Alessandra Puglisi

Poly(Ethylene Glycol)-Supported Proline: A Versatile Catalyst for the Enantioselective Aldol and Iminoaldol Reactions

(2S,4R)-4-Hydroxyproline has been anchored to the monomethyl ether of poly(ethylene glycol), MW 5000, by means of a succinate spacer to afford a soluble, polymer-supported catalyst (PEG-Pro) for enantioselective aldol and iminoaldol condensation reactions. This organic catalyst can be considered as a minimalistic version of a type I aldolase enzyme, with the polymer chain replacing the enzymes peptide backbone, and the proline residue acting as the enzymes active site. In the presence of PEG-Pro (0.25–0.35 mol equiv.), acetone reacted with enolizable and non-enolizable aldehydes and imines to afford β-ketols and β-aminoketones in good yield and high enantiomeric excess (ee), comparable to those obtained using non-supported proline derivatives as the catalysts. Extension of the PEG-Pro-promoted condensation to hydroxyacetone as the aldol donor opened an access to synthetically relevant anti-α,β-dihydroxyketones and syn-α-hydroxy-β-aminoketones, that were obtained in moderate to good yields, and good to high diastereo- and enantioselectivity. Exploiting its solubility properties, the PEG-Pro catalyst was easily recovered and recycled to promote all of the above-mentioned reactions, that occurred in slowly diminishing yields but virtually unchanged ees.

Stereoselective organic reactions promoted by immobilized chiral catalysts in continuous flow systems

The immobilization of the catalyst on a support with the aim of facilitating the separation of the product from the catalyst, and thus the recovery and recycling of the latter, can be regarded as an important improvement for a catalytic process. However, a system where a catalyst must not be removed from the reaction vessel is even more attractive: in continuous flow methods the immobilized catalyst permanently resides in the reactor where it transforms the entering starting materials into the desired products. The retention of the catalytic species inside the reaction vessel can be achieved by different techniques ranging from ultrafiltration through a MW-selective membrane to immobilization on different supports. In this review we will discuss the most significant examples of stereoselective reactions promoted by immobilized chiral catalysts and performed under continuous flow conditions, with particular attention to the more recent contributions of the last few years.

Poly(ethylene glycol)‐Supported Chiral Imidazolidin‐4‐one: An Efficient Organic Catalyst for the Enantioselective Diels–Alder Cycloaddition

A tyrosine-derived imidazolidin-4-one was immobilized on a modified poly(ethylene glycol) and converted in situ into a soluble polymer-supported catalyst for the enantioselective Diels–Alder cycloaddition of acrolein to 1,3-cyclohexadiene (up to 92% ee) and 2,3-dimethyl-1,3-butadiene (73% ee). Catalyst recycling (up to four cycles) was accompanied by some loss of the chemical efficiency and marginal erosion of the enantioselectivity.

A chiral organocatalytic polymer-based monolithic reactor

Radical copolymerisation of divinylbenzene and a properly modified enantiomerically pure imidazolidinone inside a stainless steel column in the presence of dodecanol and toluene as porogens afforded the first example of a chiral organocatalyst immobilized onto a monolithic reactor. Organocatalyzed cycloadditions between cyclopentadiene and cinnamic aldehyde were performed under continuous-flow conditions; by optimizing the experimental set up, excellent enantioselectivities (90% ee at 25 °C) and high productivities (higher than 330) were obtained, thus showing that a catalytic reactor may work efficiently to continuously produce enantiomerically enriched compounds. The same catalytic reactor was also employed to carry out three different stereoselective transformations in continuo, sequentially, inside the chiral column (Diels–Alder, 1,3-dipolar nitrone-olefin cycloaddition, and Friedel–Crafts alkylation); excellent results were obtained in the case of the former two reactions (up to 99% yield, 93% ee and 71% yield, 90% ee, at 25 °C, respectively). In addition to simplify the product recovery, the monolithic reactor performed better than the same supported organocatalyst in a stirred flask and could be kept working continuously for more than 8 days.

Enantiomerically pure phenanthroline or bipyridine containing macrocycles: a new class of ligands for asymmetric catalysis

Abstract New enantiomerically pure phenanthroline- and bipyridine-containing macrocycles have been synthesized by combination of the coordinating unit to inexpensive and readily available chiral templates. The catalytic properties of their Cu(I) complexes have been studied in the cyclopropanation of alkenes as test reaction. A simple structural modification of the chiral cavity allowed us to successfully control the trans or cis diastereoselectivity of the reaction.

