Asymmetric Synthesis of β-Indolyl Cyclopentanones and

Mar 18, 2019 - −OH group was assigned as cis to the indolyl moiety by NOE analysis.12 The ... Verma, A. K.; Choi, E. H. Biomedical Importance of Ind...
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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Asymmetric Synthesis of β‑Indolyl Cyclopentanones and Cyclopentylamides with an All-Carbon Quaternary Stereocenter via Chiral Phosphoric Acid Catalyzed Friedel−Crafts Alkylation Reactions Wei Liu,†,‡ Subramani Rajkumar,† Weihu Wu,† Ziyu Huang,† and Xiaoyu Yang*,† †

School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China University of Chinese Academy of Sciences, Beijing 100049, China

‡

Org. Lett. Downloaded from pubs.acs.org by UNIV PARIS-SUD on 04/25/19. For personal use only.

S Supporting Information *

ABSTRACT: The asymmetric Friedel−Crafts alkylation reactions of indoles with β-substituted cyclopentenimines enabled by chiral phosphoric acid catalysis has been developed, which affords adducts possessing an all-carbon stereocenter with high levels of enantioselectivities. Furthermore, the addition products could be readily converted into two types of useful but previously challenging chiral building blocks, such as β-alkyl-β-indolyl cyclopentanones and β-alkyl-β-indolyl cyclopentylamides, in one pot via in situ hydrolysis or reduction without erosion of chiral information. to β-substituted cyclopentenones has been reported, probably due to the relative low reactivity and challenge in terms of the control of enantioselectivity in the conjugate additions of cyclopentenones.6 Moreover, the racemic version of this reaction has only recently been developed, and the desired product was obtained only in 37% yield, demonstrating the low reactivity of cyclopentenone upon indole addition (Figure 1c).7 With our continuous interest in asymmetric synthesis of βindolyl cyclopentanones and cyclopentenamide derivatives,8 our attention was drawn by this challenging asymmetric reaction. With the well-known activation and stereoselectivity control ability of imine substrates by chiral phosphoric acid catalyst,9 we envision that the conjugate addition of indoles to β-substituted cyclopentenimines under chiral phosphoric acid catalysis would proceed efficiently and stereoselectively,10 establishing a protocol for asymmetric construction of chiral all-carbon quaternary stereocenters. Subsequent facile hydrolysis or reduction of the chiral imine products would yield two types of valuable but previously challenging chiral building blocks, namely β-alkyl-β-indolyl cyclopentanones and β-alkylβ-indolyl cyclopentylamides (Figure 1, bottom). Herein, we report our success in achieving asymmetric construction of an all-carbon stereocenter by asymmetric Friedel−Crafts alkylations of indoles with β-substituted cyclopentenimines under chiral phosphoric acid catalysis. 3-Methylcyclopentenone was chosen as a model cyclic enone substrate that was converted into α,β-unsaturated

T

he indole nucleus is a prominent and privileged structure in numerous natural products and synthetic compounds with significant biological and pharmacological activities.1 Therefore, the synthesis of indole derivatives has been an important research topic in organic and medicinal chemistry for a long time. Direct enantioselective functionalization of indoles is a straightforward and efficient approach to access chiral indole derivatives. In the past two decades, a great number of catalytic asymmetric indole functionalization reactions have been developed by researchers,2 for which asymmetric Friedel−Crafts alkylation represents as one of the most powerful strategies. Numerous elegant methodologies have been developed by enantioselective additions of indoles to various electrophiles, such as activated alkenes, carbonyl compounds, and imines. However, highly enantioselective 1,4additions of indoles to β,β-disubstituted activated alkenes giving an all-carbon chiral quaternary stereocenter3 are challenging4 due to the intrinsic steric hindrance. Recently, some elegant methods have been developed on asymmetric Friedel−Crafts alkylations of indoles with β,β-disubstituted activated alkenes for construction of all-carbon stereocenters; however, two electron-withdrawing groups are essentially required to activate the alkenes5 (Figure 1, a). For this reason, asymmetric construction of all-carbon stereocenters via conjugate additions of indoles to cyclic electron-deficient olefins is rare. A single example of asymmetric conjugate addition of indole to β-substituted cyclohexenone has been reported so far, which only provided the product with 74:26 er upon chiral primary amine catalysis under high-pressure conditions (Figure 1b).5a Furthermore, to the best of our knowledge, no example of enantioselective addition of indoles © XXXX American Chemical Society

