Research On Detrifluoroacetylative Nucleophilic Addition Reaction Of Fluorinated Gem-Diols

Fluorine-containing pharmaceutical agents are usually found among the best performing, most prescribed, and bestselling drugs. Indeed, it is well-established that the introduction of fluorine into biologically active compounds generally leads to an improved efficacy, membrane permeability, and higher stability toward oxidative degradation. In fact. the modern pharmaceutical industry critically depends on the new methodological developments in fluorine chemistry, shaping up the future generations of healthcare products. Consequently, the development of new methods for the preparation of fluorine containing compounds has become one of the most active areas of multidisciplinary research. Recently Colby’s group reported a new detrifluoroacetylative approach for the generation of unprotected difluoroenolates in situ, which has several practically important characteristics, such as availability of starting compounds, structural generality, operationally convenient conditions. This project mainly focused on the studies of detrifluoroacetylative nucleophilic addition of fluorinated gem-diols. The contents were listed as below:1. Detrifluoroacetylative Mannich addition reaction of a,a-difluoroenolates to various N-sulfonyl imines.The Mannich reactions of in situ generated unprotected α,α-difluoroenolates with various N-sulfonyl imines took place under operationally convenient conditions affording a novel type of fluorinated sulfonamides of high pharmaceutical potential. The reactions featured sturctural generality, excellent yields and could be easily scaled up for practical preparation of the target fluorine-containing sulfonamides.2. Asymmetric detrifluoroacetylative Mannich addition reaction of a,a-difluoroenolates to chiral CF3-sulfinylimine.CF3-sulfinylimine readily reacted with α,α-difiuoroenolates affording a novel type of β-keto-amino compounds. The reactions feature exceptional generality allowing preparation of various aromatic, hetero-aromatic and aliphatic derivatives in high yields and diastereoselectivity. The products were configurationally stable and could be transformed to more functionalized complex compounds. This practical method was also proved to be suitable for large scale preparation. The absolute configuration of products was confirmed by the X-ray diffraction analysis, and a non-chelated transition state model of mechanism was proposed.3. Asymmetric detrifluoroacetylative Mannich addition reaction of a-fluoroenolates to chiral fluorinated sulfinylimine.a-Fluorinated gem-diols containing cyclic ketone framework were firstly designed and synthesized. And then a practical method for the asymmetric synthesis of quaternary C-F α-fluoro-β-keto-amino compounds was been explored, which was predicated on the idea of detrifluoroacetylative Mannich addition reactions between the a-Fluorinated gem-diols and chiral fluorinated sulfinylimine via C-C bond cleavage. The operational ease of these transformations coupled with excellent yields, stereochemical outcome and broad structural generality bodes well for its wide range of applications for practical preparation of α-fluoro-β-keto-amino compounds. At last, the absolute configuration of products was confirmed by the X-ray diffraction analysis, and a non-chelated transition state model of mechanism was proposed.4. Catalytic enantioselective detrifluoroacetylative Aldol addition reaction of a-fluoroenolates to aldehydes.A Cu-catalyzed enantioselective detrifluoroacetylative Aldol addition reaction of a-fluoroenolates to aldehydes in the presence of base and chiral bidentate ligand was developed. The reaction was carred out under convenient conditions and tolerated a wide range of substrates, resulting in fluorinated quaternary stereogenic α-fluoro-β-hydroxy ketone products with good chemical yields, diastereo-and enantioselectivities. This catalytic asymmetric detrifluoroacetylative Aldol addition reaction provides a new approach for the preparation of biologically relevant products containing C-F quaternary stereogenic centers.5. Asymmetric detrifluoroacetylative Mannich addition reaction of α-fluoroenolates containing oxindole framework to chiral sulfinylimine.a-Fluorinated gem-diols containing oxindole framework were firstly designed and synthesized. And then a practical method for the asymmetric detrifluoroacetylative Mannich addition reaction of α-fluoroenolates containing oxindole framework to chiral sulfinylimine was been explored. More importantly, both fluorinated and non-fluorinated sulfinylimine could been applied to this reaction, but affording the products with different configurations, at last the absolute configuration of products was confirmed by the X-ray diffraction analysis, and a possible mechanism was proposed.