Intramolecular Diels-Alder Strategy in a Synthetic Approach to the ­Eleutherobin Core

Abstract

An attractive intermediate in the total synthesis of eleutherobin has been synthesised. The key step of this synthesis is an ­intramolecular Diels-Alder reaction, which leads to intermediate possessing rings A and C of the eleutherobin skeleton.

eleutherobin - intramolecular Diels-Alder reaction - ­antitumor agents - eleuthesides - sulfolene

References

<A NAME="RD08305ST-1">1</A>

Present address: Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, 56126 Pisa, Italy.

<A NAME="RD08305ST-2">2</A> Fenical W, Jensen PR, and Lindel T. inventors; U.S. Patent  5473057.  ; Chem. Abstr. 1996, 102, 194297z

<A NAME="RD08305ST-3A">3a</A> D’Ambrosio M. Guerriero A. Pietra F. Helv. Chim. Acta  1987,  70:  2019 

<A NAME="RD08305ST-3B">3b</A> D’Ambrosio M. Guerriero A. Pietra F. Helv. Chim. Acta  1988,  71:  964 

<A NAME="RD08305ST-4">4</A> Lindel T. Jensen PR. Fenical W. Long BH. Casazza AM. Carboni JM. Fairchild CR. J. Am. Chem. Soc.  1997,  119:  8744 

<A NAME="RD08305ST-5A">5a</A> Nicolaou KC. van Delft F. Ohshima T. Vourloumis D. Xu JY. Hosokawa S. Pfefferkorn J. Kim S. Li T. Angew. Chem., Int. Ed. Engl.  1997,  36:  2520 

<A NAME="RD08305ST-5B">5b</A> Nicolaou KC. Ohshima T. Hosokawa S. van Delft F. Vourloumis D. Xu JY. Pfefferkorn J. Kim S. J. Am. Chem. Soc.  1998,  120:  8674 

<A NAME="RD08305ST-5C">5c</A> Chen XT. Bhattacharya SK. Zhou BS. Gutteridge CE. Pettus TRR. Danishefsky SJ. J. Am. Chem. Soc.  1999,  121:  6563 

<A NAME="RD08305ST-6">6</A> Nicolaou KC. Xu JY. Kim S. Pfefferkorn J. Ohshima T. Vourloumis D. Hosokawa S. J. Am. Chem. Soc.  1998,  120:  8661 

<A NAME="RD08305ST-7A">7a</A> Nicolaou KC. Winssinger N. Vourloumis D. Ohshima T. Kim S. Pfefferkorn J. Xu JY. Li T. J. Am. Chem. Soc.  1998,  120:  10814 

<A NAME="RD08305ST-7B">7b</A> Telser J. Beumer R. Bell AA. Ceccarelli SM. Monti D. Gennari C. Tetrahedron Lett.  2001,  42:  9187 

<A NAME="RD08305ST-7C">7c</A> Beumer R. Bayon P. Bugada P. Ducki S. Mongelli N. Sirtori FR. Telser J. Gennari C. Tetrahedron Lett.  2003,  44:  681 

<A NAME="RD08305ST-7D">7d</A> Chandrasekhar S. Jagadeshwar V. Narsihmulu C. Sarangapani M. Krishna DR. Vidyasagar J. Vijay D. Sastry GN. Bioorg. Med. Chem. Lett.  2004,  14:  3687 

<A NAME="RD08305ST-7E">7e</A> Castoldi D. Caggiano L. Panigada L. Sharon O. Costa AM. Gennari C. Angew. Chem. Int. Ed.  2005,  44:  588 

<A NAME="RD08305ST-7F">7f</A> Castoldi D. Caggiano L. Bayon P. Costa AM. Cappella P. Sharon O. Gennari C. Tetrahedron  2005,  61:  2123 

<A NAME="RD08305ST-8A">8a</A> Carter R. Hodgetts K. McKenna J. Magnus P. Wren S. Tetrahedron  2000,  56:  4367 

<A NAME="RD08305ST-8B">8b</A> Ceccarelli SM. Piarulli U. Gennari C. Tetrahedron  2001,  57:  8531 

<A NAME="RD08305ST-8C">8c</A> Sandoval C. Redero E. Mateos-Timoneda MA. Bermejo FA. Tetrahedron Lett.  2002,  43:  6521 

<A NAME="RD08305ST-8D">8d</A> Scalabrino G. Sun X.-W. Mann J. Baron A. Org. Biomol. Chem.  2003,  1:  318 

<A NAME="RD08305ST-8E">8e</A> Friedel M. Golz G. Mayer P. Lindel T. Tetrahedron Lett.  2005,  46:  1623 

<A NAME="RD08305ST-9A">9a</A> Kim P. Nantz MH. Kurth MJ. Olmstead MM. Org. Lett.  2000,  2:  1831 

<A NAME="RD08305ST-9B">9b</A> Jung ME. Huang A. Johnson TW. Org. Lett.  2000,  2:  1835 

