Straightforward Organocatalytic Enantioselective Protonation of Silyl Enolates by Means of Cinchona Alkaloids and Carboxylic Acids

Abstract

The combination of cinchona alkaloids and carboxylic acids provides a very simple chiral proton source. By using this system, enantioselective protonation of silyl enolates was achieved affording the corresponding ketones in high yields and in up to 75% ee.

organocatalysis - enantioselective protonation - silyl enolates - cinchona alkaloids

References and Notes

For reviews, see:

1a Duhamel L. Duhamel P. Plaquevent JC. Tetrahedron: Asymmetry  2004,  15:  3653 

1b Fehr C. Angew. Chem., Int. Ed. Engl.  1996,  35:  2566 

For catalytic enantioselective protonation, see:

2a Fehr C. Stempf I. Galindo J. Angew. Chem., Int. Ed. Engl.  1993,  32:  1044 

2b Fehr C. Galindo J. Angew. Chem., Int. Ed. Engl.  1994,  33:  1888 

2c Yanagisawa A. Kikuchi T. Watanabe T. Kuribayashi T. Yamamoto H. Synlett  1995,  372 

2d Vedejs E. Kruger AW. J. Org. Chem.  1998,  63:  2792 

2e Yamashita Y. Emura Y. Odashima K. Koga K. Tetrahedron Lett.  2000,  41:  209 

2f Mitsuhashi K. Ito R. Arai T. Yanagisawa A. Org. Lett.  2006,  8:  1721 

2g Ishihara K. Kaneeda M. Yamamoto H. J. Am. Chem. Soc.  1994,  116:  11179 

2h Ishihara K. Nakamura S. Kaneeda M. Yamamoto H. J. Am. Chem. Soc.  1996,  118:  12854 

2i Sugiura M. Nakai T. Angew. Chem., Int. Ed. Engl.  1997,  36:  2366 

2j Nakamura S. Kaneeda M. Ishihara K. Yamamoto H. J. Am. Chem. Soc.  2000,  122:  8120 

2k Ishihara K. Nakashima D. Hiraiwa Y. Yamamoto H. J. Am. Chem. Soc.  2003,  125:  24 

2l Yanagisawa A. Touge T. Arai T. Angew. Chem. Int. Ed.  2005,  44:  1546 

2m Mohr JT. Nishimata T. Behenna DC. Stoltz BM. J. Am. Chem. Soc.  2006,  128:  11348 

3 Poisson T. Dalla V. Marsais F. Dupas G. Oudeyer S. Levacher V. Angew. Chem. Int. Ed.  2007,  46:  7090 

For recent authoritative reviews on this topic, see:

4a Oestreich M. Rendler S. Synthesis  2005,  1727 

4b Orito Y. Nakajima M. Synthesis  2006,  1391 

5a Mermerian AH. Fu GC. J. Am. Chem. Soc.  2003,  125:  4050 

5b Mermerian AH. Fu GC. J. Am. Chem. Soc.  2005,  127:  5604 

6 Fujisawa H. Takahashi E. Mukaiyama T. Chem. Eur. J.  2006,  12:  5082 

7

General Procedure for the Preparation of Silyl Enolates 2a-i: To a solution of (i-Pr)₂NH (1.19 mL, 8.4 mmol) at -78 ˚C in anhyd THF (50 mL) was added n-BuLi (2.5 M solution in hexanes, 3.22 mL, 8.05 mmol). The solution was stirred for 1 h at this temperature, after which the ketone 3 (7.0 mmol) was slowly added. After stirring for 1 h at -78 ˚C, freshly distilled TMSCl (0.98 mL, 7.7 mmol) was dropwise added and the resultant solution was allowed to reach r.t. before being stirred for an additional 2 h. A solution of NaHCO₃ (20 mL) was added and the mixture was extracted with Et₂O (3 × 50 mL). The combined organic layers were washed with brine and dried (MgSO₄). The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel (Et₂O-cyclohexane, 5:95) affording the pure silyl enol ether 2. All spectral data of silyl enolates 2a-e and 2g,h are reported in ref. 3. All spectral data of silyl enoalte 2f are reported in ref. 13. 2i: ^¹H NMR (300 MHz, CDCl₃): δ = 0.23 (s, 9 H), 3.56 (s, 2 H), 4.57 (s, 2 H), 6.77 (dd, J = 1.1, 8.05 Hz, 1 H), 6.92 (dt, J = 1.3, 7.5 Hz, 1 H), 7.11 (dt, J = 1.6, 7.7 Hz, 1 H), 7.17-7.32 (m, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 1.01, 33.87, 68.89, 112.85, 115.74, 121.25, 122.81, 123.24, 126.66, 128.88 (2), 129.06, 138.73, 141.35, 155.11.

