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

Isabell Haym; Margaret A. Brimble

doi:10.1055/s-0029-1217708

LETTER

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;

Abstract

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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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References

References and Notes

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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.

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.