Synthesis of febrifugine

A tin(II)-catalyzed asymmetric aldol reaction and lanthanide-catalyzed aqueous three-component reaction have been used as the key steps for the synthesis of febrifugine and isofebrifugine (Scheme 8.31).293... 

Kobayashi et aL fulfilled first asymmetric synthesis of febrifugine utilizing tin(II)-catalyzed asymmetric aldol-type reaction and lanthanide-catalyzed... 

SCHEME 11.46 Asymmetric total synthesis of febrifugine and isofebrifiigine. 

Structure and synthesis of antimalarial quinazoline alkaloid febrifugine 01YGK569. 

Hill and Edwards (34) have determined the absolute configuration of the C-2 position as S by alkaline permanganate oxidation of (—)-A-benzoyl-3-furyl-P-alanine (14) to L-(+)-A-benzoylaspartic acid, using the conditions developed by Reichstein et al. (55) for the oxidation of the furan ring. Compound 14 is the starting material for the synthesis of the (-I-) enantiomer of febrifugine according to Baker et al. 

The enantioselective synthesis of antimalarial (+)-febrifugine and (+)-isofebrifugine alkaloids was achieved through the 1,3-DC of (S)-5-alkoxy-2,3,43-lctrahydropyridine-l-oxide 76 with allyl alcohol followed by hydrogcnolytic N-O bond fission and suitable elaboration of the product <01OL953>. 

After side-chain modification, as in the synthetic 3-[p-keto-y-(3-hydroxy-2-pyridyl)-propyl]-quinazolin-4-one 66), was found to be fruitless, attempts at structural modification of febrifugine were focused on the synthesis of some methylenedioxy analogues by Chien and Cheng 44). The 5,6-, 6,7- and 7,8-methylenedioxy analogues were found to be active against PI. berghei. Toxicity of these compounds in mice is much lower than that of febrifugine and their therapeutic indices are comparable to that of the parent compound. 

Febrifugine was first isolated from roots of Dichroa febrifuga Lour. (Saxifragaceae), a Chinese medicinal plant traditionally used to treat malaria fevers. This alkaloid showed potent anti-Plasmodium activity, which was superior to quinine, and tmacceptable side effects, such as hepatotoxicity and severe emesis [128,129]. Its properties not only precluded its use as drug but also encouraged the synthesis of safer analogues [127]. 

Yasuo T, Miyo O (2005) Concise Synthesis of dl-Febrifugine. Chem Pharm Bull 53 868-869 Koepfli JB, Mead JF et al (1947) An alkaloid with high antimalarial activity from Dichroa febrifuga. J Am Chem Soc 69 1837... 

Alkaloids containing a quinazoline nucleus form a small but important group of natural products and have been isolated from a number of different families in the plant kingdom. The quinazoline alkaloids are of the four types (48), (49), (50), and (51). The structures of arborine, peganine, febrifugine, rutaecarpine, and evodi-amine have been elucidated by degradation and synthesis and are described in recent reviews on quinazoline alkaloids. ... 

Febrifugine (9) is perhaps one of the most interesting quinazoline alkaloids. Information on this alkaloid has been summarized in the earlier reviews published in this treatise (1,2) readers are also referred to the authoritative book by Armarego (33). The antimalarial activity of 9 especially provided a strong stimulus for the synthesis and biological screening of a vast number of quinazoline derivatives. 

Synthesis and Biological Evaluation of Some Quinazoline Heterocyclic. . Fig. 13.3 Febrifugine q... 

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