β‐Selective Glycosylation by Using O‐Aryl‐Protected Glycosyl Donors

New glycosyl donors have been developed that contained several para‐substituted O‐aryl protecting groups and their stereoselectivity for the glycosylation reaction was evaluated. A highly β‐selective glycosylation reaction was achieved by using thioglycosides that were protected by 4‐nitrophenyl (NP) groups, which were introduced by using the corresponding diaryliodonium triflate. Analysis of the stereoselectivities of several glycosyl donors indicated that the β‐glycosides were obtained through an S_N2‐type displacement from the corresponding α‐glycosyl triflate. The NP group could be removed by reduction of the nitro group and acylation, followed by oxidation with ceric ammonium nitrate (CAN).     

Synthesis and biological activity of l‐aminoindan‐l,3‐dicarboxylic acid,a benzo‐analogue of (1S, 3R)‐ACPD

Amino acids 1 and 2 were designed and synthesized as the conformationally constrained analogues of (1S, 3R)‐ or (1S, 3S)‐ACPDs, and the selective agonists of mGluRs. The synthesis started from (R)‐phenylglycine using Seebach′s stereocenter self‐regeneration method and intramolecular acylation as key steps. No activity was found when 1 and 2 were tested as either mGluR agonist or antagonist.     

Site‐Selective and Metal‐Free Aliphatic CH Oxidation Enabled Synthesis of [5,24,25‐D3]‐(25S)‐Δ7‐Dafachronic acid

Steroid hormones play significant roles in both worms and mammalians. (25S)‐Δ⁷‐Dafachronic acid (Δ⁷‐DA, 1 ) is a member of the dafachronic acid hormonal series that regulates both development and lifespan of C. elegans. Despite its importance, effective tools for the illumination of its mode of action are lacking. Herein, we report an efficient synthesis of trideuterated Δ⁷‐DA, [5,24,25‐D3]‐(25S)‐Δ⁷‐dafachronic acid ([D₃]‐Δ⁷‐DA, 2 ), as a useful chemical tool for subsequent biological studies. Key steps for this bioinspired synthesis approach include site‐selective aliphatic C?H oxidation mediated by methyl(trifluoromethyl)dioxirane (TFDO), and the iridium/phosphine‐oxazoline‐catalyzed late‐stage asymmetric deuterium reduction.     

Photoinitiated Thiol−Ene Reactions of Various 2,3‐Unsaturated O‐, C‐ S‐ and N‐Glycosides – Scope and Limitations Study

The photoinitiated thiol?ene addition reaction is a highly stereo‐ and regioselective, and environmentally friendly reaction proceeding under mild conditions, hence it is ideally suited for the synthesis of carbohydrate mimetics. A comprehensive study on UV‐light‐induced reactions of 2,3‐unsaturated O‐, C‐, S‐ and N‐glycosides with various thiols was performed. The effect of experimental parameters and structural variations of the alkenes and thiols on the efficacy and regio‐ and stereoselectivity of the reactions was systematically studied and optimized. The type of anomeric heteroatom was found to profoundly affect the reactivity of 2,3‐unsaturated sugars in the thiol?ene couplings. Hydrothiolation of 2,3‐dideoxy O‐glycosyl enosides efficiently produced the axially C2‐S‐substituted addition products with high to complete regioselectivity. Moderate efficacy and varying regio‐ and stereoselectivity were observed with 2,3‐unsaturated N‐glycosides and no addition occurred onto the endocyclic double bond of C‐glycosides. Upon hydrothiolation of 2,3‐unsaturated S‐glycosides, the addition of thiyl radicals was followed by elimination of the thiyl aglycone resulting in 3‐S‐substituted glycals.     

Selective ortho‐Functionalization of Adamantylarenes Enabled by Dispersion and an Air‐Stable Palladium(I) Dimer

Contrary to the general belief that Pd‐catalyzed cross‐coupling at sites of severe steric hindrance are disfavored, we herein show that the oxidative addition to C?Br ortho to an adamantyl group is as favored as the corresponding adamantyl‐free system due to attractive dispersion forces. This enabled the development of a fully selective arylation and alkylation of C?Br ortho to an adamantyl group, even if challenged with competing non‐hindered C?OTf or C?Cl sites. The method makes use of an air‐stable Pd^I dimer and enables straightforward access to diversely substituted therapeutically important adamantylarenes in 5–30 min.     

