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Synlett 2008(7): 1086-1090  
DOI: 10.1055/s-2008-1042922
LETTER
© Georg Thieme Verlag Stuttgart · New York

Construction of the CDE-Ring Framework of Erinacine E through a Pummerer-Type Cyclization

Shoji Kobayashi*, Akiko Ishii, Masahiro Toyota
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai 599-8531, Japan
Fax: +81(72)2549695; e-Mail: koba@c.s.osakafu-u.ac.jp;
Further Information

Publication History

Received 23 January 2008
Publication Date:
17 March 2008 (online)

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Abstract

The CDE-ring framework of erinacine E, a potent stimulator against nerve growth factor (NGF) synthesis, was constructed using stereocontrolled Grignard addition, silicon-promoted Pummerer-type cyclization, and ring-closing metathesis as key transformations.

Key words

erinacine - Pummerer reaction - ring-closing metathesis - stereoselective addition - cyathane diterpene

14

The C8-stereochemistry of each product was confirmed by NOE experiments after the Pummerer-type cyclization.

15

2-Iodocyclohexen-1-one ethylene ketal was synthesized from 2-cyclohexen-1-one as follows: (i) I2, pyridine, THF, r.t., 12 h, 80%; (ii) 1,2-bis(trimethylsilyloxy)ethane, TMSOTf, CH2Cl2, -20 °C, 72 h, 86%.

17

At best, a 1:1 selectivity was obtained for reduction of the C8-ketone of 13a with LiAlH4 in THF at 0 °C (98% yield). Other reductants including Zn(BH4)2, NaBH4, L-Selectride, or Red-Al gave inferior yields and selectivity.

18

Pivaloate was cleaved with DIBAL in CH2Cl2 at -78 °C.

22

To a solution of 17b (108 mg, 0.139 mmol) in CH2Cl2 (2 mL) was added MCPBA (65%, 111 mg, 0.417 mmol) at -78 °C. The mixture was stirred at -78 °C to -50 °C for 1 h, followed by addition of sat. Na2S2O3 solution, Et2O, and sat. NaHCO3 solution. The resulting mixture was stirred at r.t. for 30 min and extracted with Et2O. The combined organic phase was washed with sat. NaHCO3 solution, brine, and dried over anhyd MgSO4. Concentration of the solution gave the corresponding sulfoxide (117 mg), which was used without further purification. To a solution of sulfoxide (117 mg) and imidazole (94.6 mg, 1.39 mmol) in DMF (1.4 mL) was added TBDPSCl (107 µL, 0.417 mmol). The mixture was stirred at 80 °C for 3 h, and diluted with Et2O and sat. NaHCO3 solution. After separation of the organic phase, the aqueous phase was extracted with Et2O and the combined organic phase was washed with sat. NH4Cl solution, brine, and dried over anhyd MgSO4. After concentration, the residue was purified by flash column chromatography (silica gel; hexane-EtOAc, 40:1 → 25:1 → 10:1) to give O,S-acetal 19 (64.7 mg, 0.0835 mmol, 60%) and ketone 22 (32.3 mg, 0.0417 mmol, 30%). To a solution of 19 (33.3 mg, 0.0430 mmol) in THF (1.4 mL) was added TBAF (1.0 M solution in THF, 64.4 µL, 0.0644 mmol). The mixture was stirred at r.t. for 1.5 h. After concentration, the residue was purified by flash column chromatography (silica gel; hexane-EtOAc, 10:1 → 5:1 → 3:1 → 1:1) to give alcohol 20 (24.9 mg, 0.0403 mmol, 94%). Compound 20: [α]D 29 -2.4° (c = 0.822, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.34 (s, 3 H, Me), 1.51 (s, 3 H, Me), 1.93 (q, J = 7.6 Hz, 2 H, H9), 2.15-2.25 (m, 1 H, H10), 2.28-2.38 (m, 1 H, H10), 2.77 (dd, J = 6.4, 6.8 Hz, 1 H, H7), 3.80 (s, 3 H, MPM), 4.00 (q, J = 6.4 Hz, 1 H, H8), 4.10 (d, J = 3.6 Hz, 1 H, H3), 4.25 (dd, J = 7.6, 8.0 Hz, 1 H, H5), 4.40 (dd, J = 3.6, 8.0 Hz, 1 H, H4), 4.57 (br dd, J = 6.8, 7.6 Hz, 1 H, H6), 4.60 (d, J = 11.0 Hz, 1 H, MPM), 4.83 (d, J = 11.0 Hz, 1 H, MPM), 4.89 (d, J = 12.0 Hz, 1 H, Bn), 4.95 (d, J = 12.0 Hz, 1 H, Bn), 4.97 (br dd, J = 1.0, 10.0 Hz, 1 H, H12), 5.05 (br dd, J = 1.6, 17.0 Hz, 1 H, H12), 5.05 (s, 1 H, H1), 5.78-5.89 (m, 1 H, H11), 6.81 (d, J = 8.8 Hz, 2 H, MPM), 7.21-7.40 (m, 10 H), 7.53-7.56 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 24.7, 26.6, 30.8, 35.5, 48.8, 55.4, 68.3, 70.7, 74.4, 75.2, 77.3, 78.1, 80.2, 88.8, 94.6, 110.0, 113.7, 114.9, 127.06, 127.13, 127.2, 128.3, 129.1, 129.3, 130.9, 131.0, 136.1, 138.3, 139.4, 159.1. FT-IR (film): 3465, 3062, 3031, 2978, 2932, 2913, 2875, 2837, 1640, 1613, 1585, 1514, 1497, 1481, 1463, 1454, 1440, 1381, 1351, 1302, 1248, 1209, 1173, 1161, 1121, 1064, 1029, 913, 880, 822, 777, 739, 695 cm-1. HRMS (FAB):
m/z [M + Na]+ calcd for C36H42NaO7S: 641.2549; found: 641.2563.

