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

利用路易斯酸进行高度立体选择性霍纳-沃兹沃斯-埃蒙斯反应的新方法

基本信息

批准号：
11672104
负责人：
SANO Shigeki
金额：
$ 2.3万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672104/
关键词：
Wittig reaction Horner-Wadsworth-Emmons reaction Lewis acid fluorine asymmetric synthesis center of chirality axis of chirality α, β-unsaturated ester 四置換オレフィン

项目摘要

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.

霍纳-沃兹沃斯-埃蒙斯反应是制备α，β-不饱和酯最有效的方法之一，在生物活性化合物的合成中起着重要作用。醛与含有稳定碳负离子的α取代基的膦酸根的反应优先提供相应的E-烯烃。然而，由于HWE与酮反应的低反应性和低立体选择性，其立体选择性一直没有得到详细的研究。在氢化钠存在下，芳基烷基酮与二乙基膦乙酸乙酯的常规HWE反应得到相应的α，β不饱和酯，具有适度的E-选择性。另一方面，在SnO(SO2CF3)2和N-乙基哌啶存在下，芳基烷基酮与二乙基膦乙酸乙酯反应得到Z-选择性很高的α，β不饱和酯。在锡(II)介导的反应条件下，使用蒸馏剂双(三氟乙基)膦乙酸甲酯时，选择性和产率都有显著提高。根据实验结果，在锡(II)催化的芳基烷基酮与这些磷酸盐的HWE反应中，高Z选择性可以用涉及锡(II)络合的六元过渡态来解释。同样，2-氟-2-二乙基膦乙酸乙酯与芳基烷基酮在SnO_2CF_3_2和N-乙基哌啶的HWE反应中也表现出良好的电子选择性。此外，在手性二胺存在下，2-氟-2-二乙基膦乙酸异丙酯与4-取代环己酮和2-取代-1，3-二氧杂环-5-酮在锡(II)催化下的不对称HWE反应生成了对映体选择性高达80%ee的α，β不饱和酯。