Organocatalytic Enantioselective Synthesis of Secondary α-Hydroxy­carboxylates

Abstract

Enantioenriched secondary α-hydroxycarboxylates have been synthesized in good yields and enantioselectivities by using the cross-aldol reaction of ketones and ethyl glyoxylate with a ­proline-derived dipeptide as the catalyst.

aldol reaction - enantioselectivity - organocatalysis - ­ethyl glyoxylate - ketones - α-hydroxycarboxylate

References and Notes

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General Experimental Procedure
To a stirred solution of ethyl glyoxylate (51.0 mg, 0.5 mmol) and the ketone (0.25 mL) in CHCl₃ (0.25 mL) was added catalyst 5 (13.6 mg, 0.05 mmol) at -10 °C. The reaction mixture was stirred at this temperature for 24-72 h. The solvent was then evaporated under vacuum and the residue was purified by flash chromatography (EtOAc-hexane, 1:2) over silica gel to furnish the desired secondary α-hydroxy-carboxylate as a pure compound. ¹H NMR and ¹³C NMR data of new compounds are collected below.
Compound 5: ¹H NMR (500 MHz, CDCl₃): δ = 0.83 (t, J = 7.5 Hz, 6 H), 1.90-1.92 (m, 1 H), 1.99 (s, 3 H), 2.06-2.11 (m, 2 H), 2.96 (d, J = 3.0 Hz, 2 H), 3.79 (t, J = 8.0 Hz, 1 H), 4.12 (q, J = 4.5 Hz, 1 H), 5.08 (d, J = 2.5 Hz, 1 H), 8.10 (d, J = 9.5 Hz, 1 H, CONH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 18.3, 19.8, 21.7, 31.1, 37.6, 53.0, 57.2, 59.9, 76.6, 170.8, 173.5, 173.7 ppm.
Compound 8: ¹H NMR (500 MHz, CDCl₃): δ = 0.72-0.98 (m, 6 H), 2.00-2.40 (m, 3 H), 3.42-3.79 (m, 3 H), 4.38-4.61 (m, 3 H), 5.00-5.33 (m, 4 H), 7.20-7.52 (m, 11 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 17.8, 19.2, 31.4, 37.3 (40.0), 54.8 (56.0), 57.7 (57.3), 59.3 (59.7), 67.2, 67.7, 70.1 (69.5), 128.1 (2 C), 128.3 (2 C), 128.6 (2 C), 128.7 (2 C), 128.8 (2 C), 135.7, 136.6, 156.4 (155.6), 171.9, 172.7 (171.6) ppm.
Compound 11c: ¹H NMR (500 MHz, CDCl₃): δ = 0.91 (t, J = 8.3 Hz, 3 H), 1.28 (t, J = 7.0 Hz, 3 H), 1.20 (q, J = 7.3 Hz, 2 H), 2.43 (t, J = 7.5 Hz, 2 H), 2.87 (dd, J = 17.5, 6.5 Hz, 1 H), 2.94 (dd, J = 17.5, 4.0 Hz, 1 H), 4.21-4.30 (m, 2 H), 4.68 (dd, J = 6.5, 4.0 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 13.8, 14.3, 17.2, 45.5, 46.1, 62.1, 67.3, 174.0, 208.8 ppm.
Compound 11d: ¹H NMR (500 MHz, CDCl₃): δ = 0.88 (d, J = 7.0 Hz, 6 H), 1.24 (t, J = 7.3 Hz, 3 H), 2.09-2.13 (m, 1 H), 2.28 (d, J = 7.0 Hz, 2 H), 2.83 (dd, J = 17.5, 6.0 Hz, 1 H), 2.86 (dd, J = 17.5, 4.0 Hz, 1 H), 3.19 (br s, 1 H), 4.18-4.22 (m, 2 H), 4.42 (m, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.3, 22.7 (2 C), 24.8, 46.6, 52.5, 62.1, 67.2, 174.0, 208.5 ppm.
Compound 11e (diastereomeric mixture), major isomer: ¹H NMR (500 MHz, CDCl₃): δ = 1.30 (t, J = 7.5 Hz, 3 H), 2.25, (s, 3 H), 3.56 (s, 3 H), 3.94 (d, J = 2.5 Hz, 1 H), 4.20-4.4.28 (m, 2 H), 4.58 (d, J = 2.5 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.3, 27.4, 60.2, 62.6, 72.3, 89.0, 171.6, 208.5 ppm.
Compound 11e (diastereomeric mixture), minor isomer: ¹H NMR (500 MHz, CDCl₃): δ = 1.33 (t, J = 7.5 Hz, 3 H), 2.29 (s, 3 H), 3.44 (s, 3 H), 3.95 (d, J = 2.5 Hz, 1 H), 4.28-4.30 (m, 2 H), 4.50 (d, J = 2.0 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.5, 27.5, 59.9, 62.4, 72.1, 87.7, 171.9, 209.9 ppm.

Compound 11h (diastereomeric mixture), major isomer: ¹H NMR (500 MHz, CDCl₃): δ = 1.26 (t, J = 7.0 Hz, 3H ), 2.37 (dt, J = 15.0, 2.0 Hz, 1 H), 2.56-2.63 (m, 1 H), 3.10-3.16 (m, 2 H), 3.70 (td, J = 11.5, 3.0 Hz, 1 H), 3.83 (t, J = 11.0 Hz, 1 H), 4.02 (m, 1 H), 4.18-4.30 (m, 4 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.3, 42.5, 54.0, 62.3, 68.0, 68.1, 70.0, 173.1, 205.9 ppm.
Compound 11h (diastereomeric mixture), minor isomer: ¹H NMR (500 MHz, CDCl₃): δ = 1.27 (t, J = 7.0 Hz, 3 H), 2.47 (dt, J = 15.0, 3.5 Hz, 1 H), 2.56-2.63 (m, 1 H), 2.85-2.98 (m, 2 H), 3.77 (td, J = 10.5, 4.0 Hz, 1 H), 3.89 (t, J = 9.5 Hz, 1 H), 4.03-4.18 (m, 1 H), 4.12-4.30 (m, 3 H), 4.65 (d, J = 3.5 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.4, 42.5, 54.7, 62.4, 67.5, 68.2, 68.3, 173.4, 205.5 ppm.
Compound 11i: ¹H NMR (500 MHz, CDCl₃): δ = 1.28 (t, J = 7.0 Hz, 3 H), 2.64-2.78 (m, 2 H), 2.89-3.10 (m, 3 H), 3.13 (br s, 1 H), 3.18-3.30 (m, 2 H), 4.13 (m, 1 H), 4.25 (q, J = 7.2 Hz, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.3, 29.9, 32.6, 44.4, 56.0, 62.2, 71.0, 172.9, 208.0 ppm.

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