Final‐Stage Site‐Selective Acylation for the Total Syntheses of Multifidosides A–C

The first total syntheses of multifidosides A–C have been achieved. The synthetic strategy is characterized by catalytic site‐selective acylation of unprotected glycoside precursors in the final stage of the synthesis. High functional‐group tolerance of the site‐selective acylation, promoted by an organocatalyst, enabled the conventionally difficult molecular transformation in a predictable and reliable manner. An advantage of this strategy is to avoid the risks of undesired side reactions during the removal of the protecting groups at the final stage of the total synthesis.     

Total Synthesis and Structure Elucidation of JBIR‐39: A Linear Hexapeptide Possessing Piperazic Acid and γ‐Hydroxypiperazic Acid Residues

The total synthesis and stereochemical structural elucidation of JBIR‐39, containing four nonproteinogenic piperazic acid (Piz) residues, is reported. The synthesis includes Sc(OTf)₃‐catalyzed acylation of a Piz(γ‐OTBS) derivative with piperazic acid chloride, providing the desired Piz‐Piz(γ‐OTBS) dipeptide in high yield without epimerization. After assembling two additional Piz moieties and (S)‐isoleucic acid at the N‐terminus, amidation with the (R)‐α‐methylserine ester at the C‐terminus, and deprotection afforded the desired (2R,8S)‐hexapeptide, which is the assumed structure of JBIR‐39. Although the spectral data of the (2R,8S)‐hexapeptide was not identical to JBIR‐39, further synthesis of three stereoisomers confirmed the stereochemical structure of JBIR‐39 to be (2S,6S,8S,11R,16S,21R,26S,27S).     

Light/Palladium‐Promoted Benzylic C−H Acylation Using a Benzoyl Group as the Photo‐Directing Group

2‐Methylphenyl ketones undergo site‐selective acylation at the benzylic position when treated with acid anhydride under UV irradiation in the presence of a palladium catalyst. The benzoyl carbonyl group serves as the photo‐directing group so that the ortho benzylic C?H bond is activated site‐selectively.     

Spontaneous Aminoacylation of a RNA Sequence Containing a 3′‐Terminal 2′‐Thioadenosine

We report the synthesis of a modified 8mer RNA sequence, (C‐C‐C‐C‐A‐C‐C‐(2′‐thio)A)‐RNA 5′‐(dihydrogen phosphate) ( 9 ) containing a 3′‐terminal 2′‐thioadenosine (Schemes 2 and 3), and its spontaneous and site‐specific aminoacylation with the weakly activated amino acid thioester H Phe SPh ( 12 ). This reaction, designed in analogy to the ‘native chemical ligation’ of oligopeptides, occurs efficiently in buffered aqueous solutions and under a wide range of conditions (Table). At pH values between 5.0 and 7.4, two products, the 3′‐O‐monoacylated and the 3′‐O,2′‐S‐diacylated RNA sequences 10 and 11 are formed fast and quantitatively (Scheme 4). At pH 7.4 and 37°, the 3′‐O‐monoacylated product 10 is formed as major product in situ by selective hydrolysis of the O,S‐diacylated precursor 11 . Additionally, the preparation and isolation of the relevant 3′‐O‐monoacylated product 10 was optimized at pH 5. The here presented concept could be employed for a straightforward aminoacylation of analogously modified tRNAs.     

Synthesis of 2‐Aryl‐1‐arylmethyl‐1H‐1,3‐benzimidazole Derivatives Using Silica‐bonded Propyl‐S‐sulfonic Acid as Recyclable Solid Acid Catalyst

A highly selective synthesis of 2‐aryl‐1‐arylmethyl‐1H‐1,3‐benzimidazoles from the reaction of o‐phenylenediamine and aromatic aldehydes in the presence of silica‐bonded propyl‐S‐sulfonic acid (SBSSA) at 80°C in water in good to excellent yields was developed.     

In Situ Deprotection and Incorporation of Unnatural Amino Acids during Cell‐Free Protein Synthesis

The S30 extract from E. coli BL21 Star (DE3) used for cell‐free protein synthesis removes a wide range of α‐amino acid protecting groups by cleaving α‐carboxyl hydrazides; methyl, benzyl, tert‐butyl, and adamantyl esters; tert‐butyl and adamantyl carboxamides; α‐amino form‐, acet‐, trifluoroacet‐, and benzamides; and side‐chain hydrazides and esters. The free amino acids are produced and incorporated into a protein under standard conditions. This approach allows the deprotection of amino acids to be carried out in situ to avoid separate processing steps. The advantages of this approach are demonstrated by the efficient incorporation of the chemically intractable (S)‐4‐fluoroleucine, (S)‐4,5‐dehydroleucine, and (2S,3R)‐4‐chlorovaline into a protein through the direct use of their respective precursors, namely, (S)‐4‐fluoroleucine hydrazide, (S)‐4,5‐dehydroleucine hydrazide, and (2S,3R)‐4‐chlorovaline methyl ester. These results also show that the fluoro‐ and dehydroleucine and the chlorovaline are incorporated into a protein by the normal biosynthetic machinery as substitutes for leucine and isoleucine, respectively.     

