Febrifugine and isofebrifugine

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... 

Finally, F. A. Kuehl, Jr., C. F. Spencer and K. Folkers (46) independently obtained two crystalline alkaloids agreeing in properties with febrifugine and isofebrifugine. 

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>. 

The antimalarial properties attributed to preparations from Dichroa febrifuga by the Chinese were confirmed about 1944 and two alkaloids, febrifugine (999) and isofebrifugine (1000), were isolated eventually. After difficult structural elucidations, syntheses of ( )-febrifugine followed it proved to be half as active as the natural material, itself far better than quinine, but the therapeutic index was disappointingly low (67HC(24-l)490). 

Apparently, febrifugine (41) and isofebrifugine (42) isolated from Dichroa febrifuga have anti-moth activity. Peganum harmala has been shown to elaborate a new alkaloid, pegalol (37 R = H, OH, R = H). The seasonal patterns of peganine (37 R = H2, R = OH) distribution in the roots and ripe seeds of P. harmala have been determined. ... 

The molecular formula of febrifugine and of isofebrifugine seems to be firmly established as CieHijOjNa (43, 46), although Chu, Fu, and Kao... 

Figure 35 Quinazoline alkaloids and related quinolizidine—quinazoline systems +)-febrifugine (1543) (+)-isofebrifugine (1544) (+)-neodichroine (1545) discredited structure for (+)-hydrachine A (1546).

The structure of febrifugine (the famous Chan San alkaloid known since 200 b.c.) has been completely elucidated, but that of the isomer isofebrifugine which occurs with it is still in some doubt. All evidence points to the semiketal structure (52) and, although it is readily converted to febrifugine, it does not react with ketonic reagents. 

An aqueous solution of the oxalate (4.38 g.) is brought to pH 8 with sodium bicarbonate and extracted for 3 hours with chloroform. The residue obtained by evaporation of the extract in a vacuum is dissolved in alcohol when it deposits crystalline isofebrifugine ( Alkaloid I ) (2.74 g., m.p. 131-132°). On standing, the mother liquor deposits crude crystalline febrifugine ( Alkaloid II ), m.p. 135 142°. 

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