Enantioselective Routes to (-)-(R)-Muscone

Abstract

The macrocyclic ring of muscone was prepared by Pd-catalyzed cyclization of hexadeca-1,15-diyne, which was converted to cyclopentadec-2-enone. The stereogenic center was introduced by enantioselective Cu-catalyzed conjugate addition of dimethyl­zinc. Because the ee in this step was only moderate, a new route via cyclopentadeca-2,14-dienone was developed. Enantioselective conjugate addition to this substrate led to 14-methylcylodec-2-enone, which was hydrogenated to give (-)-(R)-muscone in high overall yield with up to 98% ee.

macrocycles - copper - palladium - asymmetric catalysis - muscone

References and Notes

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16

Synthesis of Cyclopentadeca-2,14-dienone ( 15).
Cyclopentadecanone (1.8 g, 8.0 mmol) was treated with IBX (6.7 g, 24.0 mmol) in 30 mL of DMSO and 10 mL of fluoro-benzene at 80 °C for 24 h (formation of a white precipitate was observed). The reaction was quenched by slow addition of 100 ml of 5% aq NaHCO₃ solution at 0 °C, followed by filtration over a Celite^® pad (7 × 3 cm) eluting with CH₂Cl₂ (150 mL). The organic phase was collected and the aqueous phase extracted with CH₂Cl₂ (2 × 150 mL) and Et₂O (150 mL). The organic phases were combined and the solvents removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc, 9:1) affording 1.1 g (60%) of 15 as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.18-1.35 (m, 12 H), 1.51 (m, 4 H), 2.23 (m, 4 H), 6.20 (dt, 2 H, J = 1.6, 15.6 Hz), 6.63 (dt, 2 H, J = 8.0, 15.6 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 26.7, 27.3, 27.6, 27.8, 32.2, 130.2, 148.7, 193.4. MS (EI): m/z (%) = 220 (7.5) [M⁺], 205 (1), 191 (2), 179 (11), 163 (7), 149 (13), 135 (14), 109 (19), 95 (55), 81 (67), 67 (54), 55 (81), 41 (100). R _f = 0.45 (hexane-EtOAc, 9:1).

17

Synthesis of 14-Methyl-cyclopentadec-2-enone ( 16).
The copper complex of ligand 13b (17.6 mg, 0.02 mmol, 5 mol%) was placed under argon in an ampoule equipped with a magnetic stirring bar and a Young^® valve, and dissolved in 3 mL of degassed toluene. The ampoule was sealed under argon and the mixture stirred for 30 min at -30 °C. To this green solution 2 equiv of 1.0 M dimethylzinc solution in heptane (0.8 mL, 0.8 mmol) were added dropwise under an argon stream (color change to yellow), followed by cyclo-pentadeca-2,14-dienone (88 mg, 0.4 mmol). After stirring at -30 °C for 48 h, the reaction was quenched with 3 mL of sat. aq NH₄Cl solution. After addition of 5 µL of n-tridecane as internal standard and extraction with 5 mL of Et₂O, the organic layer was filtered and analyzed by GC and GCMS. The solvents were evaporated and the reaction mixture purified by column chromatography on silica gel eluting with hexane-EtOAc 9:1 to give 16 as a colorless oil (93.7 mg, 98% yield). ¹H NMR (400 MHz, CDCl₃): δ = 0.89 (d, J = 6.8, 3 H), 1.10-1.30 (m, 18 H), 2.00-2.15 (m, 1 H), 2.20-2.35 (m, 2 H), 2.35 (d, 2 H, J = 10.0 Hz), 6.11 (dt, 1 H, 1.6, 15.6 Hz), 6.74 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.5, 24.5, 26.9, 27.0, 27.1, 27.2, 27.3, 27.5, 30.6, 31.7, 34.3, 49.2, 131.4, 148.2, 201.3. MS (EI): m/z (%) = 236 (22) [M⁺], 221 (6.5), 178 (6), 151 (4), 135 (8), 123 (14), 109 (29), 81 (57), 67 (41), 55 (100), 41 (98). R _f = 0.55 (hexane-EtOAc, 9:1). HPLC (250 mm × 4.6 mm, Daicel, Chiracel AS, detection at 223 nm, hexane-i-PrOH 98.5:1.5, 0.5 mL/min, 293K): 21.1 min (R), 24.1 min (S).