Synlett 2008(13): 1985-1988  
DOI: 10.1055/s-2008-1077965
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereospecific Synthesis of Eight-Membered Polyhydroxy Carbocycles via TIBAL-Promoted Claisen Rearrangement

Tianxiang Han, Yi Liu, Zhenjun Yang, Liangren Zhang*, Lihe Zhang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100083, P. R. of China
Fax: +86(10)82802724; e-Mail: liangren@bjmu.edu.cn;
Further Information

Publication History

Received 7 April 2008
Publication Date:
15 July 2008 (online)

Abstract

The stereoselective synthesis of novel eight-membered polyhydroxy carbocycles was achieved from d-glucose via mercuriocyclization and triisobutylaluminum (TIBAL)-promoted Claisen rearrangement. Along with rearrangement, TIBAL also promoted debenzylation and cycloaddition, and a 3,9-dioxa-bicy­clo[3.3.1]nonane derivative was formed. The stereoselectivity of mercuriocyclization was attributed to the interaction between me­curio and vinyl moities, and this interaction also assisted the mercurio derivative to exist in an abnormal conformation. The configuration and/or conformation of intermediates and products were identified by NMR spectral analyses.

    References and Notes

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16

Synthesis of 7 To alkene 6 (1.30 g, 2.30 mmol) dissolved in anhyd THF (20 mL) was added Hg(OAc)2 (0.73 g, 2.31 mmol) under argon. The reaction mixture was stirred and refluxed for 10 h, then sat. aq KCl (1 mL) was added, stirred, and refluxed for another 2 h, quenched by the addition of brine at r.t., and extracted three times with EtOAc. Organic extracts were combined, dried by Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on SiO2 (PE-EtOAc, 20:1) to give 7 as a colorless oil (1.85 g, 99.9%). ¹H NMR (400 MHz, CDCl3): δ = 7.33-7.18 (m, 20 H, arom. H), 5.96 (dd, J 7,8a = 11.0 Hz, J 7,8b = 17.5 Hz, 1 H, H-7), 5.23-5.27 (m, J 8a,7 = 11.0 Hz, J 8b,7 = 17.5 Hz, J 8a,8b = J 8b,8a = 1.5 Hz, 2 H, H-8a, H-8b), 4.66, 4.59 (dd, J = 11.5 Hz, 2 H, HCH2Ph), 4.57, 4.51 (dd, J = 12.0 Hz, 2 H, HCH2Ph), 4.35, 4.23 (dd, J = 12.0 Hz, 2 H, HCH2Ph), 4.42 (m, J 2,3 = 3.0 Hz, J 2,1a = 6.0 Hz, J 2,1b = 4.0 Hz, 1 H, H-2), 3.90 (t, J 4,3 = 3.0 Hz, J 4,5 = 4.0 Hz, 1 H, H-4), 3.87, 3.41 (dd, J = 8.5 Hz, 2 H, H-9a, H-9b), 3.67 (d, J 5,4 = 4.0 Hz, 1 H,
H-5), 3.16 (t, J 3,2 = 3.0 Hz, J 3,4 = 3.0 Hz, 1 H, H-3), 1.94 (dd, J 1a,2 = 6.0 Hz, J 1a,1b = 12.0 Hz, 1 H, H-1a), 1.65 (dd, J 1b,2 = 4.0 Hz, J 1b,1a = 12.0 Hz, 1 H, H-1b). ¹³C NMR (100 MHz, CDCl3): δ = 139.2 (C-7), 138.5, 138.4, 138.0, 137.3 (4 × Cipso), 129.1-127.5 (arom. C), 114.6 (C-8), 79.6 (C-6), 76.2 (C-3), 76.0 (C-5), 75.9 (C-9), 74.2 (C-4), 73.9, 73.7, 72.5, 72.1 (4 × CH2Ph), 67.4 (C-2), 31.6 (C-1). MS (ESI-TOF+): m/z = 818 [M + NH4]+, 823 [M + Na]+, 839 [M + K]+. Anal. Calcd for C37H39O5HgCl: C, 55.57; H, 4.92. Found: C, 55.83; H, 5.10.