Received: March 18, 2019

A

DOI: 10.1021/acs.orglett.9b00963 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

Figure 1. Asymmetric construction of chiral all-carbon quaternary stereocenters by Friedel−Crafts alkylations of indoles.

entry

R

cat.

sol

yieldb (%)

erc

1 2 3 4 5 6 7 8 9 10 11 12 13 14d 15d,e 16e,f

4-Me-Ph 4-Me-Ph 4-Me-Ph 4-Me-Ph 4-Me-Ph 4-Me-Ph 4-Me-Ph 4-Me-Ph 4-Me-Ph 4-F-Ph 4-OMe-Ph 2-Me-Ph tBu 4-OMe-Ph 4-OMe-Ph 4-OMe-Ph

A1 A2 A3 A4 A5 B1 B1 B1 B1 B1 B1 B1 B1 B1 B1 B1

toluene toluene toluene toluene toluene toluene DCM CHCl3 Et2O toluene toluene toluene toluene toluene toluene toluene

90 52 84 89 70 74 66 64 43 87 95 92 94 81 65 70

54:46 65.5:34.5 54.5:45.5 54:46 72.5:27.5 76:24 67.5:32.5 65:35 67.5:32.5 66:34 76.5:23.5 65:35 53:47 90:10 90.5:9.5 93.5:6.5

a

11

Reactions were performed with 1 (0.2 mmol), 2a (0.1 mmol), catalyst (15 mol %), and 4 Å molecular sieves (30 mg) in solvent (1 mL) at ambient temperature. bYields were determined by 1H NMR using DME as internal standard. cEnantiomeric ratio (er) was determined by chiral HPLC analysis. dReactions were performed at −20 °C. eReactions were performed in 2 mL of solvent. fReactions were performed at −38 °C.

12

ketimines 1 by condensation with various sulfonamides (Table 1). Initially, we tested reactions between N-Ts cyclopentenimine (existed as 3:2 inseparable E/Z mixture, 0.2 mmol) with indole (2a, 0.1 mmol) in the presence of TRIP catalyst (A1, 15 mol %) in toluene (1 mL) at ambient temperature. After the mixture was stirred overnight, the conjugate addition product β-indolyl cyclopentylimine was obtained in high yield without detection of the 1,2-addition product,13 which existed as an inseparable E/Z mixture of imines as well. Further hydrolysis of the imines mixture with basic alumina14 afforded β-indolyl-β-methyl cyclopentanone (3a) in 90% yield, albeit with a negligible enantiomeric ratio (er) (entry 1). Further screening of various chiral phosphoric acid catalysts (entries 2−6) indicated the 3,3′-bis(1-naphthyl) H8-BINOL derived catalyst (S)-B1 gave the best performance, which afforded the product 3a with 76:24 er after hydrolysis. Investigation of the solvents was also performed, and toluene was chosen as the optimal solvent (entries 7−9). Next, we studied the effect of arylsulfonyl groups (e.g., electron-donating aryl groups, electron-withdrawing aryl groups and sterically hindered aryl groups) attached at the imine site (entries 10− 12), which indicated p-methoxylphenylsulfonyl group substituted one (existed as 3:2 E/Z inseparable mixture) provided the product with the best enantioselectivity and excellent yield. Interestingly, the tert-butylsulfonyl-substituted substrate only provided the product with negligible er (entry 13). With the higher reactivity observed for the p-methoxylphenylsulfonyl group substituted substrate, decreasing the reaction temperature to −20 °C afforded the product 3a in 80% yield with 90:10 er (entry 14). Switching the concentration of the reaction mixture from 0.1 to 0.05 M led to a minor improvement in enantioselectivity (90.5:9.5 er, entry 15).

