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Synlett 2016; 27(03): 369-374
DOI: 10.1055/s-0035-1560594
letter
© Georg Thieme Verlag Stuttgart · New York

Diastereoselective Synthesis of (±)-Ambrox by Titanium(III)-Catalyzed Radical Tandem Cyclization

Antonio Rosales*
a   Department of Chemical and Environmental Engineering, Escuela Politécnica Superior, University of Sevilla, 41011 Sevilla, Spain   Email: arosales@us.es
b   Petrochemical Engineering, Universidad de las Fuerzas Armadas-ESPE, 050150 Latacunga, Ecuador
,
L. A. R. Foley
c   Department of Organic Chemistry, Faculty of Sciences, University of Granada, 18071 Granada, Spain   Email: joltra@ugr.es
,
Natalia M. Padial
c   Department of Organic Chemistry, Faculty of Sciences, University of Granada, 18071 Granada, Spain   Email: joltra@ugr.es
,
Juan Muñoz-Bascón
c   Department of Organic Chemistry, Faculty of Sciences, University of Granada, 18071 Granada, Spain   Email: joltra@ugr.es
,
Iris Sancho-Sanz
c   Department of Organic Chemistry, Faculty of Sciences, University of Granada, 18071 Granada, Spain   Email: joltra@ugr.es
,
Esther Roldan-Molina
c   Department of Organic Chemistry, Faculty of Sciences, University of Granada, 18071 Granada, Spain   Email: joltra@ugr.es
,
Laura Pozo-Morales
a   Department of Chemical and Environmental Engineering, Escuela Politécnica Superior, University of Sevilla, 41011 Sevilla, Spain   Email: arosales@us.es
,
Adriana Irías-Álvarez
a   Department of Chemical and Environmental Engineering, Escuela Politécnica Superior, University of Sevilla, 41011 Sevilla, Spain   Email: arosales@us.es
,
Roman Rodríguez-Maecker
b   Petrochemical Engineering, Universidad de las Fuerzas Armadas-ESPE, 050150 Latacunga, Ecuador
,
Ignacio Rodríguez-García
d   Química Orgánica, CeiA3, Universidad de Almería, 04120 Almería, Spain
,
J. Enrique Oltra*
c   Department of Organic Chemistry, Faculty of Sciences, University of Granada, 18071 Granada, Spain   Email: joltra@ugr.es
› Author Affiliations
Further Information

Publication History

Received: 06 July 2015

Accepted after revisión: 23 October 2015

Publication Date:
09 December 2015 (online)

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Dedicated to Prof. Emilio Diaz Ojeda

Abstract

A synthesis of (±)-ambrox, a compound with delicious ambergris-type scent, is presented. The key step is a highly diastereoselective titanocene(III)-catalyzed radical tandem cyclization of a farnesol derivative.

Key words

ambrox - natural products - titanocene - radical chemistry - diastereoselective synthesis

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1560594.
  • Supporting Information
 