An Enzymatic N‐Acylation Step Enables the Biocatalytic Synthesis of Unnatural Sialosides

Chitin is one of the most abundant and cheaply available biopolymers in Nature. Chitin has become a valuable starting material for many biotechnological products through manipulation of its N‐acetyl functionality, which can be cleaved under mild conditions using the enzyme family of de‐N‐acetylases. However, the chemoselective enzymatic re‐acylation of glucosamine derivatives, which can introduce new stable functionalities into chitin derivatives, is much less explored. Herein we describe an acylase (CmCDA from Cyclobacterium marinum) that catalyzes the N‐acylation of glycosamine with a range of carboxylic acids under physiological reaction conditions. This biocatalyst closes an important gap in allowing the conversion of chitin into complex glycosides, such as C5‐modified sialosides, through the use of highly selective enzyme cascades.     

Hydroxamic Acid‐Piperidine Conjugate is an Activated Catalyst for Lysine Acetylation under Physiological Conditions

Lysine acylation of proteins is an essential chemical reaction for posttranslational modification and as a means of protein modification in various applications. N,N‐Dimethyl‐4‐aminopyridine (DMAP) derivatives are widely‐used catalysts for lysine acylation of proteins; however, the DMAP moiety mostly exists in a protonated, and thus deactivated, form under physiological conditions due to its basicity. An alternative catalytic motif furnishing higher acylation activity would further broaden the possible applications of chemical lysine acylation. We herein report that the hydroxamic acid‐piperidine conjugate Ph‐HXA is a more active catalytic motif for lysine acetylation than DMAP under physiological conditions. In contrast to DMAP, the hydroxamic acid moiety is mostly deprotonated under aqueous neutral pH, resulting in a higher concentration of the activated form. The Ph‐HXA catalyst is also more tolerant of deactivation by a high concentration of glutathione than DMAP. Therefore, Ph‐HXA might be a suitable catalytic motif for target protein‐selective and site‐selective acetylation in cells.     

天然产物 6-脱氧-6氨基葡萄糖甘油糖脂的合成

天然氨基甘油糖脂sn-1,2-dipalmitoyl-3-(N-palmitoyl-6-dehydroxy-6-amino-α-glucosyl)glycerol 3 和 sn-1-palmitoyl-2-myristoyl-3-(N-stearoyl-6-dehydroxy-6-amino-α-glucosyl)glycerol 4 通过简便有效的合成策略首次被合成。其关键步骤为：三氯亚胺酯糖基供体 10 与 (S)-isopropyleneglycerol 在乙醚溶液中发生糖苷化反应,立体选择性的生成3-O-(2,3,4-tri-O-benzyl-6-dehydroxy-6-benzyloxycarbonylamino-α-D- glucopyranoyl)-1,2-O-isopropylene-sn- glycerol 7。中间体 7 经过脱除丙酮叉、与不同的脂肪酸缩合、脱除保护基和选择性的在氨基上酰化,最终得到目标化合物 3 和 4。     

Integrative Chemical Biology Approaches for Identification and Characterization of “Erasers” for Fatty‐Acid‐Acylated Lysine Residues within Proteins

Acylation of proteins with fatty acids is important for the regulation of membrane association, trafficking, subcellular localization, and activity of many cellular proteins. While significant progress has been made in our understanding of the two major forms of protein acylation with fatty acids, N‐myristoylation and S‐palmitoylation, studies of the acylation of lysine residues, within proteins, with fatty acids have lagged behind. Demonstrated here is the use of integrative chemical biology approaches to examine human sirtuins as de‐fatty‐acid acylases in vitro and in cells. Photo‐crosslinking chemistry is used to investigate enzymes which recognize fatty‐acid acylated lysine. Human Sirt2 was identified as a robust lysine de‐fatty‐acid acylase in vitro. The results also show that Sirt2 can regulate the acylation of lysine residues, of proteins, with fatty acids within cells.     

