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

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

References and Notes

• 1 Namikoshi M. Kobayashi H. Yoshimoto T. Meguro S. Chem. Lett.  2000,  29:  308 
• 2 Kobayashi H. Sunaga R. Furihata K. Morisaki N. Iwasaki S. J. Antibiot.  1995,  48:  42 
• 3a Brasholz M. Sorgel S. Azap C. Reißig HU. Eur. J. Org. Chem.  2007,  3801 
• 3b Sperry J. Wilson ZE. Rathwell DCK. Brimble MA. Nat. Prod. Rep.  2010,  27:  1117 
• 4 Raju BR. Saikia AK. Molecules  2008,  13:  1942 
• 5 Aho JE. Pihko PM. Rissa TK. Chem. Rev.  2005,  105:  4406 
• 6 Yuen TY. PhD Thesis   University of Auckland; New Zealand: unpublished work
• 7 Marsini M. Huang Y. Lindsey C. Wu K.-L. Pettus TRR. Org. Lett.  2008,  10:  1477 
• 8a Brimble MA. Williams GM. J. Org. Chem.  1992,  57:  5818 
• 8b Allen PA. Brimble MAH. Prabaharan H. Synlett  1999,  295 
• 8c Allen PA. Brimble MA. Fares FA. J. Chem. Soc., Perkin Trans. 1  2001,  379 
• 8d Brimble MA. Horner GM. Stevenson RJ. Aust. J. Chem.  1996,  49:  189 
• 8e Brimble MA. Molecules  2004,  9:  394 
• 8f Furkert DP. Brimble MA. Org. Lett.  2002,  4:  3655 
• 8g Furkert DP. Brimble MA. Org. Biomol. Chem.  2004,  2:  3573 
• 8h Meilert K. Brimble MA. Org. Lett.  2005,  7:  3497 
• 8i Meilert K. Brimble MA. Org. Biomol. Chem.  2006,  4:  2184 
• 8j Liu Y.-C. Sperry J. Rathwell DCK. Brimble MA. Synlett  2009,  793 
• 8k Sperry J. Liu YC. Brimble M. Org. Biomol. Chem.  2010,  8:  29 
• 9 Schmidt J. Ber. Dtsch. Chem. Ges.  1881,  14:  1459 
• 10 Claisen A. Claparede A. Ber. Dtsch. Chem. Ges.  1881,  14:  2460 
• 11 Deffieux D. Gaudrel-Grosay S. Grelard A. Chalumeau C. Quideau S. Tetrahedron Lett.  2009,  50:  6567 
• 12 Jung S. Park S. Kim-Pak Y. Lee H. Park K. Shin K. Ohuchi K. Shin H. Keum S. Lim S. Chem. Pharm. Bull.  2006,  3:  368 
• 13 Won S.-J. Liu C.-T. Tsao L.-T. Weng J.-R. Ko H.-H. Wang J.-P. Lin C.-N. Eur. J. Med. Chem.  2005,  103 
• 14 Sajiki H. Hattori K. Hirota K. J. Org. Chem.  1998,  63:  7990 

15

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.

16

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.