Diastereoselective Baylis-Hillman reaction: Use of Sugar Derived Aldehydes as Chiral Electrophiles [1]

Abstract

The asymmetric Baylis-Hillman reaction of sugar-derived aldehydes as chiral electrophiles with an activated olefin in dioxane: water (1:1) with 36-86% de and in good yields is described.

Key words

Baylis-Hillman reaction - sugar derived aldehydes - chiral electrophiles - activated alkene - tertiary amine

1

IICT Communication number: 020709.

References

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1

IICT Communication number: 020709.

21

The energy minimization was carried out using Sybyl 6.8 with default Tripose force field Parameters. Minimization was done first with steepest discent followed by conjugate gradient methods for a maximum of 2000 iteration each or RMS deviation of 0.005 kcal/mole which ever was earlier.

22

General experimental procedure: To the aldehyde (1 mmol) in dioxane-H₂O [(1:1), 5 mL], DABCO (1 mmol) and ethyl acrylate (3 mmol) were added and the reaction mixture stirred for 15 h at room temperature. After the complete conversion of the aldehyde, the reaction mixture was partitioned by ethyl acetate (3 ¥ 15 mL), washed with brine (25 mL), dried (Na₂SO₄) and concentrated under reduced pressure to get a residue, which was purified by chromatography (Si-gel 60-120 mesh, EtOAc:hexane, 1:9) to afford adducts 1a-c, 2a-c, 3a and 3c in 56-82% yield.

23

Spectral data for selected compounds: (S)-1a; [α]_D =
-47.39 (c 0.8, CHCl₃); ¹H NMR (200 MHz, CDCl₃, TMS): δ 1.26-1.42 (m, 6 H, 2 ¥ CH₃), 1.46 (s, 3 H, CH₃), 3.50 (s, 3 H, -OMe), 3.82 (d, 1 H, J _3,4 = 3.0 Hz, H-3), 4.20-4.36 (m, 3 H, H-4, -OCH₂-), 4.54 (d, 1 H, J _2,1 = 3.7 Hz, H-2), 4.64 (d, 1 H, J _5,4 = 8.9 Hz, H-5), 5.85 (d, 1 H, J _1,2 = 3.7 Hz, H-1), 5.96 (s, 1 H, olefinic), 6.38 (s, 1 H, olefinic); ¹³C NMR (75 MHz, CDCl₃, TMS), δ 14.49, 27.21, 30.00, 58.28, 61.25, 70.03, 80.32, 82.02, 86.35, 105.46, 112.25, 127.81, 140.06, 166.73; FABMS: m/z 303 (M⁺ + 1); Anal. calcd. for C₁₄H₂₂O₇: C, 55.62, H, 7.33; found: C, 55.51, H, 7.24. (R)-1a; [α]_D =
-28.82 (c 1, CHCl₃); ¹H NMR (300 MHz, CDCl₃, TMS): δ 1.30-1.39 (m, 6 H, 2 ¥ CH₃), 1.48 (s, 3 H, CH₃), 3.48 (s, 3 H, -OMe), 3.83 (d, 1 H, J _3,4 = 3.0 Hz, H-3), 4.28 (q, 2 H, J = 7.4 Hz, -OCH₂-), 4.40 (dd, 1 H, J _4,3 = 3.0, J _4,5 = 5.9 Hz, H-4), 4.58 (d, 1 H, J _2,1 = 3.9 Hz, H-2), 4.83 (d, 1 H, J _5,4 = 5.9 Hz, H-5), 5.95 (d, 1 H, J _1,2 = 3.9 Hz, H-1), 6.08 (s, 1 H, olefinic), 6.79 (s, 1 H, olefinic); FABMS: 303 (M⁺ + 1); Anal. calcd. for C₁₄H₂₂O₇: C, 55.62, H, 7.33; found: C, 55.68, H, 7.29. 8; [α]_D = -52. 27 (c 0.8, CHCl₃); ¹H NMR (500 MHz, CDCl₃, TMS): δ 1.32 (s, 3 H, CH₃), 1.39 (s, 3 H, CH₃), 1.48 (s, 6 H, 2 ¥ CH₃), 3.44 (s, 3 H, -OMe), 3.61 (d, 1 H, J _3,4 = 2.9 Hz, H-3), 4.23 (dd, 1 H, J _4,3 = 2.9, J _4,5 = 8.9 Hz, H-4), 4.25 (d, 1 H, J = 13.2 Hz, -CH₂), 4.37 (d, 1 H, J = 13.2 Hz, -CH₂), 4.53 (d, 1 H, J _2,1 = 3.9 Hz, H-2), 4.58 (d, 1 H,
J _4,5 = 8.9 Hz, H-5), 4.99 (s, 1 H, olefinic), 5.28 (s, 1 H, olefinic), 5.94 (d, 1 H, J _1,2 = 3.9 Hz, H-1); FABMS: m/z 301 (M⁺ + 1); Anal. calcd. for C₁₅H₂₄O₆: C, 59.98, H, 8.05; found: C, 59.87, H, 7.98. 9; [α]_D = +21.98 (c 0.6, CHCl₃); ¹H NMR (500 MHz, CDCl₃, TMS): δ 1.34 (s, 3 H, CH₃), 1.46 (s, 6 H, 2 ¥ CH₃), 1.52 (s, 3 H, CH₃), 3.38 (s, 3 H, -OMe), 3.78 (d, 1 H, J _3,4 = 3.9 Hz, H-3), 4.21 (d, 1 H, J = 13.2 Hz,
-CH₂), 4.36 (d, 1 H, J = 13.2 Hz, -CH₂), 4.43 (dd, 1H, J _4,3 = 3.9, J _4,5 = 7.8 Hz, H-4), 4.60 (d, 1 H, J _2,1 = 3.9 Hz,
H-2), 4.71 (d, 1 H, J _5,4 = 7.8 Hz, H-5), 4.96 (s, 1 H, olefinic), 5.0 (s, 1 H, olefinic), 5.99 (d, 1 H, J _1,2 = 3.9 Hz, H-1); FABMS: m/z 301 (M⁺ + 1); Anal. calcd. for C₁₅H₂₄O₆: C, 59.98, H, 8.05; found: C, 59.93, H, 8.12.