N-(Trimethylsilyl)diethylamine (TMSNEt2) significantly promotes intramolecular nucleophilic aromatic substitution (SNAr) reactions of electron-rich aryl fluorides with t-BuOK and crown ether. Although substrates bearing electron-donating groups are conventionally inert under SNAr conditions, the activation of substrates by TMSNEt2 enables the reactions to proceed even at room temperature. This method is applicable to the preparation of benzo-fused oxygen-containing heterocycles, such as 3,4-dihydro-2H-1,4-benzoxazines, 3,4-dihydro-2H-1,5-benzoxazepines, and 3,4-dihydro-2H-1-benzopyran, in good to excellent yields (56-93%).

Building on our previously reported techniques, we developed a concise and highly stereoselective synthesis method for β,β-disubstituted α,β-unsaturated esters. This synthesis comprises 3 reactions: the aldol reaction of acetic ester derivatives with ketones, the acetylation of tert-alcohols, and an elimination reaction utilizing 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). During the acetylation process, acetic anhydride and 4-dimethylaminopyridine (DMAP) facilitated the smooth acetylation of bulky tert-alcohols; however, employing DBU as a base reduced the yields. Additionally, the removal of excess DMAP effectively suppressed the formation of unwanted byproducts during the elimination step.

γ-Lactones are used as building blocks in the synthesis of several naturally occurring products and biologically active compounds. In this work, a method of constructing a γ-lactone ring with an oxygen atom substituted at the γ position, with a short reaction time, mild reaction conditions, simple operation, and stereoselectivity, was developed. Using this reaction, the synthesis of the γ-lactone ring with various substituents (mainly halogenated alkoxy groups) at the γ position is possible.

The purpose of the present study was to evaluate bitterness suppression effect of adenylic acid (AMP) as a nucleotide-derived nutrient enhancer on a bitter commercial drug. In the present study, we evaluated peripheral bitterness inhibition effect of AMP on the trimethoprim (TMP) and sulfamethoxazole (SMZ) combination formulation based on taste sensor. The taste sensor values of TMP solutions with different concentrations show large sensor output in correlation with the concentration of TMP, whereas no sensor output in shown for the SMZ solutions. Therefore, the bitterness of this combination formulation is mainly due to TMP. We evaluated the TMP bitterness inhibitory effects of AMP, sodium salt of AMP (AMP Na; sodium adenylate), sodium salt of GMP (GMP Na; sodium guanylate), and sodium salt of inosine mono-phosphate (IMP Na; sodium inosinate), and found that only AMP displayed very effective bitterness in-hibition. MarvinSketch analysis revealed that potential electrostatic interaction between cationized TMP and anionized forms (II and III) of AMP may cause bitterness suppression. 1H-NMR study suggested an interaction of TMP and AMP molecules based on chemical shift perturbations and an interaction between the phosphate group of AMP and amino group of TMP. Lastly, conventional elution analysis simulating oral cavity capacity for up to one minute were performed using commercial TMP/SMZ combination granules. The sensor output gradually increased up to 60 s. The addition of AMP solution to the eluted sample at 60 s significantly decreased the bitterness sensor output of the eluted sample.

This study aimed to evaluate the bitterness of famotidine (FAM) combined with each of three non-steroidal anti-inflammatory drugs (NSAIDs): ibuprofen (IBU), flurbiprofen (FLU), and naproxen (NAP), which have potential as fixed-dose combination (FDC) drugs. We evaluated the bitterness of FAM and each NSAID by taste sensor AN0 and C00, respectively. FAM showed high sensor output representing sensitivity to bitterness, whereas three NSAIDs did not show large sensor output, suggesting that the bitterness intensities of three NSAIDs were lower than that of FAM. The bitterness of FAM on sensor AN0 was suppressed in a concentration-dependent manner when mixed with IBU, FLU, or NAP. Among three NSAIDs, IBU most effectively inhibited bitterness on sensor output, and the gustatory sensation test confirmed that adding IBU to FAM reduced the bitterness of FAM in a concentration-dependent manner. MarvinSketch confirmed that the drugs were mostly present in an ionic solution when FAM was mixed with NSAIDs. The 1H-NMR spectroscopy analysis also revealed the presence of electrostatic interactions between FAM and NSAIDs, suggesting that the electrostatic interaction between FAM and NSAIDs might inhibit the adsorption of FAM on the bitter taste sensor membrane, thereby masking the bitter taste.

