Enantioselective Total Synthesis of Marine Natural Products Untenone A and Plakevulin A

Abstract

An enantioselective total synthesis of untenone A and plakevulin A has been achieved. Construction of a cyclopentene ­derivative, the key intermediate in this synthesis, was carried out by using a ruthenium-catalyzed ring-closing metathesis reaction of a divinyl compound, prepared from octadecanal in several steps including the Sharpless asymmetric epoxidation to generate a chiral quaternary carbon center.

natural product - total synthesis - DNA polymerase inhibitor - Sharpless asymmetric epoxidation - ring-closing metathesis

References

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Synthesis of (±)-untenone A, see:

3a Takeda K. Nakayama I. Yoshii E. Synlett  1994,  178 

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3e Miyaoka H. Watanuki T. Saka Y. Yamada Y. Tetrahedron  1995,  51:  8749 

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8a Katsuki T. Sharpless KB. J. Am. Chem. Soc.  1980,  102:  5974 

8b For reviews on Sharpless asymmetric epoxidation, see: Finn MG. Sharpless KB. In On the Mechanism of Asymmetric Epoxidation with Titanium-Tartrate Catalysts. Asymmetric Synthesis   Vol. 5:  Morrison JD. Academic Press; Tokyo: 1985.  p.247-308  

8c Pfenninger A. Synthesis  1986,  89 

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13

Preparation and Spectroscopic Data of Compound 18.
To a stirred solution of aldehyde 17 (844 mg, 2.13 mmol) in THF (11.0 mL) was added a solution of vinylmagnesium bromide in THF (2.98 mL, 2.98 mmol) at -20 °C under argon, and the mixture was allowed to stir for 1 h. After quenching by addition of sat. aq NH₄Cl, the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 40:1) to give 18 (737 mg, 82%) as a colorless oil. ¹H NMR (CDCl₃): δ = 0.14 and 0.17 (each 3 H, each s), 0.87 (3 H, t, J = 6.7 Hz), 1.19-1.33 (28 H, br m), 1.60-1.79 (4 H, m), 3.93 and 4.13 (each 0.5 H, each s), 4.32-4.48 (1 H, m), 5.01-5.30 (4 H, m), 5.73-6.00 (2 H, m). ¹³C NMR (CDCl₃): δ = 2.47, 2.48, 14.0, 22.6, 24.0, 24.5, 29.3, 29.5, 29.5, 29.6, 30.0, 30.1, 31.9, 40.0, 42.2, 44.2, 45.5, 69.4, 69.7, 79.1, 80.8, 113.4, 113.5, 113.8, 114.0, 140.8, 141.0, 141.9, 143.6. IR (thin film): 3510, 2925, 2855, 1676, 1644, 1468, 1413, 1252, 1144, 1048, 922, 842, 755 cm^-1. HRMS: m/z calcd for C₂₆H₅₂O₂Si: 424.3736; found: 424.3755. Anal. Calcd for C₂₆H₅₂O₂Si: C, 73.52; H, 12.34. Found: C, 73.50; H, 12.27.

14

Preparation and Spectroscopic Data of Compound 19.
To a stirred solution of compound 18 (100 mg, 0.24 mmol) in CH₂Cl₂ (23.5 mL) was added Grubbs’ 2nd generation ruthenium catalyst (2.00 mg, 2.36 µmol) at r.t., and the mixture was allowed to stir for 45 min. After removal of the solvent, the residue was purified by silica gel column chromatography (n-hexane-EtOAc, 7:1) to give 19 (92.9 mg, 99%) as a white solid; mp 31.5-33 °C. ¹H NMR (CDCl₃): δ = 0.06 and 0.12 (each 4.5 H, each t, J = 3.3 Hz), 0.87 (3 H, t, J = 6.7 Hz), 1.19-1.65 (30 H, br m), 1.72-1.73 and 1.78 (each 0.5 H, each m), 2.32 (0.5 H, dd, J = 7.09, 14.2 Hz), 2.45 (0.5 H, dd, J = 7.0, 13.6 Hz), 4.61 (0.5 H, m), 4.96 (0.5 H, m), 5.83-5.91 (2 H, m). ¹³C NMR (CDCl₃): δ = 2.1, 2.4, 14.1, 22.7, 24.3, 24.4, 29.3, 29.7, 30.0, 30.0, 31.9, 42.4, 43.4, 48.8, 49.6, 75.3, 76.1, 86.1, 87.3, 134.1,135.1, 140.3, 140.3. IR (thin film): 3320, 2920, 2855, 1468, 1360, 1250, 1105, 1050, 960, 880, 840, 755 cm^-1. HRMS: m/z calcd for C₂₄H₄₈O₂Si: 396.3424; found: 396.3410. Anal. Calcd for C₂₄H₄₈O₂Si: C, 72.66; H, 12.20. Found: C, 72.76; H, 12.03.

