The Synthesis and Biological Evaluation of Novel Eunicellin Analogues

James E. P. Davidson; Ryan Gilmour; Sylvie Ducki; John E. Davies; Richard Green; Jonathan W. Burton; Andrew B. Holmes

doi:10.1055/s-2004-825627

LETTER

The Synthesis and Biological Evaluation of Novel Eunicellin Analogues

James E. P. Davidson^a, Ryan Gilmour^a, Sylvie Ducki^b, John E. Davies^a, Richard Green^c, Jonathan W. Burton*^a, Andrew B. Holmes*^a
^a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax: +44(1223)334866; e-Mail: abh1@cam.ac.uk;
^b Centre for Molecular Drug Design, Cockcroft Building, University of Salford, Salford, M5 4WT, UK
^c GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK

Abstract

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Abstract

The intramolecular Diels-Alder reaction of a 2,9-disubstituted hexahydro-Δ^5,6-oxonin derivative 14 afforded two diastereomeric tricyclic eunicellin analogues 15 and 16, which were desilylated to produce the alcohols 17 and 3; these were found to be microtubule stabilising agents with activity in the micromolar range.

Key words

eunicellin - cycloaddition - lactone - microtubules

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References

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Wittig Elaboration of 13 and Intramolecular Cycloaddition of 14 to Give 15 and 16. To a stirred solution of the aldehyde 13 (93 mg, 0.2 mmol) in toluene (15 mL) was added 1-triphenylphosphoranylidene-2-propanone (187 mg, 0.59 mmol). The resultant mixture was heated to reflux for 2 h 15 min, and then allowed to cool to ambient temperature. The solvent was removed in vacuo and purification by flash chromatography (CH₂Cl₂) yielded the title compounds 15 (64 mg, 63%) and 16 (21.4 mg, 21%) as colourless oils.
Data for 15: R_f = 0.41 (CH₂Cl₂); [a]_D ²⁵ -24.6 (c 0.65 in CHCl₃). IR (CHCl₃): n_max = 3022 (w), 3019 (m), 2932 (s), 2859 (m), 1713 (s) (CO), 1473 (m), 1428 (m), 1358 (m), 1111 (s), 1089 (m), 1043 (s), 1021 (m), 943 (w), 823 (m), 610 (w) cm^-1. ¹H NMR (500 MHz, CDCl₃): d = 7.64-7.71 (4 H, m, Ar), 7.33-7.44 (6 H, m, Ar), 5.55-5.64 (1 H, m, H-6), 5.30-5.50 (1 H, br s, H-5), 5.20-5.24 (1 H, m, H-12), 4.65 (1 H, dd, J = 8.4 and 1.1 Hz, H-2), 3.95-4.03 (1 H, m, H-9), 3.48 (1 H, d, J = 8.4 Hz, H-3), 2.72-2.81 (1 H, m, H-10), 2.54 (1 H, dt, J = 11.0 and 6.8 Hz, H-14), 2.10-2.47 (4 H, m, H-1, H-4, H-13 and H-7), 2.02-2.11 (2 H, m, H-4 and H-8), 1.87-1.96 (1 H, m, H-13), 1.79 (3 H, s, CH₃CO), 1.67-1.75 (1 H, m, H-8), 1.66 (3 H, s, CH₃C=C) and 1.04 [9 