Finally, further lowering the reaction temperature to −38 °C with longer reaction time (72 h) led to the optimal conditions under which the product 3a could be obtained in 70% yield with 93.5:6.5 er (entry 16). The absolute configuration of the newly generated all-carbon quaternary stereocenter was determined as R, which was unambiguously confirmed by Xray crystallography.12 With the optimal conditions in hand, we turned our attention to exploring the substrate scope of this reaction. Thus, the reactions of cyclopentenimine 1a (E/Z mixture) with a range of substituted indoles under the optimal conditions were investigated. As shown in Scheme 1, different substitutions at the C-5 position of indoles were well tolerated, including the electron-neutral −Me group (3b), electrondonating −OMe group (3c), electron-withdrawing −F group (3d), and diversifiable −Cl and −Br groups (3e and 3f). Moreover, C-6-substituted indoles are also compatible substrates, which provided the cyclopentanone products in good yields and with high enantioselectivities (3g−k). It is worth mentioning that reaction with C-6-COOMe-substituted indole gave the product in almost enantiomeric pure form (>99.5:0.5 er, 3l). The reactions between cyclopentenimine 1a with other substituted indoles (2-, 4-, and 7-substituted ones) were also attempted, however which gave poor performances.12 The tolerance of different substitutions at the C-3 position of cyclopentenimines 1 (e.g., ethyl and n-propyl B

DOI: 10.1021/acs.orglett.9b00963 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 1. Substrate Scope for β-Alkyl-β-indolyl Cyclopentanonesa,b

Scheme 2. Substrate Scope for β-Alkyl-β-indolyl Cyclopentylamidesa,b

a Reactions were performed with 1a (0.2 mmol), 2 (0.1 mmol), catalyst B1 (0.015 mmol), 4 Å molecular sieve (30 mg) in toluene (2 mL) at −38 °C for 72 h, after which the reactions were cooled to −78 °C and reduced with L-Selectride (1.0 N, 1 mL) for 12 h. bIsolated yields. dr was determined by crude 1H NMR analysis. er was determined by HPLC analysis using a chiral stationary phase.

indole addition step would provide β-indolyl cyclopentylamides with a C-3 quaternary chiral center. As shown in Scheme 2, a variety of substituted indoles were investigated as nucleophiles. After their conjugate additions with cyclopentenimine 1a under the optimal conditions, the reaction mixtures were subsequently cooled to −78 °C and subjected to reduction with L-Selectride, which afforded the cyclopentylamides with good diastereoselectivities and high enantioselectivities (4a−e). To further demonstrate the applications of these reactions, the derivatizations of the chiral products were investigated (Scheme 3). Stereoselective reduction of the carbonyl group in

a

Reactions were performed with 1 (0.2 mmol), 2 (0.1 mmol), catalyst (S)-B1 (0.015 mmol), and 4 Å molecular sieves (30 mg) in toluene (2 mL) at −38 °C for 72 h, after which the reaction was stirred with basic alumina (1 g) for 8 h at rt. bIsolated yield. er was determined by HPLC analysis using a chiral stationary phase. cReactions were performed at −30 °C. dReactions were performed at room temperature.

Scheme 3. Derivatizations of the Chiral Products

groups) was also investigated. However, performing these reactions under the optimal conditions (−38 °C) barely afforded the desired products, again demonstrating the vulnerability of these reactions to steric hindrance. The desired products could only be obtained when these reactions were performed at ambient temperature; however, the enantiomeric ratios were only moderate (3m−o). The extension of these conditions to β-methyl cyclohexenimine substrate was also not successful, which provided the product in both low yield and enantioselectivity.12 In addition to the synthesis of cyclopentanone derivatives, we aimed to transform the addition products into β-indolyl cyclopentylamines, which are a class of conformationally restricted homotryptamine analogues with activity as selective serotonin reuptake inhibitors (SSRIs) with potent activities.15 For instance, the (1S,3R)-5-CN indole substituted derivative 5 was shown to be 10-fold more active than the straight-chain homotryptamine (Scheme 2). However, the biological activities of β-indolyl cyclopentylamine analogues with a C-3 quaternary stereocenter have never been studied, probably due to the lack of efficient methods for their asymmetric synthesis. We envisioned that stereoselective reduction of the E/Z mixture of the imine intermediates obtained in the asymmetric

