Márcio W. Paixão

Acyl Phosphonates: Good Hydrogen Bond Acceptors and Ester/Amide Equivalents in Asymmetric Organocatalysis

This study demonstrates that unsaturated acyl phosphonates are excellent hydrogen-bond acceptors in enantioselective organocatalysis. By employing chiral thioureas or squaramides as catalysts, the acyl phosphonates are effectively coordinated and activated by hydrogen bonding, thereby providing successful relay of the chirality from the catalyst to the substrate. A variety of highly stereoselective conjugate additions to alpha,beta-unsaturated acyl phosphonates were performed, using different carbon-based nucleophiles such as oxazolones, indoles, and 1,3-dicarbonyl compounds. The reaction concept has been developed to be a double nucleophilic reaction, and it is shown that the acyl phosphonates serve as masked ester or amide equivalents, which upon quenching with the second nucleophile generate the parent structures in situ. Accordingly, formal C-C bond formation reactions of ester and amide substrates are achieved, affording a broad spectrum of optically active conjugate adducts in good yields and excellent enantioselectivities. Based on the experimental results, the mechanisms for the different reactions are discussed, including the approach of the oxazolones, indoles, and 1,3-dicarbonyl compounds to the acyl phosphonate coordinated to the catalyst and the role of the catalyst for the reaction course of the nucleophiles.

Asymmetric Organocatalysis with Sulfones

Asymmetric organocatalysis has become a powerful tool for the synthesis of optically active compounds. Whereas early research mainly focused on combining simple reagents as a proof-of-concept for asymmetric organocatalysis, recent investigations are directed towards extending the concept to more target- and diversity-oriented synthesis. As a result of the many transformation possibilities and their ability to generate both nucleophilic and electrophilic reaction partners, sulfones have become especially important substrates in the field of organocatalysis.

Asymmetric Organocatalytic Formal Alkynylation and Alkenylation of α,β-Unsaturated Aldehydes

A highly stereoselective organocatalytic one-pot protocol for the formal alkynylation and alkenylation of alpha,beta-unsaturated aldehydes using novel chemistry based on beta-keto heterocyclic sulfones is presented. The organocatalytic step is catalyzed by a prolinol derivative and allows for the formation of important optically active compounds. Further transformations of the beta-keto heterocyclic sulfone moiety, based on new developments of the Smiles rearrangement through a process parallel to the Julia-Kocienski reaction, were performed leading to beta-alkynylated aldehydes and 3-alkenylated alcohols. The scopes of both transformations are demonstrated by the synthesis of various optically active alkynes and alkenes. Furthermore, different transformations of the aldehyde and the alcohol functionality were performed. Finally, the proposed mechanisms for both the alkynylation and alkenylation of alpha,beta-unsaturated aldehydes are outlined.

Effects of age on reserpine-induced orofacial dyskinesia and possible protection of diphenyl diselenide

Acute reserpine administration produces persistent oral dyskinesia in rats, an alleged animal model of tardive dyskinesia. The pathophysiology of the syndrome remains unclear, but experimental evidence suggests that neurodegeneration in the basal ganglia caused by oxidative stress plays a pivotal role in TD development. In this paper, the authors examined whether diphenyl diselenide, an organochalcogen with antioxidant properties, changes the behavioral and neurochemical effect of acute reserpine administration in old rats. The basal vacuous chewing movements (VCMs) and facial twitching (FT) duration was higher in old rats (15 months of age), when compared with adult rats (3 months of age; 0.01). Basal thiobarbituric acid-reactive species (TBARS) levels were increased only in the cortex of old rats, when compared to adult animals (p < .05). Reserpine injection (1mg/kg, s.c. for 3 days every other day) caused a significant increase on the tongue protusion (TP) frequency (p < .01) and facial twitching duration (p < .01) in old rats. Diphenyl diselenide (10 mg/kg, i.p. for 4 days, starting the day before reserpine) reversed only reserpine-induced TP increase (p < .01). Reserpine caused a significant increase in striatal TBARS levels (p < .01) and diselenide reversed (p < .01) the effect of reserpine on TBARS levels in the striatum. In subcortical parts, isolated reserpine or diselenide administration significantly increased (p < .01) the levels of TBARS, while simultaneous treatment with reserpine and diselenide reverted this effect (p < .01). The results of the present study confirmed the effects of age on orofacial dyskinesia. Diphenyl diselenide, an organochalcogen with antioxidant properties, showed modest effects on reserpine-induced orofacial dyskinesia. However, additional studies are still necessary to establish whether this compound can be considered an effective antioxidant in other models of neurotoxicity.

Target-directed organocatalysis: a direct asymmetric catalytic approach to chiral propargylic and allylic fluorides.

