A Convergent Total Synthesis of (+)-Febrifugine

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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• For racemic syntheses of febrifugine, see:
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• 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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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 (d_ABsyst, J = 6.9 Hz, 1 H), 4.63 (d_ABsyst, 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.