Highly Diastereo- and Enantioselective Synthesis of Quinuclidine Derivatives by an Iridium-Catalyzed Intramolecular Allylic Dearomatization Reaction

Open AccessCCS ChemistryRESEARCH ARTICLE1 Apr 2019Highly Diastereo- and Enantioselective Synthesis of Quinuclidine Derivatives by an Iridium-Catalyzed Intramolecular Allylic Dearomatization Reaction Lin Huang, Yue Cai, Hui-Jun Zhang, Chao Zheng, Li-Xin Dai and Shu-Li You Lin Huang State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 (China) , Yue Cai State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 (China) , Hui-Jun Zhang State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 (China) , Chao Zheng State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 (China) , Li-Xin Dai State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 (China) and Shu-Li You *Corresponding author: E-mail Address: [email protected] State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 (China) Collaborative Innovation Center of Chemical Science and Engineering, Tianjin (China) https://doi.org/10.31635/ccschem.019.20180006 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Asymmetric construction of quinuclidine derivatives has been realized by an iridium-catalyzed allylic dearomatization reaction. The catalytic system, derived from [Ir(cod)Cl]2 and the Feringa ligand, tolerates a broad range of substrates. A large array of quinuclidine derivatives can be obtained under mild conditions in good to excellent yields (68%–96%), diastereoselectivity (up to >20/1 dr), and enantioselectivity (up to >99% ee). These products feature versatile functional group diversity and can undergo diverse transformations. A model that accounts for the origin of the stereoselectivity has been proposed based on density functional theory (DFT) calculations. Download figure Download PowerPoint Introduction Quinuclidine, also named 1-azabicyclo[2.2.2]octane, exists in a number of naturally occurring compounds, biologically active agents, and privileged catalysts and ligands for asymmetric catalysis (Figure 1).1–6 In particular, quinine, a kind of cinchona alkaloid, has been recognized as a medication for the treatment of malaria and babesiosis.7,8 Quinuclidine derivatives are also widely utilized as homogeneous or heterogeneous catalysts in various asymmetric processes such as Morita–Baylis–Hillman reactions,4 Sharpless dihydroxylation reactions,5 and phase-transfer catalytic reactions.6 Therefore, the development of synthetic approaches for efficient construction of novel quinuclidine derivatives is of great significance. Figure 1 | Selected natural products and synthetic molecules containing quinuclidine scaffolds. Download figure Download PowerPoint In this regard, great efforts have been devoted to the development of new methods toward the preparation of quinuclidine derivatives.9 Traditionally, quinuclidine scaffolds can be constructed by second-order nucleophilic substitution (SN2) reaction or condensation reaction of piperidine derivatives.10–12 However, most of these reactions are racemic or chiral auxiliary-assisted processes. Quinuclidine derivatives can also be formed conveniently by introducing substituents into the quinuclidine ring,13 but the scope of this method is rather limited by the available source of starting materials. Catalytic asymmetric dearomatization reactions have emerged as a powerful tool for the transformation of planar aromatic compounds into highly enantio-enriched three-dimensional molecules.14–49 In our ongoing efforts to investigate the transition-metal-catalyzed asymmetric allylic dearomatization reactions, several straightforward protocols to access chiral spiroindolenine and spiroindoline derivatives were revealed.50–53 Recently, we reported an unprecedented synthesis of indole-annulated, medium-sized ring compounds from