Synthesis, Characterization, X-ray Molecular Structure, Antioxidant, Antifungal, and Allelopathic Activity of a New Isonicotinate-Derived meso-Tetraarylporphyrin.

The present article describes the synthesis of an isonicotinate-derived meso-arylporphyrin, that has been fully characterized by spectroscopic methods (including fluorescence spectroscopy), as well as elemental analysis and HR-MS. The structure of an n-hexane monosolvate has been determined by single-crystal X-ray diffraction analysis. The radical scavenging activity of this new porphyrin against the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical has been measured. Its antifungal activity against three yeast strains (C. albicans ATCC 90028, C. glabrata ATCC 64677, and C. tropicalis ATCC 64677) has been tested using the disk diffusion and microdilution methods. Whereas the measured antioxidant activity was low, the porphyrin showed moderate but encouraging antifungal activity. Finally, a study of its effect on the germination of lentil seeds revealed interesting allelopathic properties.

One-pot organocatalyzed synthesis of tricyclic indolizines.

Indolizines and their saturated derivatives are important structural motifs present in several biologically active compounds of both natural and synthetic origin. We describe herein a one-pot approach for the synthesis of tricyclic indolizines catalyzed by a bicyclic imidazole-alcohol. The protocol is based on an aqueous Morita-Baylis-Hillman reaction between pyridine-2-carboxaldehydes and six- or seven-membered cyclic enones, followed by sequential intramolecular cyclization and dehydration. So, in a single operational step two new bonds (C-C and C-N) are formed in an organocatalyzed process that takes place in simple conditions (stirring in water at 60 °C for 12 h) and with great atom economy (water as the sole byproduct), affording the purified compounds in yields ranging from 19 to 70%. The facility of the cyclization strongly depends on the size of the cycloalkenone ring: while MBH adducts derived from six-, seven- or eight-membered cycloenones are readily transformed into the corresponding indolizines, cyclopentenone-derived MBH adducts do not cyclize. A competition experiment revealed that cycloheptenone-derived MBH adducts cyclize faster than cyclohexenone-derived adducts. Model DFT calculations have been performed to rationalize these reactivity trends.

Synthesis of New Amino-Functionalized Porphyrins:Preliminary Study of Their Organophotocatalytic Activity.

The design, synthesis, and initial study of amino-functionalized porphyrins as a new class of bifunctional catalysts for asymmetric organophotocatalysis is described. Two new types of amine-porphyrin hybrids derived from 5,10,15,20-tetraphenylporphyrin (TPPH2), in which a cyclic secondary amine moiety is covalently linked either to a ß-pyrrolic position (Type A) or to the p-position of one of the meso phenyl groups (Type B), were prepared by condensation, reductive amination, or amidation reactions from the suitable porphyrins (either formyl or methanamine derivatives) with readily available chiral amines. A preliminary study of the possible use of Type A amine-porphyrin hybrids as asymmetric, bifunctional organophotocatalysts was performed using the chiral, imidazolidinone-catalyzed Diels-Alder cycloaddition between cyclopentadiene 28 and trans-cinnamaldehyde 29 as a benchmark reaction. The yield and the stereochemical outcome of this process, obtained under purely organocatalytic conditions, under dual organophocatalysis, and under bifunctional organophotocatalysis, were compared.

Chiral Amphiphilic Secondary Amine-Porphyrin Hybrids for Aqueous Organocatalysis.

Two chiral proline-derived amphiphilic 5-substituted-10,15,20-tris(4-sulfonatophenyl)porphyrins were prepared, and their pH-dependent supramolecular behavior was studied. In neutral aqueous solutions, the free-base form of the hybrids is highly soluble, allowing enamine-based organocatalysis to take place, whereas under acidic conditions, the porphyrinic protonated core of the hybrid leads to the formation of self-assembled structures, so that the hybrids flocculate and their catalytic activity is fully suppressed. The low degree of chirality transfer observed for aqueous Michael and aldol reactions strongly suggests that these reactions take place under true "in water" organocatalytic conditions. The highly insoluble catalyst aggregates can easily be separated from the reaction products by centrifugation of the acidic reaction mixtures, and after neutralization and desalting, the sodium salts of the sulfonated amine-porphyrin hybrids, retaining their full catalytic activity, can be recovered in high yield.