H, s, C(CH₃)₃]. ¹³C NMR (62.5 MHz, CDCl₃): d = 209.2 (C=O), 136.0, 136.0, 134.8, 134.6, 130.9, 129.5, 129.5, 127.6 and 127.47 (Ar), 133.7 (C-11), 130.9 (C-6), 127.3 (C-5), 120.5 (C-12), 84.6 (C-2), 80.4 (C-9), 71.8 (C-3), 48.9 (C-14), 45.9 (C-1), 43.6 (C-10), 31.9 (C-4), 30.8 (C-13), 27.8 (CH₃CO), 27.5 (C-8), 27.0 [C(CH₃)₃], 21.4 (C-7), 21.2 (CH₃C=C) and 19.2 [C(CH₃)₃]. MS (EI): m/z (%) = 514 (20) [M⁺], 491 (15), 472 (10), 457 (100) [M - t-Bu]⁺, 215 (10), 199 (85), 135 (40) and 77 (20). C₃₃H₄₂O₃Si requires [M]: 514.2903; found [M⁺]: 514.2884.
Data for 16: R_f = 0.55 (CH₂Cl₂), [a]_D ²⁵ +0.8 (c 0.76 in CHCl₃). IR (CHCl₃): n_max = 2931 (s), 2859 (s), 1709 (s) (CO), 1472 (w), 1428 (m), 1170 (w), 1112 (s), 1071 (s), 999 (w), 824 (m), 612 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃):
d = 7.68-7.73 (4 H, m, Ar), 7.34-7.45 (6 H, m, Ar), 5.51-5.59 (1 H, m, H-6), 5.40-5.50 (1 H, m, H-5), 5.31 (1 H, br s, H-12), 4.03 (1 H, t, J = 6.2 Hz, H-9), 3.84 (1 H, d, J = 5.8 Hz, H-2), 3.78 (1 H, dd, J = 9.0 and 2.9 Hz, H-3), 2.38-2.73 (4 H, m, H-4, H-10, H-7 and H-1), 2.20-2.28 (1 H, m, H-4), 2.07-2.20 (2 H, m, H-7 and H-8), 1.96-2.05 (1 H, m, H-13), 1.94 (3 H, s, CH₃CO), 1.84-1.92 (2 H, m, H-14 and H-13), 1.58-2.66 (1 H, m, H-8), 1.59 (3 H, s, CH₃C=C) and 1.07
[9 H, s, C(CH₃)₃]. ¹³C NMR (62.5 MHz, CDCl₃): d = 210.2 (C=O), 136.1, 136.0, 135.5, 130.8 and 127.5 (Ar), 134.1
(C-11), 129.6 (C-6), 126.4 (C-5), 118.7 (C-12), 90.3 (C-2), 84.5 (C-9), 74.1 (C-3), 48.5 (C-14), 45.5 (C-10), 41.5 (C-1), 31.2 (C-8), 30.6 (C-4), 28.7 (CH₃CO), 27.1 [C(CH₃)₃], 25.2 (C-13), 22.7 (CH₃C=C), 21.7 (C-7) and 19.3 [C(CH₃)₃]. MS (CI, NH₃): m/z (%) = 532 (10) [M + NH₄]⁺, 515 (2) [M + H]⁺, 437 (15), 259 (100). C₃₃H₄₆NO₃Si requires [M]: 532. 3247. Found [M + NH₄]⁺: 532.325.

Crystal data for 17: C₁₇H₂₄O₃, M = 276.36, trigonal, space group P3₁, (no. 144), a = b = 10.041 (3), c = 12.585 (5) Å, α = β = 90^ο, γ = 120^ο, U = 1098.8 (6) Å³, Z = 3, µ(MoK_α) = 0.084 mm^-1, 1450 reflections measured at 150 (2) K using an Oxford Cryosystems Cryostream cooling apparatus, 1332 unique (R _int = 0.039); R ₁ = 0.073, wR ₂ = 0.189 [I>2σ(I)]; goodness-of-fit on F ², S = 1.030. The structure was solved with SHELXS-97 and refined with SHELXL-97 [17] (CCDB 233639).

<A NAME="RY02204ST-17">17</A> Sheldrake GM. SHELXS-97/SHELXL-97 University of Göttingen; Germany: 1997.

<A NAME="RY02204ST-18">18</A> Beumer R. Bayón P. Bugada P. Ducki S. Mongelli N. Sirtori FR. Telser J. Gennari C. Tetrahedron 2003, 59: 8803

Microtubules did not depolymerise at 10 °C.