Enantioselective Nucleophilic Aromatic Substitution Reaction of Azlactones to Synthesize Quaternary α-Amino Acid Derivatives

Abstract

An asymmetric organocatalytic nucleophilic aromatic substitution reaction of azlactones with electron-deficient aryls was established. A variety of α-aryl α-alkyl α-amino acid esters and peptides were obtained in decent yields and stereoselectivities. A new bifunctional catalytic mode involving charge-transfer interaction and hydrogen bonding is proposed to explain the enantioselectivity.

Key words

amino acid esters - peptides - asymmetric catalysis - S_NAr reaction - electron donor–accepter complexes - organocatalysis

Publication History

Received: 20 October 2020

Accepted after revision: 25 November 2020

Accepted Manuscript online:
25 November 2020

Article published online:
16 December 2020

• References and Notes

• 1a Venkatraman J, Shankaramma SC, Balaram P. Chem. Rev. 2001; 101: 3131
• 1b Licini G, Prins LJ, Scrimin P. Eur. J. Org. Chem. 2005; 2005: 969
• 1c Cardillo G, Gentilucci L, Tolomelli A. Mini-Rev. Med. Chem. 2006; 6: 293
• 1d Hedges JB, Ryan KS. Chem. Rev. 2020; 120: 3161
• 2 Cativiela C, Ordóñez M, Viveros-Ceballos JL. Tetrahedron 2020; 76: 130875
• 3a Johansson CC. C, Colacot TJ. Angew. Chem. Int. Ed. 2010; 49: 676
• 3b Hao Y.-J, Hu X.-S, Zhou Y, Zhou J, Yu J.-S. ACS Catal. 2020; 10: 955

For selected examples of asymmetric syntheses of quaternary amino acid derivatives from amino acid derivatives by ‘chiral memory’, see:
• 4a Tomohara K, Yoshimura T, Hyakutake R, Yang P, Kawabata T. J. Am. Chem. Soc. 2013; 135: 13294
• 4b Atkinson RC, Fernández-Nieto F, Roselló MJ, Clayden J. Angew. Chem. Int. Ed. 2015; 54: 8961
• 4c Kasamatsu K, Yoshimura T, Mandi A, Taniguchi T, Monde K, Furuta T, Kawabata T. Org. Lett. 2017; 19: 352
• 4d Costil R, Fernández-Nieto F, Atkinson RC, Clayden J. Org. Biomol. Chem. 2018; 16: 2757
• 4e Leonard DJ, Ward JW, Clayden J. Nature 2018; 562: 105
• 4f Mambrini A, Gori D, Kouklovsky C, Kim H, Yoshida J.-i, Alezra V. Eur. J. Org. Chem. 2018; 6754
• 5a Bunnett JF, Zahler RE. Chem. Rev. 1951; 49: 273
• 5b Terrier F. Modern Nucleophilic Aromatic Substitution . Wiley-VCH; Weinheim: 2013
• 5c Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds. Mortier J. Wiley-VCH; Weinheim: 2016
• 5d Asymmetric Dearomatization Reactions . You SL. Wiley-VCH; Weinheim: 2016
• 6a Shirakawa S, Yamamoto K, Tokuda T, Maruoka K. Asian J. Org. Chem. 2014; 3: 433
• 6b Shirakawa S, Yamamoto K, Maruoka K. Angew. Chem. Int. Ed. 2015; 54: 838
• 7 Li G, Sun W, Li J, Jia F, Hong L, Wang R. Chem. Commun. 2015; 51: 11280
• 8a D’Anello M, Erba E, Gelmi ML, Pocar D. Chem. Ber. 1988; 121: 67
• 8b Teegardin KA, Weaver JD. Chem. Commun. 2017; 53: 4771
• 8c Marra IF. S, de Castro PP, Amarante GW. Eur. J. Org. Chem. 2019; 5830
• 8d Wang Y.-N, Xiong Q, Lu LQ, Zhang Q.-L, Wang Y, Lan Y, Xiao W.-J. Angew. Chem. Int. Ed. 2019; 58: 11013
• 8e Ma C, Sheng F.-T, Wang H.-Q, Deng S, Zhang Y.-C, Jiao Y.-C, Tan W, Shi F. J. Am. Chem. Soc. 2020; 142: 15686
• 8f Xie M.-S, Huang B, Li N, Tian Y, Wu X.-X, Deng Y, Qu G.-R, Guo H.-M. J. Am. Chem. Soc. 2020; 142: 19226
• 9a Bella M, Kobbelgaard S, Jørgensen KA. J. Am. Chem. Soc. 2005; 127: 3670
• 9b Bella M, Kobbelgaard S, Jørgensen KA. J. Org. Chem. 2006; 71: 4980
• 9c Armstrong RJ, Smith MD. Angew. Chem. Int. Ed. 2014; 53: 12822
• 9d Shirakawa S, Koga K, Tokuda T, Yamamoto K, Maruoka K. Angew. Chem. Int. Ed. 2014; 53: 6220
• 9e Ding Q, Wang Q, He H, Cai Q. Org. Lett. 2017; 19: 1804
• 9f Cardenas MM, Toenjes ST, Nalbandian CJ, Gustafson JL. Org. Lett. 2018; 20: 2037
• 9g Kondoh A, Aoki T, Terada M. Chem. Eur. J. 2018; 24: 13110
• 10a Dong S, Liu X, Chen X, Mei F, Zhang Y, Gao B, Lin L, Feng X. J. Am. Chem. Soc. 2010; 132: 10650 ; corrigendum: J. Am. Chem. Soc. 2011, 133, 13761
• 10b Dong S, Liu X, Zhang YL, Lin L, Feng X. Org. Lett. 2011; 13: 5060
• 10c Dong S, Liu X, Zhu Y, He P, Lin L, Feng X. J. Am. Chem. Soc. 2013; 135: 10026 ; corrigendum: J. Am. Chem. Soc. 2013, 135, 15964
• 10d Yu K, Liu X, Lin X, Lin L, Feng X. Chem. Commun. 2015; 51: 14897
• 10e Zhang Q, Guo S, Yang J, Yu KR, Feng X, Lin L, Liu X. Org. Lett. 2017; 19: 5826
• 10f Ruan S, Lin X, Xie L, Lin L, Feng X, Liu X. Org. Chem. Front. 2018; 5: 32
• 10g Xie L, Dong S, Zhang Q, Feng X, Liu X. Chem. Commun. 2019; 55: 87
• 11 CCDC 1973876 contains the supplementary crystallographic data for compound 3d. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures

