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

• 1a Huchet QA, Kuhn B, Wagner B, Kratochwil NA, Fischer H, Kansy M, Zimmerli D, Carreira EM, Müller K. J. Med. Chem. 2015; 58: 9041
• 1b Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 2a Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
• 2b Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J. Med. Chem. 2015; 58: 8315
• 3 Carreira EM, Fessard TC. Chem. Rev. 2014; 114: 8257
• 4a Marigo M, Fielenbach D, Braunton A, Kjærsgaard A, Jørgensen KA. Angew. Chem. Int. Ed. 2005; 44: 3703
• 4b Beeson TD, MacMillan DW. C. J. Am. Chem. Soc. 2005; 127: 8826
• 4c Steiner DD, Mase N, Barbas CF. Angew. Chem. Int. Ed. 2005; 44: 3706
• 4d Enders D, Huttl MR. M. Synlett 2005; 991

For a comprehensive review on amine catalysis, see:
• 4e Melchiorre P, Marigo M, Carlone A, Bartoli G. Angew. Chem. Int. Ed. 2008; 47: 6138

For initial fluorinations of α-branched aldehydes with up to 90% ee and moderate yields, see:
• 5a Brandes S, Niess B, Bella M, Prieto A, Overgaard J, Jørgensen KA. Chem. Eur. J. 2006; 12: 6039
• 5b Witten MR, Jacobsen EN. Org. Lett. 2015; 17: 2772
• 5c Shibatomi K, Kitahara K, Okimi T, Abe Y, Iwasa S. Chem. Sci. 2016; 7: 1388

For recent findings on organocatalytic fluorination of aldehydes bearing two chiral centers, see:
• 6a Fjelbye K, Marigo M, Clausen RP, Juhl K. Org. Lett. 2016; 18: 1170
• 6b Hu X, Lawer A, Peterson MB, Iranmanesh H, Ball GE, Hunter L. Org. Lett. 2016; 18: 662
• 7 For the synthesis of the spirocyclic structures, see: Fjelbye K, Marigo M, Clausen RP, Juhl K. Synlett 2016; DOI: 10.1055/s-0036-1588902.
• 8 For further details on the determination of absolute stereochemistry, see the Supporting Information.
• 9a Bahmanyar S, Houk KN. J. Am. Chem. Soc. 2001; 123: 11273
• 9b Mangion IK, Northrup AB, MacMillan DW. C. Angew. Chem. Int. Ed. 2004; 43: 6722
• 10 For a mechanistic study of enamine catalysis on α-branched aldehydes, see: Bures J, Armstrong A, Blackmond DG. Chem. Sci. 2012; 3: 1273
• 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).