Synlett 2007(20): 3155-3159  
DOI: 10.1055/s-2007-1000821
LETTER
© Georg Thieme Verlag Stuttgart · New York

Application of a Samarium(II)-Mediated Spirocyclisation in an Asymmetric Approach to the Cyclopentanol Motif of Stolonidiol

Lisa A. Sloana, Thomas M. Bakera, Simon J. F. Macdonaldb, David J. Procter*a
a The School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
b GlaxoSmithKline R&D Ltd, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK
Fax: +44(161)2754939; e-Mail: david.j.procter@manchester.ac.uk;
Further Information

Publication History

Received 21 August 2007
Publication Date:
03 December 2007 (online)

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Abstract

An asymmetric approach to the cyclopentanol motif of the biologically active, marine natural product stolonidiol has been developed. The approach involves the asymmetric synthesis of chiral γ,δ-unsaturated ketones and their spirocyclisation using SmI2.

Key words

samarium - radical reactions - asymmetric synthesis - natural products - spiro compounds

    References and Notes

  • For recent reviews on the use of samarium(II) iodide, see:
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Oxidation of commercially available 3-benzyloxypropan-1-ol gave 9 (py·SO3, DMSO, Et3N, CH2Cl2, 78%).

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Anhydrous MeOH (4.34 mL) was added to a stirred solution of SmI2 (0.1 M in THF, 9.20 mL, 0.92 mmol, 4 equiv) at 0 °C and the solution was stirred for 10 min. (3E)-3-[(3S)-6-(Benzyloxy)-3-(1-hydroxy-1-methylethyl)-4-oxohexyl­-idene]dihydrofuran-2 (3H)-one (20; 100 mg, 0.23 mmol, 1.0 equiv) in THF (1.5 mL) was added and the resultant solution was stirred at 0 °C for 0.5 h before the reaction was quenched by opening to air and the addition of NaCl (sat. solution in H2O, 5 mL). The aqueous layer was separated and extracted with 60% EtOAc in PE (40-60 °C) (4 × 15 mL). The com-bined organic extracts were dried (MgSO4), and concen-trated in vacuo. Purification by column chromatography [eluting with 30% EtOAc in PE (40-60 °C)], gave (5R,6R,7S)-6-[2-(benzyloxy)ethyl]-6-hydroxy-7-(1-hydroxy-1-methylethyl)-2-oxaspiro[4.4]nonan-1-one (24; 22 mg, 0.06 mmol, 28%) as a clear, colourless oil; [α]20 D
-18.1 (c = 1.85, CHCl3). ATR: 3440, 2939, 1729 (s, ester CO), 1374 (m), 1195 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.16 (s, 3 H, Me), 1.46 (s, 3 H, Me), 1.71-2.01 (m, 5 H, 1 H of CH 2CH, 1 H of CH 2CH2CH, 1 H of CH 2CH2OBn, 1 H of CH 2CH2OCO, CH), 2.17 (1 H, q, J = 7.2 Hz, 1 H of CH2), 2.28-2.34 (m, 1 H, CH2) 2.41 (1 H, dt, J = 11.4, 2.4 Hz, CH 2CH2OBn), 2.56 (1 H, q, J = 7.8 Hz, 1 H of CH 2CH2OC=O), 3.52-3.61 (m, 2 H, CH 2OBn), 3.96 (1 H, dt, J = 6.9, 0.9 Hz, 1 H of CH2OC=O), 4.05-4.11 (m, 1 H, CH2OCO), 4.16 (1 H, OH), 4.23 (d, AB system, J = 8.5 Hz, 1 H, OCH 2Ph), 4.26 (d, AB system, J = 8.5 Hz, 1 H, OCH 2Ph), 5.86 (1 H, OH), 7.27-7.34 (m, 5 H, ArCH). 