Deprotection Procedure Research Articles

Synthesis of a Novel 2-((4,5-Diphenyl-4H-1,2,4-triazol-3-yl)thio)acetaldehyde as a Bisulfite Adduct

The scope of the current work was to synthesize an S-alkylated 1,2,4-triazole-3-thiol derivative. Synthesis was carried out in two steps: in the first step, 4,5-diphenyl-4H-1,2,4-triazole-3-thiol was S-alkylated using a halogenated acetal and cesium carbonate. In the second step, several acetal deprotection procedures were tested, and the aldehyde obtained was isolated as a bisulfite adduct. The structures of the new compounds were characterized by FT-IR, 1D, and 2D NMR spectroscopic methods.

Orthogonal Glycosylation with Phosphate Acceptors for Expeditious Synthesis of Bacterial Inner Core Oligosaccharides.

We report a practical one-pot glycosylation strategy for synthesis of bacterial inner core oligosaccharides that composed of unavailable L-glycero-D-manno and D-glycero-D-manno-heptopyranose components. The glycosylation method features a new orthogonal glycosylation procedure; whereby a phosphate acceptor is coupled with a thioglycosyl donor producing a disaccharide phosphate, which can be engaged in another orthogonal glycosylation procedure to couple with a thioglycosyl acceptor. The phosphate acceptors used in above one-pot procedure are directly prepared from thioglycosyl acceptors via the in-situ phosphorylation. Such phosphate acceptor preparation protocol eliminates the traditional protection and deprotection procedures. Based on the new one-pot glycosylation strategy, two partial inner core structures of Yersinia pestis lipopolysaccharide and Haemophilus ducreyi lipooligosaccharide were acquired.

Chemoselective Catalytic Dehydrogenation of Benzylic Amines Driven by the TEtraQuinoline/FeCl2 Complex

AbstractA chemoselective dehydrogenation protocol for benzylic amines catalyzed by the TEtraQuinoline (TEQ)/FeCl2 complex is described. In combination with 2 equiv of tert‐butyl hydroperoxide, as little as 0.1 mol% of catalyst loading was sufficient to convert primary and secondary benzylic amines to the corresponding imines and dimerized imines, respectively. Subsequent hydrolysis of the imines allowed for removal of the benzyl group on the nitrogen atom. Nonaromatic carbon‐carbon multiple bonds and the O‐Bn group remained intact in the present protocol, providing a complementary deprotection procedure to reductive removal conditions exerted by Pd catalysis.

A new procedure for thioester deprotection using thioglycolic acid in both homogeneous and heterogeneous phase

Classic acetyl thioester protection/deprotection methodologies are widely used in organic synthesis, but deprotection step usually requires harsh conditions not suitable for labile substrates. In this work, a new method for thioester deprotection using a thiotransesterification approach is described. Firstly, thioglycolic acid (TGA) was identified as a good deprotecting reagent in solution. In order to develop a thiol polymer-supported reagent, TGA was anchored to a PEG-based resin through an amide bond (TG-NCO-SH). Both homogeneous and heterogeneous approaches were conveniently carried out at room temperature, in aqueous buffer at pH 8. The mild conditions were suitable for alkyl and phenyl thioesters. Moreover labile thioesters containing thiazolidine and oxazolidine scaffolds, bearing amine, ester and acetal functionalities were also deprotected. The polymer-supported TGA gave better deprotection yields compared to TGA in solution, yields ranging from 61 to 90%. The feasibility of the recovery and reuse of TG-NCO-SH reagent was explored, showing it can be reused at least five times without lossing the activity.

Organocatalyzed Ring-Opening Polymerization of Cyclic Lysine Derivative: Sustainable Access to Cationic Poly(ε-lysine) Mimics

Poly(e-lysine) has broad applications and is dominantly produced via fermentation. Our group successfully realized the chemosynthesis of poly(e-lysine) through ring-opening polymerization (ROP) of a 2,5-dimethylpyrrole-protected cyclic lysine monomer, but the complete removal of the protecting group suffers from a prolonged time and low yield. Herein, we have developed organocatalyzed ROP of a dimethyl-protected cyclic lysine that avoids the tedious deprotection procedures to prepare cationic poly(e-lysine) mimics with quaternary ammonium groups in high yields. Such poly(e-lysine) mimics not only exhibit potent antimicrobial activities but also demonstrate good biocompatibility and have no significant hemolytic activities. The antimicrobial activities of poly(e-lysine) mimics were ∼80.0% at a concentration of 100 μg/mL in comparison to 76.0% of the poly(e-lysine) control. In brief, our research provides a novel class of functional mimics of poly(e-lysine) and opens up new avenues for designing and furnishing poly(amino acid) mimetics for biological functions and applications.

