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Synlett 2007(10): 1537-1540  
DOI: 10.1055/s-2007-982539
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
Further Information

Publication History

Received 13 March 2007
Publication Date:
06 June 2007 (online)

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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

7

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).

17

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).

18

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).