15

Preparation of Compound 20.
A mixed suspension of compound 19 (386 mg, 0.97 mmol) and MnO₂ (3.86 g, 44.4 mmol) in CH₂Cl₂ was stirred for 11.5 h at r.t. After filtration of the mixture through a Celite pad, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 40:1) to give 20 (379 mg, 99%) as a white solid; mp 32.5-34.0 °C. [α]_D ²⁵ -14.9 (c 1.00, CHCl₃). ¹H NMR (CDCl₃): δ = 0.10 (9 H, s), 0.87 (3 H, t, J = 6.6 Hz), 1.18-1.35 (28 H, br m), 1.58-1.74 (2 H, m), 2.48 (2 H, s), 6.09 (1 H, d, J = 5.6 Hz), 7.43 (1 H, d, J = 5.8 Hz). ¹³C NMR (CDCl₃): δ = 2.14, 14.1, 22.7, 24.3, 29.4, 29.5, 29.5, 29.7, 29.8, 31.9, 41.9, 49.6, 81.3, 132.8, 166.8, 206.9. IR (thin film): 2924, 2854, 1726, 1464, 1252, 1200, 1078, 840 cm^-1. HRMS: m/z calcd for C₂₄H₄₆O₂Si: 394.3267; found: 394.3253. Anal. Calcd for C₂₄H₄₆O₂Si: C, 73.03; H, 11.75. Found: C, 72.90; H, 11.86.

16

Preparation and Spectroscopic Data of (-)-Untenone A (1).
To a mixed solution of compound 21 (195 mg, 0.43 mmol) in MeOH-THF (5:1, 6 mL) were added Dowex 50W-X8 (1.95 g) and MS 4 Å (975 mg) at r.t. and the resulting mixture was allowed to stir for 5 h. After filtration through a Celite pad, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 6:1) to give (-)-unte-none A (1, 102 mg, 62%) as a white solid; mp 63-65 °C. [α]_D ²⁶ -79.7 (c 1.00, CHCl₃). ¹H NMR (CDCl₃): δ = 0.88 (3 H, t, J = 6.5 Hz), 1.22-1.33 (28 H, m), 1.64-1.88 (2 H, m), 3.47 (1 H, s), 3.61 (1 H, s), 3.80 (3 H, s), 6.11 (1 H, d, J = 5.6 Hz), 7.52 (1 H, d, J = 5.6 Hz). ¹³C NMR (CDCl₃): δ = 14.1, 22.7, 23.8, 29.3, 29.4, 29.5, 29.6, 29.7, 31.9, 40.3, 52.9, 60.8, 79.9, 132.3, 167.0, 169.0, 199.9. IR (thin film): 3480, 2918, 2850, 1742, 1736, 1708, 1468, 1436, 1320, 1218, 1156, 770 cm^-1. HRMS: m/z calcd for C₂₃H₄₀O₄: 380.2926; found: 380.2924. Anal. Calcd for C₂₃H₄₀O₄: C, 72.59; H, 10.59. Found: C, 72.60; H, 10.74.

17 Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 

18 Ohkuma T. Ooka H. Ikariya T. Noyori R. J. Am. Chem. Soc.  1995,  117:  10417 

19

Preparation and Spectroscopic Data of Compound 22.
To a mixed solution of (-)-untenone A(1) (30.0 mg, 0.08 mmol) and ZnBr₂ (17.8 mg, 0.08 mmol) in THF (1.0 mL) was added 0.97 M DIBALH in hexane (0.21 mL, 0.20 mmol) at -50 °C under argon, and the resulting mixture was allowed to stir for 2 h. After quenching by addition of sat. NH₄Cl aq, the mixture was filtrated through a Celite pad, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 4:1) to give compound 22 (15.1 mg, 50%) as colorless needles; mp 70-71 °C. [α]_D ²² -54.6 (c 0.90, CHCl₃). ¹H NMR (CDCl₃): δ = 0.88 (3 H, t, J = 6.6 Hz), 1.22-1.33 (28 H, br m), 1.60-1.78 (2 H, m), 2.99 (1 H, d, J = 6.1 Hz), 3.04 (1 H, d, J = 8.2 Hz), 3.50 (1 H, s), 3.80 (3 H, s), 4.82 (2 H, ddd, J = 2.4, 5.8, 8.2 Hz), 6.04 (1 H, d, J = 5.8 Hz), 6.09 (1 H, dd, J = 2.4, 5.8 Hz). ¹³C NMR (CDCl₃): δ = 14.1, 22.7, 24.4, 29.3, 29.5, 29.6, 29.6, 29.7, 29.9, 31.9, 39.3, 52.0, 55.0, 75.8, 83.9, 134.7, 140.0, 172.9. IR (thin film): 3527, 3462, 2916, 2848, 1720, 1464, 1396, 1366, 1240, 1176, 1096, 1049, 1030, 970, 924, 800, 781 cm^-1. HRMS: m/z calcd for C₂₃H₄₂O₄: 382.3083; found: 382.3085. Anal. Calcd for C₂₃H₄₂O₄: C, 72.21; H, 11.07. Found: C, 72.70; H, 11.20.

