New chiral thiols and C2-symmetrical disulfides of Cinchona alkaloids: ligands for the asymmetric Henry reaction catalyzed by CuII complexes (original) (raw)
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Novel chiral thiolated amino alcohols were synthesized from norephedrine and thiophene carbaldehydes (methyl-or ethyl-substituted) and applied to the catalytic asymmetric Henry reaction of various aldehydes with nitromethane to provide b-hydroxy nitroalkanols in high conversion (92%). The reaction was optimized in terms of the metal, solvent, temperature and amount of chiral ligand. The corresponding catalyst with Cu(OTf) 2 and 2-propanol as the solvent provided the best enantioselectivities (up to 96% ee) of the corresponding nitroalcohols for aliphatic aldehydes.
Enantioselective Henry reaction catalyzed by copper(II)—Cinchona alkaloid complexes
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A complex derived from the enantiomeric bipiperidine and copper(II) acetate hydrate is an efficient catalyst for the enantioselective Henry reaction. The easy availability of both catalyst components, mild reaction conditions, high yield, and good to excellent enantioselectivity make the catalyst useful for everyday practice.
Catalysts, 2021
Novel chiral thiophene-2,5-bis(β-amino alcohol) ligands (L1–L5) were designed and synthesized from thiophene-2,5-dicarbaldehyde (3) with chiral β-amino alcohols (4a–e) in 4 steps with overall 23% yields. An in situ generated L-Cu(OAc)2·H2O catalyst system was found to be highly capable catalyst for the asymmetric Henry reaction of nitromethane (7) with various substituted aromatic aldehydes (6a–m) producing chiral nitroaldols product (8a–m) with excellent enantiomeric purity (up to 94.6% ee) and up to >99% chemical yields. 20 mol% of L4-Cu(OAc)2 catalyst complex in EtOH was effective for the asymmetric Henry transformation in 24 h, at ambient temperature. Ease of ligand synthesis, use of green solvent, base free reaction, mild reaction conditions, high yields and excellent enantioselectivity are all key factors that make this catalytic system robust and highly desirable for the access of versatile building block β-nitro alcohol in practical catalytic usage via asymmetric Henry re...
Cinchona alkaloids and BINOL derivatives as privileged catalysts or ligands in asymmetric synthesis
2014
During the last fifteen years organocatalysis emerged as a powerful tool for the enantioselective functionalization of the most different organic molecules. Both CC and Cheteroatom bonds can be formed in an enantioselective fashion using many types of catalyst and the field is always growing. Many kind of chiral catalysts have emerged as privileged, but among them Proline, cinchona alkaloids, BINOL, and their derivatives showed to be particularly useful chiral scaffolds. This thesis, after a short presentation of many organocatalysts and activation modes, focuses mainly on cinchona alkaloid derived primary amines and BINOL derived chiral Brønsted acids, describing their properties and applications. Then, in the experimental part these compounds are used for the catalysis of new transformations. The enantioselective Friedel-Crafts alkylation of cyclic enones with naphthols using cinchona alkaloid derived primary amines as catalysts is presented and discussed. The results of this work were very good and this resulted also in a publication. The same catalysts are then used to accomplish the enantioselective addition of indoles to cyclic enones. Many catalysts in combination with many acids as co-catalysts were tried and the reaction was fully studied. Selective N-alkylation was obtained in many cases, in combination with quite good to good enantioselectivities. Also other kind of catalysis were tried for this reaction, and considered all, the results obtained are interesting. Another aza-Michael reaction between OH-free hydroxylamines and nitrostyrene using cinchona alkaloid derived thioureas is briefly discussed. Then our attention focused on Brønsted acid catalyzed transformations. With this regard, the Prins cyclization, a reaction never accomplished in an enantioselective fashion up to date, is presented and developed. The results obtained are promising. In the last part of this thesis the work carried out abroad is presented. In Prof. Rueping laboratories, an enantioselective Nazarov cyclization using cooperative catalysis and the enantioselective desymmetrization of meso-hydrobenzoin catalyzed by Brønsted acid were studied.
