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Stereocontrol in Diphenylprolinol Silyl Ether Catalyzed Michael Additions: Steric Shielding or Curtin–Hammett Scenario?

The enantioselectivity of amine-catalyzed reactions of aldehydes with electrophiles is often explained by simple steric arguments emphasizing the role of the bulky group of the catalyst that prevents the approach of the electrophile from the more hindered side. This standard steric shielding model has recently been challenged by the discovery of stable downstream intermediates, which appear to be involved in the rate-determining step of the catalytic cycle. The alternative model, referred to as the Curtin-Hammett scenario of stereocontrol, assumes that the enantioselectivity is related to the stability and reactivity of downstream intermediates. In our present computational study, we examine the two key processes of the catalytic Michael reaction between propanal and β-nitrostyrene that are relevant to the proposed stereoselectivity models, namely the C-C bond formation and the protonation steps. The free energy profiles obtained for the pathways leading to the enantiomeric products suggest that the rate- and stereodetermining steps are not identical as implied by the previous models. The stereoselectivity can be primarily controlled by C-C bond formation even though the reaction rate is dictated by the protonation step. This kinetic scheme is consistent with all observations of experimental mechanistic studies including those of mass spectrometric back reaction screening experiments, which reveal a mismatch between the stereoselectivity of the back and the forward reactions.

On the complex •OH/•O−-induced free radical chemistry of arylalkylamines with special emphasis on the contribution of the alkylamine side chain

Abstract A full account of the •OH-induced free radical chemistry of an arylalkylamine is given taking all the possible reaction pathways quantitatively into consideration. Such knowledge is indispensable when the alkylamine side chain plays a crucial role in biological activity. The fundamental reactions are investigated on the model compound N-methyl-3-phenypropylamine (MPPA), and extended to its biologically active analog, to the antidepressant fluoxetine (FLX). Pulse radiolysis techniques were applied including redox titration and transient spectral analysis supplemented with DFT calculations. The contribution of the amine moiety to the free radical-induced oxidation mechanism appeared to be appreciable. •O− was used to observe hydrogen atom abstraction events at pH 14 giving rise to the strongly reducing α-aminoalkyl radicals (∼38% of the radical yield) and to benzyl (∼4%), β-aminoalkyl (∼24%), and aminyl radicals (∼31%) of MPPA. One-electron transfer was also observed yielding aminium radicals with low efficiency (∼3%). In the •OH-induced oxidation protonated α-aminoalkyl (∼49%), β-aminoalkyl (∼27%), benzyl radicals (∼4%), and aminium radicals (∼5%) are initially generated on the side chain of MPPA at pH 6, whereas hydroxycyclohexadienyl radicals (∼15%) were also produced. These initial events are followed by complex protonation–deprotonation reactions establishing acid–base equilibria; however, these processes are limited by the transient nature of the radicals and the kinetics of the ongoing reactions. The contribution of the radicals from the side chain alkylamine substituent of FLX totals up to ∼54% of the initially available oxidant yield.

Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,β-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas

Carboxylic acids and their corresponding carboxylate anions are generally utilized as Brønsted acids/bases and oxygen nucleophiles in organic synthesis. However, a few asymmetric reactions have used carboxylic acids as electrophiles. Although chiral thioureas bearing both arylboronic acid and tertiary amine were found to promote the aza-Michael addition of BnONH2 to α,β-unsaturated carboxylic acids with moderate to good enantioselectivities, the reaction mechanism remains to be clarified. Detailed investigation of the reaction using spectroscopic analysis and kinetic studies identified tetrahedral borate complexes, comprising two carboxylate anions, as reaction intermediates. We realized a dramatic improvement in product enantioselectivity with the addition of 1 equiv of benzoic acid. In this aza-Michael reaction, the boronic acid not only activates the carboxylate ligand as a Lewis acid, together with the thiourea NH-protons, but also functions as a Brønsted base through a benzoyloxy anion to activate the nucleophile. Moreover, molecular sieves were found to play an important role in generating the ternary borate complexes, which were crucial for obtaining high enantioselectivity as demonstrated by DFT calculations. We also designed a new thiourea catalyst for the intramolecular oxa-Michael addition to suppress another catalytic pathway via a binary borate complex using steric hindrance between the catalyst and substrate. Finally, to demonstrate the synthetic versatility of both hetero-Michael additions, we used them to accomplish the asymmetric synthesis of key intermediates in pharmaceutically important molecules, including sitagliptin and α-tocopherol.

Applicability evaluation of advanced processes for elimination of neurophysiological activity of antidepressant fluoxetine

Presence of the antidepressant fluoxetine in different water bodies has raised significant concerns due to its detrimental effects on non-targeted organisms, especially on fish. When seeking for an appropriate technology able to remove fluoxetine residue from a complex water matrix, special attention needs to be paid to the elimination of the neurophysiological activity that eventually lies behind the noxious effects of the parent compound. Our aim was to probe the applicability of advanced oxidation techniques for this purpose using in situ generated free radical system based on OH-initiated peroxyl radical-mediated processes. By performing product analysis experiments along with quantum chemical calculations, the most probable reaction paths were analyzed including aromatic hydroxylation, defluorination, O-dealkylation and C-dealkylation. The candidates for neurophysiological activity were further investigated by molecular docking. The hydroxylated derivatives are well accommodated in the binding pocket of the corresponding protein, suggesting that these compounds may retain the activity of the parent compound. From a worst-case perspective, we suggest that prolonged treatment needs to be applied to further transform hydroxylated derivatives.