Efficient and highly stereoselective synthesis of a β-Lactam inhibitor of the serine protease prostate-specific antigen

An efficient synthesis of a beta-lactam precursor of the serine protease, prostate-specific antigen inhibitor 1 has been accomplished. The synthesis relies on two completely stereoselective reactions that allow the introduction of the stereocenters at C-3 and C-4 of the azetidinone ring in a predictable manner.

Chiral hybrid inorganic-organic materials: synthesis, characterization, and application in stereoselective organocatalytic cycloadditions.

The synthesis of chiral imidazolidinones on mesoporous silica nanoparticles, exploiting two different anchoring sites and two different linkers, is reported. Catalysts 1-4 were prepared starting from l-phenylalanine or l-tyrosine methyl esters and supporting the imidazolidinone onto silica by grafting protocols or azide-alkyne copper(I)-catalyzed cycloaddition. The four catalysts were fully characterized by solid-state NMR, N2 physisorption, SEM, and TGA in order to provide structural assessments, including an evaluation of surface areas, pore dimensions, and catalyst loading. They were used in organocatalyzed Diels-Alder cycloadditions between cyclopentadiene and different aldehydes, affording results comparable to those obtained with the nonsupported catalyst (up to 91% yield and 92% ee in the model reaction between cyclopentadiene and cinnamic aldehyde). The catalysts were recovered from the reaction mixture by simple filtration or centrifugation. The most active catalyst was recycled two times with some loss of catalytic efficiency and a small erosion of ee.

Comparison of Different Polymer‐ and Silica‐Supported 9‐Amino‐9‐deoxy‐epi‐quinines as Recyclable Organocatalysts

9‐Amino‐9‐deoxy‐epi‐quinine, properly modified by suitable linkers, was anchored on highly cross‐linked polystyrene, poly(ethylene glycol), and silica. The resulting species were characterized by NMR spectroscopy and tested as supported organocatalysts in the reaction between isobutyric aldehyde and trans‐β‐nitrostyrene. Polystyrene‐ and poly(ethylene glycol)‐supported catalysts outperformed their nonsupported counterpart affording the desired product in high yield and ee (>90 % ee). Silica‐supported catalysts proved to be less efficient in terms of both chemical yield and enantioselectivity. Polystyrene‐ and poly(ethylene glycol)‐supported 9‐amino‐9‐deoxy‐epi‐quinine were then used in the same reaction with different substrates, leading to the desired products in high yield and ee, as well as in three other reactions operating with different mechanism. An investigation of the recyclability of the polystyrene‐ and poly(ethylene glycol)‐supported systems showed that these could be recovered and recycled with no loss of stereochemical activity but with a marked erosion of chemical efficiency occurring at the fifth reaction cycle. This was ascribed to chemical degradation of the alkaloid occurring during the reaction.

A Catalytic Reactor for the Organocatalyzed Enantioselective Continuous Flow Alkylation of Aldehydes

The use of immobilized metal-free catalysts offers the unique possibility to develop sustainable processes in flow mode. The challenging intermolecular organocatalyzed enantioselective alkylation of aldehydes was performed for the first time under continuous flow conditions. By using a packed-bed reactor filled with readily available supported enantiopure imidazolidinone, different aldehydes were treated with three distinct cationic electrophiles. In the organocatalyzed α-alkylation of aldehydes with 1,3-benzodithiolylium tetrafluoroborate, excellent enantioselectivities, in some cases even better than those obtained in the flask process (up to 95% ee at 25 °C), and high productivity (more than 3800 h(-1) ) were obtained, which thus shows that a catalytic reactor may continuously produce enantiomerically enriched compounds. Treatment of the alkylated products with Raney-nickel furnished enantiomerically enriched α-methyl derivatives, key intermediates for active pharmaceutical ingredients and natural products.

Immobilization of Chiral Bifunctional Organocatalysts on Poly(methylhydrosiloxane)

Takemoto promotes: Enantiomerically pure bifunctional chiral catalysts are immobilized on poly(methylhydrosiloxane). A supported Takemoto-type catalyst promoted the diethyl malonate addition to nitrostyrene in fair to good yields and up to 83 % ee, and its recyclability is demonstrated.