3a with L-Selectride at −78 °C readily provided the corresponding cyclopentanol 6a in 99% yield with 85:15 dr, without any erosion in er. The relative stereochemistry of the −OH group was assigned as cis to the indolyl moiety by NOE analysis.12 The p-methoxylphenylsulfonyl group in cyclopentylamide 4a could be facilely removed by treatment with SmI2 to give cyclopentylamine 7a with a C-3 quaternary stereocenter, whose relative configuration was also confirmed by NOE analysis. C

DOI: 10.1021/acs.orglett.9b00963 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Synthesis of Enantiopure Indole Derivatives. Synthesis 2015, 47, 1990−2016. (e) Chen, J.-B.; Jia, Y.-X. Recent progress in transitionmetal-catalyzed enantioselective indole functionalizations. Org. Biomol. Chem. 2017, 15, 3550−3567. (3) For reviews on asymmetric synthesis of all-carbon quaternary stereocenters, see: (a) Douglas, C. J.; Overman, L. E. Catalytic asymmetric synthesis of all-carbon quaternary stereocenters. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5363−5367. (b) Christoffers, J.; Baro, A. Stereoselective Construction of Quaternary Stereocenters. Adv. Synth. Catal. 2005, 347, 1473−1482. (c) Trost, B. M.; Jiang, C. Catalytic Enantioselective Construction of All-Carbon Quaternary Stereocenters. Synthesis 2006, 369−396. (d) Das, J. P.; Marek, I. Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems. Chem. Commun. 2011, 47, 4593−4623. (e) Quasdorf, K. W.; Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 2014, 516, 181− 191. (4) For selected examples not involving asymmetric addition of indoles to activated alkenes, see: (a) Qiu, H.; Li, M.; Jiang, L.-Q.; Lv, F.-P.; Zan, L.; Zhai, C.-W.; Doyle, M. P.; Hu, W.-H. Highly enantioselective trapping of zwitterionic intermediates by imines. Nat. Chem. 2012, 4, 733−738. (b) Chen, D.-F.; Zhao, F.; Hu, Y.; Gong, L.Z. C-H Functionalization/Asymmetric Michael Addition Cascade Enabled by Relay Catalysis: Metal Carbenoid Used for C-C Bond Formation. Angew. Chem., Int. Ed. 2014, 53, 10763−10767. (c) Jing, C.; Xing, D.; Hu, W. Catalytic Asymmetric Four-Component Reaction for the Rapid Construction of 3,3-Disubstituted 3-Indol3′-yloxindoles. Org. Lett. 2015, 17, 4336−4339. (d) Zhang, C.; Santiago, C. B.; Crawford, J. M.; Sigman, M. S. Enantioselective Dehydrogenative Heck Arylations of Trisubstituted Alkenes with Indoles to Construct Quaternary Stereocenters. J. Am. Chem. Soc. 2015, 137, 15668−15671. (e) Zhao, W.; Wang, Z.; Chu, B.; Sun, J. Enantioselective Formation of All-Carbon Quaternary Stereocenters from Indoles and Tertiary Alcohols Bearing A Directing Group. Angew. Chem., Int. Ed. 2015, 54, 1910−1913. (f) Tsuchida, K.; Senda, Y.; Nakajima, K.; Nishibayashi, Y. Construction of Chiral Tri- and Tetra-Arylmethanes Bearing Quaternary Carbon Centers: CopperCatalyzed Enantioselective Propargylation of Indoles with Propargylic Esters. Angew. Chem., Int. Ed. 2016, 55, 9728−9732. (5) (a) Łyżwa, D.; Dudziński, K.; Kwiatkowski, P. High-Pressure Accelerated Asymmetric Organocatalytic Friedel−Crafts Alkylation of Indoles with Enones: Application to Quaternary Stereogenic Centers Construction. Org. Lett. 2012, 14, 1540−1543. (b) Gao, J.-R.; Wu, H.; Xiang, B.; Yu, W.-B.; Han, L.; Jia, Y.-X. Highly Enantioselective Construction of Trifluoromethylated All-Carbon Quaternary Stereocenters via Nickel-Catalyzed Friedel−Crafts Alkylation Reaction. J. Am. Chem. Soc. 2013, 135, 2983−2986. (c) Chen, L.-A.; Tang, X.; Xi, J.; Xu, W.; Gong, L.; Meggers, E. Chiral-at-Metal Octahedral Iridium Catalyst for the Asymmetric Construction of an All-Carbon Quaternary Stereocenter. Angew. Chem., Int. Ed. 2013, 52, 14021− 14025. (d) Arai, T.; Yamamoto, Y.; Awata, A.; Kamiya, K.; Ishibashi, M.; Arai, M. A. Catalytic Asymmetric Synthesis of Mixed 3,3′Bisindoles and Their Evaluation as Wnt Signaling Inhibitors. Angew. Chem., Int. Ed. 2013, 52, 2486−2490. (e) Weng, J.-Q.; Deng, Q.-M.; Wu, L.; Xu, K.; Wu, H.; Liu, R.-R.; Gao, J.-R.; Jia, Y.-X. Asymmetric Friedel−Crafts Alkylation of α-Substituted β-Nitroacrylates: Access to β2,2-Amino Acids Bearing Indolic All-Carbon Quaternary Stereocenters. Org. Lett. 2014, 16, 776−779. (f) Mori, K.; Wakazawa, M.; Akiyama, T. Stereoselective construction of all-carbon quaternary center by means of chiral phosphoric acid: highly enantioselective Friedel-Crafts reaction of indoles with β,β-disubstituted nitroalkenes. Chem. Sci. 2014, 5, 1799−1803. (g) Li, N.-K.; Kong, L.-P.; Qi, Z.-H.; Yin, S.-J.; Zhang, J.-Q.; Wu, B.; Wang, X.-W. Friedel−Crafts Reaction of Indoles with Isatin-Derived β,γ-Unsaturated α-Keto Esters Using a BINOL-Derived Bisoxazoline (BOX)/Copper(II) Complex as Catalyst. Adv. Synth. Catal. 2016, 358, 3100−3112. (6) Asymmetric conjugate additions to 2-cyclopentenones are considered to be more challenging in general; for selected examples, see: (a) Perdicchia, D.; Jørgensen, K. A. Asymmetric Aza-Michael