tetrahydro-γ-carboline- or hexahydroazepino[4,3-b]indole-derived allylic carbonates via a cascade Ir-catalyzed allylic dearomatization/retro-Mannich/hydrolysis reaction (Scheme 1a).54 Notably, the spiroindolenine intermediate I was highly reactive and could not be isolated. We envisaged that if tetrahydro-β-carboline-derived allylic carbonates 1 are employed in this protocol, the retro-Mannich reaction should be avoided due to the existence of two methylene groups between the indole ring and the nitrogen atom. As a consequence, interesting indolenine-fused quinuclidine derivatives 2 might be afforded as the major products (Scheme 1b). Herein, we report such an efficient asymmetric synthesis of quinuclidine derivatives. Scheme 1 | The design plan of this study. Download figure Download PowerPoint Results Reaction development Our study commenced with the evaluation of the reaction conditions using tetrahydro-β-carboline derivative 1a as the model substrate and a catalytic system consisting of iridium precursor [Ir(cod)Cl]2 [2 mole percent (mol %)] with a chiral phosphoramidite ligand (4 mol %) in tetrahydrofuran (THF) at 50 °C (Table 1).55–85 First, the influence of various chiral phosphoramidite ligands ( L1–L8) was considered with Cs2CO3 (100 mol %) as the base (entries 1–8). The reaction with Feringa ligand ( L1)86 occurred smoothly (entry 1), delivering product 2a in good yield (74%) with a moderate dr value (5.2/1). Notably, both diasteroisomers of 2a were obtained in excellent enantiopurity (95% ee). The catalysts generated from L2 and Alexakis ligand ( L3),87 respectively, could lead to comparable yields of 2a and enantiopurity of both diasteroisomers. However, the diastereoselectivity dropped slightly (entries 2 and 3). In addition, catalysts derived from Me-THQphos ( L4) and BHPphos ( L5) developed by our group were less efficient in terms of the yield of 2a (entries 4 and 5). Further evaluation of more chiral phosphoramidite ligands ( L6–L8) only gave poor diastereoselectivity (entries 6–8). In order to improve the diastereoselectivity of the reaction, various bases including DBU, K3PO4, K2CO3, KOAc, and NaOAc were tested (entries 9–13). NaOAc was found to be the best choice concerning the yield of 2a (74%), diastereoselectivity (7.9/1 dr), and enantioselectivity (95% ee for major isomer and 96% ee for minor isomer) (entry 13). When no base was used, the reaction could not be completed even after 48 h (entry 14). Inspired by the work of Hartwig and co-workers,88 the effect of the counteranion of the iridium complex was examined by adding various silver salts including AgOAc, AgSO3Me, AgOTf, and AgBF4 (entries 15–18). To our delight, in all of these cases, 2a was obtained as a single diastereoisomer. Of particular note, in the absence of base, the reaction with AgOAc could give almost the same results (entry 19), while the reaction with AgSO3Me just gave moderate stereoselectivity (entry 20). Finally, the optimal reaction conditions were determined as described in entry 19, where desired product 2a was isolated in 86% yield with >20/1 dr and 96% ee. Table 1 | Optimization of the Reaction Conditionsa Entry L Base Time (h) Yield (%)b drc ee (major) (%)d ee (minor) (%)d 1 L1 Cs2CO3 3 74 5.2/1 95 95 2 L2 Cs2CO3 3 82 4.4/1 95 94 3 L3 Cs2CO3 3 76 2.9/1 97 97 4e L4 Cs2CO3 14 24 8.8/1 / / 5e L5 Cs2CO3 14 18 5.0/1 / / 6 L6 Cs2CO3 3 82 1.4/1 96 99 7 L7 Cs2CO3 19 76 1.4/1 97 >99 8 L8 Cs2CO3 42 28 3.0/1 89 85 9 L1 DBU 3 73 5.2/1 95 93 10 L1 K3PO4 3 80 5.4/1 95 95 11 L1 K2CO3 3 74 6.0/1 95 96 12 L1 KOAc 3 80 4.5/1 96 93 13 L1 NaOAc 12 74 7.9/1 95 96 14 L1 / 48 23 4.0/1 94 94 15f L1 NaOAc 3 80 >20/1 96 / 16g L1 NaOAc 3 82 >20/1 96 / 17h L1 NaOAc 3 68 >20/1 71 / 18i L1 NaOAc 3 83 19/1 91 / 19f L1 / 3 83 (86j) >20/1 96 / 20g L1 / 3 76 6.7/1 73 76 Notes: aReaction conditions: 1a (0.2 mmol), [Ir(cod)Cl]2 (2 mol %), L (4 mol %), and base (100 mol %) in tetrahydrofuran (THF) (2.0 mL) at 50 °C. Catalyst was prepared by nPrNH2 activation.60bCombined yield of both diastereoisomers determined by proton nuclear magnetic resonance (1H NMR) analysis using CH2Br2 (0.1 mmol) as an internal standard. cDetermined by 1H NMR analysis of the crude reaction mixtures. dDetermined by high-performance liquid chromatography (HPLC) analysis with a chiral stationary phase. eIn refluxing dioxane. fWith AgOAc (8 mol %). gWith AgSO3Me (8 mol %). hWith AgOTf (8 mol %). iWith AgBF4 (8 mol %). jIsolated yield. Under the optimized reaction conditions, various tetrahydro-β-carboline tethered allylic carbonates were explored to examine the generality of the reaction (Figure 2). Substrates bearing varied substituents at 4-, 5-, or 6-position on the indole moiety could proceed smoothly to give their corresponding quinuclidine products in good to excellent yields, excellent diastereo- and enantioselectivity ( 2a–2l, 68%–92% yields, 14/1 to >20/1 dr, 88%–96% ee). The dr values of the products were slightly lower when the seven-substituted indole-derived substrates were used ( 2m, 72% yield, 6/1 dr, 95% ee; 2n, 86% yield, 16/1 dr, 88% ee). Of particular note, the electronic property of the substituents on the indole ring does not show notable influence. Substrates bearing either an electron-withdrawing (F and Cl) or an electron-donating (Me, MeO, and BnO) group were all well tolerated. Moreover, tryptophan-derived substrates, which contain one chiral center on the piperidine ring, underwent the reactions smoothly, affording their corresponding products in good results ( 2o–2q, 91%–96% yields, 8/1 to >20/1 dr). The relatively lower dr value of 2q was probably caused by the mismatch effect between the R configuration of substrate 1q and ligand (S,S,Sa)- L1 in the transition state. The reaction of substrate bearing the gem-dimethyl groups on the carboline ring afforded two diastereoisomers of 2r in good combined yield (94%) with excellent enantiopurity (>99% ee [major isomer] and 99% ee [minor isomer]), but with poor diastereoselectivity (1.8/1 dr). When the carboline moiety and the allylic carbonate of the substrate were skipped by two methylene groups (m = 2), the target reaction also proceeded well. However, the desired products were only obtained with poor diastereomeric ratios despite the high enantiomeric purity of both diastereoisomers ( 2s, 71% yield, 95% ee [major isomer] and 94% ee [minor isomer], 1.1/1 dr; 2t, 69% yield, 1.5/1 dr). The stereochemistry of 2p (4R,4aR,11S) and the major isomer of 2q (4R,4aR,11R) were established by nuclear Overhauser enhancement spectroscopy analysis and X-ray crystallographic analysis, respectively.89 The absolute configuration of other products (major isomers) was assigned by analogy. Figure 2 | Substrate scope. Notes: Reaction conditions: 1 (0.2 mmol), [Ir(cod)Cl]2 (2 mol %), L1 (4 mol %), and AgOAc (8 mol %) in tetrahydrofuran (THF) (2.0 mL) at 50 °C. Catalyst was prepared by nPrNH2 activation.60 Combined isolated yields of both diastereoisomers are reported. The dr values are determined by proton nuclear magnetic resonance (1H NMR) analysis. Enantiomeric excess (ee) values are determined by high-performance liquid chromatography (HPLC) analysis with a chiral stationary phase. Download figure Download PowerPoint The origin of stereoselectivity Under the optimized conditions, the reactions generally exhibit high diastereoselectivity (up to 20/1 dr). It is known that in the Ir-catalyzed asymmetric allylic substitution reactions, the catalyst derived from a Feringa-type ligand can well control the stereochemistry at the allylic position. When (S,S,Sa)- L1 is utilized, only the Si-face of the allylic position is allowed to be attacked. In this regard, it is the facial selectivity of the prochiral