Catalytic Asymmetric Construction of Stereogenic Carbon Centers that Feature a gem‐Difluoroalkyl Group

Abstract

gem-Difluoroalkyl groups, characterized as a gem-difluoromethylene group substituted by a hydrogen atom or an alkyl or other functional group, are not only valuable for the modulation of the properties of organic compounds, but are also useful for the synthesis of various fluorine-containing compounds. Currently, the catalytic asymmetric construction of stereogenic carbon centers that feature a gem-difluoroalkyl group is in its infancy. This Focus Review summarizes the latest achievements and discusses the difficulties and challenges in this field. Scheme 1. Structural difference between a CF 3 group and a difluoroalkyl group. FG = functional group. Scheme 2. The presence of gem-difluoroalkyl groups in important compounds. Scheme 13. The catalytic asymmetric addition of TMSCF 2 SO 2 Ph to aldehydes. TBAF = tetrabutylammonium fluoride. Scheme 14. The catalytic asymmetric addition of TMSCF 2 SePh to ketones. Ar = 3,5-(CF 3 ) 2 C 6 H 3 . Scheme 15. The asymmetric hydrogenation of a-CF 2 R ketimines. Bn = benzyl. Scheme 16. The Mannich reaction of a-difluoromethyl aldimines 69.

Catalytic Enantioselective Desymmetrization Reactions to All-Carbon Quaternary Stereocenters

“…However, catalytic enantioselective synthesis of cyclopropanes featuring a CF 2 group is still very challenging. 129 Kirihara and co-workers reported an indirect method for enantioselective synthesis of chiral difluoromethylated cyclopropane derivatives via lipase-catalyzed desymmetrization of difluoromethylated cyclopropane-based prochiral diol 152 (Scheme 47). 130 The lipase PS from Pseudomonas cepacia (Amano) mediated monoacetylation of diol 152 to give the difluorinated quaternary cyclopropane 153 in 96% yield and 95.5/4.5 er, which was then converted to the difluorinated analogue of ACC (R)-154.…”

“…Its difluoromethylated analogue is an attractive synthetic target, as the replacement of a methylene group by a difluoromethylene one (CF 2 ) may not only modulate the properties of ACC but introduce chirality. However, catalytic enantioselective synthesis of cyclopropanes featuring a CF 2 group is still very challenging . Kirihara and co-workers reported an indirect method for enantioselective synthesis of chiral difluoromethylated cyclopropane derivatives via lipase-catalyzed desymmetrization of difluoromethylated cyclopropane-based prochiral diol 152 (Scheme ).…”

Asymmetric Triple Relay Catalysis: Enantioselective Synthesis of Spirocyclic Indolines through a One‐Pot Process Featuring an Asymmetric 6π Electrocyclization

“…Despite the moderate ee value, this represents a new method to prepare novel difluorinated spirocyclic indoline derivatives. [24] The triple sequence described above could be modularly varied by using other asymmetric imine addition reactions. [25] For example, an analogous sequence involving hydrogenation, ketimine formation, and a Mannich reaction starting from 3-alkenyl-oxindole 9 and N-methyl isatin (2 a) readily gave bis(spirooxindole) 12 in 47 % yield, > 20:1 d.r., and 67 % ee [Eq.…”

Nucleophilic Tetrafluoroethylation Employing in Situ Formed Organomagnesium Reagents

“…The incorporation of a difluoromethylene (CF 2 ) group or perfluoroalkylidene groups [(CF 2 ) n ] into organic molecules is a popular strategy for modification of various properties of molecules in life science and material science applications. − For instance, the difluoromethylene group can act as a bioisostere of ethereal oxygen, carbonyl, or CHOH groups, and the difluoromethyl group can also serve as a lipophilic hydrogen bond donor. ,− In carbohydrates, the replacement of CHOH groups with CF 2 units causes only minimal steric and ring conformation perturbation, but because of attractive dipolar interactions of C–F bonds and hydrophobic desolvation, there is, in some cases, such as in a hexafluorinated sugar derivative, a dramatic improvement of transmembrane transport observed. , In addition, tetrafluorinated sugar analogues are currently being investigated as enzyme inhibitors. − For these reasons, there is a high demand for new synthetic methods enabling the incorporation of CF 2 CF 2 groups.…”