New Approach to the Highly Stereoselective Horner-Wadsworth-Emmons Reaction Utilizing Lewis acids

Horner-Wadsworth-Emmons（HWE）反应是制备α，β-不饱和酯的最有效方法之一，α，β-不饱和酯在生物活性化合物的合成中起着重要作用。醛与带有稳定碳负离子的α-取代基的膦酸酯的反应优先提供相应的E-烯烃。然而，HWE与酮的反应的立体选择性从未被详细研究，因为它们的低反应性和低立体选择性。芳基烷基酮与二乙基膦酰基乙酸乙酯在氢化钠存在下的传统HWE反应，以适度的E-选择性得到相应的α，β-不饱和酯。在Sn（OSO_2CF_3）_2和N-乙基哌啶存在下，二乙基膦酰基乙酸乙酯与芳烷基酮反应，得到α，β-不饱和酯。一个显着的改善，在选择性和产率被发现时，仍然的试剂，甲基双（三氟乙基）膦酰基乙酸酯，使用Sn（II）介导的条件下。实验结果的基础上，高Z-选择性的Sn（II）-介导的HWE反应的芳基烷基酮与这些膦酸酯可以合理化的六元过渡态涉及Sn（II）螯合。同样，在2-氟-2-二乙基膦酰基乙酸乙酯与芳基烷基酮的HWE反应中，以Sn（OSO_2CF_3）_2和N-乙基哌啶为催化剂，也观察到了良好的E-选择性。此外，在Sn（II）催化下，2-氟-2-二乙基膦酰基乙酸异丙酯与4-取代环己酮和2-取代-1，3-二氧六环-5-酮在手性二胺存在下的不对称HWE反应得到了α，β-不饱和酯，对映选择性高达80%ee.

The Horner-Wadsworth-Emmons (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 that 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 the modest E-selectivity. On the other hand, treatment of aryl alkyl ketones with ethyl diethylphosphonoacetate in the presence of Sn(OSO_2CF_3)_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 the 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, excellent E-selectivity was observed in the HWE reactions of ethyl 2-fluoro-2-diethylphosphonoacetate with aryl alkyl ketones using Sn (OSO_2CF_3)_2 and N-ethylpiperidine. In addition, the Sn (II)-mediated asymmetric HWE reactions of isopropyl 2-fluoro-2-diethylphosphonoacetate with 4-substituted-cyclohexanones and 2-substituted-1,3-dioxan-5-ones in the presence of a chiral diamine afforded α, β-unsaturated esters with enantioselectivities of up to 80% ee.