Acyclic asymmetric quaternary stereocenters, which are composed of four carbon-carbon bonds, were finely constructed by utilizing a face-selective alkylation of enolate intermediates derived from an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,β-unsaturated esters. The present face-selective alkylation was able to employ diverse alkyl halides as an electrophile to afford various Michael adducts having an all-carbon quaternary stereocenter. With regard to the deprotection of the chiral auxiliary, N-iodosuccinimide used in our previous study did not work in the present cases; however, we found that pyridine iodine monochloride in the presence of H2O was effective to remove the bornyl group and the benzyl group on the amino group to provide the β-amino ester derivative.

Various peptides and their derivatives have been reported to exhibit antimicrobial activities. Although these activities have been examined against microorganisms, novel methods have recently emerged for conjugation of the biomaterials to improve their activities. Here, we prepared CKR12-PLGA, in which CKR12 (a mutated fragment of human cathelicidin peptide, LL-37) was conjugated with poly (lactic-co-glycolic) acid (PLGA), and compared the antimicrobial and antifungal activities of the conjugated peptide with those of FK13 (a small fragment of LL-37) and CKR12 alone. The prepared CKR12-PLGA was characterized by dynamic light scattering and measurement of the zeta potential, critical micellar concentration, and antimicrobial activities of the fragments and conjugate. Although CKR12 showed higher antibacterial activities than FK13 against Staphylococcus aureus and Escherichia coli, the antifungal activity of CKR12 was lower than that of FK13. CKR12-PLGA showed higher antibacterial activities against S. aureus and E. coli and higher antifungal activity against Candida albicans compared to those of FK13. Additionally, CKR12-PLGA showed no hemolytic activity in erythrocytes, and scanning and transmission electron microscopy suggested that CKR12-PLGA killed and disrupted the surface structure of microbial cells. Conjugation of antimicrobial peptide fragment analogues was a successful approach for obtaining increased microbial activity with minimized cytotoxicity.

2,2'-Binaphthyl-3,3'-dicarbonyl cyanide possessing two reaction sites was designed and synthesized as a new chromophoric reagent for exciton-coupled circular dichroism (ECCD), which is more effective in determination of the absolute stereochemistry of the target chiral alcohols than 2,2'-binaphthyl-3methoxycarbonyl-3'-carbonyl cyanide, which contains only one reaction site. The CD spectra of the 2,2'-binaphthyl diesters derived from chiral secondary alcohols show bisignate curves centered at 240 nm, of which the De value was roughly twice as large as that of the binaphthyl methyl monoester. (C) 2020 Elsevier Ltd. All rights reserved.

A simple and facile procedure for the preparation of 2-oxo-2H-1-pyran-3-carboxylate bearing electron-withdrawing groups at the 5-position, such as the alkylcarbonyl and alkoxycarbonyl moieties, was developed. Various 1,3-dicarbonyl compounds were treated with dimethyl (methoxymethylene)malonate in the presence of Cs2CO3 as a base in tetrahydrofuran at room temperature. This method was particularly effective in the syntheses of bicyclic structures, such as 5,6,7,8-tetrahydro-2,5-dioxo-2H-1-benzopyran-3-carboxylates.

The purpose of the study was to prepare a poly-γ-glutamic acid hydrogel (PGA gel), to evaluate physicochemical properties, its ease of swallowing using texture profile analysis (TPA) and its taste-masking effects on amlodipine besylate (AML) using the artificial taste sensor and human gustatory sensation testing. Using TPA, 0.5 and 1.0% (w/v) PGA gels in the absence of drug were within the range of acceptability for use in people with difficulty swallowing according to permission criteria published by the Japanese Consumers Affairs Agency. The elution of AML from prepared PGA gels was complete within an hour and the gel did not appear to influence the bioavailability of AML. The sensor output of the basic bitterness sensor AN0 in response to AML mixed with 0.5 and 1.0% PGA gels was suppressed to a significantly greater degree than AML mixed with 0.5 and 1.0% agar. In human gustatory sensation testing, 0.5 and 1.0% PGA gels containing AML showed a potent bitterness-suppressing effect. Finally, 1H-NMR spectroscopic analysis was carried out to examine the mechanism of bitterness suppression when AML was mixed with PGA gel. The signals of the proton nearest to the nitrogen atom of AML shifted clearly upfield, suggesting an interaction between the amino group of AML and the carboxyl group of PGA gel. In conclusion, PGA gel is expected to be a useful excipient in formulations of AML, not only increasing ease of swallowing but also masking the bitterness of the basic drug.

