| Enantiomerically enriched halo alcohols are especially significant structural elements for the construction of structurally interesting compounds and biologically active pharmaceuticals or agricultural chemicals as well as their intermediates such as (R)-Fluoxetine and (S)-Duloxetine, which are prescribed for the treatment of psychiatric disorder or some metabolic problems. The catalytic asymmetric reduction of halo ketones is one of the most direct and powerful approaches towards optically active halo alcohols. The reported methods have been focused on the noble metal Rh-or Ru-catalyzed asymmetric hydrogenation and transfer hydrogenation of a-halo ketone. Thus, the development of efficient, economical and practical asymmetric reduction methods for the preparation of structurally diverse chiral halo alcohols is of great theory interests and application values.This study focused on the developlepment of the non-precious metal copper(II)/chiral dipyridylphosphine/silane catalyst system and the research results are summarized as followes:(1) Thirteen β-or γ-halo aromatic or hetero-aromatic ketones and three ε-halo aromatic ketones have been synthesized and characterized by1H NMR,13C NMR and HRMS analysis. In addition, the nineteen racemic forms of the corresponding alcohols have also been prepared and characterized by1H NMR, I3C NMR and HRMS analysis. The chiral analytical methods of these racemic products have been established as well.(2) Systematic investigations, various fine-tunings and modifications have been made on counterions of copper salts, silanes, chiral ligands, solvents as well as reaction temperature as to establish a novel chiral catalyst system with utility and practicality. In the presence of PhSiH3as the reductant, the combination of (S)-P-Phos (or Xyl-P-Phos) ligands and Cu(OAc)2·H20, an easy-to-handle and inexpensive copper salt, led to a remarkably practical and versatile chiral catalyst system, which allowed for the hydrosilylation of a diverse spectrum of β-or y-halo aromatic ketones under air atmosphere. The stereoselective formation of a selection of synthetically interesting γ-or δ-halo alcohols bearing high degrees of enantiopurity (up to 99.9%ee) was realized.(3) The established catalyt system has been applied to the the asymmetric hydrosilylation of ε-halo-substituted aromatic ketones and α-, β-, y-halo-substituted hetero-aromatic for the first time and most of the products were afforded in>90%ees.(4) In comparison to the common hydrogenation or transfer hydrogenation systems for the asymmetric reduction of simple ketones, the present catalyst system was base free and was therefore well appropriate for the base sensitive halo ketononic substrates. The studies on the catalyst activities indicated that the reaction was completed within4h at room temperature with no substantial decrease of ee even when the substrate-to-ligand ratio was improved to10,000. Noticeably, this approach can tolerate the handling of both catalyst and reactants in air without special precautions. To our best knowledge, the present catalyst system is among the most economic, efficient, stable and practical sytems reported thus far for the access to a broad scope of chiral halo alcohols.(5) Moreover, the synthetic utility of the developed methodology was highlighted by the efficient conversions of optically enriched β-halo alcohol products to the corresponding styrene oxide, β-amino alcohol and β-azido alcohol, respectively, which constitute key intermediates for the preparation of many chiral pharmaceuticals and natural products. Particularly, the developed process has been successfully applied in the enantioselective synthesis of optically enriched antidepressant drugs (R)-Fluoxetine and (S)-Duloxetine, which provided a novel, efficient, atomically economic and environmentally friendly method for the asymmetric synthesis of these kinds of chiral drugs and exhibited the practical viability as well. |
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