Elisabetta Massolo

Stereoselective organocatalysed reactions in deep eutectic solvents: highly tunable and biorenewable reaction media for sustainable organic synthesis

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.

Organocatalytic strategies for enantioselective metal-free reductions

One of the most important chemical transformations is the reduction of multiple bonds, carbon–carbon as well as carbon–heteroatom double bonds, since it leads very often to the generation of new stereocenters in the molecule. The replacement of metal-based catalysts with equally efficient metal-free counterparts is very appealing in view of possible future applications of non toxic, low cost, and environmentally friendly promoters on an industrial scale. This perspective will focus specially, but not exclusively, on the enantioselective reduction of the carbon nitrogen double bond; despite the historical need for and continued interest in chiral amines, their synthesis remains challenging. Three metal-free catalytic methodologies available for the reduction of carbon–nitrogen double bond will be discussed: i) binaphthol-derived phosphoric acids catalyzed reductions, with dihydropyridine-based compound as the reducing agent; ii) trichlorosilane mediated reductions, in the presence of catalytic amounts of chiral Lewis bases; iii) metal-free hydrogenation of imines through FLP (Frustrated Lewis Pair) methodology, that involves the use of a combination of a strong Lewis acid with a variety of sterically encumbered Lewis bases, for examples phosphines or tertiary amines, to activate hydrogen at ambient conditions. Special attention will be devoted to the most recent applications of the last five years.

Towards the development of continuous, organocatalytic, and stereoselective reactions in deep eutectic solvents

Different deep eutectic solvent (DES) mixtures were studied as reaction media for the continuous synthesis of enantiomerically enriched products by testing different experimental set-ups. L-Proline-catalysed cross-aldol reactions were efficiently performed in continuo, with high yield (99%), anti-stereoselectivity, and enantioselectivity (up to 97% ee). Moreover, using two different DES mixtures, the diastereoselectivity of the process could be tuned, thereby leading to the formation, under different experimental conditions, to both the syn- and the anti-isomer with very high enantioselectivity. The excess of cyclohexanone was recovered and reused, and the reaction could be run and the product isolated without the use of any organic solvent by a proper choice of DES components. The dramatic influence of the reaction media on the reaction rate and stereoselectivity of the process suggests that the intimate architecture of DESs deeply influences the reactivity of different species involved in the catalytic cycle.

Enantioselective Organocatalytic Reduction of β‐Trifluoromethyl Nitroalkenes: An Efficient Strategy for the Synthesis of Chiral β‐Trifluoromethyl Amines

An efficient organocatalytic stereoselective reduction of β-trifluoromethyl-substituted nitroalkenes, mediated by 3,5-dicarboxylic ester-dihydropyridines (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-state (TS) analysis, a model of stereoselection was also proposed.

A New Class of Low-Loading Catalysts for Highly Enantioselective, Metal-Free Imine Reduction of Wide General Applicability

A new class of chiral Lewis bases for the enantioselective HSiCl3‐mediated reduction of imines was developed. Through extensive catalyst structure optimization, an extremely active species was identified that was able to promote the reduction of a large variety of functionalized substrates in high yields with enantioselectivities typically above 90 % with catalyst loadings as low as 0.1–1 mol %. The simple experimental procedure, the low cost of the reagents, the mild reaction conditions, and the straightforward isolation of the product make the methodology attractive for large‐scale applications. Its synthetic potentiality was demonstrated by the preparation of advanced intermediates of important active pharmaceutical ingredients used in the treatment of Alzheimers and Parkinsons diseases, hyperparathyroidism, neuropathic pains, and neurological disorders. The reaction was also successfully performed in flow reactors, which thus demonstrated the possibility to realize in continuo processes to yield multigram quantities of product.

Phosphazene-catalyzed desymmetrization of cyclohexadienones by dithiane addition

We report a desymmetrization of cyclohexadienones by intramolecular conjugate addition of a tethered dithiane nucleophile. Mild reaction conditions allow the formation of diversely functionalized fused bicyclic lactones. The products participate in facially selective additions from the convex surface, leading to allylic alcohol derivatives.