Protection Deprotection Research Articles

Improving the Phosphatase-Catalyzed Synthesis of 5′-Nucleotides: A Reaction Engineering Approach

5′-Phosphorylation of nucleosides is a reaction as important in nature and in industry as it is cumbersome to be performed. Whilst chemical phosphorylation relies on the use of harsh reagents, solvents, and conditions, as well as on the need for protection–deprotection steps, biocatalysis can be a tool to achieve one-step phosphorylation reactions, which are selective, protecting group-free, and occurring under mild and sustainable conditions. In this work, the wild-type non-specific acid phosphatase from Morganella morganii (PhoC-Mm) was expressed, purified, and used for the synthesis of inosine 5′-monophosphate (IMP), an important food additive, by using pyrophosphate (PPi) as an inexpensive phosphate donor in a fully aqueous medium at 30 °C. Via the fine-tuning of the reaction set-up taking into account the type of buffer, amount of PPi, mode/time of PPi addition, and enzyme and substrate concentration, PhoC-Mm could be used for catalyzing the phosphorylation of inosine (I) to IMP in a good yield and high purity (62% yield). The catalysis of the hydrolytic reaction direction, which is the primary function of phosphatases in nature, was here reversed to a certain extent by a reaction engineering approach, without the need for protein engineering strategies.

Exploiting chemoselectivity for discrete oligomer synthesis through sequential IrAAC and CuAAC reactions

By leveraging the orthogonality between CuAAC and IrAAC we have introduced the synthesis of sequence-defined oligomers without requiring protection–deprotection manipulations.

Exploiting Visible Light Triggered Formation of trans-Cyclohexene for the Contra-thermodynamic Protection of Alcohols.

We report herein a method for the contra-thermodynamic protection and thermodynamic deprotection of alcohols in which all reagents are returned to their original state. This is accomplished by the use of visible light photochemical energy to drive the formation of a highly strained trans-(Z)-cyclohexene. At STP the product ethers contain more potential energy than the starting materials and, thus, can be catalytically returned to the starting materials, effectively realizing a protection-deprotection scheme paid for with an energy currency.

Convergent synthesis of oligomannose-type glycans via step-economical construction of branch structures

Oligomannose-type glycans on glycoproteins are important signaling molecules in the glycoprotein quality control system in the endoplasmic reticulum. Recently, free oligomannose-type glycans generated by the hydrolysis of glycoproteins or dolichol pyrophosphate-linked oligosaccharides were recognized as important signals for immunogenicity. Hence, there is a high demand for pure oligomannose-type glycans for biochemical experiments; however, the chemical synthesis of glycans to achieve high-concentration products is laborious. In this study, we demonstrate a simple and efficient synthetic strategy for oligomannose-type glycans. Sequential regioselective α-mannosylation at the C-3 and C-6 positions of 2,3,4,6-unprotected galactose residues in galactosylchitobiose derivatives was demonstrated. Subsequently, the inversion of the configuration of the two hydroxy groups at the C-2 and C-4 positions of the galactose moiety was successfully carried out. This synthetic route reduces the number of the protection–deprotection reactions and is suitable for constructing different branching patterns of oligomannose-type glycans, such as M9, M5A, and M5B.

Gelation–based visual detection of fluoride ion: Strategic use of silyl protection–deprotection chemistry

• A gelation-based visual detection of fluoride ion is reported. • Fluoride ion converted a triphenylsilyl group-containing gelator (gel) into a nongelator (gel degradation). • Quantitative and semi-quantitative detection methods are reported. • Fluoride ion detection limit is considerably better than many existing gelation-based methods. We describe the design, synthesis, and visual fluoride ion detection by a new small-molecule gelator in this work. This gelator contains a triphenylsilyl group which is easily removed in the presence of fluoride ion. The strategic use of silyl group protection-deprotection chemistry enabled the detection of fluoride ion visually. We investigated two different routes for this purpose. In the first route, gels were responsive to fluoride ion and degraded in its presence. Gels degraded faster with an increase in fluoride ion concentration. Fluoride ion quantification was possible by correlating fluoride ion concentrations with gel-degradation times. In the second route, when gelation tests were performed in the presence of fluoride ion, gel formation was suppressed, and multiple visually distinguishable states were obtained. A semi-quantitative analysis for fluoride ion was achieved in this case. The performance and detection limit of this new gelator is superior to many existing gelation-based methods. Furthermore, the gels were fully characterized using SEM, TEM, FTIR, XRD, contact angle, fluorescence, and UV–vis spectroscopy techniques.

