Novel Stereocontrolled Synthesis of Highly Functionalized Cyclobutanes by Epoxide Opening through a Carbanion Intermediate in Heteroconjugate Addition

Abstract

We have demonstrated a new cyclobutane ring formation from the trans-1,2-disubstituted epoxides through intramolecular carbanion opening process. In this reaction, the nucleophilic carb­anion is generated not via α-proton abstraction but via heteroconjugate addition. These studies indicate that the different configuration of each epoxide (syn and anti) do not affect its reactivity and the reaction velocity in the cyclization step, providing multifunctionalized cyclobutanes in a regio- and stereospecific manner.

heteroconjugate addition - sulfonyl carbanion - epoxides - cyclization - cyclobutanes

References and Notes

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15

Direct generation of a carbanion by proton abstraction from α-sulfonyl group cannot be achieved due to the fact that an epoxidic proton would be abstracted to convert the epoxide into an enolate under these conditions.

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20

The cyclobutane ring structure of 9 was confirmed by X-ray crystallographic analysis (see Supporting Information), and other structures were confirmed through NMR spectroscopy.

21

General Procudure for the Synthesis of Cyclobutane by Heteroconjugate Addition Trimethylsilylacetylene (5 equiv) was dissolved in THF and cooled to -78 ˚C under argon atmosphere. To this cold solution was added a solution of methyllithium-lithium bromide complex (4 equiv) dropwise with stirring. This stirring was continued at -78 ˚C for 30 min, and then a solution of vinylsulfone-epoxide (1 equiv) in THF was added to this mixture. After stirring for further 20 min, the reaction mixture was allowed to warm to -44 ˚C, and the temperature was kept at -44 ˚C for 40 min, then at -23 ˚C for 1 h. The reaction mixture was poured into an ice-cooled sat. aq NH₄Cl. The aqueous layer was separated and extracted with Et₂O. The extracts were combined, washed with H₂O and brine, and then dried over Na₂SO₄. The solution was concentrated in vacuo, and the residue was purified by flash column chromatography to give the corresponding cyclobutane.

22

Cyclobutane 9: IR (KBr): ν_max = 3448, 2957, 2858, 1448, 1284, 1252, 1134, 1117, 842 cm^-¹. ^¹H NMR (600 MHz, CDCl₃): δ = -0.14 (3 H, s), 0.08 (6 H, s), 0.17 (9 H, s), 0.47 (3 H, s), 0.94 (9 H, s), 3.41 (1 H, br d, J = 8.6 Hz), 3.51 (1 H, dt, J = 11.5, 8.4 Hz), 3.63 (1 H, t, J = 9.5 Hz), 3.79 (1 H, dd, J = 9.7, 5.4 Hz), 4.27 (1 H, d, J = 8.1 Hz), 4.87 (1 H, br dt, J = 9.3, 4.8 Hz), 4.94 (1 H, d, J = 11.5 Hz), 4.98 (1 H, d, J = 4.1 Hz), 7.26 (2 H, t, J = 7.5 Hz), 7.36 (1 H, t, J = 7.5 Hz), 7.49 (2 H, t, J = 7.5 Hz), 7.61-7.68 (3 H, m), 7.91 (2 H, d, J = 7.5 Hz). ^¹³C NMR (150 MHz, CDCl₃): δ = -5.4, -5.4, -3.6, -2.6, -0.3, 18.3, 25.9, 45.8, 47.6, 57.4, 65.0, 70.9, 71.5, 91.6, 104.0, 127.8, 128.8, 129.0, 130.1, 134.0, 134.6, 135.8, 140.5. Anal. Calcd for C₃₁H₄₈O₅SSi₃: C, 60.34; H, 7.84. Found: C, 60.34; H, 7.98.
Cyclobutane 10: IR (KBr): ν_max = 3493, 2956, 2172, 1428, 1247, 1147, 1023, 967, 848 cm^-¹. ^¹H NMR (400 MHz, C₆D₆, 318 K): δ = 0.09 (6 H, s), 0.10 (9 H, s), 0.54 (3 H, s), 0.56 (3 H, s), 1.00 (9 H, s), 2.09 (1 H, d, J = 5.4 Hz), 3.08 (1 H, ddd, J = 9.4, 7.4, 2.3 Hz), 3.30 (1 H, dd, J = 9.1, 7.2 Hz), 3.37 (1 H, t, J = 9.1 Hz), 3.46 (1 H, dd, J = 10.5, 5.0 Hz), 3.56 (1 H, dd, J = 10.5, 5.0 Hz), 4.10 (1 H, td, J = 5.0, 2.3 Hz), 4.37 (1 H, td, J = 7.2, 5.5 Hz), 7.06-7.20 (3 H, m), 7.30-7.40 (3 H, m), 7.71-7.76 (2 H, m), 7.87-7.92 (2 H, m). ^¹³C NMR (100 MHz, C₆D₆): δ = -5.4, -5.4, -1.7, -0.7, -0.1, 18.6, 26.1, 37.2, 48.2, 56.1, 66.5, 68.4, 71.6, 87.7, 103.8, 128.7, 128.8, 129.1, 129.9, 133.3, 133.9, 138.4, 139.6. Anal. Calcd for C₃₁H₄₈O₅SSi₃: C, 60.34; H, 7.84. Found: C, 60.34; H, 7.96.

