Zr(Ot-Bu)₄-Catalyzed Tishchenko Reduction of β-Hydroxy Ketones

Abstract

Zr(OtBu)₄ was found to catalyze the Tishchenko reduction of β-hydroxy ketones giving rise to differentiated 1,3-anti-diol monoesters in high yields and excellent stereoselectivity.

catalysis - diastereoselectivity - 1,3-diols - Tishchenko reduction - zirconium

References

1 See for example: Macrolide Antibiotics   Omura S. Academic Press; New York: 1984. 

2 Review: Oishi T. Nakata T. Synthesis  1990,  635 

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13e For excellent reviews about the aldol-Tishchenko reaction see: Mahrwald R. Curr. Org. Chem.  2003,  7:  1713 

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17b in addition, the Tishchenko products were hydrolyzed to the corresponding 1,3-diols and NMR data were compared to literature precedence, see: Mascarenhas CM. Duffey MO. Liu S.-Y. Morken JP. Org. Lett.  1999,  1:  1427 

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Representative Experimental Procedure. Synthesis of Product 7b: To a stirred solution of 3-hydroxy-4-methyl-1-phenyl-1-pentanone (1, 192 mg, 1.00 mmol) and isobutyraldehyde (2, 137 µL, 1.50 mmol) in dry toluene (5 mL) was added Zr(Ot-Bu)₄ (20 µL, 0.050 mmol) at -30 °C. The resulting solution was stirred for 30 min at -30 °C before addition of 0.5 M aq HCl solution (4 mL). The layers were separated and the aqueous layer was extracted with Et₂O (3 × 15 mL). The combined organic layers were dried over MgSO₄, filtered and the solvent was removed under reduced pressure. Flash chromatography (silica gel, Et₂O-pentane 1:4) of the crude product yielded 7b as a colorless oil (238 mg, 90%).

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Representative Spectroscopic Data: Compound 7b: ¹H NMR (200 MHz, CDCl₃): δ = 0.93 [d, J = 7.0 Hz, 3 H, CH(CH ₃)₂], 0.94 [d, J = 7.0 Hz, 3 H, CH(CH ₃)₂], 1.23 [d, J = 7.0 Hz, 6 H, CH(CH ₃)₂], 1.98-1.75 [m, 3 H, CH₂, CH(CH₃)₂], 2.65 [sept, J = 7.0 Hz, 1 H, CH(CH₃)₂], 3.30 (br s, 1 H, OH), 4.54 (dd, J = 7.5, 5.5 Hz, 1 H, CHOH), 5.05 (dt, J = 8.0, 5.5 Hz, 1 H, CHOCOR), 7.40-7.25 (m, 5 H, ArH). ¹³C NMR (50 MHz, CDCl₃): δ = 17.50, 18.72, 19.18, 19.23, 32.16, 34.39, 42.14, 69.82, 75.36, 125.5, 127.3, 128.4, 144.0, 178.5. IR (film): 3489, 3063, 3029, 2968, 2877, 1731, 1470, 1389, 1269, 1201, 1162, 1052, 758, 701 cm^-1. MS (200 eV, DCI/NH₃): m/z (%) = 810 (1) [3 M + NH₄ ⁺], 546 (20) [2 M + NH₄ ⁺], 282 (50) [M + NH₄ ⁺], 247 (100) [M⁺ - OH]. Anal. Calcd (%) for C₁₆H₂₄O₃ (264.36): C, 72.69; H, 9.15. Found: C, 72.68; H, 8.92.
Compound 7f: ¹H NMR (200 MHz, CDCl₃): δ = 0.89 [s, 9 H, C(CH₃)₃], 0.93 [d, J = 7.0 Hz, 6 H, CH(CH ₃)₂], 1.20 [d, J = 7.0 Hz, 6 H, CH(CH ₃)₂], 1.47 (ddd, J = 14.0, 10.5, 2.0 Hz, 1 H, CHH), 1.65 (ddd, J = 14.0, 10.5, 2.0 Hz, 1 H, CHH), 1.95-1.75 [m, 1 H, CH(CH₃)₂], 2.50 (br s, 1 H, OH), 2.61 [sept, J = 7.0 Hz, 1 H, CH(CH₃)₂], 3.00 (dd, J = 10.5, 2.0 Hz, 1 H, CHOH), 4.95 (ddd, J = 10.5, 5.0, 2.0 Hz, 1 H, CHOCOR). ¹³C NMR (50 MHz, CDCl₃): δ = 17.63, 18.97, 19.20, 19.26, 25.94, 32.37, 33.96, 34.41, 34.42, 74.73, 75.81, 178.40. IR (film): 3518, 2967, 2876, 1714, 1389, 1267, 1204, 1163, 1070, 1011 cm^-1. MS (200 eV, DCI/NH₃): m/z (%) = 279 (2) [M + NH₃ + NH₄ ⁺], 262 (100) [M + NH₄ ⁺], 245 (5) [M + H⁺]. Anal. Calcd (%) for C₁₄H₂₈O₃ (244.37): C, 68.81; H, 11.55. Found: C, 69.08; H, 11.29.