A Simple and Feasible Synthetic Strategy towards Poly(4‐thiostyrene)

AbstractPoly(4‐thiostyrene), a historically challenging to synthesize polymer, is synthesized herein via a feasible three‐step protocol. Based on the newly developed protection–deprotection strategy, the precursor polymer containing thiomethyl groups is deprotected using Li/naphthalene to yield poly(4‐thiostyrene) after acidification. This newly developed procedure is crucial for preventing crosslinking of the thiol groups and therefore the resulting polymer is soluble in common organic solvents (e.g., chloroform, tetrahydrofuran) and can be stored long‐term, which has been challenging to accomplish over the past 60 years. The successful synthesis is confirmed by various characterization techniques including NMR, Fourier‐transform infrared spectroscopy (FTIR), and Raman analysis, which collectively are new and useful data that have generally been unavailable in previous reports. This work provides a robust approach for synthesizing this promising polymer and offers a new route to investigate thiol‐containing polymers.

Catalyst-free direct regiospecific multicomponent synthesis of C3-functionalized pyrroles

An operationally simple catalyst-free protocol for the direct regiospecific synthesis of β-(C3)-substituted pyrroles has been developed. The enamine intermediate, in situ generated from succinaldehyde and a primary amine, was trapped with activated carbonyls before the Paal-Knorr reaction in a direct multicomponent "just-mix" fashion to furnish pyrroles with overall good yields. Several C3-substituted N-alkyl/aryl/H pyrroles have been produced under open-flask conditions with high atom economy and avoiding protection-deprotection chemistry.

An Integration Strategy to Develop Dual-State Luminophores with Tunable Spectra, Large Stokes Shift, and Activatable Fluorescence for High-Contrast Imaging

An Integration Strategy to Develop Dual-State Luminophores with Tunable Spectra, Large Stokes Shift, and Activatable Fluorescence for High-Contrast Imaging

Designed Synthesis of Diversely Substituted Hydantoins and Hydantoin-Based Hybrid Molecules: A Personal Account

AbstractHydantoin and its analogues such as thiohydantoin and iminohydantoin have received substantial attention from both a chemical and a biological point of view. Several compounds of this class have shown useful pharmacological activities such as anticonvulsant, antitumor, antiarrhythmic, and herbicidal properties that have led, in some cases, to clinical applications. Because of these broad-spectrum activities, intensive research efforts have been dedicated in industry and academia to the synthesis and structural modifications of hydantoin and its derivatives. Realizing the importance of hydantoin in organic and medicinal chemistry, we also initiated a research program that successfully designed and developed new routes and methods for the formation of hydantoin, thiohydantoin, and iminohydantoin substituted at various positions, particularly at the N-1 position without following a protection–deprotection strategy. Because combinations of two or more pharmacophoric groups can lead to hybrid molecules that display a mixed mechanism of action on biological targets, we extended our developed strategy to the syntheses of new types of hydantoin-based hybrid molecules by combining hydantoin with a triazole, isoxazoline, or phosphate scaffold as a second pharmacophore to exploit their diverse biological functions.1 Introduction2 Chemistry and Properties2.1 Physical Properties2.2 Chemical Properties2.3 Biological Properties3 General Synthetic Methods4 Synthesis of Diversely Substituted Hydantoins5 Synthesis of Diversely Substituted Thiohydantoins6 Synthesis of Diversely Substituted Iminohydantoins7 Fused or Bicyclic (Thio)hydantoins8 Di- or Multivalent (Thio)hydantoins9 Hydantoin-Based Hybrid Molecules9.1 Hydantoin–Isooxazoline Hybrids9.2 Hydantoin–Triazole Hybrids9.3 Hydantoin–Phosphate Hybrids: Phosphorylated Hydantoins10 Summary and Outlook

Diversifying the xanthine scaffold for potential phosphodiesterase 9A inhibitors: synthesis and validation

