Development of Stereoselective Synthetic Methods for Fluoroolefin Amide Isosteres

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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.