Synthesis of Sterically Hindered Chiral 1,4-Diols from Different Lignan-Based Backbones

Abstract

Methods for synthetic modifications of the natural dibenzylbutyrolactone lignan hydroxymatairesinol into chiral 1,4-diols with different lignan-derived backbones have been developed. A stepwise procedure, involving alkylation and oxidation, was shown to be successful and several highly substituted 1,4-diols were prepared. Some substituted butyrolactones resisted alkylation and led to the formation unusually stable hemiketals (butyrolactols). The formation of stable hemiketals was investigated in detail, showing that different backbone structures influence the formation and reactivity of the hemiketals.

Key words

hydroxymatairesinol - chiral 1,4-diols - TADDOL - lignans - burtyrolactol

• References and Notes

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• 7 The dimethyl lactone 8a, 8b, or 8c (1 mmol) was dissolved in THF (30 mL), the solution was cooled to 0 °C, and MeMgBr (3 mL of 3 M solution in Et₂O, 9 mmol) was added dropwise during 30 min. The solution was allowed to warm to r.t. and stirred for 20–72 h. Saturated NH₄Cl (10 mL) and H₂O (10 mL) were added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted with CH₂Cl₂ (2 × 15 mL), and the combined organic phases were dried over Na₂SO₄, filtered, and the solvent evaporated. The residue was purified by column chromatography using CHCl₃–MeOH (70:1) as eluent, to give products 9a–c. Analytical Data for Compounds 9a–c Compound 9a (reaction time 72 h, yield 265 mg, 60%): ¹H NMR (600 MHz, CDCl₃): δ = 1.06 (s, 6 H), 1.23 (s, 6 H), 2.58 (dd, J = 7.1, 5.1 Hz, 2 H), 2.65 (dd, J = 14.9, 7.1 Hz, 2 H), 2.96 (dd, J = 14.9, 5.1 Hz, 2 H), 3.88 (s, 6 H), 3.90 (s, 6 H), 6.82 (d, J = 7.9 Hz, 2 H), 6.85 (d, J = 1.5 Hz, 2 H), 6.87 (dd, J = 7.9, 1.5 Hz, 2 H) ppm. ¹³C NMR (151 MHz, CDCl₃): δ = 26.3, 30.9, 33.9, 48.3, 55.9, 74.3, 111.2, 112.1, 120.5, 135.3, 147.2, 148.9 ppm. Compound 9b (reaction time 20h, yield 350 mg, 0.81 mmol, 81%) (S)-9b: ¹H NMR (600 MHz, CDCl₃): δ = 1.01 (s, 3 H), 1.44 (s, 3 H), 1.57 (s, 3 H), 1.77 (dd, J = 12.3, 10.0 Hz, 1 H), 2.07 (dd, J = 12.1, 10.2 Hz, 1 H), 2.13 (br s, 1 H), 2.20 (dd, J = 13.0, 10.2 Hz, 1 H), 2.31 (dd, J = 13.6, 10.0 Hz, 1 H), 2.47 (d, J = 13.0 Hz, 1 H), 2.64 (d, J = 13.6 Hz, 1 H), 3.87 (s, 3 H), 3.89 (s, 3 H), 3.93 (s, 3 H), 3.96 (s, 3 H), 6.68 (s, 1 H), 6.71 (s, 1 H), 6.72 (s, 1 H), 6.74 (s, 1 H) ppm. ¹³C NMR (151 MHz, CDCl₃): δ = 22.9, 26.4, 28.9, 32.8, 33.3, 54.5, 55.2, 56.0, 56.06, 56.1, 56.2, 81.7, 102.9, 112.0, 112.1, 113.4, 113.6, 132.5, 132.6, 133.0, 133.2, 147.0, 147.1, 148.6, 148.7 ppm. (R)-9b: ¹H NMR (600 MHz, CDCl₃): δ = 1.14 (s, 3 H), 1.28 (s, 3 H), 1.35 (s, 3 H), 1.69 (dd, J = 12.6, 10.6 Hz, 1 H), 2.08 (dd, J = 12.6, 10.0 Hz, 1 H), 2.13 (br. s., 1 H), 2.20 (dd, J = 12.8, 10.0 Hz, 1 H), 2.22 (dd, J = 13.2, 10.6 Hz, 1 H), 2.42 (d, J = 13.2 Hz, 1 H), 2.73 (d, J = 12.8 Hz, 1 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 3.94 (s, 3 H), 3.95 (s, 3 H), 6.66 (s, 1 H), 6.71 (s, 1 H), 6.74 (s, 1 H), 6.80 (s, 1 H) ppm. ¹³C NMR (151 MHz, CDCl₃): δ = 23.6, 24.4, 28.1, 32.9, 33.1, 55.9, 56.0, 56.1, 56.1, 56.1, 56.3, 80.5, 104.5, 111.9, 112.2, 113.3, 113.4, 132.3, 132.8, 132.9, 132.9, 147.0, 147.1, 148.6, 148.7 ppm. Compound 9c (reaction time 48 h, yield 310 mg, 0.66 mmol, 66%): ¹H NMR (600 MHz, CDCl₃): δ = 1.56 (s, 6 H), 1.65 (s, 6 H), 1.65–1.71 (m, 2 H), 1.87 (d, J = 10.6 Hz, 2 H), 2.06–2.14 (m, 2 H), 2.62 (dd, J = 13.6, 10.6 Hz, 2 H), 2.76 (d, J = 13.6 Hz, 2 H), 3.70 (br s, 2 H), 3.81 (s, 6 H), 4.17–4.23 (m, 2 H), 4.29–4.34 (m, 2 H), 6.26 (dd, J = 8.1, 1.9 Hz, 2 H), 6.44 (d, J = 1.9 Hz, 2 H), 6.50 (d, J = 8.1 Hz, 2 H) ppm. ¹³C NMR (151 MHz, CDCl₃): δ = 23.5, 30.9, 32.9, 37.7, 53.5, 55.9, 67.5, 74.4, 113.3, 113.5, 120.4, 134.5, 144.5, 148.1 ppm.
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