Practical and Efficient Route to (S)-γ-Fluoroleucine

Vouy Linh Truong; Jacques Yves Gauthier; Michael Boyd; Bruno Roy; John Scheigetz

doi:10.1055/s-2005-868494

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Synlett 2005(8): 1279-1280
DOI: 10.1055/s-2005-868494

LETTER

Practical and Efficient Route to (S)-γ-Fluoroleucine

Vouy Linh Truong*, Jacques Yves Gauthier*, Michael Boyd, Bruno Roy, John Scheigetz
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Quebec H9R 4P8, Canada
Fax: +1(514)4284900; e-Mail: vouylinh_truong@merck.com;

Further Information

Publication History

Received 18 January 2005
Publication Date:
03 May 2005 (online)

Abstract
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Abstract

A practical and efficient route to (S)-γ-fluoroleucine was developed via compound 9. Introduction of the fluorine was achieved using N,N-diethylaminosulfur trifluoride (DAST) treatment on a tertiary alcohol 8.

Key words

(S)-γ-fluoroleucine - methylmagnesium bromide - N,N-diethylaminosulfur trifluoride - oxazolidinone - continuous liquid-liquid extraction

References

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7

Experimental Procedure for the Synthesis of Compound 8.
MeMgBr (681 mL of 3 M solution in Et₂O, 2.04 mol) was added to a mixture of toluene (1 L) and THF (1 L) at -20 °C. A solution of the benzyl ester 7 (120 g, 510 mmol) in THF (500 mL) was added dropwise maintaining the temperature below -10 °C and the mixture was aged at 0 °C for 2 h. The mixture was slowly added to a mixture of H₂O (3 L) and HOAc (600 mL) and the mixture was stirred at r.t. for 2 h. The aqueous layer was separated and the organic layer was extracted with H₂O (2 × 600 mL). The product was extracted from the combined aqueous layers using CH₂Cl₂ and a continuous extractor (2 d). The CH₂Cl₂ extract was evaporated to dryness and co-evaporated with n-heptane. The residue was purified by chromatography on silica gel using EtOH and CH₂Cl₂ (1:25) to afford compound 8 (62 g, 72%). [α]_D ²⁰ -7.0 (c 1.0, MeOH). ¹H NMR (500 MHz, CD₃COCD₃): δ = 1.25 (3 H, s), 1.27 (3 H, s), 1.73 (1 H, dd, J = 13.9, 6.1 Hz), 1.81 (1 H, dd, J = 13.9, 6.6 Hz), 3.67 (1 H, s), 4.01 (1 H, dd, J = 8.4, 7.3 Hz), 4.12-4.18 (1 H, m), 4.49 (1 H, dd, J = 8.3, 8.3 Hz), 6.26 (1 H, s). ¹³C NMR (125 MHz, CDCl₃): δ = 160.05, 71.14, 71.00, 50.19, 47.66, 32.14, 28.86. Anal. Calcd for C₇H₁₃NO₃: C, 52.82; H, 8.23; N, 8.80. Found: C, 52.69; H, 8.19; N, 8.76. HRMS-FAB (glycerol, KCl): m/z [M + K]⁺ calcd for C₇H₁₃NO₃K: 198.1878; found: 198.0532.