Topics in Catalysis, 2008
The physico-chemical properties of cinchona alkaloids have been characterized in connection to their use for catalytic enantioselective conversions. Adding to the previous identification of their active site at the nitrogen atom in the quinuclidine ring and the chiral environment provided by the carbon centers of the neighboring alcohol linker, an argument is made here for the importance of the adoption of certain rotational conformations by those cinchona alkaloids in optimizing their chiral promotion. Because catalysis with cinchona alkaloids involves a liquid phase, there is a dynamic conformation isomerization process controlled by a number of factors having to do with the exact structure of the cinchona as well as with the nature of the solvent used and, in the case of heterogeneous catalysis, the presence of a solid surface. Solvents of intermediate polarity have been found to be the best for dissolving the cinchona, for establishing F. Zaera, The Physico-Chemical Properties of Cinchona Alkaloids Responsible for their Unique...-2-rapid adsorption equilibria with metal surfaces, and for promoting chiral catalysis. Protonation also leads to a dramatic change in performance, locking the cinchona molecule in a specific conformation held in place by the counter anion of the acid used, and modifying the chemical and biological activity of the system. Comparative studies with several cinchona indicate that molecular groups attached to peripheral positions also exert a great influence on the conformational and adsorption behavior of these molecules.
Cu (II)-catalyzed asymmetric henry reaction with a novel C1-symmetric aminopinane-derived ligand
Molecules (Basel, Switzerland), 2015
A novel C1-symmetric dinitrogen ligand was synthesized in high yield from commercially available (1R,2R,3R,5S)-(-)-isopinocampheylamine and 1-methyl-2-imidazolecarboxaldehyde. In combination with Cu(OAc)2H2O, this new ligand promote the reaction between nitromethane and aliphatic aldehydes with high yields (up to 97%) and moderate enantioselectivities (up to 67% ee). The reactions with benzaldehyde required prolonged reaction time that resulted in diminished yields, but accompanied with ee-values in the 55%-76% range.
Inorganic Chemistry, 2019
Chiral copper(II) and cobalt(III) complexes (1−5 and 6, respectively) derived from Schiff bases of (S)-2-(aminomethyl)pyrrolidine and salicylaldehyde derivatives were employed in a mechanistic study of the Henry reaction-type condensation of nitromethane and o-nitrobenzaldehyde in CH 2 Cl 2 (CD 2 Cl 2), containing different amounts of water. The reaction kinetics was monitored by 1 H and 13 C NMR. The addition of water had a different influence on the activity of the two types of complexes, ranging from a crucial positive effect in the case of the copper(II) complex 2 to insignificant in the case of the stereochemically inert cobalt(III) complex 6. No experimental support was found by 1 H NMR studies for the classical Lewis acid complexation of the carbonyl group of the aldehyde by the central copper(II) ion, and, moreover, density functional theory (DFT) calculations support the absence of such coordination. On the other hand, a very significant complexation was found for water, and it was supported by DFT calculations. In fact, we suggest that it is the Brønsted acidity of the water molecule coordinated to the metal ion that triggers the aldehyde activation. The rate-limiting step of the reaction was the removal of an α-proton from the nitromethane molecule, as supported by the observed kinetic isotope effect equaling 6.3 in the case of the copper complex 2. It was found by high-resolution mass spectrometry with electrospray ionization that the copper(II) complex 2 existed in CH 2 Cl 2 in a dimeric form. The reaction had a second-order dependence on the catalyst concentration, which implicated two dimeric forms of the copper(II) complex 2 in the rate-limiting step. Furthermore, DFT calculations help to generate a plausible structure of the stereodetermining transition step of the condensation.
Cinchona Alkaloids and Their Derivatives: Versatile Catalysts and Ligands in Asymmetric Synthesis
Synthesis, 2001
Cinchona alkaloids and their derivatives can catalyze an amazing array of synthetically important reactions, providing access to chiral products of high enantiopurity. A review of such asymmetric reactions, comprising the work reported in the last two decades, is presented here. Cinchona alkaloids-derived catalysts and ligands, either in monomeric form or attached to a polymeric support, are included in this review.