Development of Highly Stereoselective Reactions Utilizing Heteroatoms : New Approach to the Stereoselective Horner-Wadsworth-Emmons Reaction

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Other Title
  • ヘテロ原子の特性を活用する高立体選択的反応の開発 : HWE反応の新展開
  • ヘテロ ゲンシ ノ トクセイ オ カツヨウ スル コウリッタイ センタクテキ ハンノウ ノ カイハツ HWE ハンノウ ノ シン テンカイ

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This article reviews a new approach to stereoselective Horner-Wadsworth-Emmons(HWE) reactions. The HWE reaction is one of the most efficient methods for the preparation of α, β-unsaturated esters, which play an important role in the synthesis of biologically active compounds. The reactions of aldehydes with phosphonates bearing α-substituents which stabilize the carbanion, preferentially furnish the corresponding E-alkenes. However, the stereoselectivity of the HWE reactions with ketones has never been investigated in detail because of their low reactivity and low stereoselectivity. The conventional HWE reactions of aryl alkyl ketones with ethyl diethylphosphonoacetate in the presence of sodium hydride gave the corresponding α, β-unsaturated esters with modest E-selectivity. On the other hand, the treatment of aryl alkyl ketones with ethyl diethylphosphonoacetate in the presence of Sn(OSO2CF3)2 and N-ethylpiperidine afforded α, β-unsaturated esters in a highly Z-selective fashion. A significant improvement in the selectivity and yield was found when the Still's reagent, methyl bis(trifluoroethyl)phosphonoacetate, was used under Sn(II)-mediated conditions. On the basis of the experimental results, the high Z-selectivity in the Sn(II)-mediated HWE reactions of aryl alkyl ketones with these phosphonates can be rationalized in terms of six-membered transition state involving Sn(II) chelation. Similarly, the HWE reactions of aryl alkyl ketones with ethy12-fluoro-2-diethylphosphonoacetate in the presence of Sn(OSO2CF3)2 and N-ethylpiperidine gave the corresponding α-fluoro-α, β-unsaturated esters in a highly E-selective manner. Finally, the Sn(II)-mediated asymmetric HWE reactions of isopropyl 2-fluoro-2-diethylphosphonoacetate with 4-tert-butylcyclohexanone in the presence of a chiral diamine is described.

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 120 (5), 432-444, 2000

    The Pharmaceutical Society of Japan

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