A simple, direct one-pot organocatalytic approach to the formation of optically active propargylic fluorides is presented. The approach is based on organocatalytic alpha-fluorination of aldehydes and trapping and homologation of the intermediate providing optically active propargylic fluorides in good yields and enantioselectivities up to 99% ee. The procedure takes place by addition of NFSI, in the presence of 2-[bis(3,5-bis-trifluoromethylphenyl)trimethylsilyloxymethyl]pyrrolidine (as low as 0.25 mol %) as the catalyst, to aldehydes in combination with dimethyl 2-oxopropylphosphonate and 4-acetamidobenzenesulfonyl azide. The scope of the reaction is demonstrated by the formation of a number of optically active propargylic fluorides. It is also shown that optically active fluoro-containing triazoles can be obtained in one-pot procedures from aldehydes using click-chemistry. Furthermore, important coupling and multicomponent reactions of the optically active propargylic fluorides can be performed without affecting the enantiomeric excess. The direct one-pot formation of optically active allylic fluorides from aldehydes is also demonstrated. Finally, the mechanisms for both the formation of the propargylic and allylic fluorides are outlined.

Chiral organoselenium-transition-metal catalysts in asymmetric transformations

In recent years, there has been an increasing application of chiral selenium compounds as ligands in metal-catalyzed enantioselective transformations. One of the most important challenges in this field is the development of new chiral complexes (catalyst) generated from the reaction between a metal and appropriate chiral selenium-containing compounds (ligand). The vast majority of these ligands are easily synthesized in a few high-yielding synthetic steps, starting from readily available chiral amino alcohols. In this context, the advantages of using these compounds will be discussed, mainly with regard to their easy accessibility, modular nature and the formation of strong bonds with soft or, more rarely, hard metals. Important selective contributions within the field of chiral selenium complexes are examined, according to their applications. As final remarks, future developments and perspectives of the field are discussed.

Acceleration of arylzinc formation and its enantioselective addition to aldehydes by microwave irradiation and aziridine-2-methanol catalysts.

The formation and 2-amino alcohol catalyzed addition of arylzinc reagents from and with boronic acids, respectively, is drastically accelerated to a few minutes under microwave irradiation without loss of enantioselectivity (up to 98% ee). Of the amino acid derived catalysts tested, the conformationally restricted bulky substituted aziridine-2-methanols derived from serine show the best overall performance in the formation of diarylmethanols.

Terpene‐Derived Bifunctional Thioureas in Asymmetric Organocatalysis

Chiral hydrogen‐bond donors have played a crucial role in the progress of asymmetric catalysis as an essential tool in modern organic synthesis. Among these donors, thioureas have been found to be one of the most powerful systems in organocatalytic approaches. Within the last three years, a new generation of bifunctional thiourea catalysts has emerged as an effective way to promote highly demanding chemical transformations, frequently with success rates that are intriguingly higher than with other traditional thioureas. This new class of organocatalysts incorporates a bulky, rigid, and chiral terpene skeleton as one of the thiourea substituents, thus providing an additional and effective rigidifying (entropic) effect on the electrophile activation profile of thioureas. Structural integrations, either with additional Lewis basic nucleophile‐activating motifs or with amino groups for enamine catalysis, have enabled their implementation in a wide repertoire of stereocontrolled catalytic processes. This Review charts the development of these new catalysts, as well as their applications in a wide variety of reactions and reaction sequences, with the hope of encouraging further progress in the field of thiourea‐catalyst discovery and of bringing attention to the countless possibilities that are opened up by the tremendous success of terpene‐derived thiourea catalysts.

Human erythrocyte hemolysis induced by selenium and tellurium compounds increased by GSH or glucose: A possible involvement of reactive oxygen species

Oxidative stress can induce complex alterations of membrane proteins in red blood cells (RBCs) eventually leading to hemolysis. RBCs represent a good model to investigate the damage induced by oxidizing agents. Literature data have reported that chalcogen compounds can present pro-oxidant properties with potent inhibitory effects on cell growth, causing tissue damage and inhibit a variety of enzymes. In this study, human erythrocytes were incubated in vitro with various chalcogen compounds at 37 degrees C: diphenyl ditelluride (1), dinaphthalen diteluride (2), diphenyl diselenide (3), (S)-tert-butyl 1-diselenide-3-methylbutan-2-ylcarbamate (4), (S)-tert-butyl 1-diselenide-3-phenylpropan-2-ylcarbamate (5), selenium dioxide (6) and sodium selenite (7) in order to investigate their potential in vitro toxicity. After 6h of incubation, all the tested compounds increased the hemolysis rate, when compared to control and compound (2) had the most potent hemolytic effect. The addition of reduced glutathione (GSH) or glucose to the incubation medium enhanced hemolysis caused by chalcogen compounds. The thiol oxidase activity of these compounds was evaluated by measuring the rate of cysteine (CYS) and dithiotreitol (DTT) oxidation. DTT and cysteine oxidation was increased by all the compounds tested. The results suggest a relationship between the oxidation of intracellular GSH and subsequent generation of free radicals with the hemolysis by chalcogen compounds.

Catalytic enantioselective arylations: boron to zinc exchange as a powerful tool for the generation of transferable aryl groups

The transmetalation between boron and zinc is of great importance for application in organic synthesis, since it allows the formation of new carbon-carbon bonds between organometallic units and electrophiles. The direct arylation of aldehydes or more scarcely ketones, in a catalytic, enantioselective manner using chiral catalysts has been described recently. The enantiomerically enriched diarylmethanols obtained in these reactions are valuable precursors for important bioactive molecules. This review provides a synopsis of this ever-growing field and highlights some of the challenges that still remain.