Free Hydroxy Group Research Articles

Asymmetric Total Synthesis of Phomarol

Asymmetric Total Synthesis of Phomarol

Slow degrading poly(glycerol sebacate) derivatives improve vascular graft remodeling in a rat carotid artery interposition model

Porous synthetic grafts made of poly (glycerol sebacate) (PGS) can transform into autologous vascular conduits in vivo upon degradation of PGS. A long-held doctrine in tissue engineering is the necessity to match degradation of the scaffolds to tissue regeneration. Here, we tested the impact of degradation of PGS and its derivative in an interposition model of rat common carotid artery (CCA). Previous work indicates a complete degradation of PGS within approximately 2 weeks, likely at the fast end of the spectrum. Thus, the derivation of PGS focuses on delay degradation by conjugating the free hydroxy groups in PGS with a long chain carboxylic acid: palmitic acid, one of the most common lipid components. We evaluated two of the resultant palmitate-PGS (PPGS) in this study: one containing 9% palmitate (9-PPGS) and the other16% palmitate (16-PPGS). 16-PPGS grafts had the highest patency. Ultrasound imaging showed that the lumens of 16-PPGS grafts were similar to CCA and smaller than 9-PPGS and PGS grafts 12 weeks post-operation. Immunohistological and histological examination showed an endothelialized lumens in all three types of grafts within 4 weeks. Inflammatory responses to 16-PPGS grafts were limited to the adventitial space in contrast to a more diffusive infiltration in 9-PPGS and PGS grafts in week 4. Examination of calponin+ and αSMA+ cells revealed that 16-PPGS grafts remodeled into a distinctive bi-layered wall, while the walls of 9-PPGS grafts and PGS grafts only had one thick layer of smooth muscle-like cells. Correspondingly, the expression of collagen III and elastin displayed an identical layered structure in the remodeled 16-PPGS grafts, in contrast to a more spread distribution in 9-PPGS and PGS grafts. All the three types of grafts exhibited the same collagen content and burst pressure after 12 weeks of host remodeling. However, the compliance and elastin content of 16-PPGS grafts in week 12 were closest to those of CCA. Overall, placing the degradation of PGS derived elastomer to a window of 4–12 weeks results in vascular conduits closer to arteries in a rat carotid artery interposition model over a 12-week observation period.

Azidation of Partially Protected Carbohydrate Derivatives: Efficient Suppression of Acyl Migration

Although azidation by nucleophilic substitution is widely used in organic chemistry, it has a limitation for partially protected carbohydrate derivatives under typical reaction conditions used for azidation (heating with NaN3, phase-transfer catalyst (optional), DMF or DMSO) as it can cause substantial migration (70%) of O-acyl protective groups. Several approaches, including the use of a temporary protective group for the unprotected hydroxyl group, to avoid acyl migration have been compared. Addition of excess of ethyl trifluroacetate effectively suppressed benzoyl migration but inhibited substitution of the chlorine atom with the azido group. The most robust procedure involved addition of excess n-butyl formate to the reaction mixture. When this protocol was followed, migration of benzoyl groups in lactose derivatives with free hydroxy group at C-3′ or C-4′ was reduced to 4%, with the yield of the target, partially protected derivatives with an azido group in the aglycone approaching 92%.

2-O-Monoalkyl isosorbide ethers with C8, C10, C12 and C14 chain lengths.

The title compounds, 6-(octyloxy)hexa-hydro-furo[3,2-b]furan-3-ol, C14H26O4, 6-(decyl-oxy)hexa-hydro-furo[3,2-b]furan-3-ol, C16H30O4, 6-(do-decyl-oxy)hexa-hydro-furo[3,2-b]furan-3-ol, C18H34O4, and 6-(tetra-decyl-oxy)hexa-hydro-furo[3,2-b]furan-3-ol, C20H38O4, consist of a polar headgroup (isosorbide) and a lipophilic alkyl chain linked via an ether bridge. Isosorbide is a biobased diol, containing two fused furan rings. One inter-molecular hydrogen bond connects the mol-ecules between the free endo hy-droxy group and the opposing ether oxygen of the V-shaped head group. Thus the mol-ecule layers inter-lock like in a herringbone pattern parallel to the bc plane.

