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DOI: 10.1055/s-2008-1072736
A Convergent Total Synthesis of (+)-Febrifugine
Publikationsverlauf
Publikationsdatum:
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
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Hudson RF.Chopard PA. J. Org. Chem. 1963, 28: 2446 - 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 - 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:
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References and Notes
WHO Report, Meeting on Antimalarial Drug Development, Shangai, China, 16-17 November 2001.
10Aqueous 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.
15A better yield was observed for the oxidative cleavage of the double bond when performed in two separated steps.
16The yield for 14 corresponds to the isolated yield but the protection did not reach completion (71% conversion).
17A cross-metathesis reaction using methyl vinyl ketone and the protected allylic alcohol 15, in the presence of the Grubbs-Hoveyda catalyst failed.
18Compound 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).
19Efficient isomerization of isofebrifugine into febrifugine by heating in water has been reported by Takeuchi et al., see ref. 8d.