Novel synthetic methodologies

Iron catalyzed diastereoselective hydrogenation of chiral imines.
D. Brenna, S. Rossi, F. Cozzi, M. Benaglia Org. Biomol. Chem, 2017, 15, 5685-5688. [Link]
Abstract:Cyclopentadienone-based iron complexes were used for the first time to successfully catalyze the diastereoselective hydrogenation of enantiopure imines. Chiral amines, including valuable biologically active products, were obtained often as enantiomerically pure compounds. Computational studies helped to elucidate the chemical and stereochemical aspects of the iron-catalyzed reaction.

Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane.
R. Porta, A. Puglisi, G. Colombo, S. Rossi, M. Benaglia Beilstein J. Org. Chem, 2016, 12, 26142619. [Link]
Abstract:The metal-free reduction of nitro compounds to amines mediated by trichlorosilane was successfully performed for the first time under continuous flow conditions. Aromatic as well as aliphatic nitro derivatives were converted to the corresponding primary amines in high yields and very short reaction times with no need for purification. The methodology was also extended to the synthesis of two synthetically relevant intermediates (precursors of Baclofen and Boscalid).

2-Carboxythioester-1,3-dithiane: a Functionalized Masked Carbonyl Nucleophile for the Organocatalytic Enantioselective Michael Addition to Enones
E. Massolo, D. Brenna, F. Cozzi, L. Raimondi, N. Gaggero M. Benaglia Synlett, 2016, accepted [Link]
Abstract:A S-(2,2,2-trifluoroethyl) 1,3-dithiane-2-carbothioate has been successfully employed as acyl anion synthon in the organocatalytic enantioselective addition to enones promoted by quinine- and quinidine-derived tertiary/primary diamines. By proper selection of a co-catalyst and by optimization of the reaction parameters, convenient experimental conditions were found, that allowed to obtain the highly functionalized products in up to 90% yield and 98% ee in short reaction times. These compounds, featuring selectively removable functionalities, proved to be versatile synthetic intermediates, which could be transformed into different derivatives without any erosion of the stereochemical integrity of the molecules

HSiCl3-mediated Reduction of Nitro-derivatives to Amines: Is Tertiary amine-stabilized SiCl2 the Actual Reducing Species?
M. Orlandi, M. Benaglia, F. Tosi, R. Annunziata, F. Cozzi J Org chem, 2016, [Link]
Abstract: The mechanism of a recently reported, highly chemoselective metal-free protocol of wide general applicability for the reduction of aromatic and aliphatic nitro-derivatives to amines has been investigated. The reaction is supposed to occur through the generation of a Si(II) reducing species; quantum mechanical calculations, spectroscopic and experimental data strongly suggest the tertiary amine-stabilized dichlorosilylene to be the most probable reducing agent.

Metal-Free Reduction of Aromatic and Aliphatic Nitro Compounds to Amines: A HSiCl3-Mediated Reaction of Wide General Applicability
M. Orlandi, F. Tosi, M. Bonsignore, and M. Benaglia Org Lett, 2015, 17, 3941-3943 [Link]
Abstract: A new, mild, metal-free, HSiCl3-mediated reduction of both aromatic and aliphatic nitro groups to amines that is of wide general applicability, tolerant of many functional groups, and respectful of the stereochemical integrity of stereocenters is reported.

Stereoselective organocatalysed reactions in deep eutectic solvents: highly tunable and biorenewable reaction media for sustainable organic synthesis
E. Massolo, S. Palmieri, M. Benaglia, V. Capriati, F. M. Pernab Green. Chem., 2015, in press [Link]
Abstract: Three distinct stereoselective reactions, catalysed by using a chiral primary amine through different activation methods, have been successfully carried out for the first time in bio-based eutectic mixtures, thereby affording functionalised molecules in very high enantioselectivity. The use of these unconventional and biorenewable reaction media also provides opportunities for facilitating the recovery and the recycling of the chiral catalyst.

Stereoselective reaction of 2-carboxythioesters-1,3-dithiane with nitroalkenes: an organocatalytic strategy for the asymmetric addition of a glyoxylate anion equivalent.
E. Massolo, M. Benaglia, A. Genoni, R. Annunziata Org. Biomol. Chem., 2015, 13, 5591-5596 [Link]
Abstract: An efficient organocatalytic methodology has been developed to perform the stereoselective addition of 2-carboxythioesters-1,3-dithiane to nitroalkenes. Under mild reaction conditions γ-nitro-β-aryl-α-keto esters in up to 92% e.e. were obtained, realizing a formal catalytic stereoselective conjugate addition of the glyoxylate anion synthon. The reaction products are versatile starting materials for further synthetic transformations; for example, the simultaneous reduction of the nitro group and removal of the dithiane ring was accomplished, allowing the preparation of the GABAB receptor agonist baclofen.