Xanthine and its derivatives have been a great area of interest for the development of potent bioactive agents. In this study, two synthesis routes have been developed for 1,3,8-tri substituted xanthine derivatives. The synthesis routes exploits “xanthine” as precursor molecule as it represents maximum unsubstituted sites for maximum possible substitutions. This study divulged the reactivity pattern of three –NH groups at N1, N3 and N7 position of xanthine in the order of N7 > N3 > N1, which helped in carrying out regio-selective N-alkylation reaction at different –NH sites of xanthine. Selective protection and selective deprotection at N3 and/or N7 sites of xanthine were the key strategies for developing two synthesis schemes. Eight newly synthesized compounds C1-8 were evaluated for their biological activity against Phosphodiesterase 9A. All the compounds were found to be promising inhibitors. To gain further insight for mode of interaction with Phosphodiesterase 9A, these compounds were subjected to docking studies. The present study provides insight into the potential of ‘xanthine’ to contribute to the structural diversification of xanthine derivatives in the drug development process. Xanthine based chemical synthesis is shown to be a cost effective, fast, and highly productive method. This work can be extrapolated to find various selective xanthine based inhibitors targeting other enzymes.

Asymmetric Total Synthesis of Phomarol

Asymmetric Total Synthesis of Phomarol

Deconstructive Reorganization: De Novo Synthesis of Hydroxylated Benzofuran

AbstractAn unprecedented deconstructive reorganization strategy for the de novo synthesis of hydroxylated benzofurans from kojic acid‐ or maltol‐derived alkynes is reported. In this reaction, both the benzene and furan rings were simultaneously constructed, whereas the pyrone moiety of the kojic acid or maltol was deconstructed and then reorganized into the benzene ring as a six‐carbon component. Through this strategy, at least one free hydroxyl group was introduced into the benzene ring in a substitution‐pattern tunable fashion without protection–deprotection and redox adjustment. With this method, a large number of hydroxylated benzofuran derivatives with different substitution‐patterns have been prepared efficiently. This methodology has also been shown as the key step in a collective total synthesis of hydroxylated benzofuran‐containing natural products (11 examples).

P-Toluenesulfonyl Chloride Catalysed Facile Synthesis of O-benzyl-l-amino Acids and Their In Vitro Evaluation

Protection and subsequent deprotection of amino acid functional groups play a key role in regioselective peptide synthesis. For protection, carboxylic acid functional groups are often benzylated using p-toluenesulfonic acid catalysed Fischer-Speier esterification reaction. Such reaction involves in situ water formation, which requires subsequent separation by azeotropic distillation for forward shift of equilibrium. To eliminate the need of this corresponding step requiring additional set-up, current study investigated p-toluenesulfonyl chloride as a reasonable alternative catalyst for facile benzylation of selected mono- and di- carboxylic amino acids. Literature reports that p-toluenesulfonyl chloride not only has a better shelf life but also demonstrates better safety in case of accidental systemic absorption over p-toluenesulfonic acid. As the O-benzyl-l-amino acids are often retained without deprotection to constitute the pharmaceutical peptide systems, synthesized compounds were investigated for their biocompatibility using in vitro cytotoxicity assays.

4 + 2]-Cycloadditions of a thiazol-based tricyclic 1,4-diphosphinine and a new easy 1,4-diphosphinine protection deprotection strategy.

Diels-Alder-reactions of a thiazol-2-thione-based, tricyclic 1,4-di-phosphinine were investigated, showing that the central aromatic π-system can react with various dienophiles. The reaction with 4-phenyl-1,2,4-triazoline-3,5-dione was special as the product revealed a remarkable sensitivity towards light, thus enabling the photochemical deprotection of the tricyclic 1,4-diphosphinine.

C-H Halogenation of Pyridyl Sulfides Avoiding the Sulfur Oxidation: A Direct Catalytic Access to Sulfanyl Polyhalides and Polyaromatics.

Palladium-catalyzed oxidative C–H halogenation and acetoxylation reactions of S-unprotected sulfides, selectively directed by pyridinyl groups, allows the formation of C–X bonds (X = I, Br, Cl, OAc) by using simple halosuccinimide or phenyliodine diacetate (PIDA) oxidants. The undesired formation of sulfoxides and/or sulfones, which are usually observed under oxidative conditions, is fully obviated. Under the solvent-dependent conditions that we proposed, sulfide C–H functionalization is achieved in less than 1 h without any direct electrophilic halogenation at the pyridine moiety. N-Directed ortho-C–H activation of aryl also facilitates dibromination reactions which are hardly accessible with sulfone and sulfoxide counterparts because of their higher structural rigidity. This general method gives a straightforward access to polyhalide sulfides, without an organosulfur reduction step or protection–deprotection sequence. Polyhalide sulfides are valuable synthons that give a practical entry to new constrained polyaromatic and biphenyl sulfides, including synthetically challenging unsymmetrical examples.

