Laboratory of Homogeneous Catalysis for Sustainable Synthesis

A one pot protocol to convert nitro-arenes into N-aryl amides
E. Massolo, M. Pirola, A. Puglisi, L. S. Rossi, M. Benaglia RSC Advances, 2020, 10, 4040-4044
[Link]
Abstract: A two-step one pot, experimentally simple protocol, based on readily available and inexpensive reagents allowed to convert nitro-arenes directly to N-aryl amides. A metal-free reduction of the nitro group, mediated by trichlorosilane, followed by the addition of an anhydride afforded the corresponding N-aryl carboxyamide, that was isolated after a simple aqueous work up in good-excellent yields. When the methodology was applied to the reaction with γ-butyrolactone, the desired N-aryl butanamide derivative was obtained, featuring a chlorine atom at the γ-position, a functionalized handle that can be used for further synthetic manipulation of the reaction product. Such intermediate has been already employed as key advanced precursor of pharmaceutically active compounds.

Enantioselective synthesis of 3,4-dihydropyran-2-ones via PTC addition-cyclisation of acetylacetone to cinnamic thioesters
D. Destro, C. Bottinelli, L. Ferrari, D.C.M. Albanese, G. Bencivenni, M.W. Gillick-Healy, B.G. Kelly, M.F.A. Adamo J. Org. Chem., 2020
[Link]
Abstract: Herein, we present the first example of synthesis of 3,4-dihydropyran-2-ones from cinnamic thioesters via a stereoselective phase-transfer-catalyzed domino Michael–cyclization reaction with acetylacetone. The reaction proceeded under the catalysis of Cinchona-derived quaternary ammonium phenoxide that, in combination with inorganic bases, provided 3,4-dihydropyran-2-ones in yields of up to 93% and enantioselectivities of up to 88% enantiomeric excess.

Synthesis of Ribavirin, Tecadenoson, and Cladribine by Enzymatic Transglycosylation
M. Rabuffetti, T.Bavaro, R. Semproli, G. Cattaneo, M. Massone, C.F. Morelli, G. Speranza, D. Ubiali Catalysts, 2019, 9 335 [Link]
Abstract: Despite the impressive progress in nucleoside chemistry to date, the synthesis of nucleoside analogues is still a challenge. Chemoenzymatic synthesis has been proven to overcome most of the constraints of conventional nucleoside chemistry. A purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP) has been used herein to catalyze the synthesis of Ribavirin, Tecadenoson, and Cladribine, by a “one-pot, one-enzyme” transglycosylation, which is the transfer of the carbohydrate moiety from a nucleoside donor to a heterocyclic base. As the sugar donor, 7-methylguanosine iodide and its 20-deoxy counterpart were synthesized and incubated either with the “purine-like” base or the modified purine of the three selected APIs. Good conversions (49–67%) were achieved in all cases under screening conditions. Following this synthetic scheme, 7-methylguanine arabinoside iodide was also prepared with the purpose to synthesize the antiviral Vidarabine by a novel approach. However, in this case, neither the phosphorolysis of the sugar donor, nor the transglycosylation reaction were observed. This study was enlarged to two other ribonucleosides structurally related to Ribavirin and Tecadenoson, namely, Acadesine, or AICAR, and 2-chloro-N6-cyclopentyladenosine, or CCPA. Only the formation of CCPA was observed (52%). This study paves the way for the development of a new synthesis of the target APIs at a preparative scale. Furthermore, the screening herein reported contributes to the collection of new data about the specific substrate requirements of AhPNP.