Metalation of Catechol-Functionalized Defective Covalent Organic Frameworks for Lewis Acid Catalysis.

Covalent organic frameworks (COFs) have emerged as a fascinating crystalline porous material and are widely used in the field of catalysis. However, developing simple approaches to fabricate conjugated COFs with specific functional groups remains a significant challenge. In this study, the construction of defective COF-LZU1 with Lewis acid sites embedded into the frameworks is fulfilled by a facile solvent-assisted ligand exchange method. A monodentate ligand, protocatechualdehyde, is successfully introduced into the skeleton of COF-LZU1, which endows the defects in the structure of COF-LZU1 via replacement of the original coordinated benzene-1,3,5-tricarbaldehyde ligand. As-synthesized defective COF-LZU1 decorated with protocatechualdehyde is rich of free hydroxy groups for chelating with active metal ions. Specifically, after combining with Fe3+ , the defective COF-LZU1 shows excellent activity in catalytic alcoholysis of epoxides under mild conditions. The method reported here will open up the opportunity to incorporate different functional groups into COFs and enrich the strategies for creating new types of porous catalysts.

Chemical Profiling of Astragalus membranaceus Roots (Fish.) Bunge Herbal Preparation and Evaluation of Its Bioactivity

Astragalus membranaceus (Fish.) Bunge is a perennial herb distributed in the northern part of China, and its roots, namely, Hang qi, are included as a natural ingredient in dietary supplement formulations commonly used to treat different disorders such as respiratory infections, diabetes, and heart failure. The availability of a simple method for the determination of the quality of Astragalus herbal preparations could be a challenging issue for commercial purposes. In this study, a liquid chromatography–mass spectrometry (LC–MS)/MS based approach was used to characterize specialized metabolite recovery of 3 commercial hydroalcoholic extracts of A. membranaceus (AMG1, AMG2, AMG3) in addition to a hydroalcoholic extract of A. membranaceus root (AST). The hypoglycemic effect, cholinesterase inhibition, and antioxidant activities were also evaluated. Thirty-one compounds, of which 19 polyphenols and 12 saponins, were identified. The extracts were also quantified by using a sensitive and selective Q-Trap system for their content in flavonoids and astragalosides, selecting astragaloside I and IV as chemical markers. From our results, AMG3 preparation (Axtragyl) was the most abundant in terms of both specialized classes of metabolites, showing a fingerprint similar to that of AST. Interestingly, tested enzyme inhibition ability of flavonoids, daidzein (11) and formononetin (19), reported a higher α-glucosidase inhibition in comparison with that of acarbose used as positive control. The in silico study clarified the interactions among the molecules and the importance of having a free hydroxy group. Moreover, Axtragyl was able to exert protective effects in Caco-2 cells treated with hydrogen peroxide, confirming its ability as a potential protective agent in intestinal injury.

Quantification of hydroxy groups in carbohydrates using gas-phase N2 adsorption

Gas-phase N2 adsorption of mass-selected ions of carbohydrates containing 2–5 hydroxy groups was investigated using a tandem mass spectrometer equipped with an electrospray ionization source and cold ion trap. The maximum quantities of adsorbed N2 molecules observed in the mass spectra were consistent with the quantities of hydroxy groups in the carbohydrates. The N2 molecules were adsorbed on the hydrogen atoms of the hydroxy groups of the carbohydrates. The hydroxy groups of the carbohydrates were quantified using gas-phase N2 adsorption. Gas-phase N2-adsorption mass spectrometry detects free hydroxy groups on the surface of gas-phase ions.

