imide H and reactive aryl site H are interacting with the same O of the phosphate; in contrast, bonding of these two H to two respective O of the phosphate in TS1-R-CPA18 makes both H-bonds stronger. According to the complex coupling of multiple hydrogen bonds and π-stacking interactions, the 1.6 kcal/mol ΔΔG between TS1-R-CPA18 (6.8 kcal/mol) and TS1-S-CPA18 (8.4 kcal/mol) predicts good enantioselectivity toward the formation of (R)- 3, which is consistent with the experimental result. Furthermore, the substitution effect of the 2,4,6-trimethylbenzyl group G8 on substrate 1-G8 with CPA18 was investigated (Figure 3c). In comparison with TS1-R-CPA18, the formation of a stronger C–H⋯F hydrogen bond stabilizes TS1-R-CPA18(G8) and gives rise to a lowered cyclization energy barrier (ΔG = 5.6 kcal/mol). However, in TS1-S-CPA18(G8), the C–H⋯F hydrogen bond between the CF3 group of CPA18 and the side-CH3 group of G8 rotates substrate toward the N–H⋯O hydrogen bond and weakens the interaction of P=O⋯H–C between the CPA18 and aryl C–H bond. The distorted reaction center (eight-membered ring) thus results in an increased transition state barrier (ΔG = 8.8 kcal/mol) compared with TS1-S-CPA18. This outcome confirmed the experimentally observed higher enantioselectivity of 2,4,6-trimethylbenzyl-substituted substrates. Conclusion We demonstrate herein a conceptual and robust catalytic enantioselective spirocyclization of formanilides or formylindolines and enamides. This reaction proceeds through a sequential iridium-catalyzed hydrosilylation of tertiary formanilides with a chiral Brønsted acid-catalyzed formal cycloaddition of enamides. A new bowl-shaped multipoint-controlled chiral phosphoric acid CPA18 (OCF- CPA) bearing an o-CF3-aryl on H8-BINOL-framework displayed excellent reactivity and enantioselectivity in the reaction. The reaction proceeded under mild conditions, exhibited good functional group compatibility, and provided straightforward access to a diverse array of enantioenriched azaspirocycles. Mechanistic investigations revealed the presence of important C–H⋯F hydrogen bonding between the substrate and the CF3 group on the OCF- CPA catalyst in the enantiodetermining transition states that is crucial for the enantioselectivity of the reaction. We anticipate our ortho-CF3-aryl containing multipoint controlled catalyst OCF-CPA will find further applications in related asymmetric catalysis. Supporting Information Supporting Information is available. Conflict of Interest The authors declare no competing financial interests. Funding Information The authors thank the generous grant from the National Natural Science Foundation of China (grant nos. 21971204 and 21622203) and the Innovation Capability Support Program of Shaanxi Province (grant no. 2020TD-022). Acknowledgments The authors wish to acknowledge the chemical HPC center of NWU for DFT calculations. References 1. 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Model.2014, 54, 1371–1379. Google Scholar Previous articleNext article FiguresReferencesRelatedDetails Issue AssignmentVolume 3Issue 7Page: 1775-1786Supporting Information Copyright & Permissions© 2020 Chinese Chemical SocietyKeywordschiral phosphoric acidenamidesasymmetric catalysisazaspirocyclesformanilidesAcknowledgmentsThe authors wish to acknowledge the chemical HPC center of NWU for DFT calculations. Downloaded 966 times Loading ...