Effect of the Inserted Active-site-covering Lid Loop on the Catalytic Activity of a Mutant B. Subtilis γ-Glutamyltransferase (GGT)
M. Massone, C. Calvio, M. Rabuffetti, G. Speranza, C.F. Morelli RSC Adv., 2019, 9 34699 [Link]
Abstract: γ-Glutamylpeptides are compounds derived from the acylation of an amino acid or a short peptide by the γ-carboxyl carbon of the side chain of glutamic acid. Due to their altered chemico-physical and organoleptic properties, they may be interesting substitutes or precursors of parent compounds used in pharmaceutical, dietetic and cosmetic formulations. Some of them are naturally occurring flavor enhancers or are endowed with biological activities. Enzymatic approaches to the synthesis of γ-glutamyl derivatives based on the use of γ-glutamyltransferases (GGTs, EC 2.3.2.2) have been proposed, which should be able to alleviate the problems connected with the troublesome and low-yielding extraction from natural sources or the non-economical chemical synthesis, which requires protection/ deprotection steps. With the aim of overcoming the current limitations in the use of GGTs as biocatalysts, a mutant GGT was investigated. The mutant GGT was obtained by inserting the active-sitecovering lid loop of the E. coli GGT onto the structure of B. subtilis GGT. With respect to the wild-type enzyme, the mutant showed a more demanding substrate specificity and a low hydrolase activity. These results represent an attempt to correlate the structural features of a GGT to its different activities. However, the ability of the mutant enzyme to catalyze the subsequent addition of several γ-glutamyl units, inherited by the parent B. subtilis GGT, still represents a limitation to its full application as a biocatalyst for preparative purposes.

TetraPh-Tol-BITIOPO: a new atropisomeric 3,3’-bithiophene based phosphine oxide as an organocatalyst in Lewis base-catalyzed Lewis acid mediated reactions
V. M. Abbinante, M. Benaglia, S. Rossi; T. Benincori, R. Cirili, M. Pierini Org Biomol Chem, 2019, 17, 7474-7481.[Link]
Abstract: A new chiral phosphine oxide based on a 3,3’-bithiophene scaffold (TetraPh-Tol-BITIOPO) was synthesized, fully characterized and separated into antipodes through chiral HPLC. This new compound was successfully employed as an organocatalyst in Lewis base-catalyzed Lewis acid mediated reactions involving trichlorosilyl compounds. The new atropisomeric catalyst was able to promote the allylation of aldehydes with allyltrichlorosilane in up to 98% yield and up to 96% enantiomeric excess (ee), and the direct aldol reaction to afford β-hydroxy ketones and β-hydroxy thioesters, with good chemical yields and modest stereochemical efficiency. Computational studies helped to elucidate and to rationalize the stereochemical outcome of the reactions catalyzed by TetraPh-Tol-BITIOPO that was found to favour the formation of the isomer with an opposite absolute configuration in comparison with the products obtained with the previously reported 3,3’-bithiophene-based catalyst.

Evidences on the Role of the Lid Loop of γ-glutamyltransferases (GGT) in Substrate Selection,
C. Calvio, F. Romagnuolo, F. Vulcano, G. Speranza, C.F. Morelli Enz. Microb. Technol. , 2018, 114 55-62 [Link]
Abstract: γ-Glutamyltransferase (GGT) catalyzes the transfer of the γ-glutamyl moiety from a donor substrate such as glutathione to water (hydrolysis) or to an acceptor amino acid (transpeptidation) through the formation of a γ-glutamyl enzyme intermediate. The vast majority of the known GGTs has a short sequence covering the glutamate binding site, called lidloop. Although being conserved enzymes, both B. subtilis GGT and the related enzyme CapD from B. anthracis lack the lid loop and, differently from other GGTs , both accept poly-γ-glutamic acid (γ-PGA) as a substrate. Starting from this observation, in this work the activity of an engineered mutant enzyme containing the amino acid sequence of the lid loop from E. coli GGT inserted into the backbone of B. subtilis GGT was compared to that of the lid loop-deficient B. subtilis GGT and the lid loop-carrier E. coli GGT. Results indicate that the absence of the lid loop seems not to be the sole structural feature responsible for the recognition of a polymeric substrate by GGTs. Nevertheless, time course of hydrolysis reactions carried out using oligo-γ-glutamyl glutamines as substrates showed that the lid loop acts as a gating structure, allowing the preferential selection of the small glutamine with respect to the oligomeric substrates. In this respect, the mutant B. subtilis GGT revealed to be more similar to E. coli GGT than to its wild-type counterpart. In addition, the transpeptidase activity of the newly produced mutant enzyme revealed to be higher with respect to that of both E. coli and wild-type B. subtilis GGT. These findings can be helpful in selecting GGTs intended as biocatalysts for preparative purposes as well as in designing mutant enzymes with improved transpeptidase activity.

A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of Rasagiline and Tamsulosin.
D. Brenna, M. Pirola, L. Raimondi, A. J. Burke, M. Benaglia Bioorg. Med. Chem, 2017, doi:10.1016/j.bmc.2017.01.023 [Link]
Abstract: The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of Rasagiline and Tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds.

