PDF herunterladen
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;
Weitere Informationen

Publikationsverlauf

Received 22 January 2008
Publikationsdatum:
16. April 2008 (online)

    Lizenzen und Reprints Alle Artikel dieser Rubrik

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

  • 1 Winstanley PA. Parasitol. Today  2000,  16:  146 
    CrossrefGoogle Scholar
  • 2 Zhu S. Hudson TH. Kyle DE. Lin A. J. Med. Chem.  2002,  45:  3491 
    CrossrefGoogle Scholar
  • 3a Koepfli JB. Mead JF. Brockman JA. J. Am. Chem. Soc.  1947,  69:  1837 
    CrossrefPubMedGoogle Scholar
  • 3b Koepfli JB. Mead JF. Brockman JA. J. Am. Chem. Soc.  1949,  71:  1048 
    CrossrefPubMedGoogle Scholar
  • 5 Chien PL. Cheng CC. J. Med. Chem.  1970,  13:  867 
    CrossrefGoogle Scholar
  • 6 Pharmacology and Applications of Chinese Material Medecine   Chang HM. But PPH. World Scientific Publishing; Singapore: 1986-1987. 
    Google Scholar
  • For racemic syntheses of febrifugine, see:
  • 7a Baker BR. McEvoy FJ. Schaub RE. Joseph JP. Williams JH. J. Org. Chem.  1953,  18:  178 
    CrossrefPubMedGoogle Scholar
  • 7b Burgess LE. Gross EKM. Jurka J. Tetrahedron Lett.  1996,  37:  3255 
    CrossrefPubMedGoogle Scholar
  • 7c Takeuchi Y. Hattori M. Abe H. Harayama T. Synthesis  1999,  1814 
    CrossrefPubMedGoogle Scholar
  • 7d Takeuchi Y. Oshige M. Azuma K. Abe H. Harayama T. Chem. Pharm. Bull.  2005,  53:  868 
    CrossrefPubMedGoogle Scholar
  • For syntheses of (+)-febrifugine, see:
  • 8a Kobayashi S. Ueno M. Suzuki R. Ishitani H. Kim H.-S. Wataya Y. J. Org. Chem.  1999,  64:  6833 
    CrossrefGoogle Scholar
  • 8b Takeuchi Y. Azuma K. Takakura K. Abe H. Harayama T. Chem. Commun.  2000,  1643 
    CrossrefGoogle Scholar
  • 8c Taniguchi T. Ogasawara K. Org. Lett.  2000,  2:  3193 
    CrossrefGoogle Scholar
  • 8d Takeuchi Y. Azuma K. Takakura K. Abe H. Kim H.-S. Wataya Y. Harayama T. Tetrahedron  2001,  57:  1213 
    CrossrefGoogle Scholar
  • 8e Okitsu O. Suzuki R. Kobayashi S. J. Org. Chem.  2001,  66:  809 
    CrossrefGoogle Scholar
  • 8f Ooi H. Urushibara A. Esumi T. Iwabuchi Y. Hatakeyama S. Org. Lett.  2001,  3:  953 
    CrossrefGoogle Scholar
  • 8g Huang P.-Q. Wei B.-G. Ruan Y.-P. Synlett  2003,  1663 
    CrossrefGoogle Scholar
  • 8h Katoh M. Matsune R. Nagase H. Honda T. Tetrahedron Lett.  2004,  45:  6221 
    CrossrefGoogle Scholar
  • 8i Ashoordazeh A. Caprio V. Synlett  2005,  346 
    CrossrefGoogle Scholar
  • 8j Katoh M. Matsune R. Honda T. Heterocycles  2006,  67:  189 
    CrossrefGoogle Scholar
  • 9 Hudson RF. Chopard PA. J. Org. Chem.  1963,  28:  2446 
    CrossrefGoogle Scholar
  • 11 The allyltitanium complex (S,S)-Ti-I was prepared according to: Hafner A. Duthaler RO. Marti R. Rihs G. Rothe-Streit P. Schwarzenbach F. J. Am. Chem. Soc.  1992,  114:  2321 
    CrossrefGoogle Scholar
  • Preparation of 8Allylmagnesium chloride (1.47 mL, 2 M in THF, 2.93 mmol, 1.1 equiv) was added at 0 °C to a mixture of cyclopentadienyl[(4S,trans)-2,2-dimethyl-α,α,α′,α′-tetraphenyl-1,3-dioxolane-4,5-dimethanolato-O,O′]titanium chloride (2.12 g, 3.46 mmol, 1.3 equiv) in anhyd Et2O (30 mL). The orange mixture was stirred for 2 h at 0 °C and cooled to -78 °C. To this mixture was added dropwise a solution of the crude aldehyde 7 (498 mg, 2.66 mmol, 1 equiv) in Et2O (2.4 mL) via cannula. After 4 h at -78 °C, H2O (14 mL) was added and the mixture was stirred overnight at r.t. and then filtered through Celite. The organic phase was washed with brine (2 × 40 mL), dried over MgSO4, and concentrated in vacuo. The crude residue was purified on silica gel (PE-EtOAc, 7:3) to afford 8 (408 mg, 1.78 mmol, 67% for two steps) as a yellow oil.The ee of 8 was determined by 1H NMR after derivatization with (S)- and (R)-methoxyphenylacetic acids. See:
  • 12a Dale JA. Mosher HS. J. Am. Chem. Soc.  1973,  95:  512 
    CrossrefGoogle Scholar
  • 12b Trost BM. Belletire JL. Godleski S. McDougal PG. Balkovec JM. J. Org. Chem.  1986,  51:  2370 
    CrossrefGoogle Scholar
  • 12c Seco JM. Quiňoà E. Riguera R. Tetrahedron: Asymmetry  2001,  12:  2915 
    CrossrefGoogle Scholar
  • 13 Wipf P. Rector SR. Takahashi H. J. Am. Chem. Soc.  2002,  124:  14848 
    CrossrefPubMedGoogle Scholar
  • 14 Scholl M. Ding S. Woo Lee S. Grubbs RH. Org. Lett.  1999,  1:  953 
    Google Scholar
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.