DETAILS OF A MULTICOMPONENT BIGINELLI REACTION INVOLVING 3-OXOBUTANOYL-CONTAINING PODANDS, AROMATIC ALDEHYDES, AND 1,2,4-TRIAZOLE-3-AMINE

A reaction of 3-oxobutanoyl-containing podands with thiophene-2-carbaldehyde (or benzaldehyde) and 3-amino-1,2,4-triazole gave podands featuring a 4,7-dihydro[1,2,4]triazolo[1,5- а ]pyrimidine motif. It was established that the process was accompanied by the formation of [4,3- а ]-isomers, which occurred in a slight excess during the synthesis of a podand containing a phenyl group at position 7 and, on the other hand, were observed as the minor products during the synthesis of podands bearing a thiophen-2-yl substituent. Trace amounts of monosubstituted podands were also detected, containing a free hydroxy group along with the triazolodihydropyrimidine pharmacophore.

Nostotrebin 6 Related Cyclopentenediones and δ-Lactones with Broad Activity Spectrum Isolated from the Cultivation Medium of the Cyanobacterium Nostoc sp. CBT1153

Cyanobacteria are an interesting source of biologically active natural products, especially chemically diverse and potent protease inhibitors. On our search for inhibitors of the trypanosomal cysteine protease rhodesain, we identified the homodimeric cyclopentenedione (CPD) nostotrebin 6 (1) and new related monomeric, dimeric, and higher oligomeric compounds as the active substances in the medium extract of Nostoc sp. CBT1153. The oligomeric compounds are composed of two core monomeric structures, a trisubstituted CPD or a trisubstituted unsaturated δ-lactone. Nostotrebin 6 thus far has been the only known cyanobacterial CPD. It has been found to be active in a broad variety of assays, indicating that it might be a pan-assay interference compound (PAIN). Thus, we compared the antibacterial and cytotoxic activities as well as the rhodesain inhibition of selected compounds. Because a compound with a δ-lactone instead of a CPD core structure was equally active as nostotrebin 6, the bioactivities of these compounds seem to be based on the phenolic substructures rather than the CPD moiety. While the dimers were roughly equally potent, the monomer displayed slightly weaker activity, suggesting that the compounds show unspecific activity depending upon the number of free phenolic hydroxy groups per molecule.

Features of a multicomponent Biginelli reaction involving 3-oxobutanoyl-containing podands, aromatic aldehydes, and 1,2,4-triazol-3-amine

A reaction of 3-oxobutanoyl-containing podands with thiophene-2-carbaldehyde (or benzaldehyde) and 3-amino-1,2,4-triazole gave podands featuring a 4,7-dihydro[1,2,4]triazolo[1,5-а]pyrimidine motif. It was established that the process was accompanied by the formation of [4,3-а]-isomers, which occurred in a slight excess during the synthesis of a podand containing a phenyl group at position 7 and, on the other hand, were observed as the minor products during the synthesis of podands bearing a thiophen-2-yl substituent. Trace amounts of monosubstituted podands were also detected, containing a free hydroxy group along with the triazolodihydropyrimidine pharmacophore.

Probing the Interconversion of Labdane Lactones from the Chinese Liverwort Pallavicinia ambigua.

We report on the spontaneous, reversible intramolecular transesterification of natural labdane lactones. Through extensive spectroscopic analysis, the interconversion between the two tautomers was investigated, which could be retarded when the free hydroxy group was acetylated or the exocyclic double bond of the lactone ring was mutated. Besides, a conversion mechanism was postulated, and the energy barriers were calculated by density functional theory calculations. Furthermore, the tautomers were found to inhibit the virulence of the efflux pump-deficient Candida albicans DSY654.

A Coumarin Triflate Reagent Enables One-Step Synthesis of Photo-Caged Lipid Metabolites for Studying Cell Signaling.