18

Synthesis of 9 Compound 8 (559 mg, 0.81mmol) dissolved in anhyd DMF (5 mL) was treated with NaH (60% in oil, 323 mg, 8.10 mmol) under argon. The reaction mixture was stirred for 1 h at r.t., quenched with MeOH, and concentrated. The residue was added H2O and extracted with CH2Cl2. The organic extracts were washed twice with brine, dried by Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (PE-EtOAc-Et3N, 15:1:0.02) to yield 9 as a colorless oil (377 mg, 82.7%). ¹H NMR (300 MHz, CDCl3): δ = 7.02-6.78 (m, 20 H, arom. H), 5.88 (dd, J 7,8a = 17.5 Hz, J 7,8b = 11.0 Hz, 1 H, H-7), 5.43 (ss, J 8a,7 = 17.5 Hz, J 8a,8b = 1.5 Hz, 1 H, H-8a), 4.88 (dd, J 8b,7 = 17.5 Hz, J 8b,8a = 1.5 Hz, 1 H, H-8b), 4.70 (d, J 1a,1b = 1.5 Hz, 1 H, H-1a), 4.66 (d, J 1b,1a = 1.5 Hz, 1 H,
H-1b), 4.52 (dd, J = 11.5 Hz, 2 H, HCH2Ph), 4.39 (dd, J = 11.5 Hz, 2 H, HCH2Ph), 4.35 (dd, J = 11.5 Hz, 2 H, HCH2Ph), 4.20 (dd, J = 11.5 Hz, 2 H, HCH2Ph), 3.81 (m, J 5,4 = 8.0 Hz, J 4,5 = 8.0 Hz, J 4,3 = 8.0 Hz, 2 H, H-5, H-4), 3.58 (dd, J = 10.0 Hz, 2 H, H-9a, H-9b), 3.34 (d, J 3,4 = 8.0 Hz, 1 H, H-3). ¹³C NMR (75 MHz, CDCl3): δ = 156.0 (C-2), 139.3 (C-7), 139.0, 138.8, 138.7, 138.5 (4 × Cipso), 128.6-127.7 (arom. C), 115.3 (C-8), 94.7 (C-1), 84.2 (C-6), 82.8 (C-3), 82.2 (C-5), 80.6 (C-4), 75.6 (C-9), 74.7, 73.9, 73.5, 71.1 (4 × CH2Ph). MS (ESI-TOF+): m/z = 585 [M + Na]+, 601 [M + K]+. Anal. Calcd for C37H38O5: C, 78.98; H, 6.81. Found: C, 78.80; H, 7.02.

19

Synthesis of 1
To the solution of compound 9 (660 mg, 1.17 mmol) in toluene (20 mL) was added dropwise 1 M TIBAL (11.7 mL, 11.7 mmol) in toluene at r.t. under argon. The mixture was stirred at 80 ˚C for 2 h, cooled to 0 ˚C, and quenched with 20% aq NaOH solution. The mixture was extracted with toluene, and the organic layers were combined, dried with Na2SO4, and concentrated. The residue was purified by column chromatography (PE-acetone, 20:1) to give 1 as colorless oil (571 mg, 86.5%). ¹H NMR (300 MHz, CDCl3): δ = 7.32-7.18 (m, 20 H, arom. H), 6.02 (t, J 6,7a = J 6,7b = 8 Hz, 1 H, H-6), 4.73 (d, J 4,3 = 6 Hz, 1 H, H-4), 4.61 (dd, J = 12 Hz, 2 H, HCH2Ph), 4.58 (dd, J = 12 Hz, 2 H, HCH2Ph), 4.48 (dd, J = 12 Hz, 2 H, HCH2Ph), 4.33 (dd, J = 12 Hz, 2 H, HCH2Ph), 4.11 (t, J 1,2 = 7 Hz, J 1,8a = 7 Hz, 1 H, H-1), 4.00 (dd, J = 12 Hz, 2 H, H-9), 3.90 (t, J 3,2 = J 3,4 = 6 Hz, 1 H,
H-3), 3.63 (dd, J 2,3 = 6 Hz, J 2,1 = 7 Hz, 1 H, H-2), 3.39 (s, 1 H, OH), 2.42 (br, 1 H, H-7a), 2.22 (br, 1 H, H-7b), 2.04 (t, J 8b,8a = 13 Hz, 1 H, H-8b), 1.71 (m, J 8a,8b = 13 Hz, J 8a,1 = 7 Hz, 1 H, H-8a). ¹³C NMR (75 MHz, CDCl3): δ = 138.6, 138.4, 138.1, 138.1 (4 × Cipso), 134.2 (C-5), 131.4 (C-6), 128.4-127.4 (arom. C), 84.4 (C-3), 81.3 (C-2), 78.7 (C-4), 74.2, 72.5, 72.2, 71.2 (4 × CH2Ph), 70.4 (C-1), 32.9 (C-8), 21.3 (C-7). MS (ESI-TOF+): m/z = 565 [M + H]+, 582 [M + NH4]+, 587 [M + Na]+, 603 [M + K]+. Anal. Calcd for C37H40O5: C, 78.69; H, 7.14. Found: C, 78.84; H, 6.91.

