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

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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.