Enantioselective organocatalytic reduction of β-trifluoromethyl nitroalkenes: an efficient strategy for the synthesis of chiral β-trifluoromethyl amines.
E. Massolo, M. Benaglia, M. Orlandi, S. Rossi, G. Celentano Chemistry, Eur. J., 2015, accepted [Link]
Abstract: An efficient organocatalytic stereoselective reduction of β--trifluoromethyl-substituted nitroalkenes, mediated by 3,5-dicarboxylic esters-dihydro pyridines (Hantzsch ester type), has been successfully developed. A multifunctional thiourea-based (S)-valine derivative was found to be the catalyst of choice, promoting the reaction in up to 97% ee. The methodology has been applied to a wide variety of substrates, leading to the formation of differently substituted precursors of enantiomerically enriched β-trifluoromethyl amines. The mechanism of the reaction and the mode of action of the metal-free catalytic species were computationally investigated; on the basis of DFT transition states (TS) analysis, a model of stereoselection was also proposed.

Synthesis of highly decorated chiral 2-nitro-cyclohexane carboxylic esters through microwave-assisted organocatalyzed cascade reactions.
E. Massolo, M. Benaglia, D. Parravicini, D. Brenna, R. Annunziata Tetrahedron Letters , 2014, 55, 6639-6642 [Link]
Abstract: Starting from (E)-β-substituted-β-nitroacrylates and α,β-unsaturated ketones, a stereoselective organocatalyzed one-pot methodology allowed to synthesize highly decorated chiral 2-nitro-cyclohexane carboxylic esters. The reaction is promoted by Cinchona alkaloids-derived primary amines in the presence of an acidic co-catalyst and affords two diastereoisomers, in good yields and high enantiomeric excess (often higher than 90% e.e.). By replacing conventional heating with microwave irradiation, cleaner reactions in shortened times (from 48 hours to 30 minutes) were obtained, with improved d.r. (80:20) and high e.e. (up to 94%). The application of microwave technology to this organocatalytic methodology allowed also employing C1 substituted enones, leading to cyclohexanones with four contiguous stereocenters in two isomers only, and up to 99% enantioselectivity.

Stereoselective Synthesis of Functionalized Chiral 2-Nitrocyclohexanecarboxylic Esters via Catalytic Dienamine Addition to β-Substituted β-Nitroacrylates
E. Massolo, M. Benaglia, R. Annunziata, A. Palmieri, G. Celentano, A. Forni, Adv. Synth. Catal., 2014, 356, 493-500 [Link]
Abstract: A metal-free stereoselective catalytic addition of in situ generated dienamine to β-nitroacrylates has been developed. Starting from simple α,β-unsaturated ketones, highly functionalized chiral β-nitrocyclohexanecarboxylic esters were obtained in a single step, in good yields and up to 98% ee. By an unprecedented mechanistic pathway, starting from the synthetically readily available E-nitroacrylate, the present methodology allowed us to obtain as major product the isomer bearing a cis relative disposition between the nitro and the ester groups, which is not accessible via a classical Diels-Alder reaction.

Stereoselective addition reactions to β-nitroacrylates catalyzed by chiral metal-free bifunctional catalysts.
E. Massolo, M. Benaglia, A. Palmieri, and G. Celentano, Asian J. Org. Chem, 2014, 3, 416-420 [Link]
Abstract: Organocatalytic stereoselective addition of different nucleophiles to β-nitroacrylates have been investigated. A thiourea-based cinchona-derived bifunctional catalyst promoted the addition of 1,3-diketones to differently substituted nitroacrylates in modest to fair yields and up to 93% enantioselectivity. The 1,3 dicarbonylic functionality of the addition products was then employed to synthesize enantiomerically enriched 3,4,5-trialkyl substituted pyrazoles via reaction with hydrazine. The stereoselective addition of N-methyl indole to nitro acrylate was also preliminarily studied; the Friedel-Crafts alkylation was successfully organocatalyzed in the presence of an acid additive in very good yields and up to 55% enantioselectivity.

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