Synthesis of Substituted Isatins from the MBH Adduct of 1,5,6-Trisubstituted Isatins Using (2,4-Dinitrophenyl)hydrazine and K-10 Clay Explored as Protection-Deprotection Chemistry.

An interesting synthetic transformation of protection–deprotection chemistry in an isatin molecule is achieved. Morita–Baylis–Hillman (MBH) adduct formation used as protection of the C-3 position in the isatin molecule is reported. C–C bond cleavage in the MBH adduct of isatin with the help of phenylhydrazine and C=N bond cleavage in the phenylhydrazone derivative of isatin with the help of K10 clay are studied systematically and reported as deprotection.

Scalable Synthesis of Amaryllidaceae Isocarbostyril Alkaloids from Enantiomerically Pure 7-Azabicyclo[2.2.1]heptanone Scaffold: Total Synthesis of (+)-7-Deoxypancratistatin

A conceptually new and scalable strategy (ten linear steps, 13.9% overall yield) has been developed to synthesize (+)-7-deoxy­pancratistatin from optically pure 7-azabicyclo[2.2.1]heptanone scaffold. The crucial trans -B–C ring junction was fixed at an early stage of the synthesis by exploiting the rigid bicyclic structural framework of the starting precursor. Stereoselective installation of hydroxyl groups around the perimeter of the cyclohexenyl C-ring involved sequential epoxidation–phenylselenylation–oxydeselenylation sequence followed by dihydroxylation. The most attractive feature of this synthesis is the use of a protection–deprotection step only at the penultimate step making the protocol very efficient and atom economical.

Alcohol Protection–Deprotection Catalyzed by Fe3O4-Supported Silica Sulfuric Acid

Alcohol Protection–Deprotection Catalyzed by Fe3O4-Supported Silica Sulfuric Acid

Scalable Synthesis of Amaryllidaceae Isocarbostyril Alkaloids from Enantiomerically Pure 7-Azabicyclo[2.2.1]heptanone Scaffold: Total Synthesis of (+)-7-Deoxypancratistatin

A conceptually new and scalable strategy (ten linear steps, 13.9% overall yield) has been developed to synthesize (+)-7-deoxy­pancratistatin from optically pure 7-azabicyclo[2.2.1]heptanone scaffold. The crucial trans-B–C ring junction was fixed at an early stage of the synthesis by exploiting the rigid bicyclic structural framework of the starting precursor. Stereoselective installation of hydroxyl groups around the perimeter of the cyclohexenyl C-ring involved sequential epoxidation–phenylselenylation–oxydeselenylation sequence followed by dihydroxylation. The most attractive feature of this synthesis is the use of a protection–deprotection step only at the penultimate step making the protocol very efficient and atom economical.

Pot‐Economical Synthesis of Hydroxylated Arylethenyl‐arylethynyl‐arenes through Sequential Decarboxylative Perkin–Sonogashira Reactions

AbstractA simple, economical and one‐pot protocol is developed for construction of multiple carbon–carbon bonds having C(sp2)−C(sp2) and C(sp2)−C(sp) hybridization, as these intriguing molecular architectures exhibit significant optoelectronic and medicinal properties. To this end, a sequential reaction is devised that allows one‐pot three‐component reactions of hydroxybenzaldehydes (C6–C1 unit), halo‐phenylacetic acids (C6–C2 unit) and arylacetylenes (C6–C3 unit) resulting in the formation of highly π‐conjugated complex arylethenyl‐arylethynyl‐arenes (C6–C2–C6–C2–C6 unit) bearing a hydroxy group via sequential Perkin condensation–decarboxylation–Sonogashira coupling in polyethylene glycol with microwave irradiation. The process avoids protection–deprotection manipulations, generates CO2 and H2O as by‐products and is successfully extended for the efficient construction of a wide series of novel aliphatic/alicyclic/(hetero)aromatic arylethenyl‐arylethynyl‐arenes with pendant hydroxy functionality, which could undergo further chemical modification to achieve target biological and physical properties.