Enantioselective Fluorination of Spirocyclic β-Prolinals Using Enamine Catalysis

Abstract

A series of spirocyclic carbaldehydes were successfully fluorinated using enamine catalysis, furnishing the corresponding tertiary fluorides in both high yields and enantioselectivities. The fluorinated spirocycles provide a set of novel building blocks interesting from a medicinal chemistry point of view.

Key words

spirocycles - organocatalysis - enantioselective catalysis - fluorination - asymmetric synthesis

• References and Notes

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• 11 General Procedure for the Enantioselective Fluorination of Aldehydes To a solution of 1a–h in MTBE (0.5 M) was added catalyst (R)-9 (10 mol%), and the mixture was stirred for 5 min at r.t. after which N-fluorobenzenesulfonimide (NFSI, 1.2 equiv) was added, and the resulting mixture was stirred at 40 °C for 18 h. Subsequently, the reaction mixture was diluted with MTBE and passed through a filter directly onto SiO₂ for flash chromatographic purification to yield the desired product. Benzyl (S)-8-Fluoro-8-formyl-2-oxa-6-azaspiro[3.4]octane-6-carboxylate (2a) The enantioselective fluorination procedure provided 2a (76 mg, 0.259 mmol, 71% yield, 79% ee) as a colorless oil. ¹H NMR (600 MHz, CDCl₃): δ = 10.10–10.07 (m, 1 H), 7.39–7.30 (m, 5 H), 5.14–5.12 (m, 2 H), 4.88–4.39 (m, 4 H), 4.06–3.50 (m, 4 H); conformers and hydrate formation. ¹³C NMR (151 MHz, CDCl₃): δ = 196.7 (d, J = 33.2 Hz), 196.4 (d, J = 33.0 Hz), 154.6, 154.4, 136.3, 136.0, 128.6, 128.5, 128.5, 128.3, 128.2, 128.1, 128.0, 97.6, 97.5, 96.3, 96.2, 96.1, 96.0, 76.4–76.2 (m), 74.2–73.7 (m), 73.2–72.8 (m), 67.5, 67.3, 55.9, 55.7, 55.1, 54.9, 53.4, 52.9, 51.8–51.0 (m), 50.9, 29.8–29.0 (m); conformers. ¹⁹F NMR (471 MHz, CDCl₃): δ = –173.08, –174.16; conformers. ESI-HRMS: m/z calcd for C₁₅H₁₇FNO₄ [MH⁺]: 294.1136; found: 294.1137. [α]_D ²² +9.9 (c 0.27, CHCl₃, 79% ee).