Giovanni W. Amarante

Gold(I)-Catalyzed Diastereo- and Enantioselective 1,3-Dipolar Cycloaddition and Mannich Reactions of Azlactones

Azlactones participate in stereoselective reactions with electron-deficient alkenes and N-sulfonyl aldimines to give products of 1,3-dipolar cycloaddition and Mannich addition reactions, respectively. Both of these reactions proceed with good to excellent diastereo- and enantioselectivity using a single class of gold catalysts, namely C(2)-symmetric bis(phosphinegold(I) carboxylate) complexes. The development of the azlactone Mannich reaction to provide fully protected anti-α,β-diamino acid derivatives is described. 1,3-Dipolar cycloaddition reactions of several acyclic 1,2-disubstituted alkenes and the chemistry of the resultant cycloadducts are examined to probe the stereochemical course of this reaction. Reaction kinetics and tandem mass spectrometry studies of both the cycloaddition and Mannich reactions are reported. These studies support a mechanism in which the gold complexes catalyze addition reactions through nucleophile activation rather than the more typical activation of the electrophilic reaction component.

Dualistic Nature of the Mechanism of the Morita-Baylis-Hillman Reaction Probed by Electrospray Ionization Mass Spectrometry

The Morita-Baylis-Hillman (MBH) reaction allows chemists to form new sigma C-C bonds in a single-step straightforward manner and thus to construct densely functionalized molecules for further chemical manipulation. Using electrospray ionization for transferring ions directly from solution to the gas phase, and mass (and tandem mass) spectrometry for mass and structural assignments, new key intermediates for the rate-determining step of the MBH reaction have been successfully intercepted and structurally characterized. These ESI-MS data provide experimental evidence supporting recent suggestions, based on kinetic experiments and theoretical calculations, for the dualist nature of the proton-transfer step of the MBH mechanism.

Recent Advances in Asymmetric Counteranion‐directed Catalysis (ACDC)

As expected, chemists have dedicated efforts in the development of asymmetric catalytic reactions based on lessons from nature. The decisive presence of the chiral anions in many natural chiral catalysts inspires the design of new asymmetric catalytic systems based on them. Thus, in this Minireview the recent contributions of asymmetric counteranion‐directed catalysis (ACDC) are reported. Discussions about development of new concepts, designed of catalysis and application of them in different reactions also are exposed.

Azlactone Reaction Developments

Azlactones (also known as oxazolones) are heterocycles usually employed in the stereoselective synthesis of α,α-amino acids, heterocycles and natural products. The versatility of the azlactone scaffold arises from the numerous reactive sites, allowing its application in a diversity of transformations. This review aims to cover classical and recent applications of oxazolones, especially those involving stereoselective processes. After a short introduction on their structures and intrinsic reactivities, dynamic kinetic resolution (DKR) processes as well as reactions involving stereoselective formation of a new σ C-C bond, such as alkylation/allylation/arylation, aldol, ene, Michael and Mannich reactions will be exposed. Additionally, cycloadditions, Steglich rearrangement and sulfenylation reactions will also be discussed. Recent developments of the well-known Erlenmeyer azlactones will be described. For the most examples, the proposed mechanism, activation modes and/or key reaction intermediates will be exposed to rationalize both the final product and the observed stereochemistry. Finally, this review gives an overview of the synthetic utility of oxazolones.

Chiral brønsted Acid-catalyzed stereoselective Mannich-type reaction of azlactones with aldimines.

A highly diastereo- and enantioselective Mannich-type reaction of azlactones with aldimines catalyzed by a chiral phosphoric acid is described. Only 3 mol % catalyst was required to prepare the Mannich adducts in good yields with high stereochemical control (up to >19:1 dr, >99:1 er). Moreover, the final product contains two consecutive stereogenic centers, one of which is quaternary.