For selected reviews, see
• 12a Dong S, Feng X, Liu X. Chem. Soc. Rev. 2018; 47: 8525
• 12b Chou H.-C, Leow D, Tan C.-H. Chem. Asian J. 2019; 14: 3803
• 13 Chiral Guanidine-Catalyzed Asymmetric S_NAr Reaction; General Procedure A dry tube was charged with G-3 (8.3 mg, 15 mol%), K₃PO₄·H₂O (116 mg, 0.5 mmol), and the appropriate fluoroarene 2 (0.2 mmol). Under a N₂ atmosphere, CHCl₃ (0.3 mL) was added, and the mixture was stirred at 35 °C for 30 min, then cooled to –60 °C for 10 min. The appropriate azlactone 1 (0.1 mmol) was added with stirring, and the mixture was stirred at –60 °C for about 72 h until 1 was fully consumed (TLC). MeOH (1 mL) and DAMP (1.2 mg, 10 mol%) were then added, and the mixture was stirred for about 15 mins at 35 °C. The product was purified by flash column chromatography [silica gel, PE–DCM (1:1)]. Methyl α-(2,4-dinitrophenyl)-N-(4-Fluorobenzoyl)-l-phenylalaninate (3b) White solid; yield: 39.7 mg (85%; 89% ee); mp 186–188 °C; [α]_D ¹⁶ –26.4 (c 0.664, CH₂Cl₂). UPC² (chiral IB-3 column, CO₂ /MeOH = 90:10, flow rate 1.5 mL/min, λ = 254 nm): t _R (minor) = 4.1 min; t _R (major) = 5.3 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.57–8.51 (m, 1 H), 8.46–8.40 (m, 1 H), 8.29–8.21 (m, 1 H), 7.60–7.51 (m, 2 H), 7.32–7.19 (m, 3 H), 7.14–6.93 (m, 5 H), 4.33 (d, J = 18.8 Hz, 1 H), 3.85 (s, 3 H), 3.75 (d, J = 18.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.4, 166.4 (d, J = 251.7 Hz), 165.6, 148.3, 147.1, 140.3, 133.4, 130.8, 130.1, 129.4 (d, J = 9.1 Hz), 129.2 ( d, J = 3.2 Hz), 128.5, 128.0, 126.4, 119.8, 116.0 (d, J = 22.1 Hz), 64.0, 53.8, 40.5. ¹⁹F NMR (376 MHz, CDCl₃): δ = –106.6. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₃H₁₉FN₃O₇ = 468.1202; found: 468.1191.