Efficient Synthesis of the
Spiroacetal Core of Paecilospirone via Oxidative Radical
Cyclisation

Morgan Jay-Smith; Daniel P. Furkert; Jonathan Sperry; Margaret A. Brimble

doi:10.1055/s-0030-1260564

LETTER

Efficient Synthesis of the Spiroacetal Core of Paecilospirone via Oxidative Radical Cyclisation

Morgan Jay-Smith, Daniel P. Furkert, Jonathan Sperry, Margaret A. Brimble*
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand
Fax: +64(9)3737422; e-Mail: m.brimble@auckland.ac.nz;

Abstract

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Abstract

The spiroacetal core of the microtubule assembly inhibitor paecilospirone has been prepared using two separate oxidative cyclisation methods.

Key words

paecilospirone - microtubule - spiroacetal - oxidative radical cyclisation - DDQ

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References

References and Notes

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Spiroacetal 5 Iodine (67 mg, 0.26 mmol) and iodobenzene diacetate (84 mg, 0.26 mmol) were added to a solution of benzyl alcohol 6 (30 mg, 0.13 mmol) in cyclohexane (5 mL), and the reaction mixture was irradiated with a 60 W desk lamp. After stirring for 1 h at r.t., the reaction mixture was diluted with hexane-EtOAc (1:1, 20 mL total) and shaken with sat. aq Na₂S₂O₃ (4 mL) until colourless. The mixture was washed with brine, extracted with EtOAc, and the aqueous layer was further extracted with EtOAc. The combined organic phases were then dried over anhyd MgSO₄ and the solvent removed in vacuo. Purification via flash column chromatography using hexane-EtOAc (9:1) as eluent afforded the title compound 5 (18 mg, 0.076 mmol, 61%) as a pale yellow oil. R _f = 0.40 (2:1, hexane-EtOAc). IR: 2923, 2868, 1656, 1582, 1487, 1456, 1373, 1232, 1110, 1004, 904, 746 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.21 (1 H, ddd, J = 13.2, 5.6, 2.0 Hz, CH₂, PhCH₂CH ₂), 2.45 (1 H, td, J = 13.2, 5.6 Hz, CH₂, PhCH₂CH ₂), 2.88 (1 H, ddd, J = 16.0, 5.6, 2.0 Hz, CH₂, PhCH ₂CH₂), 3.29 (1 H, ddd, J = 16.0, 13.6, 6.0 Hz, CH₂, PhCH ₂CH₂), 5.05 (1 H, d, J = 12.4 Hz, CH₂, PhCH₂O), 5.30 (1 H, d, J = 12.4, CH₂, PhCH₂O), 6.79 (1 H, dd, J = 8.0, 1.2 Hz, Ar, PhH), 6.90 (1 H, td, J = 3.6, 0.8 Hz, Ar, PhH), 7.10 (1 H, t, J = 7.6 Hz, Ar, PhH), 7.15 (1 H, d, J = 7.6 Hz, Ar, PhH), 7.33 (1 H, dt, J = 7.2, 0.8 Hz, Ar, PhH), 7.38-7.44 (3 H, m, Ar, PhH). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.8 (CH₂, PhCH₂CH₂), 30.2 (CH₂, PhCH₂ CH₂), 71.7 (CH₂, PhCH₂O), 108.2 (q, spiroacetal), 117.1 (CH, Ar), 120.8 (CH, Ar), 121.3 (CH, Ar), 121.7 (q, Ar), 122.0 (CH, Ar), 127.4 (CH, Ar), 127.9 (CH, Ar), 129.1 (CH, Ar), 129.4 (CH, Ar), 140.0 (2 × q, 2 × Ar), 153.2 (q, Ar). MS (ESI⁺): m/z (%) = 239(100) [MH⁺]. HRMS: m/z calcd for C₁₆H₁₅O₂ [M + H]⁺: 239.1072; found: 239.1075.

Spiroacetal 17 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (67 mg, 0.30 mmol) was added to a solution of compound 14 (70 mg, 0.20 mmol) in CH₂Cl₂-H₂O (9:1, 3.3 mL total). The dark green reaction was stirred for 90 min at r.t. and then filtered through cotton wool. The reaction mixture was washed with brine, extracted with EtOAc, and the aqueous layer was further extracted with EtOAc. The combined organic phases were then dried over anhyd MgSO₄ and the solvent removed in vacuo. Purification by flash column chromatography using hexane-EtOAc (9:1) afforded the title compound 17 (45 mg, 0.19 mmol, 95%) as a yellow oil. R _f = 0.59 (2:1, hexane-EtOAc). IR: 2854, 1611, 1512, 1486, 1456, 1246, 1033, 820, 757 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 5.05 (1 H, d, J = 12.4 Hz, CH₂, PhCH₂O), 5.33 (1 H, d, J = 12.4 Hz, CH₂, PhCH₂O), 5.87 (1 H, d, J = 9.6 Hz, PhCH=CH), 6.90 (2 H, t, J = 10.0 Hz, PhCH=CH, PhH), 6.98 (1 H, t, J = 7.6 Hz, Ar, PhH), 7.20-7.22 (2 H, m, Ar, PhH), 7.34 (1 H, dt, J = 7.6, 0.8 Hz, Ar, PhH), 7.39-7.40 (2 H, m, Ar, PhH), 7.42-7.46 (1 H, m, Ar, PhH). ^¹³C NMR (100 MHz, CDCl₃): δ = 71.8 (CH₂, PhCH₂O), 107.7 (q, spiroacetal), 116.6 (CH, PhCH=CH), 119.7 (q, Ar), 121.1 (CH, PhCH=CH), 121.2 (CH, Ar), 121.5 (CH, Ar), 123.2 (CH, Ar), 126.9 (CH, Ar), 127.0 (CH, Ar), 128.1 (CH, Ar), 129.6 (CH, Ar), 129.6 (CH, Ar), 139.7 (q, Ar), 140.2 (q, Ar), 151.5 (q, Ar). MS (ESI⁺): m/z (%) = 237(100) [MH⁺]. HRMS: m/z calcd for C₁₆H₁₃O₂ [M + H]⁺: 237.0910; found: 237.0915.