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

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Synlett 2004(8): 1434-1436
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

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Publication History

Received 15 March 2004
Publication Date:
08 June 2004 (online)

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

References

1 Kennard O. Watson DG. Riva di Sanseverino L. Tursch B. Bosmans R. Djerassi C. Tetrahedron Lett. 1968, 2879

Crossref Google Scholar
2a Bernardelli P. Paquette LA. Heterocycles 1998, 49: 531

Crossref Google Scholar
2b Sung P.-J. Chen M.-C. Heterocycles 2002, 57: 1705

Crossref Google Scholar
3a MacMillan DWC. Overman LE. J. Am. Chem. Soc. 1995, 117: 10391

Google Scholar
3b Overman LE. Pennington LD. Org. Lett. 2000, 2: 2683

Google Scholar
3c MacMillan DWC. Overman LE. Pennington LD. J. Am. Chem. Soc. 2001, 123: 9033

Google Scholar
3d Gallou F. MacMillan DWC. Overman LE. Paquette LA. Pennington LD. Yang J. Org. Lett. 2001, 3: 135

Google Scholar
3e Corminboeuf O. Overman LE. Pennington LD. Org. Lett. 2003, 5: 1543

Google Scholar
3f Corminboeuf O. Overman LE. Pennington LD. J. Am. Chem. Soc. 2003, 125: 6650

Google Scholar
4a Paquette LA. Moradei OM. Bernadelli P. Lange T. Org. Lett. 2000, 2: 1875

Crossref Google Scholar
4b Friedrich D. Doskotch RW. Paquette LA. Org. Lett. 2000, 2: 1879

Crossref Google Scholar
4c Bernardelli P. Moradei OM. Friedrich D. Yang J. Gallou F. Dyck BP. Doskotch RW. Lange T. Paquette LA. J. Am. Chem. Soc. 2001, 123: 9021

Crossref Google Scholar
4d Friedrich D. Paquette LA. J. Nat. Prod. 2002, 65: 126

Crossref Google Scholar
5 Molander GA. St Jean DJ. Haas J. J. Am. Chem. Soc. 2004, 126: 1642

Crossref PubMed Google Scholar
6 Xu Q. Weeresakare M. Rainier JD. Tetrahedron 2001, 57: 8029

Crossref Google Scholar
7a Jung ME. Pontillo J. J. Org. Chem. 2002, 67: 6848

Crossref Google Scholar
7b Jung ME. Pontillo J. Tetrahedron 2003, 59: 2729

Crossref Google Scholar
8 Chai Y. Vicic DA. McIntosh MC. Org. Lett. 2003, 5: 1039

Crossref PubMed Google Scholar
9 Congreve MS. Holmes AB. Hughes AB. Looney MG. J. Am. Chem. Soc. 1993, 115: 5815

Crossref Google Scholar
10 Anderson EA. Davidson JEP. Harrison JR. O’Sullivan PT. Burton JW. Collins I. Holmes AB. Tetrahedron 2002, 58: 1943

Crossref Google Scholar
11 Petasis NA. Bzowej EI. J. Am. Chem. Soc. 1990, 112: 6392

Crossref Google Scholar
12 Burton JW. Clark JS. Derrer S. Stork TC. Bendall JG. Holmes AB. J. Am. Chem. Soc. 1997, 119: 7483

Google Scholar
13 Carling RW. Clark JS. Holmes AB. J. Chem. Soc., Perkin Trans. 1 1992, 83

Crossref Google Scholar
14 Griffith WP. Ley SV. Whitcombe GP. White AD. Chem. Commun. 1987, 1625

Google Scholar
17 Sheldrake GM. SHELXS-97/SHELXL-97 University of Göttingen; Germany: 1997.

Google Scholar
18 Beumer R. Bayón P. Bugada P. Ducki S. Mongelli N. Sirtori FR. Telser J. Gennari C. Tetrahedron 2003, 59: 8803

Crossref Google Scholar

15

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.

16

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).

19

Microtubules did not depolymerise at 10 °C.