23

To a solution of diene 25 (27.9 mg, 0.0433 mmol) in CH2Cl2 (4.3 mL) was added second generation Grubbs’ catalyst (1.4 mg, 1.6 µmol). The mixture was stirred at r.t. for 9 h and quenched with Et3N (1 mL). After concentration, the residue was purified by flash column chromatography (silica gel; hexane-EtOAc, 5:1 → 3:1) to give the tricyclic product 5 (22.4 mg, 0.0363 mmol, 84%); [α]D 29 +21.8° (c = 1.24, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.35 (s, 3 H), 1.58 (s, 3 H), 1.79-1.88 (m, 1 H), 2.08-2.23 (m, 1 H), 2.29-2.43 (m, 2 H), 3.02 (d, J = 10.0 Hz, 1 H), 3.53 (dt, J = 3.0, 10.0 Hz, 1 H), 3.78 (s, 3 H), 4.10 (d, J = 4.0 Hz, 1 H), 4.18 (d,
J = 8.4 Hz, 1 H), 4.41 (dd, J = 4.0, 8.4 Hz, 1 H), 4.73 (d, J = 10.0 Hz, 1 H), 4.78 (d, J = 10.0 Hz, 1 H), 4.91 (br s, 1 H), 4.94 (d, J = 12.0 Hz, 1 H), 5.02 (d, J = 12.0 Hz, 1 H), 5.29 (br s, 1 H), 5.66 (ddd, J = 4.0, 6.8, 13.0 Hz, 1 H), 5.77 (br d, J = 13.0 Hz, 1 H), 6.77 (d, J = 8.8 Hz, 2 H), 7.18 (d, J = 8.8 Hz, 2 H), 7.24-7.35 (m, 5 H), 7.45 (br d, J = 7.6 Hz, 2 H), 7.54 (br d, J = 7.6 Hz, 2 H). 13C NMR (100 MHz, CDCl3):
δ = 24.4, 24.9, 26.2, 31.7, 55.4, 68.2, 71.0, 74.2, 76.3, 76.8, 78.5, 79.7, 88.7, 94.4, 110.4, 113.9, 127.0, 127.3, 127.4, 128.3, 129.2, 129.4, 130.1, 131.1, 135.3, 135.6, 139.0, 159.5. FT-IR (KBr): 3398, 3060, 2984, 2933, 2871, 2837, 1612, 1585, 1514, 1481, 1457, 1439, 1379, 1303, 1250, 1211, 1173, 1136, 1118, 1075, 1026, 970, 881, 845, 822, 738, 694 cm-1. HRMS (FAB): m/z [M + Na]+ calcd for C36H40NaO7S: 639.2392; found: 639.2413.