Synthesis of Chiral Fluorides by Sequential Organocatalyzed Desymmetrization of Glutaric Anhydrides and Photoredox-Catalyzed Decarboxylic Fluorination

Abstract

We have developed an efficient method for the preparation of chiral fluorinated compounds by sequential organocatalyzed desymmetrization of 3-substituted glutaric anhydrides and photoredox-catalyzed decarboxylic fluorination. Chiral fluorides can be prepared in yields of up to 58% and with excellent enantioselectivities of up to 98% ee.

Key words

sequential catalysis - organocatalysis - photoredox catalysis - fluoro compounds - asymmetric catalysis - desymmetrization

Publication History

Received: 30 June 2020

Accepted after revision: 26 August 2020

Article published online:
22 September 2020

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• 12 Alkyl 3-Aryl-4-fluorobutanoates 3; General Procedure MTBE (15 mL) was added to a mixture of the appropriate 3-arylglutaric anhydride 1 (0.5 mmol) and catalyst A4 (0.05 mmol), and the mixture was stirred at –20 °C for 30 min. MeOH (5 mmol) was added, and stirring was continued at –20 °C for 24 h. When the reaction was complete, the solvent was evaporated under reduced pressure without further purification. The residue was dissolved in 1:1 MeCN–H₂O (5.0 mL) and Ir(ppy)₂(dtbbpy)PF₆ (I) (0.010 mmol, 2 mol%), Selectfluor (1.5 mmol), and Na₂HPO₄ (1 mmol) were added. The mixture was irradiated by 40 W (456 nm) blue LEDs for 12 h at 25 °C under N₂ until the reaction was complete. The reaction was then quenched with aq NaCl, the mixture was extracted with Et₂O, and the extracts were purified by preparative TLC.
• 13 Methyl (R)-4-Fluoro-3-phenylbutanoate (3a) Purified by preparative TLC (PE–EtOAc, 10:1) to give a white oil; yield: 56.8 mg (58%, ee 92%); [α]_D ²⁰ = –37.9 (c 2.15, CHCl₃). HPLC [Daicel Chiralpak OD-H, hexane–i-PrOH (98:2), flow rate: 1.0 mL/min, T = 25 °C, λ = 220 nm]: t _R = 8.292 min (major), t _R = 14.765 min (minor). ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.29 (m, 2 H), 7.28–7.22 (m, 3 H), 4.68–4.41 (m, 2 H), 3.62 (s, 3 H), 3.59–3.46 (m, 1 H), 2.89 (dd, J = 16.0, 6.9 Hz, 1 H), 2.70 (dd, J = 16.0, 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.2, 139.5, 128.7, 127.8, 127.4, 86.1 (J = 173.0 Hz), 51.7, 42.6, 36.3. ¹⁹F NMR (376 MHz, CDCl₃): δ = –219.8. ESI (FTMS): m/z [M + Na]⁺ calcd for C₁₁H₁₃FNaO₂: 219.0798; found: 219.0801.