Mattia Riccardo Monaco

Activation of Carboxylic Acids in Asymmetric Organocatalysis

Organocatalysis, catalysis using small organic molecules, has recently evolved into a general approach for asymmetric synthesis, complementing both metal catalysis and biocatalysis. Its success relies to a large extent upon the introduction of novel and generic activation modes. Remarkably though, while carboxylic acids have been used as catalyst directing groups in supramolecular transition-metal catalysis, a general and well-defined activation mode for this useful and abundant substance class is still lacking. Herein we propose the heterodimeric association of carboxylic acids with chiral phosphoric acid catalysts as a new activation principle for organocatalysis. This self-assembly increases both the acidity of the phosphoric acid catalyst and the reactivity of the carboxylic acid. To illustrate this principle, we apply our concept in a general and highly enantioselective catalytic aziridine-opening reaction with carboxylic acids as nucleophiles.

Organocatalytic asymmetric hydrolysis of epoxides.

The hydrolytic ring opening of epoxides is an important biosynthetic transformation and is also applied industrially. We report the first organocatalytic variant of this reaction, exploiting our recently discovered activation of carboxylic acids with chiral phosphoric acids via heterodimerization. The methodology mimics the enzymatic mechanism, which involves an enzyme-bound carboxylate nucleophile. A newly designed phosphoric acid catalyst displays high stereocontrol in the desymmetrization of meso-epoxides. The methodology shows wide generality with cyclic, acylic, aromatic, and aliphatic substrates. We also apply our method in the first highly enantioselective anti-dihydroxylation of simple olefins.

Catalytic asymmetric synthesis of thiols.

The synthesis of enantiopure thiols is of significant interest for industrial and academic applications. However, direct asymmetric approaches to free thiols have previously been unknown. Here we describe a novel organocascade that is catalyzed by a confined chiral phosphoric acid and furnishes O-protected β-hydroxythiols with excellent enantioselectivities. The method relies on an asymmetric thiocarboxylysis of meso-epoxides, followed by an intramolecular trans-esterification reaction. By varying the reaction conditions, the intermediate thioesters can also be obtained chemoselectively and enantioselectively.

Catalytic Enantioselective Conversion of Epoxides to Thiiranes.

A highly efficient and enantioselective Brønsted acid catalyzed conversion of epoxides to thiiranes has been developed. The reaction proceeds in a kinetic resolution, furnishing both epoxide and thiirane in high yields and enantiomeric purity. Heterodimer formation between the catalyst and sulfur donor affords an effective way to prevent catalyst decomposition and enables catalyst loadings as low as 0.01 mol %.

Photocatalytic Benzylic Fluorination

Significance: A photocatalytic benzylic fluorination is reported by Chen and co-workers. Promoted by visible light, the photoexcitation of the ketone organocatalyst generates a short-lived diradical species, which abstracts a benzylic hydrogen from the starting material. Subsequently, the fluorine source delivers the F-atom and regenerates the catalyst. The methodology is operationally convenient and converts a large variety of substrates into the corresponding monoand difluorinated products using a simple compact fluorescent light (CFL) bulb and commercially available Selectfluor (A) and Selectfluor II (B). Comment: In the last few years, the interest of the scientific community in the synthesis of fluorinated compounds has risen impressively due to the importance of these substances in pharmaceutical and material sciences. Therefore, the development of selective and mild procedures for the introduction of fluorine atoms, even in a racemic fashion, is very attractive. Here, the authors present a solid protocol to achieve this target. A wide variety of substrates was reacted to give the fluorinated products in good to excellent yields, highlighting the efficiency of the disclosed photocatalytic system. O

Isoxazolidinones via Asymmetric Decarboxylative Protonation

86 T . TI T E, M . S AB B AH , V . L E V A C H E R , J . F . B R I È R E * ( N OR M A N D I E U N I V E R S I T É , U N I V E R S I T É D E R O U E N , AN D C E N T R E N A T I O N A L D E L A R E C H E R C H E S C I E N T I F I QU E , M O N T S A I N T A I G NA N , F R A N C E ) Organocatalysed Decarboxylative Protonation Process from Meldrum’s Acid: Enantioselective Synthesis of Isoxazolidinones Chem. Commun. 2013, 49, 11569–11571.

Asymmetric Protonation in Dienamine-Catalysis

Significance: The Deng group reports the catalytic enantioselective isomerization of β,γ-unsaturated cyclohex-3-en-1-ones 1 to the corresponding chiral α,β-unsaturated cyclic enones 2. The authors designed a new class of cinchona alkaloid-derived catalysts bearing substituted anilines as tunable handles. In particular, combining the newly synthesized catalysts A and B with carboxylic acid co-catalysts, they developed two different systems to achieve the synthesis of the two enantiomers of the desired products. Comment: During the last few years interest has grown towards asymmetric primary amine catalyzed γ-functionalization of enones via dienamine intermediates. These methodologies mainly rely on the remote control of the stereochemistry achievable with the cinchona-alkaloid skeletons. Herein, the authors tackle the challenge of asymmetric γ-protonation and report the development of new bifunctional catalysts, which allow such transformations. Moreover, the usefulness of the process is highlighted by the first asymmetric total synthesis of the marine sesquiterpenoid isoacanthodoral (3). O

Photocatalytic Anti-Markovnikov Hydroetherification

Significance: A direct photocatalytic antiMarkovnikov hydroetherification has been described by the Nicewicz group. The reported procedure is promoted by the commercially available sensitizer 9-mesityl-10-methylacridinium perchlorate (A) and the H-atom donor 2-phenylmalonitrile (B). The authors suggest that the methodology is based on two different redox cycles. A primary one, which initiates the reaction by a single-electron transfer (SET) and a supporting one, which simultaneously facilitates the hydrogen exchange and serves as an electron-redox mediator. Comment: The study of catalytic antiMarkovnikov additions of nucleophiles to olefins has gained great interest in the last decades since it had been described as one of the ‘top ten challenges for catalysis’ [J. Haggin Chem. Eng. News 1993, 71 (22), 23]. In this work, the authors describe the addition of alcohols to alkenes via a newly developed two-component organic photoredox catalytic system. The reaction affords a wide range of cyclic ethers with complete selectivity, which reflects the thermodynamic equilibrium between the three radical intermediates I, II and III. Proposed catalytic cycle: HO R2 R1 (0.5–2 equiv) catalyst A (5 mol%)