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Synlett 2009(14): 2315-2319  
DOI: 10.1055/s-0029-1217708
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Novel Approach to Monobenzannulated Spiroketals Using Styrenes in the Kulinkovich Reaction

Isabell Haym, Margaret A. Brimble*
Department of Chemistry, The University of Auckland, 23 Symonds St., Auckland 1142, New Zealand
Fax: +64(9)3737422; e-Mail: m.brimble@auckland.ac.nz;
Further Information

Publication History

Received 26 May 2009
Publication Date:
31 July 2009 (online)

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Abstract

The synthesis of a series of 5,6-monobenzannulated spiroketals is reported. The use of various styrenes in a Kulinkovich reaction with an appropriately functionalized aliphatic ester affords cyclopropanol products which under basic conditions underwent ring opening to form ketone precursors to the spiroketals. Deprotection of the hydroxyl groups and subsequent cyclization afforded monobenzannulated spiroketals related to the core structure of berkelic acid.

Key words

Kulinkovich reaction - ring opening - cyclopropanol - spiroketal - berkelic acid

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General Procedure - Kulinkovich Reaction
A solution of Ti(Oi-Pr)4 (2.16 mmol) in THF (5 mL) was cooled to an internal temperature of -40 ˚C. c-C6H11MgCl (6.49 mmol) was added at such a rate that the internal temperature did not exceed -35 ˚C. Styrene (0.72 mmol) was added and the orange-brown suspension stirred for 2 h at -35 ˚C. Ester (0.72 mmol) was added and the suspension warmed to r.t. whereupon a brown color developed. After stirring for 1 h, the suspension was diluted with EtOAc (75 mL) and poured into sat. NH4Cl solution (75 mL). The emulsion was stirred vigorously for 30 min then filtered through a pad of Celite®. The aqueous layer was extracted with EtOAc (3 × 75 mL), then the combined organic phases were dried over MgSO4, filtered, and the solvent removed in vacuo. The crude product was purified by flash chromatog-raphy (hexane-EtOAc, 2:1) to afford the cyclopropanol.
1-[3-(Benzyloxy)propyl]-2-[2-(ethoxymethoxy)-4-methoxyphenyl]cyclopropanol (21) Yellow oil. R f  = 0.23 (hexane-EtOAc, 2:1). IR (film): ν = 3440, 2928, 1711, 1610, 1505, 1453, 1360, 1279, 1254, 1199, 1156, 1100, 1075, 996, 842, 736, 689 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 0.89 (dd, J = 7.3, 5.7 Hz, 1 H, H-2), 1.12-1.29 (m, 4 H, CH3, H-3), 1.56 (dd, J = 14.4, 7.4 Hz, 2 H, H-1′), 1.70 (quin, J = 6.3 Hz, 2 H, H-2′), 2.30 (dd, J = 9.9, 7.3 Hz, 1 H, H-3), 3.48 (t, J = 5.8 Hz, 2 H, H-3′), 3.74 (q, J = 7.1 Hz, 2 H, OCH 2CH3), 3.78 (s, 3 H, OMe), 4.47 (s, 2 H, OCH2Ph), 5.25 (q, J = 6.3 Hz, 2 H, OCH2O), 6.45 (dd, J = 8.4, 2.5 Hz, 1 H, H-5′), 6.73 (d, J = 2.5 Hz, 1 H, H-3′), 6.79 (d, J = 8.4 Hz, 1 H, H-6′), 7.27-7.34 (m, 5 H, OBn). ¹³C NMR (75 MHz, CDCl3): δ = 15.1 (CH3), 17.1 (CH2, C-3), 25.9 (CH2, C-2′), 26.1 (CH, C-2), 31.4 (CH2, C-1′), 55.3 (CH3, OMe), 64.2 (q, C-1), 70.7 (CH2, OCH2CH3), 72.9 (CH2, OCH2Ph), 93.4 (CH2, OCH2O), 101.4 (CH, C-4′′), 105.6 (CH, C-5′′), 127.6 (CH, C-6′′), 127.7 (CH, C-2′′′,
C-6′′′), 128.2 (CH, C-4′′′), 128.4 (CH, C-3′′′, C-5′′′), 148.7 (q, C-1′′, C-1′′′), 159.0 (q, C-2′′, C-3′′). MS (EI, 70eV):
m/z (%) = 247 (16), 409 (100) [M+ + Na], 793 (2 M+ + Na]. HRMS (EI): m/z [M+ + Na] calcd for C23H30NaO5: 409.1991; found: 409.1985.

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General Procedure - Ring Opening of Cyclopropanols Cyclopropanol (0.34 mmol) was added to dioxane (3 mL) and 0.2 N NaOH solution (6 mL). The reaction was stirred at reflux for 3 d, then neutralized to pH 7 with 2 M HCl. The aqueous layer was extracted with Et2O (5 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and the solvent removed in vacuo. The crude product was purified by flash chromatography (hexane-EtOAc, 4:1) to afford the ketone.


6-(Benzyloxy)-1-[2-(ethoxymethoxy)-4-methoxy-phenyl]hexan-3-one (26) Yellow oil. R f  = 0.38 (hexane-EtOAc, 4:1). IR (film): ν = 2927, 1712, 1610, 1587, 1506, 1444, 1361, 1284, 1256, 1199, 1154, 1100, 1077, 997, 842, 737, 698 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.22 (t, J = 7.1 Hz, 3 H, OCH2CH 3), 1.88 (quin, J = 6.7 Hz, 2 H, H-5), 2.50 (t, J = 7.3 Hz, 2 H, H-4), 2.66 (t, J A,B = 7.7 Hz, 2 H, H-2), 2.81 (t, J A,B = 7.4 Hz, 2 H, H-1), 3.46 (t, J = 6.4 Hz, 2 H, H-6), 3.71 (q, J = 7.0 Hz, 2 H, OCH 2CH3), 3.77 (s, 3 H, OMe), 4.47 (s, 2 H, OCH2Ph), 5.22 (s, 2 H, OCH2O), 6.46 (dd, J = 8.3, 2.6 Hz, 1 H, H-5′), 6.70 (d, J = 2.5 Hz, 1 H, H-3′), 7.01 (d, J = 8.0 Hz, 1 H, H-6′). ¹³C NMR (75 MHz, CDCl3): δ = 15.1 (CH3), 23.8 (CH2, C-5), 24.3 (CH2, C-1), 39.4 (CH2, C-4), 43.2 (CH2, C-2), 55.3 (CH3, OMe), 64.3 (CH2, OCH2CH3), 69.4 (CH2, C-6), 72.8 (CH2, OCH2Ph), 93.1 (CH2, OCH2O), 101.4 (CH, C-3′), 105.8 (CH, C-5′), 127.5 (CH, C-4′′), 127.6 (CH, 2′′, C-6), 128.4 (CH, C-3′′, C-5′′), 130.1 (q, C-1′), 130.2 (CH, C-6′), 138.7.9 (q, C-1′′), 156.0 (q, C-2′), 159.2 (q, C-4′), 210.8 (q, C-3). MS (EI, 70eV): m/z (%) = 97 (19), 151 (55), 177 (82), 207 (27), 235 (67), 253 (19), 275 (17), 311 (46), 341 (31), 385 (5) [M+], 409 (100) [M+ + Na]. HRMS (EI): m/z [M+ + Na] calcd for C23H30NaO5: 409.1991; found: 409.1985.