Andrea Gualandi

Pyrrole macrocyclic ligands for Cu-catalyzed asymmetric Henry reactions.

New chiral perazamacrocycles containing four pyrrole rings have been synthesized by the [2+2] condensation of (R,R)-diaminocyclohexane and 5,5-(alkane-2,2-diyl)bis(1H-pyrrole-2-carbaldehydes). These macrocycles, differing for the alkyl/aryl meso-substituents, were used as ligands in the copper-catalyzed Henry reactions of aromatic and aliphatic aldehydes with nitroalkanes. In the optimized experimental conditions, the condensations of nitromethane and aromatic and aliphatic aldehydes in the presence of catalytic amounts of copper diacetate and methyl-substituted macrocyclic ligand (2:1 ratio) in ethanol at room temperature provided products often with high enantiomeric excesses (up to 95% ee). The positive influence of the macrocyclic structure on the efficiency/enantioselectivity of the catalytic system was demonstrated by comparison with the outcomes of Henry reactions performed using analogous macrocyclic ligands (trianglamines) and open-chain ligands derived from (R,R)-diaminocyclohexane.

C-hexaphenyl-substituted trianglamine as a chiral solvating agent for carboxylic acids

Chiral hexaazamacrocycles with a trianglamine structure and C(3)-symmetry, containing six ring substituents and twelve stereocenters have been tested as chiral solvating agents (CSAs) for α-substituted carboxylic acids. Excellent results have been obtained with a hexaphenyl-substituted macrocycle. The optimal ratio between the macrocycle and racemic acid, allowing for baseline separation of the enantiomers signals in the (1)H NMR spectrum, was dependent on the type of acid, in particular on its degree of acidity. The analyte and the CSA could be separated and recovered by a simple acid-base extraction and reused without purification. The conformations of the free and protonated hexaamino macrocycles were inferred by CD spectroscopic studies and DFT calculations.

Creating Chemical Diversity in Indole Compounds by Merging Au and Ru Catalysis

Sequential dual‐metal catalyzed reactions are successfully applied to create chemical diversity in indole polycyclic alkaloids. Gold‐catalyzed intramolecular allylic alkylation of indoles with alcohols, followed by Ru‐assisted ring‐closing metathesis opens up access to a large variety of functionalized tetrahydrocarbazoles and tetrahydro‐β‐carbolines in a straightforward manner. The gold‐catalyzed alkylation allows complex molecular architectures to be realized in a highly regio‐ and stereocontrolled manner.

Catalytic hydrogenation of meso-octamethylporphyrinogen (calix[4]pyrrole).

Hydrogenation of meso-octamethylporphyrinogen (calix[4]pyrrole) with a number of heterogeneous catalysts under different experimental conditions has been investigated. GC-MS analyses of the reaction mixtures showed the formation of one to four products in low to moderate yields: three of them were diastereoisomers of the product derived from half-hydrogenation of the substrate, and displayed alternating pyrrolidine and pyrrole rings, while the fourth was the all-cis saturated product. An acidic medium was necessary to achieve hydrogenation. However, the use of too strongly acidic solvents or additives was detrimental to the stability of the substrate and/or the catalyst.

Organocatalytic Stereoselective α-Formylation of Ketones

Organocatalytic stereoselective a-alkylation of the carbonyl moiety represents a difficult and challenging transformation. An interesting solution for this goal was presented by Jacobsen, Trost, Hartwig, Stoltz, and Braun. These authors have introduced valuable chiral technologies for the enantioselective alkylation of metal enolates. Despite the fact that brilliant solutions have been introduced for the stereoselective alkylation of aldehydes, the enantioselective catalytic a-alkylation of simple ketones still remains a fundamental problem in chemical synthesis. Recently, MacMillan was able to translate the catalytic principle of singly occupied molecular orbital (SOMO) activation into ketonic systems, providing an unprecedented direct and enantioselective a-alkylation of ketones. Very recently another quite interesting approach based on Brønsted acid catalysis was reported. The lacking of methodologies for the stereoselective alkylation of ketones is connected to the different steric and electronic properties with respect to catalyst interactions. Particularly in organocatalysis the activation modes (enamine catalysis, iminium catalysis, SOMO catalysis) between these carbonyl subclasses is often difficult (if not achievable in many cases). Recently, we have presented a general methodology for the a-alkylation of aldehydes. Our system is based on the easy reaction of enamine in SN1-type reactions (Scheme 1). [15] In particular, we have discovered that the commercially available benzodithiolylium tetrafluoborate easily reacts with enamine formed in situ in the presence of the MacMillan catalyst. The procedure is quite versatile and useful for the synthesis of natural products. We wanted to extend our alkylation procedure using ketones as substrates. Therefore we set up a model reaction using cyclohexanone and benzodithiolylium as prototypical substrates (Scheme 1), in the presence of several organocatalysts (Table S1, see the Supporting Information, SI), including primary and secondary amines. Tryptophan was selected for further optimization. Many different tryptophan derivatives were investigated in the reaction (Table S2, see SI), but the enantiomeric excesses were not improved. Unfortunately, after these encouraging preliminary results (Scheme 1) we found that the conditions were not quite reproducible and the reaction was very capricious, particularly when other ketones were used. The enantiomeric excesses measured varied from reaction to reaction. The major problem encountered was the quite fast background reaction. In fact, the reaction between cyclohexanone and benzodithiolylium occurred without an organocatalyst and was probably driven by traces of acids liberated during the process that are able to promote the formation of the corresponding enol of the ketone. The difficulties and the lack of reproducibility hampered the optimization of the process promoted by tryptophan. We reasoned that other heterocyclic substrates, such as benzoimidazolium or benzothiazolium, bearing a stabilized cationic charge, could be used in the stereoselective formylation of ketones with enamines. In fact 3-methylbenzothiazoline hydrolysis has been reported to be accomplished in mild conditions by AgNO3 in aqueous acetonitrile-phosphate buffer (0.05 m, pH 7) and the use of benzothiazole as a formyl equivalent has been previously investigated in literature. To test this hypothesis, we have prepared the substrates indicated in the Figure 1 and subjected them to a model reaction with cyclopentanone in the presence of different organocatalysts.