Catalytic Enantioselective and Diastereoselective Allylic Alkylation with Fluoroenolates: Efficient Access to C3‐Fluorinated and All‐Carbon Quaternary Oxindoles

Abstract

Synthetically versatile 3,3-disubstituted fluorooxindoles exhibiting vicinal chirality centers were obtained in high yields and with excellent enantio-, diastereo- and regioselectivity by catalytic asymmetric fluoroenolate alkylation with allylic acetates. The reaction proceeds under mild conditions and can be upscaled without compromising the asymmetric induction. The unique synthetic usefulness of the products is highlighted with the incorporation of additional functionalities and the formation of 3-fluorinated oxindoles exhibiting an array of four adjacent chirality centers. A new C-F bond functionalization path that provides unprecedented means for stereoselective generation of a chiral quaternary carbon center in the alkaloid scaffold is introduced.

Palladium‐Catalyzed Asymmetric Allylic Alkylations of Colby Pro‐Enolates with MBH Carbonates: Enantioselective Access to Quaternary C−F Oxindoles

“…Drawing inspiration from the work by Wolf on catalytic allylic alkylations of 3‐fluorooxindole derived enolates 1 and Lu on regiodivergent allylic alkylations of MBH carbonates, we decided to pursue the S N 2 mode of reactivity between pro‐enolates 2 and MBH carbonates 3 , giving rise to the expected products 5 featuring two consecutive stereogenic centers, including a C−F quaternary carbon. Here, we report a successful accomplishment of this project providing a reliable general access to the target compounds 5 with practically useful values of chemical yields (average >85 %), diastereo‐ (average >10:1) and enantioselectivity (average >90 % ee ).…”

“…However, the search for appropriate chiral ligand matching characteristics of starting compounds 2 a and 3 a was far from straightforward. For example, application of ligands of type L1 , used by Trost, and L2 – L4 by Wolf, for the reactions of conventional enolate derived from 3‐fluorooxindole 1 (Scheme ), gave unexciting results (Table , entries 2–5). Interestingly, although all ligands L1 – L4 showed similar values to the innate level diastereoselectivity, the chemoselectivity was seriously compromised resulting in noticeable amounts of by‐product 4 a .…”

“…[1,2,6] Some successi nt his area has been achieved with the development of enantioselective electrophilic fluorination, [7] whereas the alternative approaches still represent af ormidable challenge. [8] Owingt ot he multifaceted biological properties of oxindole derivatives, an umber of research groupsh ave reported catalytic enantioselective elaboration of 3-fluorooxindole-derived enolates 1 (Scheme 1) by aldol or Mannich reactions, [9] conjugate additions [10] and allylic alkylations [11] offering efficient access to av ariety of structurally novel compounds of high biological importance.C onsistent with our long-standing interest in catalytic asymmetric synthesis of fluorine-containing compounds, [12] we wanted to develop the Colby pro-enolates of type 2 [8b, [13][14][15][16] as synthetic alternatives to the conventional fluoro-enolates. [17] In particular, we reported the design of 3fluorooxindole derived pro-enolates 2, [18] and their unusual reactivity with imines [18,19] and dialkyl azodicarboxylates.…”

Organocatalytic Decarboxylative Cyanomethylation of Difluoromethyl and Trifluoromethyl Ketones

“…First, a series of difluoromethyl ketones was synthesized by following previously reported literature protocols. [16] After minor changes of the reaction procedure described above, we were able to prepare the β-difluoromethyl-β-hydroxynitriles 5a – 5h (Scheme 3). The cyanomethylation of the phenyl, tolyl, and 2-napthyl ketones 4a – 4c gave 5a – 5c in 92–99% yield.…”

Stereoselective Synthesis of 3,3’‐Bisindolines by Organocatalytic Michael Additions of Fluorooxindole Enolates to Isatylidene Malononitriles in Aqueous Solution

“…[6] The alternative approach based on C-C bond formation with 3-fluorooxindoles bears relatively unexplored synthetic potential. [7] …”