Reações de organocatálise com aminas quirais: aspectos mecanísticos e aplicações em síntese orgânica

The philosophy of organocatalysis is based on the utilization of organic compounds to catalyze organic transformations without the intervention of metals. This area has attracted much attention of the synthetic chemistry community on the last years, which can be confirmed by the explosion of published papers dealing with this subject. Phosphorus compounds, urea and thiourea derivatives, alkaloids, guanidine derivatives, for example, have already been used as organocatalysts. In this review we have focused on the use of chiral amines as organocatalyst. We have also chosen some outstanding examples to demonstrate the potentiality of this strategy in the synthesis of natural products and biologically active compounds.

Novel thalidomide analogues from diamines inhibit pro-inflammatory cytokine production and CD80 expression while enhancing IL-10.

Thalidomide is used to treat a variety of diseases including erythema nodosum leprosum, an inflammatory complication of leprosy. However, this drug has severe teratogenic activity and novel thalidomide analogues might be used to treat diseases without this severe side effect. A series of diamine compounds containing two hydrolyzed phthalimide units were chosen as analogues of thalidomide and evaluated regarding their capacity to regulate the production of molecules involved in inflammatory responses. TNF-α, IL-12 and IL-10 production, and the expression of CD80 and CD86 were investigated in LPS plus IFN-γ-stimulated J774A.1 cells by ELISA and flow cytometry, respectively. The expression of TNF-α and IL-10 mRNA was analyzed by real time RT-PCR. TNF-α, IL-6, IFN-γ, CXCL9 and CXCL10 production by human peripheral blood mononuclear cells (PBMC) were evaluated by flow cytometry. Compounds 3, 6 and 9 greatly inhibited TNF-α and IL-12 production while enhancing IL-10. In addition, CD80 expression was inhibited, but not CD86. The compounds inhibited TNF-α production by PBMC more than thalidomide and also had an inhibitory effect on the production of IL-6, IFN-γ, CXCL9 and CXCL10. Levels of mRNA for TNF-α were reduced after treatment with the compounds, suggesting post- transcriptional effects. The compounds had no effect on cell viability. Our results indicate that the novel diamine compounds 3, 6 and 9 inhibit critical pro-inflammatory cytokines and stimulate IL-10, which make them attractive candidate drugs for the treatment of certain inflammatory conditions and cancer.

Chemoselective Reduction of Azlactones Using Schwartz’s Reagent

Highly chemoselective addition of Schwartzs reagent to widely available azlactones is described. This method allows the preparation of challenged functionalized α-amino aldehydes, in good to high isolated yields at room temperature, after only 2 min reaction. The presence of sensitive functionalities or electronic factors does not compromise the potential of the method. The use of an excess of the reducing reagent gave a very functionalized allylic alcohol derivative in 86% yield.

Catalyst free decarboxylative trichloromethylation of aldimines

A catalyst free decarboxylative trichloromethylation of imines to afford different trichloromethyl sulfonyl and sulfinyl amines has been presented. Only DMSO as a solvent at room temperature was necessary to provide the corresponding products in good to high isolated yields. A highly diastereoselective version was carried out, leading to the sulfinylimine with good yield and near perfect diastereoselectivity. Regarding the reaction profile, ATR-FTIR spectroscopy was employed to support the entire mechanism and also to provide details on the trichloroacetate salts behavior against electrophiles and in the presence of different solvents.

Hyphenating the curtius rearrangement with Morita-Baylis-Hillman adducts: synthesis of biologically active acyloins and vicinal aminoalcohols

Using Morita-Baylis-Hillman adducts as substrates, the Curtius rearrangement was performed in a sequence that allowed the synthesis of several hydroxy-ketones (acyloins) with great structural diversity and in good overall yields. These acyloins in turn were easily transformed into 1,2-anti aminoalcohols through a highly diastereoselective reductive amination step. The synthetic utility of these approaches was exemplified by performing the syntheses of (±)-bupropion, a drug used to treat the abstinence syndrome of smoker and (±)-spisulosine, a potent anti-tumoral compound originally isolated from a marine source.