Synthetic Studies on a Marine Natural Product, Palmerolide A: Synthesis of C1-C9 and C15-C21 Fragments

Krishna P. Kaliappan; Parthasarathy Gowrisankar

doi:10.1055/s-2007-982539

LETTER

Synthetic Studies on a Marine Natural Product, Palmerolide A: Synthesis of C1-C9 and C15-C21 Fragments

Krishna P. Kaliappan*, Parthasarathy Gowrisankar
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
Fax: +91(22)5723480; e-Mail: kpk@chem.iitb.ac.in;

Abstract

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Abstract

An efficient cross metathesis and Pd-catalyzed allylic rearrangement have been successfully used to construct the northern hemisphere of a cytotoxic marine natural product, palmerolide A.

Key words

Grubbs’ catalyst - cross metathesis - Pd(II)-catalyzed allylic rearrangement - marine natural product - Mitsunobu reaction

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References

References and Notes

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Experimental Procedure for Compound 18 To a solution of acetate 17 (230 mg, 0.54 mmol) in anhyd THF (10 mL) was added PdCl₂(MeCN)₂ (6 mg, 4 mol%) at 0 °C under nitrogen. After being stirred at 0 °C for 30 min, the mixture was further stirred at r.t. for another 1 h. The solvent was evaporated and the residue was further purified by flash chromatography (silica gel, 5-10% EtOAc-hexanes) to afford the E/Z mixture of acetate (200 mg, 0.47 mmol, 87%). To a solution of the above acetate (160 mg, 0.37 mmol) in CH₂Cl₂ (3.4 mL) and buffer (pH 7, 390 µL) was added DDQ (102 mg, 0.45 mmol) at 0 °C. After being stirred at the same temperature for 1 h, the reaction mixture was quenched with sat. NaHCO₃ (8 mL) and the aqueous layer was extracted with CH₂Cl₂ (4 × 10 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10-20% EtOAc-hexanes) to give the Z-isomer 19, (8 mg, 0.026 mmol, 7%) as a colorless oil and the E-isomer 18 (80 mg, 0.26 mmol, 70%) as a pale yellow oil in a ratio of 1:10.
Data for compound 18: R _f = 0.8 (20% EtOAc-hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 7.37-7.27 (m, 5 H), 5.43 (tq, J = 7.0, 1.2 Hz, 1 H), 4.60 (d, J = 7.0 Hz, 2 H), 4.51 (s, 2 H), 3.95 (m, 1 H), 3.53 (d, J = 0.6 Hz, 1 H), 3.52 (s, 1 H), 2.47 (br s, 1 H), 2.23-2.06 (m, 2 H), 2.05 (s, 3 H), 1.89-1.84 (m, 1 H), 1.75 (d, J = 1.2 Hz, 3 H), 0.96 (d, J = 7.0 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.0, 139.3, 137.9, 128.3, 127.6, 127.5, 121.1, 74.4, 73.3, 70.9, 61.1, 44.2, 37.6, 20.9, 16.5, 10.7. IR (neat): 3477 (br), 2966, 2931, 2868, 1733, 1450, 1373, 1239, 1098, 1027, 743 cm^-1. HRMS (ESI-TOF): m/z calcd for [C₁₈H₂₆O₄ + Na]⁺: 329.1729; found: 329.1723. [α]_D ²⁰ 4.3 (c 1.45, CHCl₃).

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Procedure for the Synthesis of Compound 28 A solution of methyltriphenylphosphonium bromide (273 mg, 0.76 mmol) in dry toluene (12 mL) was heated to reflux and about 10 mL of toluene were distilled off azeotropically to remove moisture. To the above suspension was added KOt-Bu (86 mg, 0.76 mmol), the mixture was stirred at 105 °C for 1 h, and then cooled to 0 °C. A solution of aldehyde (180 mg, 0.58 mmol) in dry toluene (0.5 mL) was added dropwise to the above suspension with stirring, and the resulting mixture was stirred at 0 °C for 1 h. After addition of sat. NH₄Cl (5 mL), the resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 5-15% EtOAc-hexanes) to give 28 (116 mg, 0.38 mmol, 65% for two steps) as a colorless oil. R _f = 0.57 (30% EtOAc-hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 7.25 (dt, J = 8.9, 2.1 Hz, 2 H), 6.94 (dt, J = 15.6, 7.0 Hz, 1 H), 6.87 (dt, J = 8.9, 2.2 Hz, 2 H), 5.79 (dt, J = 15.5, 1.5 Hz, 1 H), 5.71 (ddd, J = 17.1, 10.4, 7.9 Hz, 1 H), 5.26-5.18 (m, 2 H), 4.39 (AB pattern, J = 11.6 Hz, 2 H), 3.80 (s, 3 H), 3.72 (s, 3 H), 3.77-3.67 (m, 1 H), 2.19-2.14 (m, 2 H), 1.64-1.46 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 167.0, 159.0, 149.2, 138.8, 130.6, 129.3, 120.9, 117.2, 113.7, 79.6, 69.6, 55.1, 51.3, 34.8, 31.9, 23.8. IR (neat): 2948, 2838, 1724, 1657, 1613, 1514, 1463, 1248, 1201, 1172, 1036, 928 cm^-1. HRMS (ESI-TOF): m/z calcd for [C₁₈H₂₄O₄ + Na]⁺: 327.1572; found: 327.1588. [α]_D ²⁰ 34.3 (c 2.15, CHCl₃).

