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Synlett 2005(9): 1421-1424  
DOI: 10.1055/s-2005-869830
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Hélène Bruyèrea, Simona Samaritania,, Stéphanie Ballereaua, Alain Tomasb, Jacques Royer*a
a Synthèse et structure de molécules d’intérêt pharmacologique, UMR 8638, (CNRS-Université René Descartes), Faculté de pharmacie, 4 avenue de l’Observatoire, 75270 Paris cedex 06, France
b Laboratoire de cristallographie et RMN biologiques, UMR 8015, (CNRS-Université René Descartes), Faculté de pharmacie, 4 avenue de l’Observatoire, 75270 Paris cedex 06, France
Fax: +33(1)43291403; e-Mail: jacques.royer@univ-paris5.fr;
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Publication History

Received 24 March 2005
Publication Date:
04 May 2005 (online)

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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.

Key words

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

1

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

12

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.

13

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.

14

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

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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.

17

NOESY experiment for compound 14.

18

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

20

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.