Enantioselective Fluorination of α-Substituted β-Diketones Using β,β-Diaryl Serines

Abstract

We report the enantioselective fluorination of α-substituted β-diketones using β,β-diaryl serines as a primary amine organocatalyst. The reaction affords the corresponding fluorinated products in yields of 74 to 99% with excellent enantioselectivity (75–95% ee). Moreover, for synthetic applications, the diol, aldols, and the allylic fluoride were synthesized from 2a, maintaining excellent enantioselectivity (94% ee). The control experiment reveals that the CO2H group of the β,β-diaryl serines plays an important role in inducing the high enantioselectivity.

Alkali Carbonates Improve β,β-Diaryl Serine-Catalyzed Enantioselective α-Fluorination of β-Dicarbonyl Compounds

“…The absolute configuration of the fluorinated carbon in 2a′ was found to be the S-configuration by comparing with a previous result. 18 A control experiment using 1a′ with the optimal condition as shown in Scheme 3 revealed that the carboxylic acid group of the β,β-diaryl serine catalyst played an important role to induce enantioselectivity (i, Figure 1). The reaction with C6-CO 2 Me gave a racemic product, and this result is almost identical to the reaction without a β,β-diaryl serine catalyst.…”

“…Numerous endeavors have been undertaken to expand the scope of asymmetric organocatalysis, including the design of novel organocatalysts exhibiting unique structures or functions. , Recently, our group developed a β,β-diaryl serine catalyst as a new primary amine catalyst, and highly enantioselective α-fluorination of acyclic α-substituted β-diketones was achieved with a β,β-diaryl serine bearing bulky substituents on the β-position (i, Scheme ). Despite yielding high enantioselectivity, this reaction needs a long time even with an excess of the fluorinating reagent, 2.0 equiv of Selectfluor. Moreover, only acyclic β-diketones were examined in the previous investigation, whereas acyclic β-ketoesters, β-ketoamides, and cyclic β-dicarbonyl compounds have not been tested.…”

Oxidation: C–X Bond Formation (X = Halogen, S, Se)

“…The carboxylic group of β,βdiaryl serine plays an important role in enhancing the electrophilicity of the fluorine donor and in positioning the reaction partners in the transition state (Scheme 4b). 9 Scheme 4 Aminocatalysis for asymmetric -fluorination of -keto carbonyls Well-established silylated ,-diaryl prolinol derivatives were found to be efficient enamine organocatalysts in the fluorination of N-Boc-pyrrolidine-3-carboxaldehyde disubstituted at C4 including spirocyclic substituents. A series of eight fluorinated spirocyclic pyrrolidine carbaldehydes were synthesized in high yields and enantioselectivities (Scheme 5a).…”

Synthesis of Chiral Tertiary Allylic- and Propargylic Fluorides from Nonaflates of Chiral α-Fluorinated β-Keto Dicarbonyl Compounds

“…Recently, we developed a highly enantioselective α-fluorination of acyclic α-substituted-β-dicarbonyl compounds 1 , such as β-diketones, β-ketoesters, and β-ketoamides, using a β,β-diaryl serine catalyst (Scheme ). Moreover, for the synthetic applications of 1 , the synthetic transformation of C2 of the benzoyl group was intensively investigated. One of applications revealed that 1 can serve as a good precursor to synthesize chiral tertiary allylic fluorides using reactions that included Horner–Wadsworth–Emmons reactions (top, Scheme ).…”

“…One of applications revealed that 1 can serve as a good precursor to synthesize chiral tertiary allylic fluorides using reactions that included Horner–Wadsworth–Emmons reactions (top, Scheme ). On the other hand, the investigation of the acetyl group at C1 has not yet been explored. It is widely known that the treatment of an acetyl group with bases generates its enolate, which can subsequently react with a sulfonylating reagent to form an alkenyl sulfonate .…”