Synthesis and Biological Evaluation of Furano-Epothilone C

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.

epothilone - total synthesis - furans - ring closure - macrocycles

References

<A NAME="RY02804ST-1">1</A> Höfle G, Bedorf N, and Reichenbach HGBF. inventors;  DE-4138042.  ; Chem. Abstr. 1993, 120, 52841

<A NAME="RY02804ST-2">2</A> Gerth K. Bedorf N. Höfle G. Irschik H. Reichenbach H. J. Antibiot.  1996,  49:  560 

<A NAME="RY02804ST-3A">3a</A> Bollag DM. McQueney PA. Zhu J. Jensens O. Koupal L. Liesch J. Goetz ME. Lazarides C. Woods M. Cancer Res.  1995,  55:  2325 

<A NAME="RY02804ST-3B">3b</A> Kowalski RJ. Giannakakou P. Hamel E. J. Biol. Chem.  1997,  272:  2534 

<A NAME="RY02804ST-4A">4a</A> Schinzer D. Eur. Chem. Chron.  1996,  1:  7 

<A NAME="RY02804ST-4B">4b</A> Kalesse M. Eur. Chem. Chron.  1997,  2:  7 

<A NAME="RY02804ST-4C">4c</A> Wessjohann L. Angew. Chem., Int. Ed. Engl.  1997,  36:  739 ; Angew. Chem. 1997, 109, 739

<A NAME="RY02804ST-4D">4d</A> Nicolaou KC. Roschangar F. Vourloumis D. Angew. Chem. Int. Ed.  1998,  37:  2014 ; Angew. Chem. 1998, 110, 2120

<A NAME="RY02804ST-5A">5a</A> Wartmann M. Altmann K.-H. Curr. Med. Chem.  2002,  2:  123 

<A NAME="RY02804ST-5B">5b</A> Harris CR. Kuduk SD. Danishefsky SJ. Chemistry for the 21st Century  2001,  8 

<A NAME="RY02804ST-6">6</A> Höfle G. Bedorf N. Steinmetz H. Schomburg D. Gerth K. Reichenbach H. Angew. Chem., Int. Ed. Engl.  1996,  35:  1567 ; Angew. Chem. 1996, 108, 1671

<A NAME="RY02804ST-7A">7a</A> Schinzer D. Limberg A. Bauer A. Böhm OM. Cordes M. Angew. Chem., Int. Ed. Engl.  1997,  36:  523 ; Angew. Chem. 1997, 109, 543

<A NAME="RY02804ST-7B">7b</A> Schinzer D. Limberg A. Böhm OM. Chem.-Eur. J.  1996,  2:  1477 

<A NAME="RY02804ST-7C">7c</A> Schinzer D. Limberg A. Bauer A. Böhm OM. Chem.-Eur. J.  1999,  5:  2483 

<A NAME="RY02804ST-7D">7d</A> Schinzer D. Bauer A. Schieber J. Chem.-Eur. J.  1999,  9:  2492 

<A NAME="RY02804ST-7E">7e</A> Schinzer D. Bauer A. Schieber J. Synlett  1998,  861 

<A NAME="RY02804ST-8A">8a</A> Taylor RE. Chen Y. Org. Lett.  2001,  3:  2221 

<A NAME="RY02804ST-8B">8b</A> Taylor RE. Galvin GM. Hilfiker KA. Chen Y. J. Org. Chem.  1998,  63:  9580 

<A NAME="RY02804ST-8C">8c</A> Taylor RE. Haley JD. Tetrahedron Lett.  1997,  38:  2061 

<A NAME="RY02804ST-8D">8d</A> Yoshikawa N. Yamada YMA. Das J. Sasai H. Shibasaki M. J. Am. Chem. Soc.  1999,  121:  4168 

<A NAME="RY02804ST-8E">8e</A> Sawada D. Shibasaki M. Angew. Chem. Int. Ed.  2000,  39:  209 ; Angew. Chem. 2000, 112, 215

<A NAME="RY02804ST-8F">8f</A> Sawada D. Kanai M. Shibasaki M. J. Am. Chem. Soc.  2000,  122:  10521 

<A NAME="RY02804ST-8G">8g</A> Koch G. Loiseleur O. Altmann K.-H. Synlett  2004,  693 

<A NAME="RY02804ST-8H">8h</A> Altmann K.-H. Mini-Rev. Med. Chem.  2003,  3:  149 

<A NAME="RY02804ST-8I">8i</A> Klar U. Skuballa W. Buchmann W. Schwede B. Bunte T. Hoffmann J. Lichtner RB. ACS Symposium Series  2001,  796:  131 

<A NAME="RY02804ST-9">9</A> Lautens M. Kumanovic S. J. Am. Chem. Soc.  1995,  117:  1954 

<A NAME="RY02804ST-10">10</A>

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

<A NAME="RY02804ST-11">11</A>

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

<A NAME="RY02804ST-12">12</A> Schinzer D. In Modern Aldol Reactions   Vol. 1: 
Mahrwald R. Wiley-VCH; Weinheim: p.311-328 

<A NAME="RY02804ST-13">13</A>

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 [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone].

<A NAME="RY02804ST-14">14</A>

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.

<A NAME="RY02804ST-15">15</A> Altmann K.-H. Bold G. Caravatti G. End N. Florsheimer A. Guagnano V. O’Reilly T. Wartmann M. Chimia  2000,  54:  612 

<A NAME="RY02804ST-16">16</A> Schinzer D. Bourguet E. Ducki S. Chem.-Eur. J.  2004,  in press