Helical Polycarbenes Bearing D-Prolinol Ester Pendants: An Efficient Catalyst for Asymmetric Michael Addition Reaction

a novel diazoacetate monomer (1) carrying tert-butyloxycarboryl (Boc) protected D-prolinol ester was designed and synthesized successfully. Molecular weight-controlled polymerization of 1 using the complex of π-allylPdCl coordinated Wei-phos (LR) ligand gives a series of helical polycarbenes (poly-1ms) with well-defined molecular weights (Mns) and low polydispersity (Mw/Mns). Removing the protecting Boc groups on the D-prolinol ester pendants leads to the formation of helical poly-1m-As, which showed high optical activity. Furthermore, the poly-1m-As showed high catalytic ability on asymmetric Michael addition reaction (up to 76% ee and 94/6 dr). Both the enantioselectivity and diastereoselectivity of the Michael addition reaction were increased comparing to D-prolinol as catalyst. Moreover, the helical polycarbene catalyst can be easily recovered and reused at least four times without significant loss of its enantioselectivity and diastereoselectivity.

Asymmetric Sequential Michael Addition and Cyclization Reactions of 2-(2-Nitrovinyl)phenols Catalyzed by Bifunctional Amino-Squaramides

In this work, we describe the Michael addition–cyclization reaction of 2-(2-nitrovinyl)phenol with two different reactive Michael donors, which lead to chiral benzopyran derivatives. Specifically, bifunctional amino-squaramides with one or two chiral units in the side chains were evaluated as catalysts in these transformations. Furthermore, the utility of selected green solvents as reaction media for these processes was also tested. The best result was achieved with methyl-cyclopentanone-2-carboxylate as the Michael donor in ethyl (–)-l-lactate with quinine-based amino-squaramide as catalyst (yield 72%, dr >99:1, ee 99%).

Identification of Potential Drug Targets of Broad-Spectrum Inhibitors with a Michael Acceptor Moiety Using Shotgun Proteomics

The Michael addition reaction is a spontaneous and quick chemical reaction that is widely applied in various fields. This reaction is performed by conjugating an addition of nucleophiles with α, β-unsaturated carbonyl compounds, resulting in the bond formation of C-N, C-S, C-O, and so on. In the development of molecular materials, the Michael addition is not only used to synthesize chemical compounds but is also involved in the mechanism of drug action. Several covalent drugs that bond via Michael addition are regarded as anticarcinogens and anti-inflammatory drugs. Although drug development is mainly focused on pharmaceutical drug discovery, target-based discovery can provide a different perspective for drug usage. However, considerable time and labor are required to define a molecular target through molecular biological experiments. In this review, we systematically examine the chemical structures of current FDA-approved antiviral drugs for potential Michael addition moieties with α, β-unsaturated carbonyl groups, which may exert an unidentified broad-spectrum inhibitory mechanism to target viral or host factors. We thus propose that profiling the targets of antiviral agents, such as Michael addition products, can be achieved by employing a high-throughput LC-MS approach to comprehensively analyze the interaction between drugs and targets, and the subsequent drug responses in the cellular environment to facilitate drug repurposing and/or identify potential adverse effects, with a particular emphasis on the pros and cons of this shotgun proteomic approach.

DFT Study on the Reaction Mechanism of Cyclization of 2-Hydroxy Chalcone Catalyzed by Bronsted Acid with M06-2X Functional

Flavanones are one of the flavonoid group that has wide variety of applications such as a precursors in drug discovery. In the laboratory, flavanone is often synthesized from chalcone compounds. The conversion of chalcone to flavanone can be catalyzed by bronsted acid. The reaction mechanism for this process is proposed through the Michael addition reaction, however, the energetic details and the rate determining step for this reaction is not certainly known. This research aimed to investigate the reaction mechanism for chalcone-flavanone conversion with the present of bronsted acid as catalyst and also studied the effect of the solvent on the reaction energy profile with computational method. In this study, the modeling of the reaction mechanism for the said reaction was carried out using the DFT computational method with M06-2X functional. The computation was done both in the gas phase and in present of the solvent effect using the PCM models. The results showed that the mechanism of chalcone-flavanone conversion occurred in three steps which are protonation, cyclization, and then tautomerization. Based on these calculations, the rate determining step was the tautomerization reaction, which exhibited the same results with or without the solvent effects. Copyright © 2021 by Authors, Published by BCREC Group. This is an open access article under the CC BY-SA License (https://creativecommons.org/licenses/by-sa/4.0).

Synthesis of biologically active heterocyclic compounds from allenic and acetylenic nitriles and related compounds

Cyclic and polycyclic compounds containing moieties such as imidazole, pyrazole, isoxazole, thiazoline, oxazine, indole, benzothiazole and benzoxazole benzimidazole are prized molecules because of the various pharmaceutical properties that they display. This led Prof. Landor and co-workers to engage in the synthesis of several of them such as alkylimidazolenes, oxazolines, thiazolines, pyrimidopyrimidines, pyridylpyrazoles, benzoxazines, quinolines, pyrimidobenzimidazoles and pyrimidobenzothiazolones. This review covers the synthesis of biologically active heterocyclic compounds by the Michael addition and the double Michael addition of various amines and diamines on allenic nitriles, acetylenic nitriles, hydroxyacetylenic nitriles, acetylenic acids and acetylenic aldehydes. The heterocycles were obtained in one step reaction and in most cases, did not give side products. A brief discussion on the biological activities of some heterocycles is also provided.

pH-responsive delivery vehicle based on RGD-modified polydopamine-paclitaxel-loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) nanoparticles for targeted therapy in hepatocellular carcinoma

A limitation of current anticancer nanocarriers is the contradiction between multiple functions and favorable biocompatibility. Thus, we aimed to develop a compatible drug delivery system loaded with paclitaxel (PTX) for hepatocellular carcinoma (HCC) therapy. A basic backbone, PTX-loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) PHBV nanoparticle (PHBV-PTX-NPs), was prepared by emulsion solvent evaporation. As a gatekeeper, the pH-sensitive coating was formed by self-polymerization of dopamine (PDA). The HCC-targeted arginine-glycine-aspartic acid (RGD)-peptide and PDA-coated nanoparticles (NPs) were combined through the Michael addition. Subsequently, the physicochemical properties of RGD-PDA-PHBV-PTX-NPs were characterized by dynamic light scattering-autosizer, transmission electron microscope, fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetry and X-ray spectroscopy. As expected, the RGD-PDA-PHBV-PTX-NPs showed robust anticancer efficacy in a xenograft mouse model. More importantly, they exhibited lower toxicity than PTX to normal hepatocytes and mouse in vitro and in vivo, respectively. Taken together, these results indicate that the RGD-PDA-PHBV-PTX-NPs are potentially beneficial for easing conflict between multifunction and biocompatible characters of nanocarriers.

Michael Addition of Indoles to Enones Catalyzed by a Cationic Iron Salt

Indoles are one of the most valuable nucleophiles in Michael additions catalyzed by a proper Lewis acid. In this paper, we found that a cationic iron salt is effective to carry out the Michael addition of indoles. β-Mono- and disubstituted enones reacted smoothly with indoles under our conditions. The cationic iron catalyst is very active, and the maximum TON was up to 425. Moreover, cationic iron-catalyzed conditions enabled a chemoselective Michael addition of a substrate possessing both enone and α,β-unsaturated ester moieties.