Synthesis and Biological Evaluation of Furano-Epothilone C

Dieter Schinzer; Oliver M. Böhm; Karl-Heinz Altmann; Markus Wartmann

doi:10.1055/s-2004-829071

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Synlett 2004(8): 1375-1378
DOI: 10.1055/s-2004-829071

LETTER

Synthesis and Biological Evaluation of Furano-Epothilone C

Dieter Schinzer*^a, Oliver M. Böhm^a, Karl-Heinz Altmann^b, Markus Wartmann^c
^a Chemisches Institut, Otto-von-Guericke Universität Magdeburg, Universitätsplatz 2, 39106 Magdeburg, Germany
Fax: +49(391)6712223; e-Mail: dieter.schinzer@vst.uni-magdeburg.de;
^b ETH Zürich, Department of Chemistry and Applied BioSciences, Institute of Pharmaceutical Sciences, Winterthurerstr. 190, 8057 Zürich, Switzerland
^c Novartis Institutes for Biomedical Research, DA Oncology, Novartis Pharma AG, 4002 Basel, Switzerland

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Publication History

Received 22 April 2004
Publication Date:
22 June 2004 (online)

Abstract
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Abstract

An efficient synthesis of furano-epothilone C (1) is described by the use of an aldol reaction and a ring-closing metathesis (RCM) for the closure of the macrocyclic ring system. This new type of analog contains a furan ring in the C8-C10 region of the macrocycle. The biology of this new class of epothilone C analog has been studied.

Key words

epothilone - total synthesis - furans - ring closure - macrocycles

References

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10

All new compounds gave spectral and analytical spectrometric data consistent with the assigned structure.

11

Böhm O. M.; planned thesis, University of Magdeburg 2004.

13

Crystal data for compound 13: C₃₈H₆₁NO₆SSi₂, monoclinic, C2, a = 2260.7 (2), b = 1427.7 (2), c = 1555.6 (2) pm, α = 90°, β = 108.894 (3)°, γ = 90°, U = 4.7503 (10) nm³, Z = 4, µ = 0.155 mm^-1, T = 143 (2) K, colorless prism, 0.45 × 0.35 × 0.15 mm, Siemens SMART CCD, 16635 intensities, θ = 1.38°-28.28°. Structure refinement: least squares fit on F², abs config with x = 0.07 (9), wR ₂ = 0.1679, S 1.016, max 689, min -288 enm^-3. Crystallographic data of 11 have been deposited at the Cambridge Crystallographic Data Centre under the number CCDC 236809; copies may be obtained without charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033.

14

Analytical data for 1: ¹H NMR (400 MHz, C₆D₆): δ = 6.78 (s, 1 H), 6.54 (s, 1 H), 6.17 (br d, 3.0 Hz, 1 H), 5.77 (br d, J = 3.0 Hz, 1 H), 5.57 (ddd, J = 10.7 Hz, 9.5 Hz, 6.0 Hz, 1 H), 5.44-5.37 (m, 1 H), 5.42 (dd, J = 8.9 Hz, 2.9 Hz, 1 H), 4.93 (br d, J = 6.6 Hz, 1 H), 4.07 (dd, J = 10.8 Hz, 2.6 Hz, 1 H), 3.41 (br dd, J = 15.7 Hz, 9.5 Hz, 1 H), 3.32 (Ψ-quint, J = 6.8 Hz, 1 H), 3.08 (br dd, J = 15.7 Hz, 6.0 Hz, 1 H), 2.56-2.48 (m, 1 H), 2.28 (dd, J = 15.7 Hz, 10.8 Hz, 1 H), 2.26 (s, 3 H), 2.15-2.07 (m, 1 H), 2.14 (d, J = 1.2 Hz, 3 H), 1.91 (dd, J = 15.7 Hz, 2.6 Hz, 1 H), 1.15 (d, J = 6.8 Hz, 3 H), 0.99 (s, 3 H), 0.91 (s, 3 H). ¹³C NMR (100 MHz, C₆D₆): δ = 217.48 (s), 170.51 (s), 164.70 (s), 154.07 (s), 153.37 (s), 153.36 (s), 137.62 (s), 128.35 (d), 126.45 (d), 120.26 (d), 116.45 (d), 108.20 (d), 106.70 (d), 78.02 (d), 72.95 (d), 69.44 (d), 52.75 (s), 47.60 (d), 38.95 (t), 31.05 (t), 27.10 (t), 22.61 (q), 19.73 (q), 18.74 (q), 15.69 (q), 14.92 (q). MS (EI): m/z (%) = 487 (37) [M⁺], 469 (31) [M⁺ - H₂O], 381 (5), 328 (18), 310 (37), 300 (100) [C7 - C23⁺], 190 (42), 168 (51), 149 (75). HRMS (EI): m/z calcd for C₂₆H₃₃NO₆S: 487.20286; found: 487.2027.