Asymmetric Synthesis of Fluorinated Flavanone Derivatives by an Organocatalytic Tandem Intramolecular Oxa‐Michael Addition/Electrophilic Fluorination Reaction by Using Bifunctional Cinchona Alkaloids

Abstract

Flavanones are a large family of natural products with many important biological activities, such as antitumor and anti-inflammatory properties. [1, 2] However, despite intensive research devoted to the synthesis of flavanone derivatives, [3] only a limited number of methods, particularly catalytic asymmetric methods, are available for the asymmetric synthesis of this class of compound.[4] Structurally, the asymmetric, intramolecular oxa-Michael addition reaction of a phenol to chalcone would provide an easy access to chiral flavanones due to the ready availability of the starting materials. However, it was not until 2007 that a breakthrough based on this strategy, by using an organocatalytic method, was accomplished, by Scheidt and co-workers, [4d] probably due to the low reactivity of the substrates. They addressed this challenge by utilizing an activated, unsaturated ketone, 1, as the substrate and bifunctional chiral thioureas as catalysts (Scheme 1). Recently, Feng and co-workers [4g] reported a metal-catalyzed version of the same reaction employing chiral N,N'-dioxide nickel(II) complexes with excellent results. In view of these results, there is still the potential for the development of new organocatalysts to effect an asymmetric intramolecular oxa-Michael addition as a route to synthesize chiral flavanones.On the other hand, the introduction of a fluorine atom into a compound often results in important changes in its biological activity, which can lead to potential applications in medicinal chemistry and the pharmaceutical industry. [5] One of the most challenging subjects in the field of synthetic fluorine chemistry is the enantioselective construction of the C À F bond at a stereogenic carbon center.[6] Since the first asymmetric fluorination reagents were reported by Differding and Lang [7a] in 1988 and the first catalytic enantioselective fluorination was disclosed by Hintermann and Togni [7b] in 2000, this intriguing field of catalytic asymmetric fluorination has been blooming. [8,9] Our group has developed a onepot tandem reaction for the synthesis of fluorinated flavanones, from b-ketoesters and aldehydes, with excellent diastereoselectivities.[10] On the basis of these results, we envisaged that by using an appropriate bifunctional catalyst, an organocatalytic, asymmetric, intramolecular oxa-Michael addition of 1 would produce enantioenriched 2, which could then be subjected to electrophilic fluorination to provide novel, chiral, fluorinated flavanone derivatives (Scheme 1). Herein, we report the details of this research.Cinchona alkaloids and their derivatives were selected as catalysts to be investigated due to their easy availability and well-documented power as bifunctional organocatalysts in

Racemic hemiacetals as oxygen-centered pronucleophiles triggering cascade 1,4-addition/Michael reaction through dynamic kinetic resolution under iminium catalysis. Development and mechanistic insights

“…Consequently, the reported examples of organocatalytic and enantioselective conjugate addition of oxygen pronucleophiles are limited to the use of oximes, 7 phenols, 8 enols, 9 alkoxyboronates, 10 hydroxylamines, 11 or peroxides 12 under iminium or H-bonding activation. 13 Organocatalytic cascade processes initiated by conjugate addition of O -nucleophiles have been mainly focused on the epoxidation of α,β-unsaturated carbonyls with peroxides 14 and some limited examples of conjugate addition followed by aldol, 15 Mannich, 16 Henry, 17 α-amination 18 and α-fluorination 19 have also been published. However, with respect to 1,4-addition/Michael cascade processes, all cases reported are strictly limited to the use of aliphatic alcohols or phenols as oxygen-centered pronucleophiles (Scheme 1).…”

Catalytic Asymmetric Syntheses of 2‐Aryl Chromenes

“…An organocatalytic intramolecular oxa‐Michael addition/electrophilic fluorination tandem reaction for the synthesis of various chiral monofluorinated flavanones was reported by Zhao in 2009 (Scheme ) . A series of cinchona alkaloids were selected as catalysts to be investigated due to their easy availability and well‐documented power as bifunctional organocatalysts.…”

Synthesis of (−)-Verbenone-Derived Triazolium Salts and Their Application in Enantioselective Intramolecular Stetter Reaction

“…Notably, these natural products have been shown to exhibit biological activities including anti-tumor, anti-inflammatory, antimicrobial, estrogenic, and antiestrogenic properties [5]. In spite of all these interesting properties, limited strategies for the general and efficient preparation of these compounds have been investigated in a stereoselective manner thus far [7][8][9][10][11][12].…”