A facile and convenient synthesis of trisubstituted (E)-α,β-unsaturated esters was developed by improving our previously established method. The new method circumvented the separation of the intermediates, which have an activating group of the hydroxyl group in β-hydroxy esters, furnishing α,β-unsaturated esters in shorter steps than the previous method: an acetylation of β-hydroxy group and subsequent E1cB reaction proceeded in tandem. In addition, the new method can not only employ a diastereomeric mixture of the substrate for the E1cB reaction, it has a wide substrate scope as well, which would enable the synthesis of various trisubstituted (E)-α,β-unsaturated esters.

The purpose of the study was to evaluate the ability of different beverages to mask the bitterness of zopiclone and eszopiclone in tablet formulations using the artificial taste sensor and human gustatory sensation testing. The beverages tested for bitterness-masking effects were: Mugicha, Sports beverage, Lactic acid drink, Orange juice and a diluted simple syrup (an 8.5% sucrose solution). The bitterness intensities estimated by the taste sensor of zopiclone or eszopiclone one-tablet solutions mixed with the various beverages, corresponded well with the observed bitterness intensities measured by gustatory sensation testing. The Sports beverage, Lactic acid drink and Orange juice significantly suppressed the bitterness intensity of both zopiclone and eszopiclone 1-tablet solutions compared with water when tested in the artificial taste sensor. Sports beverage, Lactic acid drink and Orange juice all contain citric acid as acidifier, so it was postulated that citric acid was involved in the mechanism of bitterness intensity suppression of zopiclone and eszopiclone 1-tablet solutions by these three beverages. It was then shown that citric acid suppressed the bitterness intensity of a zopiclone one-tablet sample solution in a dose-dependent manner. 1H-NMR spectroscopic analysis of mixtures of citric acid with zopiclone suggested that the carboxyl groups of citric acid interact with the amine group on zopiclone. This study therefore showed that the bitterness intensities of zopiclone and eszopiclone can be suppressed by citric-acid-contained beverages and suggests that this bitterness suppression is due to a direct electrostatic interaction between citric acid and the two drugs.

The new ligands with improved enantioselectivity, recyclable catalytic asymmetric transfer hydrogenation (RCATH) reaction efficiency, and physical properties were synthesized. The new ligands were synthesized and used in RCATH. Among them, ligands 2e and 2f provided high enantioselectivity and reaction efficiency compared to a previously reported ligand 1 used in RCATH.

A practical method for the synthesis of chiral β2,3-amino esters having various substituents was developed, which is characterized by an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,β-unsaturated esters. We found that a highly face-selective protonation occurred by the quick addition of water to the enolate intermediate derived from the Michael addition reaction to afford N-protected β2,3-amino esters in moderate to excellent yields. This finding was made possible by the facile preparation of geometrically pure trisubstituted (E)-α,β-unsaturated esters, which was established recently by our group. The subsequent deprotection of the amino group in the Michael adduct by using N-iodosuccinimide (NIS) efficiently provided β2,3-amino esters having various substituents.

Using dimethylsulfoxonium methylide as the methylene-transfer reagent, 8-methoxy-2 a,8b-dihydrobenzo [b] cyclobute [d]pyran-3-ones were exclusively converted into the corresponding dihydrodibenzofuran derivatives. The use of a methoxy group as the substituent and its position are crucial to the success of this transformation.

Using dimethylsulfoxonium methylide as the methylene transfer reagent, 2a,8b-dihydrobenzo[b]cyclobute[d]pyran-3-ones were converted into 2,2'-biphenol derivatives as major products and dihydrodibenzofurans as minor products. The reaction mechanism was extrapolated from a deuteration experiment with CD2=S(O)(CD3)2.

AbstractUsing dimethylsulfoxonium methylide as the methylene‐transfer reagent, various α‐pyrones are converted into dihydrofurans as major products and 1‐methylthiopyran‐1‐oxides as minor products.

A tandem "quadruple" Michael addition reaction of (+)-borny-lamide with two equivalents of a Michael acceptor having two alpha, beta-unsaturated ester moieties spontaneously proceeded to afford one diastereomer with seven contiguous chiral centers in 27% yield. Meanwhile, a stepwise "double-double" Michael addition, in which the very slow addition of the first one equivalent of the acceptor substrate to the bornylamide was followed by a further addition of another Michael acceptor bearing two alpha, beta-unsaturated ester moieties, provided a compound with a similar set of seven contiguous chiral centers on a different carbon skeleton in 48% yield. Both quadruple and double-double Michael adducts were one of 128 possible diastereomers, namely, each Michael addition in those two reactions proceeded in 72% and 83% yields on average, respectively. We showed the importance of adding speed of the Michael acceptor to the bornylamide in controlling the quadruple and double-double Michael addition reactions.