Development of Stereoselective Synthetic Methods for Fluoroolefin Amide Isosteres

在“氟代烯烃酰胺等排体立体选择性合成方法的开发”研究过程中，我们开发了几个新的反应。从模拟电子特征和空间需求的角度来看，最近提出构象固定的（Z）-氟烯烃等同于（s-Z）-酰胺。因此，我们研究了立体选择性Horner-Wadsworth-Emmons（HWE）反应及相关的立体选择性合成（Z）-氟代烯烃的反应，发展了以异丙基溴化镁为催化剂，醛与2-氟-2-二乙基膦酰基乙酸的立体选择性HWE反应，主要产物为（Z）-α-氟代-α，β-不饱和羧酸（非对映体过量高达100%）。此外，2-酰基-2-氟-2-二乙基膦酰基乙酸乙酯的串联立体选择性还原-烯化反应，使用硼氢化钠在乙醇中的发展。一锅法合成的α-氟-α，β-不饱和酯具有良好的（Z）-选择性（非对映体过量高达100%）。一个合理的机制，涉及非对映体选择性还原预测的Felkin-Anh模型，随后由烯烃化类似的HWE反应，已被提出。另一方面，以异甘露醇和异山梨醇衍生物为手性助剂，研究了手性膦酰基乙酸酯与σ-对称的4-叔丁基环己酮和4-苯基环己酮的非对映选择性HWE反应。得到了手性轴为α-氟-α，β-不饱和酯，其非对映体比例高达14：86（aR：aS）。这种新的HWE反应可用于具有手性轴的氟代烯烃酰胺电子等排体的有机合成。

In the course of studies on "Development of Stereoselective Synthetic Methods for Fluoroolefin Amide Isosteres", we have developed several new reactions. Conformationally fixed (Z)-fluoroolefins were recently suggested to be equivalent to (s-Z)-amide from the standpoint of a mimic of the electronic features and the steric demands. Thus, we investigated the stereoselective Horner-Wadsworth-Emmons (HWE) and related reactions for the Stereoselective synthesis of (Z)-fluoroolefins.We have developed the stereoselective HWE reaction of aldehydes with 2-fluoro-2-diethylphosphonoacetic acid utilizing i-PrMgBr for the synthesis of (Z)-α-fluoro-α,β-unsaturated carboxylic acids as the major products (up to 100% diastereomeric excess). In addition, a tandem stereoselective reduction-olefination reaction of ethyl 2-acyl-2-fluoro-2-diethylphosphonoacetate employing NaBH4 in EtOH was developed. The one-pot reaction gave α-fluoro-α,β-unsaturated esters with excellent (Z)-selectivity (up to 100% diastereomeric excess). A plausible mechanism involving a diastereoselective reduction predicted by the Felkin-Anh model, followed by olefination similar to the HWE reaction, has been proposed. This one-pot reaction may be expanded to provide wide application for convenient syntheses of fluoroolefin peptide isosteres.On the other hand, the diastereoselective HWE reaction of chiral phosphonoacetates with σ-symmetric 4-tertbutylcyclohexanone and 4-phenylcyclohexanone was investigated by employing isomannide and isosorbide derivatives as chiral auxiliaries. α-Fluoro-α,β-unsaturated esters with an axis of chirality were obtained in diastereomer ratio up to 14:86 (aR:aS). This novel HWE reaction may find application in the organic synthesis of fluoroolefin amide isosteres possessing an axis of chirariy.