nucleophile which determines the dr values of the product obtained. At this stage, density functional theory (DFT) calculations90 (M06-2X/SDD/6-31G**) were employed to shed some light on the origin of this selectivity. First, the formation of 2a was selected as the model for calculations. Two transition states, TS-2a-( Si , Si ) and TS-2a-( Si , Re ), leading to the major (4R,4aR) and minor isomer (4R,4aS) of 2a, respectively, were located (Figure 3). The calculated Gibbs free energy of TS-2a-( Si , Si ) is lower than that of TS-2a-( Si , Re ) by 1.2 kcal/mol, which is in agreement with the experimental results. In the optimized structure of TS-2a-( Si , Si ), the relative position of the positively charged allyl moiety and the electron-rich indole ring is –synclinal [defined by the dihedral angle D (Ca–Cb–Cc–Cd), the same below]. Therefore, some favorable interaction between these two overlapped parts might exist to help stabilize this transition state. On the other hand, in TS-2a-( Si , Re ) the relative position of the allyl moiety and the indole ring is not well overlapped in an antiperiplanar conformation, and thus, less stabilization effect can be expected in this structure. We believe that the existence of such a stabilization effect in TS-2a-( Si , Si ) accounts for the inherent preference of the formation of (4R,4aR) isomer of 2a.91 To be noted, the strength of this weak nonbonding effect might be sensitive to external perturbations. Therefore, it is reasonable that varied dr values are obtained when different solvents and counter anions to the Ir-catalyst are employed. Figure 3 | Optimized structures of TS-2a-( Si, Si) and TS-2a-( Si, Re) and their calculated relative Gibbs free energy (in kcal/mol). (a) and (b) side views; (c) and (d) Newman projection along the forming Cb–Cc bond. The ligands associated to the Ir center are omitted for clarity. The allyl moiety and the indole ring are in green and pink, respectively. Download figure Download PowerPoint Notably, when gem-dimethyl groups or an additional methylene group were introduced to certain positions of the substrates, the diastereoselectivity of the reaction dropped significantly ( 2r, 1.8/1 dr; 2s, 1.1/1 dr; and 2t, 1.5/1 dr). Similar computational investigations were also applied for two additional models. As shown in Figure 4, the difference of Gibbs free energy in the two competitive transition states TS-2r-( Si , Si ) and TS-2r-( Si , Re ) that lead to the two isomers of 2r, respectively, is reduced to 0.8 kcal/mol. The major geometric feature of these two transition states is rather similar to that of TS-2a-( Si , Si ) and TS-2a-( Si , Re ). The positively charged allyl moiety and the electron-rich indole ring are well overlapped in TS-2r-( Si , Si ) (–synclinal) but not in TS-2r-( Si , Re ) (antiperiplanar). However, the existence of the gem-dimethyl groups causes stronger steric repulsion in the formal case, which is exemplified by the existence of closer hydrogen atom pairs in TS-2r-( Si , Si ) (B[H1⋯H4] = 2.15 Å, B(H3⋯H4) = 2.09 Å, and B[H5⋯H6] = 2.10 Å) compared with that in TS-2r-( Si , Re ) (B[H2⋯H4] = 2.37 Å, B[H3⋯H4] = 2.16 Å, and B[H5⋯H6] = 2.06 Å). In this regard, the preference that is brought about by the overlap between the allyl moiety and the indole ring is diminished and the energetic gap between TS-2r-( Si , Si ) and TS-2r-( Si , Re ) reduces. The situation of the substrates with an elongated tether is very similar (Figure 5). For model transition state TS-2s'-( Si , Si ), in order to keep the allyl moiety and the indole ring in an overlap position (–synclinal), a stronger ring strain must be suffered by the forming bridged cyclic system, while in TS-2s'-( Si , Re ), the antiperiplanar conformation does not require such a strong ring strain.92 As a consequence, the energetic gap between TS-2s'-( Si , Si ) and