13C NMR (100 MHz, CDCl3): δ = 29.9 (CH2CH2OCO), 30.0 (CH2 CH2CH), 30.5 (Me), 30.9 (Me), 33.9 (CH2CH2CH), 36.9 (CH2CH2OBn), 54.2 (C qCOO), 55.4 (CH), 65.3 (CH2OBn), 65.4 (CH2OCO), 72.4 (OCH2Ph), 72.5 (C qOHCH2CH2OBn), 86.0 (C qMe2OH), 127.6 (ArCH), 128.2 (4 × ArCH), 138.0 (ArC q), 182.9 (ester CO). MS (CI mode): m/z (%) = 349 (85) [M+], 331 (40), 308 (40), 219 (100), 195 (50). HRMS: m/z [M + H]+ calcd for C20H29O5: 349.2010; found: 349.2006. Further elution gave (5S,6S,7S)-6-[2-(benzyloxy)ethyl]-6-hydroxy-7-(1-hydroxy-1-methylethyl)-2-oxaspiro[4.4]nonan-1-one (25; 18.5 mg, 0.05 mmol, 23%) as a clear, colourless oil; [α]20 D -15.9 (c = 1.32, CHCl3). ATR: 2343 (m), 2947 (m), 1744 (s, ester CO), 1453 (m), 1372 (m), 1183 (m) cm-1. 1H NMR (500 MHz, CDCl3): δ = 1.16 (s, 3 H, Me), 1.29 (s, 3 H, Me), 1.53-1.56 (m, 2 H, CH 2CH), 1.87-1.91 (m, 2 H, 1 H of CH 2CH2CH, 1 H of CH 2CH2OCO), 2.03-2.10 (m, 2 H, 1 H of CH 2CH2CH, 1 H of CH 2CH2OBn), 2.42-2.48 (m, 2 H, 1 H of CH 2CH2OBn, 1 H of CH 2CH2OCO), 2.60 (1 H, t, J = 10.0 Hz, CH), 3.62-3.68 (m, 2 H, CH 2OBn), 4.01 (dt, J = 2.6, 5.1 Hz, 2 H, CH2OCO), 4.33 (d, AB system, J = 11.6 Hz, 1 H, OCH 2Ph), 4.43 (d, AB system, J = 11.6 Hz, 1 H, OCH 2Ph), 7.19-7.40 (m, 5 H, ArCH). 13C NMR (100 MHz, CDCl3): δ = 23.2 (CH2CH2CH), 29.2 (Me), 30.1 (CH2 CH2CH), 30.9 (Me), 31.3 (CH2CH2OCO), 33.1 (CH2CH2OBn), 56.2 (C qCOO), 57.4 (CH), 65.2 (CH2OCO), 66.6 (CH2OBn), 72.5 (C qOHCH2CH2OBn), 72.9 (OCH2Ph), 83.9 [C qMe2OH], 127.7 (ArCH), 128.0 (2 × ArCH), 128.3 (2 × ArCH), 137.8 (C qAr), 181.6 (ester CO). MS (CI mode): m/z (%) = 349 (40) [M+], 313 (100), 307 (100), 291 (30), 225 (35), 221 (40), 200(50), 183 (85), 108 (40). HRMS: m/z [M + H]+ calcd for C20H29O5: 349.2010; found: 349.2010. Further elution gave 3-[6-(benzyloxy)-4-oxohexyl]dihydrofuran-2 (3H)-one (26; 23 mg, 0.08 mmol, 33%) as a clear, colourless oil. IR (neat): 2918 (m), 2353 (m), 1765 (s, ketone CO), 1710 (s, ester CO), 1371 (m), 1103 (m) cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.39-1.48 (m, 1 H, COOCH2CH 2], 1.68 (app. pent, J = 5.4 Hz, 2 H, (COCH2CH 2CH2CH), 1.80-2.00 (m, 2 H, 1 H of COCH 2CH2, 1 H of COOCH2CH 2), 2.34-2.42 (m, 1 H, COCH 2), 2.45-2.54 (m, 3 H, COCHCH2, COCHCH 2), 2.69 (t, J = 4.5 Hz, 2 H, BnOCH2CH 2), 3.74 (t, J = 4.5 Hz, 2 H, BnOCH 2), 4.16 (dt, J = 5.1, 6.8 Hz, 1 H, COOCH 2), 4.32 (dt, J = 2.1, 6.8 Hz, 1 H, COOCH 2), 4.50 (s, 2 H, OCH 2Ph), 7.26-7.36 (m, 5 H, ArCH). 13C NMR (100 MHz, CDCl3): δ = 21.1 (COCH2 CH2CH2), 28.5 (OCH2 CH2), 29.7 (COCH2), 39.2 (CH), 42.8 (CH2CHCO), 42.9 (CH2CH2OBn), 65.3 (CH2OBn), 66.5 (CH2OCO), 73.2 (OCH2Ph), 127.7 (3 × ArCH), 128.4 (2 × ArCH), 138.0 (ArC q), 179.2 (ester CO), 208.6 (ketone CO). MS (CI mode): m/z (%) = 309 (20) [MNH4 +], 308 (100), 291 (10). HRMS: m/z [M + NH4]+ calcd for C17H26O4N: 308.1856; found: 308.1859.

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CCDC 605754 contains the supplementary crystallographic data for this paper (compound 27). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.