A new class of low-loading catalysts for a highly enantioselective, metal-free imine reduction of wide general applicability
D. Brenna, R. Porta, E. Massolo, L. Raimondi, M. Benaglia ChemCatChem, 2017, 9, 941-945. [Link]
Abstract: A new class of chiral Lewis bases for the enantioselective HSiCl3-mediated reduction of imines has been developed. Through an extensive catalyst structure optimization, an extremely active species was identified, able to promote the reduction of a large variety of functionalized substrates in high yields and enantioselectivities typically above 90% with catalyst loading as low as 0.1-1% mol. The simple experimental procedure, the low cost of the reagents, the mild reaction conditions, and straightforward isolation of the product, make the methodology attractive also for large scale applications. Its synthetic potentiality was demonstrated by the preparation of advanced intermediates of important APIs, used in the treatment of Alzheimer and Parkinson diseases, hyperparathyroidism, neuropathic pains and neurological disorders.The reaction has also been successfully performed in flow reactors, thus demonstrating the possibility to realize in continuo processes yielding multigram quantities of product

Regioselective O-Sulfonylation of N,N-Bis(2-hydroxyalkyl)tosylamides as a Synthetic Key Step to Enantiopure Morpholines
F. Foschi, D. Albanese, I. Pecnikaj, A. Tagliabue, M. Penso Org. Lett., 2017, 19, 70-73. [Link]
Abstract: The synthesis of enantiopure 2,6-disubstituted morpholines was realized through sequential ring opening of two different optically pure oxiranes by a tosylamide, under solid–liquid phase-transfer catalysis (SL-PTC) conditions, mono-O-sulfonylation of the resulting tosylamido-2,2′-diol, and cyclization to the morpholine. The crucial step, the regioselective formation of the monosulfonate, was controlled by taking advantage of the different stereo, electronic, and coordination properties of the oxirane-derived side chains in the diol backbone. As an application of this protocol, a new morpholine-3-carboxamide was synthesized starting from threonine.

Solventless Synthesis of Quaterphenyls and Terphenyls from Chalcones and Allylsulfones under Phase Transfer Catalysis Conditions
D. C. M. Albanese, S. Brunialti D. Destro Catalysts, 2016, 9, 142. [Link]
Abstract: Easily available chalcones and allyl sulfones along with cheap solid NaOH and polyethyleneglycol (PEG) 1000 have been used to directly generate the meta-terphenyl or quaterphenyl motifs under Phase Transfer Catalysis solventless conditions. The new approach provides an economic and environmentally friendly solution to removal of hazardous bases as well as organic solvents.

Kinetics versus thermodynamics in the proline catalyzed aldol reaction
M. Orlandi, M. Benaglia, M. Ceotto Chem. Sci., 2016 [Link]
Abstract: In this paper the equilibrium properties of the proline catalyzed aldol reaction was studied. The use of well-established methodologies, like reaction progress kinetic analysis and linear free energy relationship analysis, led to the quantification of the reaction reversibility and to its correlation with the substrate electronic activation. Due to these experimental observations, common computational approaches based on a one way transition state analysis become unsuitable. Therefore, a computational model based on the integration of a system of kinetic differential equations associated to the multiple equilibrium reactions was proposed. Such a model was found to successfully rationalize the chemical and stereochemical outcomes of this paradigmatic reaction for the first time.

Phosphine Oxide Catalyzed, Tetrachlorosilane-Mediated Enantioselective Direct Aldol Reactions of Thioesters
S. Rossi, R. Annunziata, F. Cozzi, L. Raimondi, Synthesis, 2015, [Link]
Abstract: The stereoselective direct aldol reaction of S-phenyl thioesters and aromatic aldehydes promoted by tetrachlorosilane was realized for the first time; the proposed mechanism involves the formation of a chiral cationic hypervalent silicon species and requires the presence of catalytic amounts of a Lewis base, like a chiral phosphine oxide. The reaction affords syn ß­hydroxy thioesters as major isomers in good yields, high diastereoselectivity (up to 99:1), and up to 92% enantiomeric excess. The absolute configuration of the major isomer was established by converting the product into the corresponding ß­hydroxy ester. The scope of the reaction was also investigated by employing differently substituted thioesters in combination with different aromatic aldehydes.