Aryl groups, supplement of amino protecting group chemistry!

Amino group protective strategy has consequently emerged in multistep organic synthesis. Easy and selective deprotection procedures are crucial to facilitate the chemical transformation. Recently, Zhang’s group from Henan Normal University collaborating with Chen’s group of Nankai University developed a novel strategy for the regiospecific cleavage of inert aryl CN bonds in N-aryl amides by hypervalent iodine(V) reagents. These procedures allow removal of sort of aryl groups under mild conditions to give primary amides in high efficiency. It bestows these aryl groups with the characteristics of amino protecting groups that might be the supplement of amino protecting group chemistry.

A High-Yielding Synthesis of EIDD-2801 from Uridine.

A simple reordering of the reaction sequence allowed the improved synthesis of EIDD‐2801, an antiviral drug with promising activity against the SARS‐CoV‐2 virus, starting from uridine. Compared to the original route, the yield was enhanced from 17 % to 61 %, and fewer isolation/purification steps were needed. In addition, a continuous flow procedure for the final acetonide deprotection was developed, which proved to be favorable toward selectivity and reproducibility.

Pyrrole-Protected β-Aminoalkylzinc Reagents for the Enantioselective Synthesis of Amino-Derivatives.

Chiral β‐aminoalkylzinc halides were prepared starting from optically pure commercial β‐amino‐alcohols. These amino‐alcohols were converted to the corresponding N‐pyrrolyl‐protected alkyl iodides which undergo a zinc insertion in the presence of LiCl (THF, 25 °C, 10–90 min). Subsequent Negishi cross‐coupling or acylation reactions with acid chlorides produced amino‐derivatives with retention of chirality. Diastereoselective CBS‐reductions of some prepared N‐pyrrolyl‐ketones provided 1,3‐subsituted N‐pyrrolyl‐alcohols with high diastereoselectivity. Additionally, a deprotection procedure involving an ozonolysis allowed the conversion of the pyrrole‐ring into a formamide without loss of optical purity.

Novel applications of modification of thiol enzymes and redox-regulated proteins using S-methyl methanethiosulfonate (MMTS)

S-Methyl methanethiosulfonate (MMTS) is used in experimental biochemistry for alkylating thiol groups of protein cysteines. Its applications include mainly trapping of natural thiol-disulfide states of redox-sensitive proteins and proteins which have undergone S-nitrosylation. The reagent can also be employed as an inhibitor of enzymatic activity, since nucleophilic cysteine thiolates are commonly present at active sites of various enzymes. The advantage of using MMTS for this purpose is the reversibility of the formation of methylthio mixed disulfides, compared to irreversible alkylation using conventional agents. Additional benefits include good accessibility of MMTS to buried protein cysteines due to its small size and the simplicity of the protection and deprotection procedures. In this study we report examples of MMTS application in experiments involving oxidoreductase (glyceraldehyde-3-phosphate dehydrogenase, GAPDH), redox-regulated protein (recoverin) and cysteine protease (triticain-α). We demonstrate that on the one hand MMTS can modify functional cysteines in the thiol enzyme GAPDH, thereby preventing thiol oxidation and reversibly inhibiting the enzyme, while on the other hand it can protect the redox-sensitive thiol group of recoverin from oxidation and such modification produces no impact on the activity of the protein. Furthermore, using the example of the papain-like enzyme triticain-α, we report a novel application of MMTS as a protector of the primary structure of active cysteine protease during long-term purification and refolding procedures. Based on the data, we propose new lines of MMTS employment in research, pharmaceuticals and biotechnology for reversible switching off of undesirable activity and antioxidant protection of proteins with functional thiol groups.