Asymmetric Total Synthesis of (−)‐Englerin A through Catalytic Diastereo‐ and Enantioselective Carbonyl Ylide Cycloaddition

An asymmetric total synthesis of the guaiane sesquiterpene (?)‐englerin A, a potent and selective inhibitor of the growth of renal cancer cell lines, was accomplished. The basis of the approach is a highly diastereo‐ and enantioselective carbonyl ylide cycloaddition with an ethyl vinyl ether dipolarophile under catalysis by dirhodium(II) tetrakis[N‐tetrachlorophthaloyl‐(S)‐tert‐leucinate], [Rh₂(S‐TCPTTL)₄], to construct the oxabicyclo[3.2.1]octane framework with concomitant introduction of the oxygen substituent at C9 on the exo‐face. Another notable feature of the synthesis is ruthenium tetraoxide‐catalyzed chemoselective oxidative conversion of C9 ethyl ether to C9 acetate.     

Synthesis of 2‐Chirally Substituted 3,3′‐Biquinazoline‐4,4′‐diones

A facile route for the synthesis of 2‐substituted biquinazolinones incorporating a chiral center into one of their lateral appendage, via condensation of 4H‐3,1‐benzoxazin‐4‐one with 3‐amino‐2S‐substituted‐quinazolin‐4‐ones, is described. The methodology is straightforward and does not require chromatographic purification at any stage. The products are obtained in good yields as mixture of diastereoisomers, which can be enriched with the major diastereoisomer by simple recrystallization. The functional groups in the lateral chain can be easily modified allowing the synthesis of a variety of 3,3′‐biquinazoline‐4,4′‐diones. The synthesis of symmetrically 2,2′ chirally disubstituted biquinazolinones via acylation/dehydration sequence of bisanthraniloyl hydrazine is also described.     

A Tailor‐Made Chimeric Thiamine Diphosphate Dependent Enzyme for the Direct Asymmetric Synthesis of (S)‐Benzoins

Thiamine diphosphate dependent enzymes are well known for catalyzing the asymmetric synthesis of chiral α‐hydroxy ketones from simple prochiral substrates. The steric and chemical properties of the enzyme active site define the product spectrum. Enzymes catalyzing the carboligation of aromatic aldehydes to (S)‐benzoins have not so far been identified. We were able to close this gap by constructing a chimeric enzyme, which catalyzes the synthesis of various (S)‐benzoins with excellent enantiomeric excess (>99 %) and very good conversion.     

Stereoselective Total Synthesis of (11β)‐11‐Methoxycurvularin

A simple and highly efficient stereoselective total synthesis of (11β)‐11‐methoxycurvularin ( 5 ), a polyketide natural product, was achieved. The synthesis commenced with a Cu‐mediated regioselective opening of (2S)‐2‐methyloxirane ( 6 ) and comprised a Keck asymmetric allylation and intramolecular Friedel–Crafts acylation as key steps (Scheme 2).     

Discovery of New S‐Glycosides and N‐Glycosides of Pyridine‐biphenyl System with Antiviral Activity and Induction of Apoptosis in MCF7 Cells

Glycosylation of small molecule‐based drugs can dramatically improve the biological activities of the parent scaffold. In the current study, S‐glycosides and N‐glycosides of polyfunctionalized pyridine‐biphenyl system tethered with benzotriazole moiety were designed and synthesized. S‐Glycosides of pyridine‐2‐thione derivatives 5a – h and N‐glycosides of pyridine‐2‐one derivatives 9a , b were synthesized by a facile, convenient, and high‐yielding procedure. The epimers glucose and galactose, acetylated or deacetylated, were used to form the glycone part. The structures of these compounds were confirmed by microanalysis and spectroscopic data (IR, ¹ H–NMR, and ¹³C‐NMR). The anticancer activities of the target compounds, in comparison with standard cisplatin, were assessed by MTT assay against MCF7 cell line. Compounds 4f , 4g , 5f , and 5h exhibited the highest cytotoxic effect on MCF7. The anticancer effect of these four compounds induced the apoptosis as evident by the up‐regulated expression of the apoptotic genes Bax and p53 and down‐regulated expression of the anti‐apoptotic gene BCl₂. S‐Glycoside derivatives are more active than N‐glycosides. Moreover, the nontoxic doses of the tested compounds were evaluated in MA104, FRHK4, BGM, Hep2, and Vero cells. Compounds 4a – d and 5a – d were also evaluated for their antiviral effect against HSV‐1, HAV, and rotavirus Wa strain. The compounds' results showed less, moderated, and high antiviral activities. The docking study for these compounds with MDM2 revealed that deacetylated galactose is important for binding with the receptor as it facilitates the formation of hydrogen bond in the receptor. Rapid overlay of chemical structures analysis was employed to understand the compounds' similarity on the basis of their shape structure using the Tanimoto scores.