Development of Efficient Synthetic Reactions Using Enamines and Enamides Carrying Oxygen Atom Substituent on Nitrogen Atom.

We have developed efficient synthetic reactions using enamines and enamides carrying oxygen atom substituent on nitrogen, such as N-alkoxyenamines, N,α-dialkoxyenamines, N-alkoxyanamides, and N-(benzoyloxy)enamides. The umpolung reaction by polarity inversion at the ß-position of N-alkoxyenamines afforded α-alkyl-, α-aryl-, α-alkenyl-, and α-heteroarylketones by using aluminum reagent as nucleophiles. Furthermore, one-pot umpolung α-phenylation of ketones has been also developed. We applied this method to umpolung reaction of N,α-dialkoxyenamine, generated from N-alkoxyamide to afford α-arylamides. The vicinal functionalization of N-alkoxyenamines has been achieved with the formation of two new carbon-carbon bonds by using an organo-aluminum reagent and subsequent allyl magnesium bromide or tributyltin cyanide. A sequential retro-ene arylation has been developed for the conversion of N-alkoxyenamides to the corresponding tert-alkylamines. The [3,3]-sigmatropic rearrangement of N-(benzoyloxy)enamides followed by arylation afforded cyclic ß-aryl-ß-amino alcohols bearing a tetrasubstituted carbon center. The resulting products were converted into the corresponding sterically congested cyclic ß-amino alcohols, as well as the dissociative anesthetic agent Tiletamine.

Chondroitin Sulfate N-acetylgalactosaminyltransferase-2 Impacts Foam Cell Formation and Atherosclerosis by Altering Macrophage Glycosaminoglycan Chain.

OBJECTIVE: Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfate N-acetylgalactosaminyltransferase-2), in macrophage foam cell formation. Approach and Results: ChGn-2-deficient mice showed decreased and shortened glycosaminoglycans. ChGn-2-/-/LDLr-/- (low-density lipoprotein receptor) mice generated less atherosclerotic plaque after being fed with Western diet despite exhibiting a metabolic phenotype similar to that of the ChGn-2+/+/LDLr-/- littermates. We demonstrated that in macrophages, ChGn-2 expression was upregulated in the presence of oxLDL (oxidized LDL), and glycosaminoglycan was substantially increased. Foam cell formation was significantly altered by ChGn-2 in both mouse peritoneal macrophages and the RAW264.7 macrophage cell line. Mechanistically, ChGn-2 enhanced oxLDL binding on the cell surface, and as a consequence, CD36-an important macrophage membrane scavenger receptor-was differentially regulated. CONCLUSIONS: ChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.

γ-C (sp3)-H bond functionalisation of α,ß-unsaturated amides through an umpolung strategy.

The nucleophilic γ-phenylation and γ-alkylation of α,ß-unsaturated amides have been developed. This umpolung reaction allows the regioselective introduction of phenyl and alkyl groups to a vinylketene N,O-acetal, which is generated in situ from an α,ß-unsaturated N-alkoxyamide, followed by N-O bond cleavage in a two-step, one-pot process.

Chondroitin sulfate N-acetylgalactosaminyltransferase-2 deletion alleviates lipoprotein retention in early atherosclerosis and attenuates aortic smooth muscle cell migration.