Photorelease of caged compounds is among the most powerful experimental approaches for studying cellular functions on fast timescales. However, its full potential has yet to be exploited, as the number of caged small molecules available for cell biological studies has been limited by synthetic challenges. Addressing this problem, a straightforward, one‐step procedure for efficiently synthesizing caged compounds was developed. An in situ generated benzylic coumarin triflate reagent was used to specifically functionalize carboxylate and phosphate moieties in the presence of free hydroxy groups, generating various caged lipid metabolites, including a number of GPCR ligands. By combining the photo‐caged ligands with the respective receptors, an easily implementable experimental platform for the optical control and analysis of GPCR‐mediated signal transduction in living cells was developed. Ultimately, the described synthetic strategy allows rapid generation of photo‐caged small molecules and thus greatly facilitates the analysis of their biological roles in live cell microscopy assays.

Characterization of alkaline phosphatase PhoK from Sphingomonas sp. BSAR-1 for phosphate monoester synthesis and hydrolysis

The biocatalytic activity of a so far underexploited alkaline phosphatase, PhoK from Sphingomonas sp. BSAR-1, was extensively studied in transphosphorylation and hydrolysis reactions. The use of high-energy phosphate donors and oligophosphates as suitable phosphate donors was evaluated, as well as the hydrolytic activity on a variety of phosphate monoesters. While substrates bearing free hydroxy group displayed only moderate reactivity as acceptors for transphosphorylation by PhoK, strong hydrolytic activity on a broad variety of phosphate monoesters under alkaline conditions was observed. Site-directed mutagenesis of selected amino acid residues in the active site provided valuable insights on their involvement in enzyme catalysis. The key residue Thr89 so far postulated to engage in enzyme phosphorylation was confirmed to be crucial for catalysis and could be replaced by serine, albeit with much lower catalytic efficiency.

Chemoenzymatic synthesis of hydroxytyrosol monoesters and their suppression effect on nitric oxide production stimulated by lipopolysaccharides.

Fatty acid monoesters of hydroxytyrosol [2-(3,4-dihydroxyphenyl)ethanol] were synthesized in two steps from tyrosol (4-hydroxyphenylethanol) by successive Candida antarctica lipase B-catalyzed chemoselective acylation on the primary aliphatic hydroxy group over phenolic hydroxy group in tyrosol, and 2-iodoxybenzoic acid (IBX)-mediated hydroxylation adjacent to the remaining free phenolic hydroxy group. Examination of their suppression effects on nitric oxide production stimulated by lipopolysaccharides in RAW264.7 cells showed that hydroxytyrosol butyrate exhibited the highest inhibition (IC50 7.0 μM) among the tested compounds.

Synthesis and structure of functionalized podands containing 4,7-dihydrotetrazolo[1,5-а]pyrimidine ring. Differently substituted dihydropyrimidine podands

The reaction of 3-oxobutanoate-containing polyethers with benzaldehyde and 5-aminotetrazole in the presence of polyphosphoric acid was used to synthesize podands containing two terminal tetrazolo[1,5-а]dihydropyrimidine groups. Byproducts were isolated and identified as podands containing different substituents – one 4,7-dihydrotetrazolo[1,5-а]pyrimidine ring system and a free hydroxy group at the other terminus of the polyether chain. Analogous differently substituted podands, including one 3,4-dihydropyrimidine-2(1H)-thione moiety, were isolated from the reactions of 3-oxobutanoate-containing polyethers with benzaldehyde and thiourea.

A Ring Contraction of 2,3-Di- O-Silylated Thiopyranosides To Give Thiofuranosides under Mildly Acidic Conditions.

A pyranose ring contraction of ethyl 1-thio-β-d-galactopyranosides has been discovered that proceeds with retention of aglyconunder mildly acidic conditions (aq TFA in CH2Cl2). Key factors for success of this rearrangement are the presence of bulky silyl (TIPS or TBDPS) substituents at both O-2 and O-3 and a free hydroxy group at C-4 (derivatives with acid-labile protective groups at O-4 will also engage in this reaction). The rearrangement cleanly proceeds for 2,3-di- O-TIPS derivatives with two hydroxy groups at C-4 and C-6, acid-labile TES groups at O-4 and O-6, or one acyl substituent (Bz, ClAc) at O-6. A possibility to switch the direction of the debenzylidenation reaction in 4,6- O-benzylidene-2,3-di- O-TIPS/TBDPS derivatives by the choice of an acid (TFA, which cleanly gives furanose, versus AcOH, which cleaves benzylidene acetal only) may present an advantage in the divergent synthesis of selectively protected glycosyl donors (either in furanose or pyranose form) useful for the synthesis of biologically important oligosaccharides.