A deprotection procedure using SO3H silica gel to remove non-silyl protecting groups

Protecting groups are indispensable in organic synthesis and there is a great need for a variety of deprotection methods. Here, we investigated the scope of the application of a deprotection procedure using SO3H silica gel, which we have previously reported as a desilylation procedure. Under these conditions, -OMOM, -OSEM, -OTHP, and -OAc groups and dimethyl acetal were cleaved. Pivaloyloxy, benzyloxy and methoxy carbonyl groups remained intact and selective deprotection of TBS groups in the presence of other protecting groups was accomplished. We succeeded in cleaving an acetyl group on a secondary alcohol in a highly polar nortropine derivative. Our findings here provide another deprotection option and would be helpful in the synthesis of multifunctional compounds.

Synthesis and Anticonvulsant Activity of α-Amino Acid Amide Derivatives

Background: Epilepsy is a disease of the central nervous system that affects approximately 50 million individuals worldwide. Although several new drugs have been marketed in the last 25 years, almost one-third of patients are not protected. In many cases, currently available drugs produce undesirable side effects. As a result, a need exists for novel anticonvulsants with unique mechanisms of action and minimal side effects. Methods: A mixed anhydride coupling procedure and standard deprotection procedures were utilized to prepare 36 α-amino acid amides. All final products were evaluated in mice and rats utilizing a standard battery of anticonvulsant tests. Results: α-Amino acids containing a 2,6-dimethylanilide group exhibited anticonvulsant activity in the maximal electroshock seizure test and 6 Hz test in mice and rats. A small, branched-chain on the α- carbon generally maintained or enhanced anticonvulsant activity in the maximal electroshock seizure test. The (R)-α-amino acid amides were typically more potent and slightly more neurotoxic than the corresponding (S)-enantiomers. The valine dimethylanilide (R)-42 was highly active in the MES test in mice (ED50 = 3.6mg/kg) and rats (ED50 = 3.8 mg/kg). (R)-42 also demonstrated excellent anticonvulsant activity in the 6 Hz, picrotoxin, and corneal kindled mouse tests. Furthermore, (R)-42 did not lower seizure threshold when evaluated in the intravenous metrazol seizure test. Conclusion: α-Amino acid 2,6-dimethylanilides exhibited potent activity in a variety of anticonvulsant tests in mice and rats. The valine derivative (R)-42 represents a promising compound for potential use in complex partial seizures.

Solid-phase synthesis and structural characterisation of phosphoroselenolate-modified DNA: a backbone analogue which does not impose conformational bias and facilitates SAD X-ray crystallography.

Oligodeoxynucleotides incorporating internucleotide phosphoroselenolate linkages have been prepared under solid-phase synthesis conditions using dimer phosphoramidites. These dimers were constructed following the high yielding Michaelis-Arbuzov (M-A) reaction of nucleoside H-phosphonate derivatives with 5'-deoxythymidine-5'-selenocyanate and subsequent phosphitylation. Efficient coupling of the dimer phosphoramidites to solid-supported substrates was observed under both manual and automated conditions and required only minor modifications to the standard DNA synthesis cycle. In a further demonstration of the utility of M-A chemistry, the support-bound selenonucleoside was reacted with an H-phosphonate and then chain extended using phosphoramidite chemistry. Following initial unmasking of methyl-protected phosphoroselenolate diesters, pure oligodeoxynucleotides were isolated using standard deprotection and purification procedures and subsequently characterised by mass spectrometry and circular dichroism. The CD spectra of both modified and native duplexes derived from self-complementary sequences with A-form, B-form or mixed conformational preferences were essentially superimposable. These sequences were also used to study the effect of the modification upon duplex stability which showed context-dependent destabilisation (-0.4 to -3.1 °C per phosphoroselenolate) when introduced at the 5'-termini of A-form or mixed duplexes or at juxtaposed central loci within a B-form duplex (-1.0 °C per modification). As found with other nucleic acids incorporating selenium, expeditious crystallisation of a modified decanucleotide A-form duplex was observed and the structure solved to a resolution of 1.45 Å. The DNA structure adjacent to the modification was not significantly perturbed. The phosphoroselenolate linkage was found to impart resistance to nuclease activity.

N-(2-Hydroxypropyl)methacrylamide-Based Linear, Diblock, and Starlike Polymer Drug Carriers: Advanced Process for Their Simple Production.

