Xl l jlo

133 -trans

131-S O

rrrifn k (+)-isofebrifugine

Scheme 30 Synthesis of stereoisomers of febrifugine and isofebrifugine [290,291]

Mannich-type three-component reaction as the key steps (Scheme 30) [290, 291].

The key intermediate 132 was prepared by a novel aqueous three-component reaction involving 131-R, 2-methoxyaniline, 2-methoxy-3-(p-methoxybenzyloxy)-1-propene using ytterbium dodecyl sulfate, Yb(DS)3 (Lewis acid-surfactant-combined catalyst). Piperidine derivatives 133-trans and 133-cis were prepared from 132, and coupled with 4-hydroxyquinazoline (2) using potassium hydroxide, respectively [300], followed by deprotec-tion afforded antipode of natural febrifugine and isofebrifugine, respectively. Similarly another pair of 14 and 15 were prepared from 131-S. These unambiguous total syntheses of stereoisomers revised the absolute configurations of natural febrifugine and isofebrifugine from (2;S,3'R) and (2'R,3;R) to (2;R,3'S) and (2'S,3;S) (Scheme 30). Thereafter, many unique synthetic routes to 14 and 15 have been developed by several groups. For example, Kobayashi et al. has developed more flexible new routes to febrifugine and isofebrifugine using the Sc(OTf)3 (or other Lewis acid)-catalyzed coupling reaction between tin(II) enolate (or silyl enol ether) of 3-acetonyl-4(3H)-quinazolinone and 2,3-diacetoxy-N-benzyloxycarbonylpiperidine as the key-step [292,296-298].

S N1

0 0

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