TS-2s'-( Si , Re ) is minimized to only 0.3 kcal/mol. Figure 4 | Optimized structures of TS-2r-( Si, Si) and TS-2r-( Si, Re) and their calculated relative Gibbs free energy (in kcal/mol). (a) and (b) side views; (c) and (d) Newman projection along the forming Cb–Cc bond. The ligands associated to the Ir center are omitted for clarity. The allyl moiety and the indole ring are in green and pink, respectively. Download figure Download PowerPoint Figure 5 | Optimized structures of TS-2s'-( Si, Si) and TS-2s'-( Si, Re) and their calculated relative Gibbs free energy (in kcal/mol). (a) and (b) side views; (c) and (d) Newman projection along the forming Cb–Cc bond. The ligands associated to the Ir center are omitted for clarity. The allyl moiety and the indole ring are in green and pink, respectively. Download figure Download PowerPoint In short, our computational results qualitatively reproduced the trend of dr values observed in three kinds of substrates. The preference of the formation of (4R,4aR) isomers largely originates from the beneficial interaction between the allyl moiety and the indole ring in the corresponding transition states. However, the diastereoselectivity will be lowered if this stabilizing effect is neutralized by some steric repulsion or ring strain that is operating in the favorable transition state. Synthetic applications To demonstrate the synthetic utility of this newly developed reaction, a gram-scale synthesis of a chiral quinuclidine derivative was carried out. Under the standard conditions, the reaction of 1p on a 3.76 mmol scale gave the desired product 2p with 76% yield (0.85 g) with >20/1 dr (Scheme 2). Scheme 2 | Gram-scale reaction. Download figure Download PowerPoint The quinuclidine derivatives obtained herein readily undergo diverse transformations (Scheme 3). Subjecting 2p to a Pd/C-catalyzed hydrogenation reaction afforded product 3 with 87% yield with >20/1 dr. Reduction of 2p with sodium cyanoborohydride furnished product 4 with 77% yield with >20/1 dr. In the meantime, the imine group of 2p could be easily converted to enamine by reacting with methyl chloroformate. Scheme 3 | Transformations of the products. Download figure Download PowerPoint Conclusion In summary, we have developed a method for enantioselective synthesis of indolenine-fused quinuclidine derivatives via an Ir-catalyzed, intramolecular, asymmetric allylic dearomatization reaction. In general, good to excellent yields, diastereoselectivity, and enantioselectivity can be obtained for a broad spectrum of substrates under mild conditions. The products obtained herein undergo diverse transformations. DFT calculations have been applied to propose a working model accounting for the origin of the stereoselectivity. Conflicts of Interest The authors declare no competing interests. Acknowledgments We thank the National Key Research and Development Program of China (2016YFA0202900), the National Basic Research Program of China (2015CB856600), the National Natural Science Foundation of China (21332009, 21572252, and 21772219), the Science and Technology Commission of Shanghai Municipality (16XD1404300, 18QA1404900, and 16490712200), the Strategic Priority Research Program (XDB20000000), the Key Research Program of Frontier Sciences (QYZDYSSWSLH012), and the Youth Innovation Promotion Association (2017302) of the Chinese Academy of Sciences for their generous financial support. References 1. Maehara S.; Simanjuntak P.; Kitamura C.; Ohashi K.; Shibuya H.Bioproduction of Cinchona Alkaloids by the Endophytic Fungus Diaporthe sp. Associated with Cinchona Ledgeriana.Chem. Pharm. Bull.2012, 60, 1301–1304. Google Scholar 2. Díaz J. G.; Sazatornil J. G.; Rodríguez M. L.; Mesía L. R.; Arana G. V.Five New Alkaloids from the Leaves of Remijia p eruviana.J. Nat. 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