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

Lisa A. Sloan; Thomas M. Baker; Simon J. F. Macdonald; David J. Procter

doi:10.1055/s-2007-1000821

LETTER

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

Lisa A. Sloan^a, Thomas M. Baker^a, Simon J. F. Macdonald^b, 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;

Abstract

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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

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Referenzen

References and Notes

For recent reviews on the use of samarium(II) iodide, see:

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9

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.