For the purpose of generation of a new macrolide antibiotic which is effective against constitutive erm-resistant Streptococcus pneumoniae, a variety of novel 11-azalides were designed and synthesized starting from 16-membered macrolides, leucomycins. One step macrocyclization by a linear dialdehyde and a primary amine via reductive amination firstly gave 15-membered 11-azalide, and optimized 11-N-arylalkyl-azalide was effective against inducible erm-resistant S. pneumoniae. Then, 14-membered to 16-membered 11-azalides or 11-azalactams were systematically prepared in application of a formylcarboxylic acid, and biologically evaluated. As a result, 16-membered 11-azalide was chosen as a lead compound for further medicinal chemistry. Finally 16-membered 15-β-substituted-11-azalide was generated as a clinical candidate through determination of the position of an arylalkyl group to be inserted and its stereochemistry, optimization of the arylalkyl group and the C-3 position, and exploration of a neutral sugar moiety for enhancement of stability against metabolism. This molecule exhibited strong activities against not only constitutive erm-resistant S. pneumoniae but resistant S. pneumoniae with mef gene and resistant Streptococcus pyogenes.
Because of the defined double-helical structure and programmed nature, DNA is an excellent molecule for the creation of various multidimensional nanostructures and the programmed placement of functional molecules and materials. DNA origami is an emerging strategy in the DNA nanotechnology field for designing defined two-dimensional DNA nanostructures. In this review, we focus on and describe the following DNA origami-based researches; (i) DNA origami-templated molecular assembly, (ii) programmed DNA origami assembly, (iii) design and construction of various three-dimensional DNA origami structures, (iv) programmed functionalization of DNA origami and combination with top-down nanotechnology, (v) single molecular observation on designed DNA origami, and (vi) DNA nanomachines working on DNA origami.
In this article, the authors summarize a variety of stereoselective carbon-carbon bond-forming reactions realized by the use of sugar-derived chiral templates, which have been one of the active concerns in the authors’ group in these fifteen years. Representative chiral templates prepared from D-glucose, D-galactose, or D-mannose are introduced first. Then, the utility of these templates for stereoselective carbon-carbon bond-forming reactions are outlined. These reactions include, 1)1,4-conjugate additions, 2)α-alkylations of esters, 3)Diels-Alder cycloadditions, 4)1,3-dipolar cycloadditions, and 5)α,α-dialkylation for the construction of an all-carbon asymmetric quaternary center. The use of a D-glucose derivative equipped with two bulky silyl ethers at C2 and C3 is emphasized throughout the article as the most effective chiral template.
Transition-metal-catalyzed transformation to produce various kinds of carbonyl compounds is one of the most powerful synthetic methods. Among them, transition-metal-catalyzed addition reactions of carbonyl compounds to carbon-carbon multiple bonds such as alkynes are environmentally friendly because all atoms of the substrates are retained in the products. Although the addition of aldehydes to alkynes, hydroacylation, has been intensively studied, the addition of acid chlorides, formamides, and formates has not been fully developed. One plausible explanation for it is the occurrence of competing decarbonylation reactions. In addition, relatively lower reactivity of formamides or formates limits the application as substrates in these addition reactions. In this paper, we overview recent results on the transition-metal-catalyzed addition reactions of carbonyl functionalities to alkynes.
Biosystems at the molecular level consist of numerous organic reactions. Thus, it is possible that we completely miss unknown reactions and/or their reactivities; the author envisioned a new strategy for useful chemical transformations, including applications to the natural products synthesis. In addition, such synthetic investigations could lead to the accumulation of many reactivity profiles, which may provide feedback to better understand biosystems. In the last decade, we have focused on concerted 6π-azaelectrocyclization, which is a “traditional and old”, but not “widely utilized” reaction. In this personal account, the author provides a brief review on how we discovered the new reactivity profile of azaelectrocyclization, how we applied this discovery to natural products synthesis, and how we eventually used feedback from the reaction to visualize in vivo dynamics of biomolecules and living cells as well as to establish methods for clinical and pharmaceutical applications; we offer a unique category in synthetic chemical biology. While elucidating the inhibitory mechanism of a hydrolytic enzyme by aldehyde-containing natural products, we discovered a reaction involving a rapid 6π-azaelectrocyclization of azatrienes generated from aldehyde with lysine residues. The electrocyclic reaction of the 1-azatriene system, a cyclization precursor, exhibited a substituent effect. Structure-reactivity studies showed that azaelectrocyclization, which usually proceeds in low yield at high temperatures, produced a cyclized 1,2-dihydropyridine quantitatively in less than 5 min at room temperature. Asymmetric chiral piperidine synthesis and a one-pot library synthesis of pyridines on solid-supports were applied to synthesize pyridine/indole alkaloid-type natural products. Additionally, we developed lysine-based labeling and engineering of biomolecules and living cells based on the rapid 6π-azaelectrocyclization. Both DOTA as a metal chelating agent and fluorescent groups, as well as oligosaccharide structures were introduced efficiently and selectively into surface lysines within 10 min at concentrations as low as 10−8 M. The DOTA-labeled somatostatin and glycoproteins were then radiometallated with 68Ga; the receptor-mediated accumulation of somatostatin in pancreas and the oligosaccharide-dependent circulatory residence of glycoproteins were visualized by microPET for the first time. Furthermore, we succeeded to image the trafficking of the fluorescence-labeled lymphocytes noninvasively, while the N-glycan-engineered lymphocytes targeted the colon carcinoma in tumor mouse model; the tumor-targeting artificial cells were thus synthesized using the author’s 6π-azaelectrocyclization.
β-Adrenoceptors (β-ARs) are classified into three types; β1-, β2-, and β3-ARs. In humans, the detrusor muscle has recently been reported to be the predominant site of β3-AR mRNA expression. The relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through β3-AR activation, suggesting that β3-adrenergic receptor agonists may represent as potential drugs for treating overactive bladder (OAB). In this paper, we described that the synthesis and discovery of novel class of biphenyl analogues containing an carboxylic acid moiety and acylsulfonamide, which has been identified highly potent and selective human β3-AR agonists with good oral bioavailability. We also described scalable process for our clinical candidate of FK4664 and AS1714955. Furthermore, in a metabolism study of benzoic acid analogues conducted in human hepatocytes, we identified an acylglucuronide conjugated metabolite (M-2), and the M-2 metabolite of FK4664 was prepared with high selectivity.
α-Oxo gold carbenoids are now accessible by intermolecular oxidation of alkynes by pyridine/quinoline-N-oxides in the presence of suitable gold (I) catalysts. In this review, a concise history of this chemistry and its applications to the syntheses of oxetan-3-ones, azetidin-3-ones, and 2,5-disubstituted oxazoles are described.