  • References and Notes

  • 1 Ambrox is the registered trademark of Firmenich for compound 1.
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  • 15 Cp2TiCl-Catalyzed Cyclization of 3 Strictly deoxygenated THF (15 mL) was added to a mixture of [Cp2TiCl2] (25 mg, 0.1 mmol) and Mn dust (440 mg, 8.0 mmol) under Ar, and the suspension was stirred at r.t. until it turned green (about 15 min). Then a solution of 2,4,6-collidine (0.9 mL, 7.0 mmol) and TMSCl (0.5 mL, 4.0 mmol) in THF (5 mL) was added, the mixture was stirred for 5 min, a solution of 3 (280 mg, 1 mmol) in THF (5 mL) was finally added, and the mixture was stirred at r.t. for 12 h. Then 2 N HCl was added, and the mixture was extracted with Et2O. The combined organic layers were dried with anhydrous Na2SO4, and the solvent was removed. The residue was dissolved in THF, and 1 M solution of TBAF in THF (1.2 mmol) was added. The new mixture was stirred for 30 min, diluted with Et2O, and washed with brine. The organic layer was dried with anhydrous Na2SO4 and the solvent removed. The residue was purified by flash chromatography (hexane–EtOAc, 9:1) to yield 112 mg of the cyclization compound 4 (40%), and 112 mg of starting material 3 was recovered (40%). Only the isomer 4 was isolated. 1H NMR and 13C NMR spectra of compound 4 were consistent with that of the original isolation literature.11a
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  • 22 Synthesis of Mesylate 6 To a solution of isodrimenediol (5, 238 mg, 1.0 mmol) and DMAP (12 mg, 0.1 mmol) in pyridine (4 mL) was added MsCl (81 μL, 1.05 mmol), and the whole mixture was stirred for 2 h at r.t. The reaction mixture was diluted with sat. brine and extracted with Et2O. The organic layer was washed with 2 N aq HCl, 7% aq NaHCO3, dried with anhydrous Na2SO4, and the solvent was removed. The residue was purified by flash chromatography (hexane–EtOAc, 9:1) to yield 300 mg of mesylate 6 (95%), isolated as a waxy mass. Analytical Data for Mesylate 6 1H NMR (500 MHz, CDCl3): δ = 4.92 (s, 1 H), 4.62 (s, 1 H), 4.45 (dd, J = 10.0, 3.9 Hz, 1 H), 4.34 (dd, J = 9.8, 8.9 Hz, 1 H), 3.26 (dd, J = 11.7, 4.2 Hz, 1 H), 2.98 (s, 3 H), 2.43 (ddd, J = 13.2, 4.3, 2.4 Hz, 1 H), 2.11 (dd, J = 8.6, 3.2 Hz, 1 H), 2.02 (td, J = 13.0, 4.8 Hz, 1 H), 1.78–1.69 (m, 3 H), 1.66–1.54 (m, 2 H), 1.45–1.35 (m, 2 H), 1.13 (dd, J = 12.5, 2.8 Hz, 1 H), 1.00 (s, 3 H), 0.78 (s, 3 H), 0.76 (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 145.1 (C), 108.0 (CH2), 78.3 (CH), 66.4 (CH2), 54.8 (CH), 54.2 (CH), 39.1 (C), 38.9 (C), 37.6 (CH3), 37.2 (CH2), 37.0 (CH2), 28.2 (CH3), 27.5 (CH2), 23.3 (CH2), 15.4 (CH3), 15.2 (CH3).
  • 23 Preparation of Nitrile 7 To a solution of mesylate 6 (252 mg, 0.8 mmol) in DMSO (5 mL) was added NaCN (196 mg, 4 mmol), and the mixture of reaction was stirred for 12 h at 100 °C. The reaction mixture was diluted with sat. brine and extracted with Et2O. The organic layer was dried with anhydrous Na2SO4, and the solvent was removed. The residue was purified by flash chromatography (hexane–EtOAc, 9:1) to yield 97 mg of the nitrile 7 (49%) and 53 mg of the diexo-olefin 11 (30%), both isolated as waxy mass. Analytical Data for Nitrile 7 1H NMR (401 MHz, CDCl3): δ = 4.96 (s, 1 H), 4.62 (s, 1 H), 3.25 (dd, J = 11.6, 4.3 Hz, 1 H), 2.56–2.40 (m, 2 H), 2.34 (dd, J = 16.7, 10.6 Hz, 1 H), 2.17–2.00 (m, 2 H), 1.80–1.50 (m, 4 