20

Preparation and Spectroscopic Data of p -Bromo-benzoate of 22 and (+)-Plakevulin A (2).
To a solution of compound 22 (37.0 mg, 0.10 mmol) in THF (2.0 mL) were added PPh₃ (107 mg, 0.41 mmol), 40% DEAD in toluene solution (0.16 mL, 0.42 mmol) and p-bromobenzoic acid (70.1 mg, 0.35 mmol) at r.t. under argon, and the resulting mixture was allowed to stir for 6 h. After quenching by addition of sat. NaHCO₃ aq, the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 5:1) to give p-bromobenzoate (39.4 mg, 72%) as a white solid; mp 59-62 °C. [α]_D ²⁰ +89.9 (c 0.60, CHCl₃). ¹H NMR (CDCl₃): δ = 0.88 (3 H, t, J = 6.6 Hz), 1.16-1.46 (28 H, br m), 1.82-1.88 (2 H, m), 2.32 (1 H, s), 3.11 (1 H, d, J = 4.3 Hz), 3.79 (3 H, s), 5.99-6.06 (2 H, m), 6.27 (1 H, m), 7.58 (2 H, dd, J = 1.8, 6.8 Hz), 7.87 (2 H, dd, J = 1.8, 6.8 Hz). ¹³C NMR (CDCl₃): δ = 14.1, 22.7, 24.2, 29.3, 29.6, 29.6, 29.7, 29.9, 31.9, 40.8, 52.3, 57.9, 81.2, 85.4, 128.3, 128.7, 131.2, 131.3, 131.7, 140.2, 165.4, 171.7. IR (thin film): 3486, 2924, 2852, 1724, 1590, 1268, 1172, 1114, 1100, 1012, 758 cm^-1. HRMS: m/z [M + 1] calcd for C₃₀H₄₆O₅Br: 565.2528; found: 565.2534. Anal. Calcd for C₃₀H₄₅O₅Br: C, 63.71; H, 8.02. Found: C, 63.81; H, 8.03.
To a mixed solution of the p-bromobenzoate of 22 (45.0 mg, 0.08 mmol) in MeOH-THF (1:1, 1.0 mL) was added K₂CO₃ at r.t., and the mixture was allowed to stir for 1.5 h. After quenching by addition of sat. NH₄Cl aq, the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 2:1) to give (+)-pla-kevulin A (2, 28.0 mg, 92%) as colorless needles; mp 74-75 °C. [α]_D ²² +24.1 (c 0.60, CHCl₃). ¹H NMR (CDCl₃): δ = 0.88 (3 H, t, J = 6.7 Hz), 1.19-1.38 (28 H, br m), 1.75-1.86 (2 H, m), 2.02 (1 H, d, J = 14.7 Hz), 2.45 (1 H, s), 2.83 (1 H, d, J = 5.3 Hz), 3.79 (3 H, s), 5.30-5.38 (1 H, m), 5.84 (1 H, dd, J = 1.6, 5.7 Hz), 5.94 (1 H, dd, J = 1.8, 5.7 Hz). ¹³C NMR (CDCl₃): δ = 14.1, 22.7, 24.5, 29.4, 29.6, 29.7, 29.9, 31.9, 40.6, 52.1, 60.5, 78.2, 84.9, 135.7, 137.0, 172.6. IR (thin film): 3430, 2916, 2848, 1728, 1464, 1436, 1380, 1366, 1265, 1198, 1085, 994, 862, 786, 722 cm^-1. HRMS: m/z [M + 1] calcd for C₂₃H₄₃O₄: 383.3161; found: 383.3138. Anal. Calcd for C₂₃H₄₂O₄: C, 72.21; H, 11.07. Found: C, 71.96; H, 10.95.

21

The melting point of optically active 2 has not been reported in the literature.