In conclusion, we have successfully established an asymmetric protocol for the construction of a chiral all-carbon quaternary center via asymmetric Friedel−Crafts reactions of indoles with β-substituted cyclopentenimines under chiral phosphoric acid catalysis. The chiral adducts could be readily transformed into chiral β-alkyl-β-indolyl cyclopentanones and β-alkyl-β-indolyl cyclopentylamides upon in situ hydrolysis or reduction in one pot, respectively. With the success of applying this strategy to enhance reaction reactivity and also to achieve high levels of stereoselectivity control, we anticipate further application of this strategy to other challenging asymmetric conjugate addition reactions, which are currently under investigation in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00963. Experimental procedures, NMR spectra, HPLC traces, and X-ray and analytical data for all new compounds (PDF) Accession Codes

CCDC 1902200 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xiaoyu Yang: 0000-0002-0756-0671 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge NSFC (Grant No. 21702138), Shanghai Pujiang Program (Grant No. 17PJ1406300), “Thousand Talents Plan” Youth program, and the ShanghaiTech University startup funding for financial support. Dr. Na Yu (Analysis Center, School of Physical Science and Technology, ShanghaiTech University) is acknowledged for assistance with single-crystal crystallography. We thank Prof. Baihua Ye for manuscript proofreading and helpful discussions.

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DOI: 10.1021/acs.orglett.9b00963 Org. Lett. XXXX, XXX, XXX−XXX