An Organocatalytic Asymmetric Synthesis of Chiral β,β-Diaryl-α-amino Acids via Addition of Azlactones to In Situ Generated para-Quinone Methides.

An organocatalytic intermolecular C-C bond formation process leading to the efficient synthesis of chiral β,β-diaryl-α-amino acid derivatives is described. In the presence of a suitable chiral phosphoric acid catalyst, a range of para-hydroxybenzyl alcohols serve as efficient precursors to para-quinone methides and then react with azlactones in 1,6-conjugate addition reactions. The asymmetric control has been carefully optimized together with diastereocontrol enabled by identification of the reversible feature of the C-C bond formation and subsequent inhibition by protection of the free hydroxy group in one pot. Compared with previous approaches, including those with pre-synthesized para-quinone methides, this protocol provides an alternative and complementary step- and pot-economical approach for the synthesis of chiral β,β-diaryl-α-amino acid derivatives.

Stereoretentive Reactions at the Anomeric Position: Synthesis of Selenoglycosides

AbstractReported is the stereospecific cross‐coupling of anomeric stannanes with symmetrical diselenides, resulting in the synthesis of selenoglycosides with exclusive anomeric control. The reaction proceeds without the need for directing groups and is compatible with free hydroxy groups as demonstrated in the preparation of glycoconjugates derived from mono‐, di‐, and trisaccharides and peptides (35 examples). Given its generality and broad substrate scope, the glycosyl cross‐coupling method presented herein can find use in the synthesis of selenium‐containing glycomimetics and glycoconjugates.

Stereoretentive Reactions at the Anomeric Position: Synthesis of Selenoglycosides.

Reported is the stereospecific cross-coupling of anomeric stannanes with symmetrical diselenides, resulting in the synthesis of selenoglycosides with exclusive anomeric control. The reaction proceeds without the need for directing groups and is compatible with free hydroxy groups as demonstrated in the preparation of glycoconjugates derived from mono-, di-, and trisaccharides and peptides (35 examples). Given its generality and broad substrate scope, the glycosyl cross-coupling method presented herein can find use in the synthesis of selenium-containing glycomimetics and glycoconjugates.

Early/Late Heterobimetallic Tantalum/Rhodium Species Assembled Through a Novel Bifunctional NHC-OH Ligand.

The straightforward synthesis of a new unsymmetrical hydroxy-tethered N-heterocyclic carbene (NHC) ligand, HL, is presented. The free ligand exhibits an unusual OH-carbene hydrogen-bonding interaction. This OH-carbene motif was used to yield 1) the first tantalum complex displaying both a Fischer- and Schrock-type carbene ligand and 2) a unique NHC-based early/late heterobimetallic complex. More specifically, the protonolysis chemistry between the ligand's hydroxy group and imido-alkyl or alkylidene-alkyl tantalum precursor complexes yielded the rare monometallic tantalum-NHC complexes [Ta(XtBu)(L)(CH2 tBu)2 ] (X=N, CH), in which the alkoxy-carbene ligand acts as a chelate. In contrast, HL only binds to rhodium through the NHC unit in [Rh(HL)(cod)Cl] (cod=cycloocta-1,5-diene), the hydroxy pendant arm remaining unbound. This bifunctional ligand scaffold successfully promoted the assembly of rhodium/tantalum heterobimetallic complexes upon either 1) the insertion of [Rh(cod)Cl]2 into the Ta-NHC bond in [Ta(NtBu)(L)(CH2 tBu)2 ] or 2) protonolysis between the free hydroxy group in [Rh(HL)(cod)Cl] and one alkyl group in [Ta(NtBu)(CH2 tBu)3 ].