We developed a new simplified method for the synthesis of well-defined linear, diblock, or starlike N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer drug carriers using controlled reversible addition-fragmentation chain transfer polymerization. The prepared monodispersed polymers are after the drug attachment intended for enhanced anticancer therapy. This new approach significantly reduces the number of required synthetic steps and minimizes the consumption of organic solvents during the synthesis. As a result, highly defined linear, diblock, and starlike copolymers designed for pH-triggered drug activation/release in tumor tissue were formed in sufficient amounts for further physicochemical and biological studies. Within the synthesis, we also developed a new procedure for the selective deprotection of tert-butoxycarbonyl hydrazide and amine groups on hydrophilic HPMA copolymers, including the one-pot removal of polymer end groups. We studied and described in detail the kinetics and efficacy of the deprotection reaction. We believe the simplified synthetic approach facilitates the preparation of polymer conjugates bound by the pH-sensitive hydrazone bond and their application in tumor treatment.

Novel 18F-Labeled PET Imaging Agent FV45 Targeting the Renin-Angiotensin System.

Renin–angiotensin system (RAS) plays an important role in the regulation of blood pressure and hormonal balance. Using positron emission tomography (PET) technology, it is possible to monitor the physiological and pathological distribution of angiotensin II type 1 receptors (AT1), which reflects the functionality of RAS. A new 18F-labeled PET tracer derived from the clinically used AT1 antagonist valsartan showing the least possible chemical alteration from the valsartan structure has been designed and synthesized with several strategies, which can be applied for the syntheses of further derivatives. Radioligand binding study showed that the cold reference FV45 (Ki 14.6 nM) has almost equivalent binding affinity as its lead valsartan (Ki 11.8 nM) and angiotensin II (Ki 1.7 nM). Successful radiolabeling of FV45 in a one-pot radiofluorination followed by the deprotection procedure with 21.8 ± 8.5% radiochemical yield and >99% radiochemical purity (n = 5) enabled a distribution study in rats and opened a path to straightforward large-scale production. A fast and clear kidney uptake could be observed, and this renal uptake could be selectively blocked by pretreatment with AT1-selective antagonist valsartan. Overall, as the first 18F-labeled PET tracer based on a derivation from clinically used drug valsartan with almost identical chemical structure, [18F]FV45 will be a new tool for assessing the RAS function by visualizing AT1 receptor distributions and providing further information regarding cardiovascular system malfunction as well as possible applications in inflammation research and cancer diagnosis.

Synthesis of a biotinylated keratan sulfate tetrasaccharide composed of dimeric Galβ1-4GlcNAc6Sβ

We successfully synthesized the biotinylated keratan sulfate tetrasaccharide, Galβ1-4GlcNAc6Sβ1-3Galβ1-4GlcNAc6Sβ in a stereocontrolled manner. The suitably protected Galβ1-4GlcNPhth unit was converted to the corresponding donor and acceptor. Optimization in 2 + 2 coupling using AgOTf, CuBr2, and n-Bu4NBr in CH3NO2 at a low temperature afforded the desired tetrasaccharide that suppressed glycal formation. The subsequent chemoselective removal of the protecting group at O-6 of two GlcNAcs, sulfation, and deprotection procedures as well as biotinylation gave the target compound.

Silica Gel Stabilized Na and Na/K Alloys: Highly Effective, Versatile and Environmentally Friendly Reducing Agents

Na and Na/K alloys in the liquid phase can be absorbed into amorphous silica gel at loadings up to 40 wt%. Further heating of these so-called stage 0 materials at 150 or 400 °C furnishes stage I and stage II materials, respectively, as free-flowing powders that can be handled under much safer conditions than the corresponding starting materials. Stage I Na and Na2K possess valuable reducing properties and they have found a variety of low impact applications in organic synthesis, including, e.g., the reductive deprotection of several functional groups, the development of safer protocols to operate the Bouveault–Blanc and the Birch reductions, and a new and particularly efficient approach to the Grignard and Darzens reactions. 1 Introduction 2 Reductive Deprotection Procedures 3 Bouveault–Blanc Reduction of Esters 4 Ammonia-Free Birch Reductions 5 Synthesis of Alkyldiaryl- and Dialkylarylphosphines 6 C–C Bond Forming Reactions 7 Further Applications 8 Conclusion

A Pot-Economical Approach to the Total Synthesis of Sch-725674.