Glycosaminoglycans (GAGs) play an integral role in low-density lipoprotein (LDL) retention in the vascular intimal layer and have emerged as attractive therapeutic targets for atherosclerosis. GAG biosynthesis involves the cooperation of numerous enzymes. Chondroitin sulfate N-acetylgalactosaminyltransferase-2 (ChGn-2) is a vital Golgi transferase that participates in enzymatic elongation of GAGs. Here, we investigated the effects of ChGn-2 gene deletion on the development of atherosclerosis. Partial carotid artery ligation was performed on ChGn-2-/-/LDLr-/- and ChGn-2+/+/LDLr-/- mice to induce diffuse intimal thickening (DIT). Aortic smooth muscle cells (ASMCs) were isolated to investigate cellular LDL binding and migration. Histological analysis of human coronary artery sections revealed that ChGn-2 was expressed in early and advanced atherosclerotic lesions. Deletion of the ChGn-2 gene significantly reduced LDL retention in the DIT mouse model. Furthermore, LDL binding, visualized using rhodamine-labeled LDLs, was dramatically reduced. Interestingly, a functional assay of ASMCs prepared from ChGn-2-/- mice displayed abrogation of platelet-derived growth factor (PDGF)-mediated migration via reduced PDGF receptor phosphorylation. Taken together, these findings indicate that ChGn-2 is functionally involved in the progression of atherosclerosis both in its early and advanced stages. Therefore, ChGn-2 may serve as a plausible target to treat atherosclerotic-related diseases in the future.

Copper-Catalyzed Cycloisomerization of Cyclopropenylimine for Synthesis of Pyrroles.

Copper-catalyzed cycloisomerization of 3-iminocyclopropenes for synthesis of pyrroles has been developed. The reaction allows regioselective construction of pyrroles with various substitution patterns, including fully substituted pyrroles. The method was successfully applied to synthesis of steroidal pyrroles as well as a N-fused pyrrole.

Chiral isoxazolidine-mediated stereoselective umpolung α-phenylation of methyl ketones.

An effective asymmetric α-phenylation of methyl ketones with triphenylaluminium in the presence of (+)-benzopyranoisoxazolidine has been developed. The reaction proceeds via the in situ formation of a chiral N-alkoxyenamine and the subsequent diastereoselective nucleophilic phenylation to provide α-phenylated products in moderate to good yields, with high enantioselectivities.

Nucleophilic Arylation of N,O-Ketene Acetals with Triaryl Aluminum Reagents: Access to α-Aryl Amides through an Umpolung Process.

A novel approach for the umpolung α-arylation of amides is presented. By the nucleophilic phenylation of O-silyl N,O-ketene acetals, generated in situ from N-alkoxy amides, a phenyl group can be introduced onto the α-carbon atom of amides through N-O bond cleavage in a two-step, one-pot process. The asymmetric synthesis of α-aryl amides through the diastereoselective arylation of a chiral N,O-ketene acetal is also described.

Gold-Catalyzed [3+2]/Retro-[3+2]/[3+2] Cycloaddition Cascade Reaction of N-Alkoxyazomethine Ylides.

A novel cascade reaction has been developed for the synthesis of 2,6-methanopyrrolo[1,2-b]isoxazoles based on the gold-catalyzed generation of an N-allyloxyazomethine ylide. This reaction involves sequential [3+2]/retro-[3+2]/[3+2] cycloaddition reactions, thus providing facile access to fused and bridged heterocycles which would be otherwise difficult to prepare using existing synthetic methods. Notably, this reaction allows the efficient construction of three C-C bonds, one C-O bond, one C-N bond and one C-H bond, as well as the cleavage of one C-C bond, one C-O bond and one C-H bond in a single operation. The intermolecular cycloaddition of an N-allyloxyazomethine ylide and the subsequent application of the product to the synthesis of tropenol is also described.

tert-Butyl Iodide Mediated Reductive Fischer Indolization of Conjugated Hydrazones.

A novel reductive Fischer indolization of readily available N-aryl conjugated hydrazones with tert-butyl iodide has been developed. In this reaction, tert-butyl iodide is used as anhydrous HI source, and the generated HI acts as a Brønsted acid and a reducing agent. This operationally simple method allows access to various indole derivatives. Furthermore, the procedure can be applied to the synthesis of biologically active compounds.

Regiodivergent Ring-Opening Reaction of Trichloromethylcyclopropane Carboxylates.

