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Synlett 2008(8): 1216-1218  
DOI: 10.1055/s-2008-1072736
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Convergent Total Synthesis of (+)-Febrifugine

Bora Sieng, Oscar Lozano Ventura, Véronique Bellosta, Janine Cossy*
Laboratoire de Chimie Organique, ESPCI, CNRS, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax: +33(1)40794660; e-Mail: janine.cossy@espci.fr;
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Publication History

Received 22 January 2008
Publication Date:
16 April 2008 (online)

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Abstract

Febrifugine was synthesized in ten steps from N-Boc 4-aminobutan-1-ol by a convergent approach.

Key words

total synthesis - allyltitanation - Wittig reaction - febrifugine - antimalarial activity

    References and Notes

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4

WHO Report, Meeting on Antimalarial Drug Development, Shangai, China, 16-17 November 2001.

10

Aqueous workup has to be precluded. The treatment of 6 under Swern conditions followed by classical aqueous workup lead only to the formation of the hemiaminal which is then totally unreactive with allyltitanium complex (S,S)-Ti-I.

15

A better yield was observed for the oxidative cleavage of the double bond when performed in two separated steps.

16

The yield for 14 corresponds to the isolated yield but the protection did not reach completion (71% conversion).

17

A cross-metathesis reaction using methyl vinyl ketone and the protected allylic alcohol 15, in the presence of the Grubbs-Hoveyda catalyst failed.

18

Compound 17: [α] d 25 -22.1 (c 1.17, CHCl3). IR (neat): 2979, 1678, 1612, 1365, 1118, 1028, 775, 734, 697 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.29 (dd, J = 8.0, 1.5 Hz, 1 H), 7.90 (s, 1 H), 7.80-7.73 (m, 2 H), 7.51 (ddd, J = 8.0, 6.8, 1.6 Hz, 1 H), 6.94 (dd, J = 16.0, 5.8 Hz, 1 H), 6.46 (dd, J = 16.0, 1.3 Hz, 1 H), 4.99 (d, J = 1.6 Hz, 2 H), 4.65 (dABsyst, J = 6.9 Hz, 1 H), 4.63 (dABsyst, J = 6.9 Hz, 1 H), 4.30, (m, 1 H), 3.61 (br t, J = 6.8 Hz, 2 H), 3.39 (s, 3 H), 1.76-1.60 (m, 4 H), 1.51 (s, 18 H). 13C NMR (100 MHz, CDCl3): δ = 191.0 (s), 160.9 (s), 152.8 (2 s), 148.6 (d), 148.2 (s), 146.4 (d), 134.4 (d), 127.6 (d), 127.4 (d), 126.8 (d), 126.3 (d), 121.9 (s), 95.1 (t), 82.3 (2s), 75.2 (q), 55.8 (d), 52.6 (t), 45.9 (t), 31.8 (t), 28.1 (6 q), 24.6 (t).

19

Efficient isomerization of isofebrifugine into febrifugine by heating in water has been reported by Takeuchi et al., see ref. 8d.