Raquel A. C. Leão

Evaluation of Coumarin and Neoflavone Derivatives as HCV NS5B Polymerase Inhibitors

Coumarins and coumestans represent an important family of compounds with diverse pharmacological properties. We recently identified coumestans as novel inhibitors of hepatitis C virus NS5B polymerase and predicted their binding in thumb pocket‐1 (TP‐1) of NS5B. As the coumarins are structurally related to coumestans by virtue of their common A‐ and B‐rings, we postulated them to also exhibit similar binding interaction with NS5B and inhibit its polymerase function. We therefore investigated 24 coumarin and neoflavone derivatives as candidate NS5B inhibitors and identified 14 compounds inhibiting NS5B polymerase activity with IC50 values between 17 and 63 μm. Of these, the newly synthesized 6,8‐diallyl‐5,7‐dihydroxycoumarin (8a) was produced in three steps in high chemical yield from floroglucinol and found to be the most potent of this series, exhibiting activity similar to the reference coumestan LQB‐34. The binding site of 8a was mapped to TP‐1 of NS5B by counter screening against P495L NS5B mutant, employed as a screen for TP‐1 site binders. NS5B‐TP‐1‐8a interaction map provided insight into 8a binding and offered clues for future SAR optimization.

Process intensification for tertiary amine catalyzed glycerol carbonate production: translating microwave irradiation to a continuous-flow process

Different products of interest can be produced from glycerol and glycerol carbonate (GC) has received much attention in recent years because of its physical properties, nontoxicity and water solubility. Herein we report a process intensification protocol for glycerol carbonate production mediated by tertiary amine catalysis where a 24 kg per L per day productivity was obtained with 79% isolated yield and a 5 hour operation time without losing efficiency.

Consecutive lipase immobilization and glycerol carbonate production under continuous-flow conditions

Several value-added products can be produced from glycerol and among these products glycerol carbonate (GC) has received much attention in recent years because of its physical properties and wide application in the chemical, pharmaceutical and food industries. As a continuation of our efforts to produce GC under environmentally acceptable conditions, we proposed a consecutive approach where lipase B from Candida antarctica was immobilized on Accurel MP1000 (CalBAcc) under continuous-flow conditions followed by glycerol carbonate production by a cascade process of triacylglycerol hydrolysis, biodiesel synthesis and esterification of the remaining glycerol with dimethyl carbonate towards GC production. Results of the immobilization of lipase B from Candida antarctica on a continuous-flow protocol demonstrated that a short residence time of 25 minutes could lead to 83% of protein loading. Screening of glycerol carbonate production in a packed bed reactor revealed that CalBAcc and N435 showed the best results of conversion and selectivity, with more selectivity by CalBAcc, that could lead to quantitative yields and excellent selectivities of the desired glycerol carbonate at residence times of 176 minutes when working with soybean and palm oil. Comparatively, the results obtained with CalBAcc were better than the ones with Novozym 435 since no full conversion was observed.

Studies on the continuous-flow synthesis of nonpeptidal bis-tetrahydrofuran moiety of Darunavir

The use of continuous-flow chemistry has shown to be an important tool in improving API manufacture. In the present paper, we report the use of continuous-flow reactors in the synthesis of the bicyclic side chain of antiretroviral Darunavir.

Continuous flow dynamic kinetic resolution of rac-1-phenylethanol using a single packed-bed containing immobilized CAL-B lipase and VOSO4 as racemization catalysts

Herein, we report a method for the continuous flow DKR of rac-1-phenylethanol catalyzed by CAL-B and VOSO4, using a single packed-bed containing both catalysts. Taking advantage of continuous flow techniques to circumvent compatibility issues, the DKR of rac-1-phenylethanol could be performed continuously to give enantiopure (R)-esters with excellent conversions and high productivities.

Studies on the dynamic resolution of Crizotinib intermediate

Crizotinib is an anti-cancer agent approved for treatment of non-small cell lung carcinoma. Retrosynthetic analysis revels 1-(2,6-dichloro-3-fluorophenyl)ethanol as an important intermediate, which can be made available by different biocatalytic approaches. Herein we report our results on the kinetic and dynamic resolution towards the desired chiral intermediate for Crizotinib synthesis. The results obtained show that very good conversions and high selectivity could be obtained for the kinetic resolution (45% conv. and E>200) while dynamic kinetic resolution under continuous-flow conditions afforded the desired product in 57% conversion and 98% e.e.

New Palladacycle-Derived Acylhydrazones as Pre-catalysts in Mirozoki-Heck Coupling and Oxyarylations

New acylhydrazone-based palladacycles are prepared and evaluated as pre-catalysts in Mirozoki-Heck and oxyarylation reactions.

New Palladacycles Derived Acylhydrazones and Hydrazones as Pre-catalyst in Mirozoki-Heck Coupling and Oxyarylations

Some of our selected results are described in Scheme 1, Table 1. The four palladacycle precatalyst showed in Figure 1 were used in low catalytic loading and promote the Heck-Mizoroki arylation of methyl acrylate by iodobenzene leading to 3 in good chemical yield (entries 1-4). Palladacycles 1b and 1c also promoted the arylation of styrene by iodobenzene in moderate chemical yields (entries 5 and 6). Finally, palladacycles 1a-c catalyzed the oxyarylation of dihydronaphthalen by ortho-iodophenol in MeCN/H2O (1:3) in reasonable chemical yields (entries 7-9). Compound 5 could also be obtained in only 40 min, under microwave irradiation, although in this case the chemical yield decreased (entry 10). 3 Scheme 1. Palladacycles 1 and 2 as precatalysts in HeckMizoroki arylation and oxyarylation reactions.

Synthesis of Coumarins Through Zinc Chloride-Catalyzed Hydroarylation of Acetylenic Esters by Phenols

Coumarins comprise a class of natural products and many of them exhibit a broad range of biological activities. 1a,b Several routes have been described to prepare coumarins. 2a-c In 1965 Kaufman and colworkers reported the hydroarylation of the ethyl propiolate (2a) by fluoroglucinol (1a) in the presence of stoichiometric amount of ZnCl2 leading to the coumarin 3a in good yield. 2a The protocol reported by Kaufman was very few explored in the literature and no attempts to perform the hydroarylation in the presence of catalytic amounts of ZnCl2 was described. Herein we wish to report the zinc chloride-catalyzed hydroarylation of acetylenic esters 2 by phenols 1 leading to coumarins 3.