Reagent-controlled regiodivergent ring-opening reactions of trichloromethylcyclopropane carboxylates have been developed. The regioselectivity of bond cleavage is completely controlled by the proper choice of silver salts; the treatment of trichloromethylcyclopropane with AgBF4 led to C2-C3 bond cleavage and fluorination to afford fluorinated ß,γ-unsaturated ester with high stereoselectivity, while the reaction with AgOAc in THF gave a γ,δ-unsaturated ester through the reductive cleavage of the C1-C2 bond.

Direct synthesis of benzofuro[2,3-b]pyrroles through a radical addition/[3,3]-sigmatropic rearrangement/cyclization/lactamization cascade.

A straightforward synthetic method for the construction of benzofuro[2,3-b]pyrrol-2-ones by a novel domino reaction through a radical addition/[3,3]-sigmatropic rearrangement/cyclization/lactamization cascade has been developed. The domino reaction of O-phenyl-conjugated oxime ether with an alkyl radical allows the construction of two heterocycles with three stereogenic centers as a result of the formation of two C-C bonds, a C-O bond, and a C-N bond in a single operation, leading to pyrrolidine-fused dihydrobenzofurans, which are not easily accessible by existing synthetic methods. Furthermore, asymmetric synthesis of benzofuro[2,3-b]pyrrol-2-one derivatives through a diastereoselective radical addition reaction to a chiral oxime ether was also developed.

α-Heteroarylation of ketones via the umpolung reaction of N-alkoxyenamine.

A new method has been developed for the umpolung α-heteroarylation of ketones via an N-alkoxyenamine. The treatment of ketones with tris(heteroaryl)aluminum reagents in the presence of isoxazolidine gave the corresponding α-heteroarylated ketones in moderate to good yields.

Michael addition-aromatization reaction of dienylimines bearing a leaving group and its application to the preparation of thiol-selective labeling reagents capable of forming strong carbon-sulfur bonds.

The reaction of a dienylimine with thiols was found to proceed smoothly to afford the corresponding indolines bearing aromatic carbon-sulfur bonds as a result of a Michael addition-aromatization sequence. Furthermore, this reaction was applied to the development of fluorogenic dienylimines that could be used as thiol-selective fluorescent labeling reagents.

Copper-catalyzed synthesis of trisubstituted isoxazoles via a cascade cyclization-migration process.

An atom-economical, catalytic, and regioselective synthesis of 3,4,5-trisubstituted isoxazoles has been successfully developed. Treatment of O-arylmethyl alkynyl oxime ethers with 5 mol % of Cu(OTf)(2) in chlorobenzene at reflux gave 4-arylmethylisoxazoles in good to excellent yields via the sequential intramolecular addition of the oxime moiety to the alkyne with subsequent 1,3-migration of the arylmethyl group.

Benzofuran derivatives inhibit 11ß-hydroxysteroid dehydrogenase type 1 activity in rat adipose tissue.

Excess glucocorticoids promote visceral obesity and insulin resistance. The main regulator of intracellular glucocorticoid levels are 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which converts inactive glucocorticoid into bioactive glucocorticoid such as cortisol in humans and corticosterone in rodents; therefore, the inhibition of 11ß-HSD1 has considerable therapeutic potential for metabolic diseases including obesity and diabetes. Benzofuran is a key structure in many biologically active compounds such as benzbromarone, malibatol A and (+)-liphagal. The aim of this study was to investigate the inhibitory effect of benzofuran derivatives on 11ß-HSD1 in mesenteric adipose tissue from rodents. 11ß-HSD1 activity was determined by incubation of rat mesenteric adipose tissue microsomes in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) with and without benzofuran derivatives (Compounds 1-14). The corticosterone produced was measured by HPLC. More than 40% of 11ß-HSD1 inhibition was observed in Compounds 1, 5, 7 and 8. Moreover, Compounds 7 and 8 inhibited the 11ß-HSD1 activity in adipose microsomes dose- and time-dependently, as well as in 3T3-L1 adipocytes. Compounds 7 and 8 did not inhibit 11ß-HSD type 2 (11ß-HSD2), whereas Compounds 1 and 5 inhibited 11ß-HSD2 by 18.7% and 56.3%, respectively. Further, a kinetic study revealed that Compounds 7 and 8 acted as non-competitive inhibitors of 11ß-HSD1. Ki (nmol/h/mg protein) values of Compounds 7 and 8 were 17.5 and 24.0, respectively, with IC50 (µM) of 10.2 and 25.6, respectively. These data indicate that Compounds 7 and 8 are convincing candidates for seed compounds as specific inhibitors of 11ß-HSD1 and have the potential to be developed as anti-obesity drugs.