A pot-economical total synthesis of antifungal Sch-725674, 1, is reported. The approach takes advantage of a number of one-pot, sequential transformations, including a phosphate tether-mediated one-pot, sequential RCM/CM/chemoselective hydrogenation protocol, a one-pot tosylation/acrylation sequence, and a one-pot, sequential Finkelstein reaction/Boord olefination/acetonide deprotection procedure to streamline the synthesis route by reducing isolation and purification procedures, thus saving time. Overall, an asymmetric route has been developed that is efficiently accomplished in seven pots from phosphate (S,S)-triene and with minimal purification.

Synthesis of α‐Tertiary Amine Derivatives by Intermolecular Hydroamination of Unfunctionalized Alkenes with Sulfamates under Trifluoromethanesulfonic Acid Catalysis

AbstractAn efficient and mild trifluoromethanesulfonic acid‐catalyzed hydroamination of unfunctionalized alkenes to afford α‐tertiary amine derivatives at temperatures as low as room temperature is reported. 2,2,2‐Trifluoroethyl sulfamate was found to be the optimal nitrogen source because its good solubility in both organic solvents and water facilitated both conversion and purification. The reaction conditions were compatible with a variety of substrate functional groups and afforded moderate to good yields. The desired amine compounds could be obtained easily by means of a mild, one‐pot, redox‐neutral deprotection procedure. Caryolane amine was synthesized with excellent chemo‐ and regioselectivities by means of a cascade hydroamination reaction of β‐caryophyllene.magnified image

Homogeneous synthesis of amino‐reserved chitosan‐graft‐polycaprolactone in an ionic liquid and the application in cell cultivation

AbstractThe homogeneous preparation of amino‐reserved chitosan‐graft‐polycaprolactone copolymer (ACS‐g‐PCL) was achieved in 1‐butyl‐3‐methylimidazolium acetate via a protection − ring‐opening graft polymerization − deprotection procedure. The molar substitution of PCL (MSPCL) in ACS‐g‐PCL copolymers was in the range 17.1 − 45.6 and could be well controlled by altering reaction conditions. The resultant ACS‐g‐PCL copolymers were soluble in some common organic solvents such as dimethylsulfoxide, ethanol and toluene. As the increment of MSPCL increased, the hydrophilicity of the ACS‐g‐PCL copolymers decreased. Eventually, ACS‐g‐PCL microspheres with a diameter of 100–200 µm were fabricated by an emulsion evaporation method. Among them, the ACS‐g‐PCL copolymer with an MSPCL of 26.8 formed into porous microspheres. The fluorescence microscopy and cytotoxicity results suggested that all of the microspheres, especially the ACS‐g‐PCL microspheres with MSPCL of 17.1 and 26.8, showed high cell adhesion and cytocompatibility to the human osteosarcoma cell line (MG‐63), indicating their great prospects in tissue engineering. © 2015 Society of Chemical Industry

Furan–chitosan hydrogels based on click chemistry

The modification of polymers by click chemistry has increased abruptly over the past years. In this study, furan groups were attached onto chitosan chain via reaction of 6-azido-6-deoxy chitosan and furfuryl propargyl ether. With this purpose, 6-azido-6-deoxy chitosan was synthesized by bromination and the subsequent nucleophilic substitution with sodium azide on the C6 hydroxyl groups of a previously amino-protected N-phthaloyl chitosan. Then, 6-azido-6-deoxy chitosan was reacted with furfuryl propargyl ether by the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction, resulting in an o-substituted furan–chitosan derivative with a degree of substitution of 10 %. The structure of all derivatives was analyzed and confirmed by means of infrared and nuclear magnetic resonance spectroscopies. Clicked chitosan with furan side groups was cross-linked with a bismaleimide to produce a polymer network via Diels–Alder reaction at 75 °C. The system presented a sol–gel transition with some syneresis. The gelation process was monitored by the evolution of the viscoelastic properties of the reaction mixture. The generated chitosan–furan–maleimide polymer network exhibited the typical pattern of a soft polymer hydrogel, in which both moduli were almost frequency independent with values lower than 10 Pa. These weak mechanical properties were interpreted as a consequence of the polymer degradation, which took place during the N-phthaloyl deprotection procedure.