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27

Cyclobutane 20: [α]_D ^²7 -14.5 (c 1.15, CHCl₃). IR (KBr): ν_max = 3525, 3031, 2172, 1305, 1148 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = -0.02 (9 H, s), 0.40 (3 H, s), 0.41 (3 H, s), 2.61 (1 H, m), 2.91 (1 H, td, J = 9.0, 3.0 Hz), 2.95 (1 H, t, J = 9.0 Hz), 3.38 (2 H, d, J = 6.0 Hz), 3.48 (1 H, t, J = 9.0 Hz), 3.57 (1 H, dd, J = 11.5, 6.5 Hz), 3.64 (1 H, dd, J = 11.5, 6.5 Hz), 3.98 (1 H, td, J = 6.0, 3.0 Hz), 4.38 (1 H, d, J = 11.5 Hz), 4.44 (1 H, d, J = 11.5 Hz), 7.25-7.76 (15 H, m). ^¹³C NMR (100 MHz, CDCl₃): δ = -1.4, -1.1, -0.1, 27.1, 39.6, 40.8, 60.5, 64.1, 70.5, 71.9, 73.4, 87.2, 104.0, 127.9, 127.9, 127.9, 128.4, 128.4, 129.1, 129.7, 133.5, 133.6, 137.4, 137.7, 138.3. Anal. Calcd for C₃₃H₄₂O₅SSi₂: C, 65.32; H, 6.98. Found: C, 65.32; H, 7.04.

28

Cyclobutane 24: [α]_D ^²² -34.2 (c 0.56, CHCl₃). IR (KBr):
ν_max = 3358, 3066, 3030, 1287, 1136 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.03 (9 H, s), 0.55-0.66 (2 H, m), 0.72-0.84 (4 H, m), 0.89 (9 H, t, J = 7.5 Hz), 2.77 (1 H, tdd, J = 10.5, 7.5, 2.5 Hz), 3.26 (1 H, ddd, J = 10.5, 6.0, 1.0 Hz), 3.69 (1 H, dd, J = 12.5, 2.5 Hz), 3.73 (1 H, dd, J = 10.0, 5.0 Hz), 3.83 (1 H, dd, J = 10.0, 5.0 Hz), 3.86 (1 H, dd, J = 12.5, 7.5 Hz), 4.20 (1 H, dd, J = 10.5, 1.0 Hz), 4.56 (1 H, d, J = 11.5 Hz), 4.61 (1 H, d, J = 11.5 Hz), 4.98 (1 H, td, J = 6.0, 3.0 Hz), 7.28-7.39 (5 H, m), 7.48-7.54 (2 H, m), 7.61-7.67 (1 H, m), 7.92-7.96 (2 H, m). ^¹³C NMR (100 MHz, CDCl₃): δ = -0.4, 3.7, 8.2, 32.5, 43.2, 46.6, 60.7, 63.1, 67.6, 72.5, 73.2, 90.2, 104.8, 127.8, 127.9, 128.4, 128.9, 129.1, 133.8, 137.8, 140.9. Anal. Calcd for C₃₁H₄₆O₅SSi₂: C, 63.44; H, 7.90. Found: C, 63.44; H, 7.97.