A Concise Synthesis of (S)-γ-Fluoroleucine Ethyl Ester

Christian Nadeau; Francis Gosselin; Paul D. O’Shea; Ian W. Davies; Ralph P. Volante

doi:10.1055/s-2005-923593

LETTER

A Concise Synthesis of (S)-γ-Fluoroleucine Ethyl Ester

Christian Nadeau*^a, Francis Gosselin^a, Paul D. O’Shea^a, Ian W. Davies^b, Ralph P. Volante^b
^a Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Route Transcanadienne, Kirkland, Québec H9H 3L1, Canada
Fax: +1(514)4284936; e-Mail: christian_nadeau@merck.com;
^b Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA

Abstract

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Abstract

We report herein a six-step, chromatography-free, through-process for the asymmetric synthesis of (S)-γ-fluoroleucine ethyl ester sulfate salt (6) that proceeds in 25% overall yield from inexpensive ethyl glyoxylate. This approach features a Ti/Zn-catalyzed glyoxylate-ene reaction-olefin hydrofluorination-amine alkylation as key steps.

Key words

(S)-γ-fluoroleucine ethyl ester - asymmetric synthesis - enantioselective glyoxylate-ene reaction - olefin hydrofluorination - amine alkylation

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References

References and Notes

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Spectral data for compound 6: [α]_D ²⁰ +9.9 (c 0.52, EtOH) {lit.⁷: [α]_D ²⁵ +9.8 (c 0.52, EtOH)}; mp 104-105 °C. IR (NaCl, thin film): ν = 3419 (br), 2986, 2942, 1742, 1520, 1377, 1291, 1204, 1171, 1050 cm^-1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 8.34 (br, 3 H), 4.21 (q, J = 7.1 Hz, 2 H), 4.17 (app t, J = 6.7 Hz, 1 H), 2.21 (ddd, J = 6.6, 15.0, 22.9 Hz, 1 H), 2.09 (ddd, J = 6.6, 15.0, 20.8 Hz, 1 H), 1.41 (d, J = 21.6 Hz, 3 H), 1.41 (d, J = 21.6 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.0, 95.1 (d, J = 165.5 Hz), 62.5, 49.5 (d, J = 1.1 Hz), 41.4 (d, J = 21.8 Hz), 26.9 (d, J = 23.6 Hz), 26.8 (d, J = 23.7 Hz), 14.3. ¹⁹F NMR (375 MHz, DMSO-d ₆): δ = -138.3. HRMS (ES): m/z calcd for [C₈H₁₆FNO₂ + Na]⁺: 200.1063; found: 200.1067. Enantiomeric excess was determined by HPLC with a 4.6 mm × 15.0 cm Crownpack CR(+) column (0.3% HClO₄ in H₂O pH = 1.5-1.6, hold 20 min, 1 mL/min, 205 nm, 25 °C; R enantiomer t _R = 5.6 min; S enantiomer t _R = 7.6 min; 96% ee.