Spectral Data for Selected Compounds
Data for ketone 11: R _f = 0.34 (30% EtOAc-hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 8.24 (dt, J = 8.8, 2.1 Hz, 2 H), 8.12 (dt, J = 9.2, 2.2 Hz, 2 H), 7.29-7.23 (m, 5 H), 5.72 (dt, J = 7.7, 5.1 Hz, 1 H), 4.46 (s, 2 H), 3.42 (d, J = 6.2 Hz, 2 H), 2.93 (dd, J = 16.5, 7.7 Hz, 1 H), 2.82 (dd, J = 16.5, 5.5 Hz, 1 H), 2.26-2.19 (m, 1 H), 2.17 (s, 3 H), 1.06 (d, J = 7.0 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 205.1, 163.9, 150.4, 138.0, 135.6, 130.6, 128.2, 127.6, 127.5, 123.4, 73.1, 72.7, 71.9, 45.7, 37.1, 30.1, 12.1. IR (neat): 2933, 2863, 1725, 1607, 1528, 1411, 1349, 1275, 1169, 1102 cm^-1. HRMS (ESI-TOF): m/z calcd for [C₂₁H₂₃O₆N + Na]⁺: 408.1423; found: 408.1422. [α]_D ²⁰ -10.7 (c 0.67, CHCl₃).
Data for compound 12: R _f = 0.35 (20% EtOAc-hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 7.37-7.27 (m, 5 H), 6.79 (dd, J = 16.2, 7.0 Hz, 1 H), 6.11 (dd, J = 16.2, 1.5 Hz, 1 H), 4.52 (s, 2 H), 3.42 (d, J = 6.7 Hz, 2 H), 2.72-2.65 (m, 1 H), 2.25 (s, 3 H), 1.10 (d, J = 6.7 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 198.7, 150.2, 138.1, 130.6, 128.4, 127.6, 127.5, 73.9, 73.1, 36.9, 26.8, 16.0. IR (neat): 2965, 2856, 1676, 1626, 1528, 1454, 1360, 1257, 1099, 982, 739, 699 cm^-1. HRMS (ESI-TOF): m/z calcd for [C₁₄H₁₈O₂ + Na]⁺: 241.1204; found: 241.1214. [α]_D ²⁰ -15.8 (c 1.13, CHCl₃).
Data for compound 16: R _f = 0.28 (10% EtOAc-hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 7.36-7.27 (m, 5 H), 7.19 (dt, J = 8.8, 2.1 Hz, 2 H), 6.84 (dt, J = 8.8, 2.1 Hz, 2 H), 4.46 (d, J = 1.5 Hz, 2 H), 4.43 (d, J = 7.3 Hz, 2 H), 4.08 (dt, J = 7.9, 4.3 Hz, 1 H), 3.78 (s, 3 H), 3.49 (dd, J = 8.8, 6.7 Hz, 1 H), 3.33 (dd, J = 9.2, 6.1 Hz, 1 H), 2.74 (dd, J = 16.2, 8.2 Hz, 1 H), 2.52 (dd, J = 16.2, 4.6 Hz, 1 H), 2.13 (s, 3 H), 2.04-1.99 (m, 1 H), 0.96 (d, J = 7.0 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 207.8, 159.1, 138.5, 130.8, 129.5, 129.4, 128.4, 127.7, 127.6, 113.7, 76.0, 73.0, 72.3, 55.3, 46.5, 37.5, 31.1, 12.4. IR (neat): 2917, 2861, 1715, 1611, 1513, 1457, 1361, 1301, 1248, 1173, 1078, 822 cm^-1. HRMS (ESI-TOF): m/z calcd for [C₂₂H₂₈O₄ + Na]⁺: 379.1885; found: 379.1880. [α]_D ²⁰ 9.7 (c 1.05, CHCl₃). Data for compound 30: R _f = 0.55 (25% EtOAc-hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 7.34-7.26 (m, 7 H), 6.92-6.84 (m, 3 H), 5.74 (d, J = 15.9 Hz, 1 H), 5.74-5.67 (m, 1 H), 5.37-5.19 (m, 4 H), 4.57-4.43 (m, 5 H), 4.27 (d, J = 11.3 Hz, 1 H), 3.8 (s, 3 H), 3.78-3.68 (m, 1 H), 3.38-3.27 (m, 2 H), 2.37-2.13 (m, 4 H), 2.03-1.96 (m, 1 H), 2.01 (s, 3 H), 1.74 (s, 3 H), 1.72-1.47 (m, 4 H), 0.97 (d, J = 6.7 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.9, 166.0, 159.0, 148.8, 138.9, 138.4, 138.3, 130.7, 129.3, 128.3, 127.6, 127.5, 121.6, 121.4, 117.2, 113.7, 79.8, 73.1, 72.5, 71.5, 69.7, 61.0, 55.2, 42.2, 36.8, 35.0, 32.0, 23.8, 20.9, 16.4, 11.4. IR (neat): 2961, 2930, 2851, 2361, 1738, 1715, 1513, 1454, 1260, 1245, 1091, 1027, 801 cm^-1. HRMS (ESI-TOF): m/z calcd for [C₃₅H₄₆O₇ + Na]⁺: 601.3141; found: 601.3146. [α]_D ²⁰ 9.8 (c 0.60, CHCl₃).