Highly Stereoselective 1,4-Addition of the Enolate Generated from 6-Deoxy-d-Glucopyranoside-Derived Propionyl Ester to Methyl Crotonate: Application to Total Synthesis of (-)-Lasiol

Abstract

1,4-Addition of the enolate generated from methyl 6-deoxy-2,3-di-O-(t-butyldimethylsilyl)-4-O-propionyl-α-d-gluco-pyranoside to methyl crotonate provided a single anti-adduct with exceptionally high stereoselectivity. From this adduct, (-)-lasiol, an acyclic monoterpene alcohol isolated from the males of Lasius meridionalis ants, was synthesized concisely.

asymmetric synthesis - 1,4-addition - d-glucose - chiral auxiliary - (-)-lasiol

References

Reviews on this subject, see:

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4

Synthesis of Methyl 6-deoxy-4-O-[(2S,3S)-4-methoxy-carbonyl-2,3-dimethylbutanoyl]-2,3-di-O-tert-butyl-dimethylsilyl-α-d-glucopyranoside (4). The following reaction was carried out under Ar. To a cooled (-78 °C) stirred solution of 2 (1.05 g, 2.27 mmol) in THF (21 mL) was added NaHMDS (1.0 M solution in THF, 3.40 mL, 3.40 mmol). The solution was stirred at -78 °C for 30 min and then methyl crotonate (0.359 mL, 3.40 mmol) was added. After being stirred at -78 °C for 30 min and at 0 °C for 1.5 h, the reaction mixture was quenched with sat. aq NH₄Cl (2 mL). This was diluted with EtOAc (60 mL) and washed with sat. aq NH₄Cl (30 mL × 3). The organic layer was dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc-hexane = 1:40-1:20) to provide 965 mg (75%) of 4 (anti/syn = >95:5, dr of anti = >95:5 based on ¹H NMR analysis) as a colorless oil and 153 mg (15%) of 2 was recovered. Compound 4: TLC, R_f 0.52 (EtOAc-hexane = 1:5). IR (neat): 2930, 1740, 1470, 1385, 1360, 1250 cm^-1. ¹H NMR (270 MHz): δ = 0.03, 0.09, 0.10, 0.11 (each s, each 3 H), 0.83, 0.92 (each s, each 9 H),1.02 (d, J = 7.0 Hz, 3 H), 1.07 (d, J = 7.0 Hz, 3 H),1.14 (d, J = 6.3 Hz, 3 H), 2.15 (dd, J = 9.9, 15.9 Hz, 1 H), 2.36-2.46 (m, 1 H), 2.40 (dd, J = 3.8, 15.9 Hz, 1 H), 2.56 (dq, J = 3.0, 7.0 Hz, 1 H), 3.37 (s, 3 H), 3.65 (dd, J = 3.5, 9.1 Hz, 1 H), 3.67 (s, 3 H), 3.74 (dq, J = 6.3, 9.6 Hz, 1 H), 3.90 (t, J = 9.1 Hz, 1 H), 4.61 (d, J = 3.5 Hz, 1 H), 4.68 (dd, J = 9.1, 9.6 Hz, 1 H). ¹³C NMR (75 MHz): δ = 2 × -4.48, -3.34, -2.90, 11.50, 17.65, 17.81, 17.91, 18.41, 3 × 25.86, 3 × 26.15, 32.73, 37.29, 43.82, 51.57, 54.99, 65.40, 71.80, 74.40, 76.79, 100.01, 173.13, 174.25. HRMS: m/z [M⁺ - t-Bu] calcd for C₂₃H₄₅O₈Si₂: 505.2653, found: 505.2656.

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9 Schneider C. Eur. J. Org. Chem.  1998,  1661 