H), 1.45–1.28 (m, 2 H), 1.12 (dd, J = 12.5, 2.6 Hz, 1 H), 1.00 (s, 3 H), 0.77 (s, 3 H), 0.68 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 145.7 (C), 120.0 (C), 108.2 (CH2), 78.2 (CH), 54.1 (CH), 52.9 (CH), 39.1 (C), 39.0 (C), 37.1 (CH2), 37.0 (CH2), 28.2 (CH3), 27.5 (CH2), 23.3 (CH2), 15.4 (CH3), 14.0 (CH2), 13.7 (CH3). Analytical Data for Diexo-olefin 11 1H NMR (500 MHz, CDCl3): δ = 4.81 (t, J = 2.1 Hz, 1 H), 4.77 (s, 1 H), 4.67 (s, 1 H), 4.53 (s, 1 H), 3.25 (dd, J = 10.3, 4.2 Hz, 1 H), 2.47 (br d, J = 12.6 Hz, 1 H), 2.15–2.06 (m, 1 H), 1.82–1.49 (m, 6 H), 1.12 (dd, J = 12.5, 2.5 Hz, 1 H), 1.00 (s, 3 H), 0.95 (s, 3 H), 0.83 (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 160.9 (C), 149.4 (C), 109.3 (CH2), 103.5 (CH2), 78.8 (CH), 51.7 (CH), 39.9 (C), 39.4 (C), 35.6 (CH2), 35.3 (CH2), 28.3 (CH3), 27.7 (CH2), 22.3 (CH2), 20.8 (CH3), 15.5 (CH3).
  • 24 Synthesis of Aldehyde 8 To a solution of nitrile 7 (247 mg, 1.0 mmol) in toluene (3 mL) was added 1 M DIBAL in toluene (1.19 mL, 1.19 mmol) at –78 °C. The mixture of reaction was stirred for 30 min at the same temperature. After addition of acetone (0.75 mL), the reaction mixture was diluted with 2 M aq HCl and extracted with Et2O. The organic layer was washed with sat. brine, dried over anhydrous Na2SO4, and the solvent was removed. The residue was purified by flash chromatography (hexane–EtOAc, 9:1) to yield 212 mg of the aldehyde 8 (85%) as waxy mass. Analytical Data for aldehyde 8 1H NMR (500 MHz, CDCl3): δ = 9.64 (dd, J = 3.1, 0.9 Hz, 1 H), 4.84 (s, 1 H), 4.41 (s, 1 H), 3.28 (dd, J = 11.6, 4.5 Hz, 1 H), 2.52 (ddd, J = 16.8, 10.8, 3.2 Hz, 1 H), 2.46–2.40 (m, 2 H), 2.35–2.30 (m, 1 H), 2.09 (td, J = 13.1, 5.0 Hz, 1 H), 1.81–1.51 (m, 5 H), 1.42 (qd, J = 13.0, 4.3 Hz, 1 H), 1.21 (dd, J = 12.5, 2.8 Hz, 1 H), 1.02 (s, 3 H), 0.80 (s, 3 H), 0.72 (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 203.0 (CH), 147.9 (C), 108.4 (CH2), 78.6 (CH), 54.3 (CH), 50.6 (CH), 39.8 (CH2), 39.1 (C), 38.6 (C), 37.3 (2 × CH2), 28.3 (CH3), 27.7 (CH2), 23.5 (CH2), 15.4 (CH3), 14.6 (CH3).
  • 25 Preparation of Alcohol 9 To a solution of 8 (187 mg, 0.75 mmol) in MeOH (3.7 mL) was added NaBH4 (37 mg, 0.98 mmol) at 0 °C. The mixture of reaction was stirred for 30 min at the same temperature. After addition of acetone (0.6 mL), the reaction mixture was condensed to give a residue, which was diluted with sat. brine and extracted with Et2O. The organic layer was dried with anhydrous Na2SO4, and the solvent was removed. The crude of reaction was purified by flash chromatography (hexane–EtOAc, 85:15) to yield 179 mg of the alcohol 9 (95%) isolated as waxy mass. Analytical Data for Alcohol 9 1H NMR (500 MHz, CDCl3): δ = 4.87 (br s, 1 H), 4.56 (br s, 1 H), 3.74 (ddd, J = 10.1, 7.3, 4.3 Hz, 1 H), 3.53 (dt, J = 10.1, 7.0 Hz, 1 H), 3.27 (dd, J = 11.8, 4.3 Hz, 1 H), 2.41 (ddd, J = 12.8, 4.3, 2.5 Hz, 1 H), 2.00 (td, J = 13.0, 5.1 Hz, 1 H), 1.82–1.56 (m, 7 H), 1.55–1.45 (m, 2 × OH), 1.40 (dd, J = 12.8, 4.2 Hz, 1 H), 1.21 (m, 1 H), 1.13 (dd, J = 12.5, 2.8 Hz, 1 H), 1.00 (s, 3 H), 0.78 (s, 3 H), 0.70 (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 148.2 (C), 106.8 (CH2), 78.8 (CH), 62.4 (CH2), 54.6 (CH), 52.5 (CH), 39.1 (C), 39.1 (C), 38.1 (CH2), 37.1 (CH2), 28.3 (CH3), 27.9 (CH2), 27.2 (CH2), 23.9 (CH2), 15.41 (CH3), 14.5 (CH3).
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