Phosphine‐Catalyzed Asymmetric Umpolung Addition of Trifluoromethyl Ketimines to Morita–Baylis–Hillman Carbonates

Abstract

A novel phosphine-catalyzed, highly enantioselective umpolung addition of trifluoromethyl ketimines to Morita-Baylis-Hillman carbonates was developed and it provides facile access to optically active trifluoromethyl amines with a chiral tertiary stereocenter under mild reaction conditions. The salient features of this reaction include general substrate scope, mild reaction conditions, good yields, high enantioselectivity, ease of scale-up to gram scale, and further transformations of the products.

Catalytic Asymmetric Synthesis of Trifluoromethylated γ‐Amino Acids through the Umpolung Addition of Trifluoromethyl Imines to Carboxylic Acid Derivatives

“…With this strategy direct enantioselective synthesis of chiral γ-amino acids not yet accessible by existing enantioselective C-N bond forming methods, such as γ, γ-disubstituted and β, γ-disubstituted γ-amino acids, is possible. Zhang and coworkers [16] reported the development of a phosphine nucleophilic catalyst for the activation of a Morita-Baylis-Hillman carbonate for the nucleophilic addition of trifluoromethyl imines to generate enantiomerically enriched α-methylene γ-trifluoromethylated γ-amino acids (Scheme 1c). …”

Sulfonate N‐Heterocyclic Carbene–Copper Complexes: Uniquely Effective Catalysts for Enantioselective Synthesis of C−C, C−B, C−H, and C−Si Bonds

“…[177] In 2016, Zhang disclosed an enantioselective Morita-Baylis-Hillman type process catalyzed by ap hosphine and involving N-benzyl ketimines;enantioselectivities were high and a-tertiary NH 2amines were obtained after acidic workup (Scheme 80). [178] With Allenes, B 2 (pin) 2 ,and N-H Ketimines. Theability of different Cu-based catalysts to promote diastereo-and enantioselective addition of 2-B(pin)-substituted allyl groups to N-H ketimines varies widely (Scheme 81 a).…”

Recent developments in the asymmetric organocatalytic Morita−Baylis−Hillman reaction

“…In another area, Zhang et al recently developed the highly enantioselective phosphine-catalysed umpolung addition of trifluoromethyl ketimines 122 to MoritaÀBaylisÀHillman carbonate 123, allowing a novel route to chiral trifluoromethyl amines 124. 78 As shown in Scheme 43, the process was promoted by 10 mol% of novel phosphine catalyst 125 in toluene at room temperature and led to a range of products 124 in good to high yields (70e91%) and uniformly excellent enantioselectivities (90e99% ee). It was compatible to various aryl trifluoromethyl ketimines (R ¼ aryl) bearing diverse functional groups, such as halogens, electrondonating-as well as electron-withdrawing groups at the para position of the phenyl ring, providing the corresponding products with 93e99% ee and good yields (70e91%).…”