5-Phenyl-10,15,20-Tris(4-sulfonatophenyl)porphyrin: Synthesis, Catalysis, and Structural Studies.

A convenient protocol for the preparation of 5-phenyl-10,15,20-tris(4-sulfonatophenyl)porphyrin, a water-soluble porphyrin with unique aggregation properties, is described. The procedure relies on the one-pot reductive deamination of 5-(4-aminophenyl)-10,15,20-tris(4-sulfonatophenyl)porphyrin, that can be in turn easily obtained from 5,10,15,20-tetraphenylporphyrin by a known three-step sequence involving mononitration, nitro to amine reduction and sulfonation of the phenyl groups. This method provides the title porphyrin in gram scale, and compares very favorably with the up to now only described procedure based on the partial sulfonation of TPP, that involves a long and tedious chromatographic enrichment of the final compound. This has allowed us to study for the first time both the use of its zwitterionic aggregate as a supramolecular catalyst of the aqueous Diels⁻Alder reaction, and the morphology of the aggregates obtained under optimized experimental conditions by atomic force microscopy and also by transmission electron cryomicroscopy.

Cooperative Effects Between Arginine and Glutamic Acid in the Amino Acid-Catalyzed Aldol Reaction.

Catalysis of the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde by mixtures of L-Arg and of L-Glu in wet dimethyl sulfoxide (DMSO) takes place with higher enantioselectivity (up to a 7-fold enhancement in the anti-aldol for the 1:1 mixture) than that observed when either L-Glu or L-Arg alone are used as the catalysts. These results can be explained by the formation of a catalytically active hydrogen-bonded complex between both amino acids, and demonstrate the possibility of positive cooperative effects in catalysis by two different α-amino acids. Chirality 28:599-605, 2016. © 2016 Wiley Periodicals, Inc.

Expedient Organocatalytic Syntheses of 4-Substituted Pyrazolidines and Isoxazolidines.

The efficient organocatalytic synthesis of heterocyclic systems of biological relevance is a subject of growing interest. We have found that the pyrrolidine/benzoic acid-catalyzed reaction of α-substituted propenals such as methacrolein, 2-benzylpropenal and 2-(n-hexyl)propenal with activated hydrazines takes place in very good yields (83%-99.6%) under very mild conditions to afford 4-substituted pyrazolidin-3-ols (as diastereomer mixtures); subsequent oxidation with PCC affords the corresponding-4-substituted-3-pyrazolidinones in essentially quantitative yields. In a similar way, 4-substituted isoxazolidinones are obtained with N-Cbz-hydroxylamine as a reagent. The use of chiral diarylprolinol trimethylsilyl ethers as catalysts allows the synthesis of several of these compounds in optically active form, in some cases with excellent enantioselectivity (up to 96:4 er). A preliminary evaluation of the biological activity shows that some of these compounds exhibit interesting antibacterial and antifungal activities.

A closer look at spontaneous mirror symmetry breaking in aldol reactions.

The aldol reaction between acetone and 4-nitrobenzaldehyde run in the nominal absence of any enantioselective catalyst was monitored by chiral HPLC with the aid of an internal standard. The collected data show the presence of a detectable initial enantiomeric excess of the aldol product in the early stages of the reaction in about 50 % of the experiments. Only a small fraction of the reaction contained the non-racemic aldol product after 24 h. This temporary emergence of natural optical activity could be the signature of a coupled reaction network that leads to a spontaneous mirror-symmetry-breaking process, which originates at very low conversions (i.e., strongly depends on events taking place at the very first stages of the process). The reaction is not autocatalytic in the aldol product, which rules out a simple Frank-type reaction network as the source of the observed symmetry breaking. On the other hand, the isolation and characterisation of a double-aldol adduct suggested a reaction network that involved both indirect autocatalysis and indirect mutual inhibition between the enantiomers of the reaction product.

Absolute asymmetric synthesis in enantioselective autocatalytic reaction networks: theoretical games, speculations on chemical evolution and perhaps a synthetic option.