<A NAME="RD08305ST-9C">9c</A> Winkler JD. Quinn KJ. MacKinnon CH. Hiscock SD. McLaughlin EC. Org. Lett.  2003,  5:  1805 

<A NAME="RD08305ST-9D">9d</A> Ritter N. Metz P. Synlett  2003,  2422 

<A NAME="RD08305ST-10">10</A> Samaritani S. Bruyère H. Ballereau S. Royer J. C. R. Chim.  2005,  8:  in press 

<A NAME="RD08305ST-11">11</A> Bruyère H. Ballereau S. Selkti M. Royer J. Tetrahedron  2003,  59:  5879 

<A NAME="RD08305ST-12">12</A>

Compound 6: ¹H NMR (400 MHz, CDCl₃): δ = 1.88 (s, 3 H), 3.29 (dd, J = 18.8, 5.1 Hz, 1 H), 3.47 (dd, J = 18.8, 7.7 Hz, 1 H), 3.70-3.90 (m, 2 H), 4.00 (dd, J = 6.1 Hz, 1 H), 5.77 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 18.0, 44.7, 56.2, 63.2, 119.0, 135.9, 171.0.

<A NAME="RD08305ST-13">13</A>

Compound 10a: ¹H NMR (400 MHz, CDCl₃): δ = 1.66 (s, 3 H), 1.89 (s, 3 H), 2.00-2.10 (m, 5 H), 2.20 (dt, J = 16.1, 2.8 Hz, 1 H), 3.30-3.60 (m, 4 H), 3.60-3.80 (m, 3 H), 4.09 (d, J = 9.5 Hz, 1 H), 4.50 (s, 1 H), 5.69 (br s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 18.4, 19.3, 21.1, 25.3, 50.1, 55.9, 66.5, 72.9, 83.4, 86.3, 117.2, 138.5, 167.9, 170.4. HRMS: m/z calcd for C₁₆H₂₃NO₅S + H: 342.1375; found: 342.1381.

<A NAME="RD08305ST-14">14</A>

The crystal structure has been deposited at the Cambridge Crystallographic Data Centre; deposition number CCDC 268676.

<A NAME="RD08305ST-15">15</A> Agarwal SG. Thappa RK. Dhar KL. Atal CK. Indian J. Chem., Sect. B.  1981,  20:  164 

<A NAME="RD08305ST-16">16</A>

Compound 14: ¹H NMR (400 MHz, CDCl₃): δ = 0.93 (d, J = 6.8 Hz, 6 H), 1.45 (dt, J = 13.8, 11.4 Hz, 1 H), 1.60-1.70 [m, 7 H containing at 1.64 (s, 3 H) and at 1.70 (s, 3 H)], 1.70-1.8 0(m, 1 H), 2.00-2.20 (m, 6 H), 2.23 (ddd, J = 14.0, 5.7, 3.0 Hz, 1 H), 2.50 (dt, J = 11.4, 5.6 Hz, 1 H), 2.71 (t, J = 7.3 Hz, 1 H), 3.30-3.50 (m, 4 H), 4.49 (dd, J = 11.5, 2.9 Hz, 1 H), 4.51 (s, 1 H), 5.42 (br s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 17.9, 20.8, 21.1, 23.7, 25.3, 26.7, 27.6, 34.7, 36.9, 41.9, 50.1, 79.8, 84.1, 104.7, 121.8, 132.2, 168.6, 172.3, 172.6. HRMS: m/z calcd for C₂₂H₃₁NO₄ + Na: 396.2151; found: 396.2169.

<A NAME="RD08305ST-17">17</A>

NOESY experiment for compound 14.

<A NAME="RD08305ST-18">18</A>

Comparable chemical shifts and coupling constants for protons H-8, H-1, H-10 and H-14 were observed.

<A NAME="RD08305ST-19">19</A> Schlessinger RH. Pettus LH. J. Org. Chem.  1998,  63:  9089 

<A NAME="RD08305ST-20">20</A>

Compound 15: ¹H NMR (400 MHz, CDCl₃): δ = 0.92 (d, J = 7.1 Hz, 6 H), 1.20-1.30 (m, 1 H), 1.50-1.70 (m, 7 H), 1.70-1.80 (m, 1 H), 1.90-2.10 (m, 1 H), 2.10-2.30 (m, 2 H), 2.54 (dt, J = 11.0, 7.0 Hz, 1 H), 2.76 (t, J = 7.0 Hz, 1 H), 4.44 (dd, J = 11.9, 2.6 Hz, 1 H), 5.40 (br s, 1 H), 6.16 (d, J = 5.7 Hz, 1 H), 7.45 (d, J = 5.7 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 20.8, 20.9, 21.3, 23.5, 26.8, 27.2, 33.7, 37.0, 41.2, 79.3, 87.7, 121.6, 122.0, 136.2, 147.5, 157.0, 171.5.