8 For a preceding example of matched/mismatched catalyst-ion pair combination, see: Martin NJA. List B. J. Am. Chem. Soc.  2006,  128:  13368 

9

General Procedure for the Enantioselective Protonation of Silyl Enolates 2a-i: To a solution of silyl enol ether 2 (0.5 mmol) and (DHQ)₂AQN (43 mg, 0.05 mmol) in DMF (0.5 mL) at -10 ˚C was added citric acid (0.100 g, 0.525 mmol) as a solution in DMF (0.5 mL). The reaction was stirred at -10 ˚C until complete disappearance of the starting material (monitored by GC). The solution was diluted with Et₂O (10 mL), washed with NaHCO₃ (10 mL), brine (3 × 10 mL), dried over MgSO₄ and concentrated. The residue was filtered through a short pad of silica gel (Et₂O as eluent) to give the pure ketone 3 which was analyzed by chiral HPLC. Chromatographic conditions for enantioseparation of ketones 3a-e and 3g-h are reported in ref. 3. HPLC conditions for enantioseparation of ketone 3f: Daicel Chiralcel OJ-H, heptane-i-PrOH, 95:5, flow rate: 1 mL/min, t _R =15.30 min (major), t _R = 17.09 min (minor). HPLC conditions for enantioseparation of ketone 3i: Daicel Chiralcel OJ-H, heptane-i-PrOH, 90:10, flow rate: 1 mL/min, t _R = 14.21 min (major), t _R = 18.68 min (minor).

10

Preparation of 2-Fluoro-1-tetralone 3f: To a solution of 2-(ethoxycarbonyl)tetralone 1 ^³ (1.107 g, 5 mmol) in MeCN (40 mL) was added TiCl₄ (0.15 mL, 0.75 mmol) at r.t. After 5 min SelectfluorTM (2.157 g, 6.1 mmol) was added and the resulting mixture was stirred at r.t for an additional 3 h. The reaction was carefully quenched with NaHCO₃ (50 mL) and extracted with Et₂O (4 × 40 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO₄ and concentrated. The residue was purified by flash chromatography (SiO₂, 20% Et₂O in cyclohexane) to afford 2-fluoro-2-(ethoxycarbonyl)tetralone in 98% yield as a pale yellow oil. All spectral data were consistent with those previously reported.^²m
To a solution of 2-fluoro-2-(ethoxycarbonyl)tetralone (1.157 g, 4.9 mmol) dissolved in EtOH-H₂O (5:1, 30 mL) was added KOH (0.825 g, 14.7 mmol). The resulting mixture was refluxed for 1.5 h, cooled to r.t., quenched with a sat. aq NH₄Cl solution (25 mL) and extracted with Et₂O (5 × 30 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO₄ and concentrated. The residue was purified by flash chromatography on silica gel (Et₂O-cyclohexane, 2:8) to afford 2-fluoro-1-tetralone 3f in 76% yield as a pale yellow oil. All spectral data were consistent with those previously reported.^²m

11 For the preparation of chromanone 3i, see: Kirkiacharian BS. Gomis M. Synth. Commun.  2005,  35:  563 

12 Kawasaki M. Toyooka N. Matsui Y. Tanaka A. Goto M. Kakuda H. Kawabata S. Kometani T. Heterocycles  2005,  65:  761 

13 Bélanger E. Cantin K. Messe O. Tremblay M. Paquin J.-F. J. Am. Chem. Soc.  2007,  129:  1034