10

Synthesis of (-)-Lasiol (3). The following reaction was carried out under Ar. To a cooled (-78 °C) stirred solution of 4 (681 mg, 1.21 mmol) in CH₂Cl₂ (13.5 mL) was added DIBAL-H (1.01 M solution in toluene, 1.44 mL, 1.45 mmol). The resulting solution was stirred at -78 °C for 1 h and then quenched with H₂O (5 mL). The resulting precipitates were removed by filtration through a Celite-pad and washed well with EtOAc. The combined filtrate and washings were concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc-toluene = 1:60) to provide 556 mg (86%) of 5 as a colorless oil. Compound 5: TLC, R_f 0.46 (EtOAc-hexane = 1:3). IR (neat): 2935, 1740, 1475, 1360, 1250 cm^-1. ¹H NMR (270 MHz): δ = 0.03, 0.09, 0.10, 0.10 (each s, each 3 H), 0.83, 0.92 (each s, each 9 H), 1.03 (d, J = 6.5 Hz, 3 H), 1.08 (d,
J = 6.5 Hz, 3 H), 1.08 (d, J = 6.5 Hz, 3 H), 2.32 (ddd, J = 1.8, 10.3, 17.6 Hz, 1 H), 2.51-2.57 (m, 3 H), 3.37 (s, 3 H), 3.65 (dd, J = 3.4, 9.4 Hz, 1 H), 3.72 (dq, J = 6.5, 9.4 Hz, 1 H), 3.90 (t, J = 9.4 Hz, 1 H), 4.60 (d, J = 3.4 Hz, 1 H), 4.68 (t, J = 9.4 Hz, 1 H), 9.76 (d, J = 1.8 Hz, 1 H). ¹³C NMR (75 MHz): δ = -4.46, -4.41, -3.32, -2.91, 11.33, 17.81, 17.93, 18.11, 18.41, 3 × 25.86, 3 × 26.14, 29.89, 43.92, 46.77, 55.02, 65.30, 71.79, 74.38, 76.80, 100.03, 174.25, 201.24. HRMS: m/z [M⁺ - t-Bu] calcd for C₂₂H₄₃O₇Si₂: 475.2547, found: 475.2549.
The following reaction was carried out under Ar. To a cooled (0 °C) stirred solution of (isopropyl)triphenylphosphonium iodide (1.31 g, 3.03 mmol) in THF (20 mL) was added n-BuLi (2.66 M solution in hexane, 1.14 mL, 3.03 mmol). The solution was stirred at 0 °C for 4 min. The resulting deep red solution was cooled to -78 °C for 15 min, then a solution of 5 (534 mg, 1.01 mmol) in THF (10 mL) was added dropwise. After being stirred at -78 °C for 30 min then at 0 °C for 1 h, the reaction mixture was quenched with sat. aq NH₄Cl (2 mL). The mixture was diluted with EtOAc (28 mL) and washed with sat. aq NH₄Cl (14 mL × 3). The organic layer was dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc-hexane = 1:60) to provide 432 mg (76%) of 6 as a colorless oil. Compound 6: TLC, R_f 0.83 (EtOAc-hexane = 1:5). IR (neat): 2930, 1740, 1475, 1360, 1250 cm^-1. ¹H NMR (270 MHz): δ = 0.05, 0.09, 0.10, 0.11 (each s, each 3 H), 0.84, 0.92 (each s, each 9 H), 0.92-0.95 (m, 3 H), 1.08 (d, J = 7.0 Hz, 3 H), 1.14 (d, J = 6.2 Hz, 3 H), 1.58, 1.69 (each s, each 3 H), 1.79-2.02 (m, 3 H), 2.53 (dq, J = 2.9, 7.0 Hz, 1 H), 3.37 (s, 3 H), 3.66 (dd, J = 3.4, 9.0 Hz, 1 H), 3.72 (dq,
J = 6.2, 9.8 Hz, 1 H), 3.91 (t, J = 9.0 Hz, 1 H), 4.61 (d, J = 3.4 Hz, 1 H), 4.69 (dd, J = 9.0, 9.8 Hz, 1 H), 5.02-5.06 (m, 1 H). ¹³C NMR (75 MHz): δ = 2 × -4.49, -3.36, -2.91, 11.97, 17.22, 17.80, 17.86, 18.06, 18.37, 25.79, 3 × 25.87, 3 × 26.14, 31.15, 36.71, 44.07, 54.91, 65.55, 71.85, 74.38, 76.49, 100.00, 122.73, 132.62, 174.76. HRMS: m/z
[M⁺ - t-Bu] calcd for C₂₅H₄₉O₆Si₂: 501.3068, found: 501.3065. The following reaction was carried out under Ar. To a cooled (-78 °C) stirred solution of 6 (950 mg, 1.70 mmol) in CH₂Cl₂ (20 mL) was added DIBAL-H (1.01 M solution in toluene, 8.41 mL, 8.50 mmol). The solution was stirred at -78 °C for 15 min, then quenched with H₂O (5 mL). The resulting precipitates were removed by filtration through a Celite-pad and washed well with EtOAc. The combined filtrate and washings were concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc-hexane = 1:15) to provide 244 mg (92%) of (-)-lasiol (3) (anti/syn = >95:5 based on ¹H NMR analysis, >95% ee based on the corresponding (R)- and (S)-MTPA esters) as a colorless oil, and 642 mg (93%) of 1 was recovered. (-)-Lasiol (3): TLC, R_f 0.32 (EtOAc-hexane = 1:5); [α]_D ²³ -12.1 (c 0.995, n-hexane) {lit. (-)-lasiol [α]_D ²²
-12.9 (c 1.02, n-hexane)}. IR (neat): 3340 (br), 2920, 1455, 1375 cm^-1. ¹H NMR (270 MHz): δ = 0.87 (d, J = 7.0 Hz, 3 H), 0.93 (d, J = 7.0 Hz, 3 H), 1.47-1.68 (m, 2 H), 1.60, 1.70 (each s, each 3 H), 1.74-1.86 (m, 1 H), 1.99-2.08 (m, 1 H), 3.46 (dd, J = 7.0, 10.6 Hz, 1 H). 3.64 (dd, J = 5.1, 10.6 Hz,
1 H), 5.09-5.15 (m, 1 H). ¹³C NMR (75 MHz): δ = 13.78, 16.97, 17.80, 25.81, 31.40, 35.51, 40.25, 66.11, 123.55, 132.04. HRMS: m/z [M⁺] calcd for C₁₀H₂₀O: 156.1514, found: 156.1508.

11 Dale JA. Mosher HS. J. Am. Chem. Soc.  1973,  95:  512 

12

Kuwahara and Mori also confirmed the enantiomeric purities of their (+) and (-)-lasiols using the Mosher’s ester method, see refs. 6,7.

13

We also conducted chrial HPLC analysis of racemic lasiol prepared separately. Unfortunately, we could not find reliable HPLC conditions for complete separation of the enantiomers.

14 Mori K. Ueda H. Tetrahedron  1982,  38:  1227