Highly Enantioselective Amination Reactions of Fluorinated Keto Esters Catalyzed by Novel Chiral Guanidines Derived from Cinchona Alkaloids

Abstract

Novel Cinchona alkaloid-derived guanidines catalyze stereoselective aminations of fluorinated keto esters, affording products with fluorinecontaining quaternary stereogenic centers in excellent yields and with moderate to high enantioselectivities.Keywords: asymmetric amination; chiral guanidines; Cinchona alkaloids; fluorination substituent; organocatalysis Fluorine-containing molecules are very important in the pharmaceutical industry.[1] Fluorinated molecules often display distinctive characteristics compared to their parent compounds, owing to the unique properties of the fluorine atom and the resulting C À F bond(s). Therefore, the asymmetric construction of fluorinated molecules has become a fascinating and intensively investigated research area in organic synthesis. [2] The catalytic synthesis of chiral fluorinated quaternary carbon centers is a formidable synthetic challenge, and a number of excellent approaches based on metal catalysis appeared in the literature recently. Togni made the seminal discovery by utilizing Ti(IV)/ TADDOL complexes to achieve the catalytic enantioselective fluorination of b-keto esters in 2000.[3] Sodeoka and co-workers later developed the chiral palladium(II)-bisphosphine-catalyzed enantioselective fluorination of b-keto esters, b-ketophosphonates, and N-Boc-protected oxindoles.[4] Similar palladium species were employed by Kim et al. for the fluorination of a-cyanoacetates.[5] By using bisoxazoline-copper(II) complexes, Ma and Cahard achieved the electrophilic fluorination of b-keto esters.[6] Recently, Shibata and Toru disclosed the dbfox-Ph/Ni(II) complex-catalyzed, highly enantioselective fluorination of carbonyl compounds. Subsequently, the same group described an elegant desymmetrization-like fluorination of malonates that was promoted by DNFOXD-Ph and ZnA C H T U N G T R E N N U N G (OAc) 2 . [7] In an interesting approach, the groups of Stoltz, Nakamura, and Tunge investigated Pd(II)-mediated decarboxylative allylation reactions to construct fluorinated quaternary centers. [8] In contrast to the widespread methods based on transition metals, approaches employing organic catalysts have received attention only in the past few years.[9] Recently, organocatalytic approaches employing fluorinated substrates in asymmetric C À C bond forming reactions have been demonstrated to be very useful in the synthesis of optically enriched fluorinecontaining molecules.[10] By utilizing a-fluorinated-bketo esters as pronucleophiles, we achieved highly enantioselective organocatalytic Michael additions to nitroolefins [10a] and Mannich reactions with N-Bocimines.[10b] To further develop this synthetic methodology to access structurally interesting and biologically important fluorinated molecules, we became interested in the direct amination of a-fluorinated-b-keto esters, since such reactions yield a-fluoro-a-amino acids [11] possessing quaternary carbon centers. Although asymmetric amination reactions of b-keto esters were well-explored in the literature, aminations of fluori...

Asymmetric Synthesis of Quaternary α‐Amino Acids and Their Phosphonate Analogues

“…In a similar study, the Lu group developed quinidine-derived guanidine C57, which efficiently catalyzed the a-amination of a-fluoro-b-ketoesters 195 with 188 (Scheme 64). [80] a-Fluoro-a-hydrazinated-b-ketoesters 196 were obtained in good to excellent yields and enantioselectivities. Scheme 60.…”

Recent Advances in Catalytic Enantioselective Synthesis of Fluorinated α‐ and β‐Amino Acids

“…In addition, Lu et al devised a cinchona alkaloid derived bifunctional chiral guanidine 17, and applied to the same amination, enabling the synthesis of chiral α-amino α-fluoro-β-ketoesters 11 with 78-> 99% yields and 42-92% ee values. [28] The catalytic asymmetric Michael addition involving α-fluoro-α-nitro esters has emerged as an alternative strategy to synthesize optically active α-fluoro-α-amino acid derivatives. However, only two examples have been reported until now.…”

Enantioselective Synthesis of Isatin‐Derived α‐(Trifluoromethyl)imine Derivatives: Phosphine‐Catalyzed γ‐Addition of α‐(Trifluoromethyl)imines and Allenoates

“…They found that C‐4‐selective γ‐addition occurred when 2‐aryl‐4‐alkyloxazol‐5‐(4 H )‐ones were used as pronucleophiles, and C‐2‐selective γ‐addition took place when 2‐alkyl‐4‐aryloxazol‐5‐(4 H )‐ones were used as pronucleophiles. In recent years, prochiral fluorinated synthons have also been included in organocatalytic reactions, giving rise to many useful organofluorine compounds . Only one report has been published on the umpolung addition reactions of secondary carbon pronucleophiles,[12f] and no reports on trifluoromethyl‐containing secondary carbon pronucleophiles have been published.…”