20

Compound 10: white solid. ¹H NMR (500 MHz, CDCl3):
δ = 7.26-7.19 (m, 15 H, H-arom.), 5.74 (dd, J 10,11a = 18 Hz, J 10,11b = 11 Hz, 1 H, H-10), 5.26 (dd, J 11a,10 = 18 Hz, J 11a,11b = 2 Hz, 1 H, H-11a), 5.09 (dd, J 11b,10 = 11 Hz, J 11b,11a = 2 Hz, 1 H, H-11b), 4.87 (dd, J = 12 Hz, 2 H, HCH2Ph), 4.82 (dd, J = 12 Hz, 2 H, HCH2Ph), 4.66 (dd, J = 12 Hz, 2 H, HCH2Ph), 4.58 (t, J 7,6 = J 7,8 = 9 Hz, 1 H,
H-7), 4.13 (d, J 2a,2b = 12 Hz, 1 H, H-2a), 4.02 (d, J 4a,4b = 12 Hz, 1 H, H-4a), 3.79 (dd, J 6,5 = 5 Hz, J 6,7 = 9 Hz, 1 H, H-6), 3.75 (dd, J 5,6 = 5 Hz, J 5,4b = 3 Hz, 1 H, H-5), 3.54 (dd, J 4b,4a = 12 Hz, J 4b,5 = 3 Hz 1 H, H-4b), 3.39 (d, J 8,7 = 9 Hz, 1 H, H-8), 3.22 (d, J 2b,2a = 12 Hz, 1 H, H-2b). ¹³C NMR (125 MHz, CDCl3): δ = 139.0, 138.6, 138.3 (3 × Cipso), 136.8 (C-10), 128.4-127.4 (arom. C), 115.5 (C-11), 84.4 (C-8), 83.7 (C-7), 80.9 (C-6), 75.5, 75.3, 73.2 (3 × CH2Ph), 74.6 (C-1), 69.6 (C-5), 68.8 (C-2), 63.8 (C-4). MS (ESI-TOF+): m/z = 490 [M + NH4]+, 495 [M + Na]+, 511 [M + K]+. Anal. Calcd for C37H40O5: C, 76.25; H, 6.83. Found: C, 76.50; H, 7.05.

21

Synthesis of 2
To the solution of Ph3P (296 mg, 1.13 mmol) in anhyd THF (3 mL) previously cooled in an ice bath was added dropwise 2.2 M DEAD in toluene (0.5 mL, 1.13 mmol) under argon. After 30 min, this solution was added dropwise to the solution of compound 1 (254 mg, 0.45 mmol) and benzoic acid (100 mg, 0.82 mmol) in anhyd THF under argon in an ice bath. The mixture was stirred for 30 min at 0 ˚C, then stirred at 45 ˚C for 3 h. When the volatiles were removed, the residue was purified by column chromatography (PE-acetone, 40:1) to yield 10 as colorless oil (290 mg, 96.5%). Compound 10 (362 mg, 0.54 mmol) dissolved in MeOH (10 mL) was treated with K2CO3 (372 mg, 2.69 mmol) and stirred at r.t. for 12 h. The reaction mixture was subsequently filtered and concentrated, and the residue was purified by column chromatography (PE-acetone, 20:1) to afford 2 as colorless oil (254 mg, 82.7%). ¹H NMR (500 MHz, CDCl3): δ = 7.31-7.21 (m, 20 H, arom. H), 6.03 (t, J 6,7a = J 6,7b = 8.5 Hz, 1 H, H-6), 4.67 (dd, J = 12.0 Hz, 2 H, HCH2Ph), 4.62 (dd, J = 12.0 Hz, 2 H, HCH2Ph), 4.47 (dd, J = 12.0 Hz, 2 H, HCH2Ph), 4.43 (dd, J = 12.0 Hz, 2 H, HCH2Ph), 4.41 (m, J 2,1 = 2.5 Hz, J 2,3 = 6.0 Hz, 1 H, H-2), 4.07-3.98 (m, 3 H,
H-1, H-9a, H-9b), 3.83 (t, J 3,2 = 6.0 Hz, J 3,4 = 5.0 Hz, 1 H,
H-3), 3.69 (d, J 4,3 = 5.0 Hz, 1 H, H-4), 2.36 (br, 1 H, H-7a), 2.10 (m, 1 H, H-7b), 2.00 (m, 1 H, H-8a), 1.70 (m, 1 H, H-8b). MS (ESI-TOF+): m/z = 565 [M + H]+, 582 [M + NH4]+, 587 [M + Na]+, 603 [M + K]+. Anal. Calcd for C37H40O5: C, 78.69; H, 7.14. Found: C, 78.64; H, 7.02.