Asymmetric Sharpless Dihydroxylation Reaction of Chiral Bishomoallylic Alcohols: Application to the Synthesis of the C1–C10–C5 Fragment of FR225654

Abstract

Toward the synthesis of FR225654, an antidiabetic natural product, the Sharpless asymmetric dihydroxylation of chiral bishomoallylic alcohols, never reported in the literature, was examined. Employing the pyrimidine class of ligands, a high level of matched diastereoselectivity was obtained. An application to the stereoselective synthesis of the C1–C10–C5 fragment of FR225654 was performed.

Key words

stereoselective synthesis - natural products - dihydroxy­lation - diols - diastereoselectivity

• References and Notes

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• 10 Typical Procedure for the Sharpless Asymmetric Dihydroxylation K₂CO₃ (415 mg, 3 mmol), K₃Fe(CN)₆ (1.18 g, 3 mol), K₂OsO₂(OH)₄ (4 mg, 0.01 mmol), ligand (0.025 mol), and MeSO₂NH₂ (95 mg, 1 mmol) were added to a vigorously magnetically stirred solution of olefin (1 mmol) in a 1:1 mixture of t-BuOH–H₂O (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C and monitored by TLC. Upon completion, the reaction mixture was quenched with solid Na₂SO₃ (1.5 g), warmed to r.t., and stirred for an additional 60 min. The product was extracted with EtOAc, washed with brine, dried over MgSO₄, concentrated, and purified on silica gel to afford an inseparable mixture of the required diol and the corresponding diastereomer.Spectroscopic Data of Diol 14 (Major Isomer)�1H NMR (300 MHz, CDCl3): δ = 7.26 (d, J = 8.6 Hz, 2 H), 6.89 (d, J = 8.6 Hz, 2 H), 4.47 (s, 2 H), 3.80 (s, 3 H), 3.42 (dd, J = 4.2, 9.0 Hz, 1 H), 3.38 (d, J = 12.0 Hz, 1 H), 3.32 (d, J = 12.0 Hz, 1 H), 3.21 (m, 1 H), 2.11 (m, 1 H), 1.68 (dd, J = 7.8, 14.6 Hz, 1 H), 1.36 (dd, J = 3.3, 14.6 Hz, 1 H), 1.16 (s, 3 H), 0.93 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.1, 12 9.3, 113.7, 76.6, 72.8, 71.8, 70.9, 55.0, 4 4.3, 28.6, 23.5, 19.5 ppm.Spectroscopic Data of Diol 16 (Minor Isomer)1H NMR (300 MHz, CDCl3): δ = 7.26 (d, J = 8.6 Hz, 2 H), 6.89 (d, J = 8.6 Hz, 2 H), 4. 46 (s, 2 H ), 3.80 (s, 3 H), 3.48 (m, 1 H), 3.38 (d, J = 11.0 Hz, 1 H), 3.32 (d, J = 11.0 Hz, 1 H), 3.19 (m, 1 H), 1.95 (m, 1 H), 1.63 (dd, J = 6.0, 14.4 Hz, 1 H), 1.45 (dd, J = 4.8, 14.4 Hz, 1 H), 1.16 (s, 3 H), 0.95 (d, J = 6 . 9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3) δ = 159.1, 129.3, 113.7, 76.4, 72.6, 71.8, 69.0, 55.0, 44.0, 29.1, 24.3, 19.3 ppm. IR (neat): ν = 3360, 2932, 1611, 1513, 1462, 1246, 1033, 819, 771 cm–1. ESI-HRMS: m/z calcd for C15H24NaO4+ [MNa+]: 291.1567; found: 291.1570.�For spectroscopic data of all diols, see the Supporting Information.�

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• 14 For the osmylation of (R)- and (S)-12 and (R)- and (S)-13 in the absence of chiral ligands, see general procedure (ref. 10), however, without ligand.
• 15 Analytical Data for 25 ¹H NMR (400 MHz, CDCl₃): δ = 4.28–4.01 (br s, 2 H), 3.56 (dd, J = 3.6, 10.5 Hz, 1 H), 3.27 (dd, J = 9.0, 10.5 Hz, 1 H), 2.40 (d, J = 16.8 Hz, 1 Hz), 2.33 (d, J = 16.8 Hz, 1 H), 1.93 (m, 1 H), 1.58 (m, 2 H), 1.28 (s, 3 H), 0.86 (d, J = 6.9 Hz, 3 H), 0.13 (s, 9 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 103.7, 87.9, 71.7, 68.9, 47.3, 36.1, 31.8, 25.4, 19.6, 0.1 ppm. IR (neat): ν = 3276, 2958, 2927, 2175, 1460, 1423, 1376, 1248, 1032, 758 cm^–1. ESI-HRMS: m/z calcd for C₁₂H₂₄NaO₂Si⁺ [MNa⁺]: 251.1438; found: 251.1439. The relative configuration of 25 was confirmed by NMR experiments (NOESY analysis) of the corresponding γ-lactone (Figure 2).