Benzyl radical addition reaction through the homolytic cleavage of a benzylic C-H bond.

Direct generation of a benzyl radical by C-H bond activation of toluenes and the addition reaction of the resulting radical to an electron deficient olefin were developed. The reaction of dimethyl fumarate with toluene in the presence of Et(3)B as a radical initiator at reflux afforded 2-benzylsuccinic acid dimethyl ester in good yield.

Palladium-catalyzed cross coupling reaction of N-alkoxyimidoyl bromides and its application to one-pot synthesis of N-arylamines.

The synthetic utility of N-alkoxyimidoyl halides is demonstrated using the palladium-catalyzed cross-coupling reaction. The Sonogashira and Suzuki-Miyaura coupling reactions of N-alkoxyimidoyl bromides produced versatile ketoxime ethers in good to excellent yields. A one-pot reaction of the imidoyl bromides with arylboronic acid and allylmagnesium bromide to produce N-arylamines via Suzuki-Miyaura coupling followed by domino reaction involving sequential addition-eliminative rearrangement-addition reactions was developed.

Efficient entry into 2-substituted tetrahydroquinoline systems through alkylative ring expansion: stereoselective formal synthesis of (+/-)-martinellic acid.

A new efficient synthesis of 2-substituted tetrahydroquinolines has been achieved by the domino reaction of N-indanyl(methoxy)amines, which consists of three types of reactions: elimination of an alcohol, the rearrangement of an aryl group, and the addition of an organolithium or magnesium reagent. The synthetic utility of this approach is demonstrated by the stereoselective formal synthesis of (+/-)- martinellic acid.

In Practical Training, a Questionnaire Survey and Analysis to Pharmacy Students of the Utilization Situation of the Course Contents of Pharmacy School.

Pharmacy education comprises basic pharmacy (organic chemistry, biochemistry, and physical chemistry) and applied pharmacy (clinical pharmacy, pharm aceutics, and chemical hygiene). Students are expected to apply these subjects studied in pharmacy school during their practical pharmacy training. However, knowledge gained in university does not appear to be fully utilized in practice. We hypothesized that this is due to a lack of connection between pre-practical training education and actual practical training. Thus, we conducted a questionnaire study among pharmacy students to verify this hypothesis. We sent a questionnaire to 601 students in their sixth year of the pharmacy course at Chiba University, Teikyo University, or Kobe Pharmaceutical University who had undergone long-term practical training. The questionnaire asked about the utility of each subject of study and the reason for the judgement regarding the utility. Four hundred and forty-two students replied (response rate, 73.5%). A small proportion of students found the basic pharmacy subjects useful: physical chemistry, 5%; organic chemistry, 10%; and biochemistry, 24%. In contrast, more than half of the students found the clinical pharmacy subjects useful: pharmacology, 85%; pharmaceutics, 55%; pathophysiology, 75%; pharmacotherapeutics, 84%; and pharmaceutical regulations, 58%. Analysis of the comments left in the free-description section on the questionnaire revealed that most students did not have any opportunity to use their knowledge of the basic subjects during practical training, and furthermore, did not learn the processes involving the use of such subjects to solve clinical problems. Universities and pharmacists need to collaborate so that students can learn such processes.