36 有機リチウムの不斉タンデム型共役付加-閉環反応の開発とLycorine類の不斉全合成への展開(口頭発表の部)

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We have been involved in development of asymmetric reactions using diether 2 as a chiral chelating ligand and have succeeded in asymmetric addition of organolithium reagents to α,β-unsaturated carboxylates (Scheme 1). The addition of organolithium reagent to α,β-unsaturated carboxylate gives lithium enolate intermediate, whose intermolecular trapping with another α,β-unsaturated carboxylate moiety would produce highly functionalized chiral cyclohexane building blocks, such as 4 (Scheme 2). We planned asymmetric synthesis of Amaryllidaceae alkaloids, lycorine (1) and related compounds using 4 as a key intermediate. The investigation of the key tandem asymmetric conjugate addition-cyclization reaction using chiral ligand 2 revealed that the bulky ortho-substituent, TMS group of aryllithium 6b using important to achieve the first addition step in high enantioselectivity (Scheme 3). Besides, the ethylenedioxy group of α,β-unsaturated carboxylate 3 improves diastereoselectivity in the cyclization step probably because the replacement of H with O makes 1,3-diaxial interaction more unfavorable in the transition state that gives trans-cis isomers 8 (Figure 2). With enantiomerically enriched cyclohexane 9 in hand, we started the asymmetric synthesis of lycorines (Scheme 4). Treatment of 9 with ethanolic HCl gave carboxylic acid 10, whose Curtius rearrangement gave carbamate 11 in good yield. Formation of the tetracyclic core was achieved via lactam formation and Bishler-Napieralski reaction to give ketone 14. Formal synthesis of 1-deoxylycorine was accomplished via double bond formation by IBX oxidation of silyl enolate and reduction of the resulting enone 15. Introduction of 2-hydroxy functionality to ketone 14 was achieved stereoselectively by Magnus' chemistry (Scheme5). Formation of double bond followed by reduction gave 2-epi-lycorine diacetate (23) after acetylation of the resulting 2-epi-lycorine (22).
2007-08-24

36 有機リチウムの不斉タンデム型共役付加-閉環反応の開発とLycorine類の不斉全合成への展開(口頭発表の部)

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