Asymmetric Organozincate Additions to Ethyl 2,2,2-Trifluoropyruvate

Francis Gosselin; Robert A. Britton; Jeffrey Mowat; Paul D. O’Shea; Ian W. Davies

doi:10.1055/s-2007-984911

LETTER

Asymmetric Organozincate Additions to Ethyl 2,2,2-Trifluoropyruvate

Francis Gosselin*^a, Robert A. Britton*^a, Jeffrey Mowat^a, Paul D. O’Shea^a, Ian W. Davies^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: francis_gosselin@merck.com;
^b Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA

Abstract

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Abstract

A chromatography-free synthesis of enantiomerically enriched chiral α-trifluoromethyl α-hydroxy acids prepared via an asymmetric (R)-BINOL-mediated organozincate addition to ethyl 2,2,2-trifluoropyruvate (1) is reported.

Key words

zincate - BINOL - α-keto ester - asymmetric organometallic addition - trifluoropyruvate

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References

References and Notes

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6 Coppola GM. Schuster HF. α-Hydroxy Acids in Enantioselective Synthesis VCH; Weinheim: 1997.

Enantioselective Friedel-Crafts reaction with ethyl 2,2,2-trifluoropyruvate:

7a Zhuang W. Gatherwood N. Hazell RG. Jørgensen KA. J. Org. Chem. 2001, 66: 1009

7b Török B. Abid M. London G. Esquibel J. Török M. Mhadgut SC. Yan P. Surya Prakash GK. Angew. Chem. Int. Ed. 2005, 44: 3086

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8

Hemiketals prepared by reaction of the metal alkoxides of MeOH, 2-PrOH, phenol and BINOL consistently exhibited a singlet with a chemical shift between δ = -85.4 and -85.8 ppm by ¹⁹F NMR spectroscopic analysis with benzotrifluoride as internal standard (δ = -61.5 ppm).

For a practical example, see:

9a Tan L. Chen C.-y. Tillyer RD. Grabowski EJJ. Reider PJ. Angew. Chem. Int. Ed. 1999, 38: 711

Other examples include:

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10b Chen Y. Yekta S. Yudin AK. Chem. Rev. 2003, 103: 3155

11 A similar BINOL-derived zincate species has been reported as a Lewis acid catalyst for enantioselective Diels-Alder cycloadditions: Ward DE. Souweha MS. Org. Lett. 2005, 7: 3533

12

Experimental Procedure
(R)-(+)-1,1′-Bi(2-naphthol) (5.1 g, 17.6 mmol, 120 mol%) was dissolved in anhyd 1,2-dichloroethane (35 mL) and THF (8.75 mL) and the solution was cooled to -40 °C. A solution of Et₂Zn (13.4 mL, 14.7 mmol, 100 mol%, 1.1 M in toluene) was added over 30 min. Caution: gas evolution! Proper venting required! The mixture was stirred at r.t. for 1 h, cooled to -40 °C and a solution of EtMgCl (8.8 mL, 17.6 mmol, 120 mol%, 2 M in THF) was added over 15 min. The solution was warmed to r.t. for 1 h and then cooled to -40 °C. Ethyl 2,2,2-trifluoropyruvate (1.95 mL, 2.50 g, 14.7 mmol) was added dropwise via syringe pump over 6 h. The mixture was let stir 18 h and then quenched with 2 N aq HCl (25 mL). The organic layer was washed with 1 N aq NaOH (3 × 20 mL). The organic layer was then treated with 8 N KOH (200 mol%) at reflux for 2 h. The solution was cooled to r.t. and the layers were separated. The aqueous layer was washed with MTBE (20 mL) and then acidified to pH 1 with 6 N HCl. The aqueous layer was extracted with MTBE (20 mL), dried with MgSO₄, and concentrated under vacuum to afford (2R)-2-hydroxy-2-(trifluoromethyl)butanoic acid (2b) as a white solid in 74% yield and 74% ee; mp 120-122 °C. ¹H NMR (500 MHz, acetone-d ₆): δ = 1.96 (m, 1 H), 1.81 (m, 1 H), 0.88 (t, 3 H, J = 7.5 Hz). ¹³C NMR (125 MHz, acetone-d ₆): δ = 170.4, 123.6 (q, J = 284 Hz), 77.6 (q, J = 28.5 Hz), 24.7, 6.4. ¹⁹F NMR (470 MHz, CDCl₃, internal standard PhCF₃ at -61.5 ppm): δ = -77.3. Chiral GC analysis (methyl ester): Cyclodex-B column, 50 °C for 1 min, 5 °C/min to 95 °C, hold at 95 °C for 1 min, 20 °C/min to 200 °C, injector 180 °C, detector 250 °C, split 10:1, 13.5 psi He, S-enantio-mer at 6.10 min, R-enantiomer at 6.83 min.