The Soai reaction and the Viedma deracemization of racemic conglomerate crystal mixtures are experimental pieces of evidence of the ability of enantioselective autocatalytic coupled networks to yield absolute asymmetric synthesis. Thermodynamically open systems or systems with non-uniform energy distributions may lead to chiral final states and, in systems able to come into thermodynamic equilibrium with their surroundings, to kinetically controlled absolute asymmetric synthesis. The understanding of network parameters and of the thermodynamic scenarios that may lead to spontaneous mirror symmetry breaking (SMSB) could assist in the development of new methods for asymmetric synthesis and enantioselective polymerizations (e.g., replicators), and to frame reasonable speculations on the origin of biological homochirality.

Spontaneous emergence of chirality in the limited enantioselectivity model: autocatalytic cycle driven by an external reagent.

The model of limited enantioselectivity (LES) in closed systems, and under experimental conditions able to achieve chemical equilibrium, can give rise to neither spontaneous mirror symmetry breaking (SMSB) nor kinetic chiral amplifications. However, it has been recently shown that it is able to lead to SMSB, as a stationary final state, in thermodynamic scenarios involving nonuniform temperature distributions and for compartmentalized separation between the two autocatalytic reactions. Herein, it is demonstrated how SMSB may occur in LES in a cyclic network with uniform temperature distribution if the reverse reaction of the nonenantioselective autocatalysis, which gives limited inhibition on the racemic mixture, is driven by an external reagent, that is, in conditions that keep the system out of chemical equilibrium. The exact stability analysis of the racemic and chiral final outcomes and the study of the reaction parameters leading to SMSB are resolved analytically. Numerical simulations, using chemical kinetics equations, show that SMSB may occur for chemically reasonable parameters. Numerical simulations on SMSB are also presented for speculative, but reasonable, scenarios implying reactions common in amino acid chemistry.

The Viedma deracemization of racemic conglomerate mixtures as a paradigm of spontaneous mirror symmetry breaking in aggregation and polymerization.

Simulations of a chemical kinetics model, based on the free-energy relationships of classical primary nucleation theory, show that the deracemization phenomenon in systems of achiral or fast racemizing compounds yielding enantiopure crystals as the more stable solid phase is a true spontaneous mirror symmetry breaking process (SMSB). That is, the achievement of a stationary chiral state is more stable than the racemic one. The model translates the free-energy relationships determined by the existence of a critical size cluster to a chemical kinetics model, in which the consideration of forward and backward reaction rate constants avoids the misuse of network parameters that violate thermodynamic constraints (microreversibility principle), which would lead to apparent in silico SMSB. The model provides qualitative agreement for deracemizations by mechanical attrition of visible crystals, as well as for those obtained under temperature gradients. The analysis of the effect of the system parameters to obtain a SMSB scenario shows that the network possesses the principal characteristics of SMSB networks: 1) an enantioselective autocatalytic stage, corresponding to the non-linear kinetics of enantioselective (homochiral) cluster-to-cluster growth, and 2) the mutual inhibition step originating in the backward flow of chiral clusters towards smaller achiral clusters, or even to a racemizing monomer. The application of such a SMSB kinetic model to enantioselective polymerizations and to chiral biopolymers is discussed.

Mirror symmetry breaking with limited enantioselective autocatalysis and temperature gradients: a stability survey.

We analyze limited enantioselective (LES) autocatalysis in a temperature gradient and with internal flow/recycling of hot and cold material. Microreversibility forbids broken mirror symmetry for LES in the presence of a temperature gradient alone. This symmetry can be broken however when the auto-catalysis and limited enantioselective catalysis are each localized within the regions of low and high temperature, respectively. This scheme has been recently proposed as a plausible model for spontaneous emergence of chirality in abyssal hydrothermal vents. Regions in chemical parameter space are mapped out in which the racemic state is unstable and bifurcates to chiral solutions.

Catalytic asymmetric defluorinative allylation of silyl enol ethers.

