Asymmetric Synthesis of cis-(S,R)-3-Amino-4-fluoro-1-methylpyrrolidine

Abstract

The development of the stereoselective synthesis of cis-(S,R)-3-amino-4-fluoro-1-methylpyrrolidine is described starting from chiral, non-racemic 1-[(3S,4S)-3-azido-4-hydroxypyrrolidin-1-yl]-2,2,2-trifluoroethan-1-one. Two sets of deoxyfluorination conditions are developed for achieving inversion of the chiral center with high or complete stereoselectivity.

Key words

stereoselective - azides - deoxyfluorination - sulfuryl fluoride - pyrrolidines

• References and Notes

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• 10 Characterization of 1. Yield: 99 mg (94%); white solid; mp 264–266 °C. ¹H NMR (400 MHz, D₂O): δ = 5.55 (dt, J = 51.7, 3.5 Hz, 1 H), 4.36 (dtd, J = 23.4, 8.9, 3.5 Hz, 1 H), 4.01 (m, 1 H), 3.88 (m, 1 H), 3.82–3.52 (m, 2 H), 3.00 (s, 3 H). ¹³C NMR (101 MHz, D₂O): δ = 90.4 (d, J = 183.82 Hz), 59.6 (d, J = 21.21 Hz), 54.4, 50.3 (d, J = 17.17 Hz), 42.6. ¹⁹F NMR (376 MHz, D₂O): δ = –196.7. ¹⁹F NMR (376 MHz, CD₃OD): δ = –198.1. HRMS (ESI): m/z [M + H – 2 HCl]⁺ calcd for C₅H₁₂FN₂: 119.0979; found: 119.0978.