The stereocontrolled installation of alkyl fragments at the alpha position of ketones is a fundamental yet unresolved transformation in organic chemistry. Herein we report a new catalytic methodology able to construct α-allyl ketones via defluorinative allylation of silyl enol ethers in a regio-, diastereo- and enantioselective manner. The protocol leverages the unique features of the fluorine atom to simultaneously act as a leaving group and to activate the fluorophilic nucleophile via a Si-F interaction. A series of spectroscopic, electroanalytic and kinetic experiments demonstrate the crucial interplay of the Si-F interaction for successful reactivity and selectivity. The generality of the transformation is demonstrated by synthesising a wide set of structurally diverse α-allylated ketones bearing two contiguous stereocenters. Remarkably, the catalytic protocol is amenable for the allylation of biologically significant natural products.

Organocatalytic enantioselective pyrazol-3-one addition to maleimides: reactivity and stereochemical course.

The enantioselective synthesis of pyrazol-3-ones has not been extensively studied in organic synthesis. Here in we report the first asymmetric addition of pyrazolones to maleimides catalyzed by bifunctional thiourea catalysts.

Enantioselective organocatalytic oxyamination of unprotected 3-substituted oxindoles.

An enantioselective α-oxyamination of unprotected 3-substituted oxindoles with nitrosobenzene catalyzed by tertiary amine-thiourea bifunctional organocatalysts has been developed and affords the corresponding 3-amino-2-oxindole derivatives in good yields and with moderate to excellent enantioselectivities (up to > 99.9 : 0.1 er when the product is isolated by direct filtration from the reaction mixture). The absolute configuration of the major enantiomers of the products has been established both by chemical correlation and by comparison between the theoretically calculated and the experimental ECD.

Highly enantioselective cascade synthesis of spiropyrazolones.

An efficient synthesis of spiropyrazolones based on organocatalysis is described. The reaction between pyrazolones, enolizable aldehydes and enals is catalyzed by secondary amine catalysts and affords the final spiro compounds bearing four contiguous chiral centers in good yields and excellent diastereo- and enantioselectivities.

Enantioselective organocatalytic asymmetric allylic alkylation. Bis(phenylsulfonyl)methane addition to MBH carbonates.

The highly enantioselective asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates with bis(phenylsulfonyl)methane is presented. The reaction is simply catalyzed by cinchona alkaloid derivatives affording the final alkylated products in good yields and enantioselectivities.

Asymmetric organocatalytic rearrangement reactions.

Rearrangement reactions often lead to the regio- and stereoselective formation of carbon-carbon or carbon-heteroatom bonds, and allow the construction of otherwise hard-to-access molecular frameworks. Research disclosed in the present decade, especially in the last two years, has shown that organocatalytic modes of activation can be successfully applied to a variety of rearrangements. In this Minireview we discuss the advances achieved so far in asymmetric organocatalytic rearrangement reactions.

Enantioselective organocatalytic addition of oxazolones to 1,1-bis(phenylsulfonyl)ethylene: a convenient asymmetric synthesis of quaternary alpha-amino acids.

A new, easy, and highly enantioselective method for the synthesis of quaternary alpha-alkyl-alpha-amino acids based on organocatalysis is reported. The addition of oxazolones to 1,1-bis(phenylsulfonyl)ethylene is efficiently catalyzed by simple chiral bases or thioureas. The reaction affords alpha,alpha-disubstituted alpha-amino acid derivatives with complete C4 regioselectivity and with excellent yields and enantioselectivities. This methodology is complementary to previously reported enantioselective approaches to quaternary alpha-amino acids and allows the synthesis of alpha-phenyl-alpha-alkyl-alpha-amino acids and alpha-tert-butyl-alpha-alkyl-alpha-amino acids. It has distinct advantages in terms of operational simplicity, enviromentally friendly conditions, and suitability for large-scale reactions.

Enantioselective organocatalytic addition of azlactones to maleimides: a highly stereocontrolled entry to 2,2-disubstituted-2H-oxazol-5-ones.

The first highly diastereo- and enantioselective organocatalytic synthesis of 2,2-disubstituted-2H-oxazol-5-ones is described. The addition of oxazolones to maleimides is promoted by bifunctional thiourea catalysts, which afford the corresponding 2,2-disubstituted-2H-oxazol-5-ones with total regio- and stereocontrol.