Deprotection Of Amines Research Articles

Selective acylation of chitosan oligomers by several cyclic anhydrides as a 13C NMR quantification method

The chemistry of chitosan is a promising way to afford biobased and biodegradable complex materials using highly reactive compounds such as anhydrides. However, the potential applications are limited due to the absence of control over the acylation and the lack of precise characterization. After a model study on glucosamine, a selective acylation method of amines or alcohols of chitosan oligomers using anhydrides has been developed. The N-acylation of chitooligosaccharides has been achieved using several anhydrides and the O-acylation has been achieved in three steps: (1) Amine protection using p-anisaldehyde (2) O-acylation (with four anhydrides), and (3) Amine deprotection by removing the protective anisyl groups. Functionalized chitooligosaccharides have been characterized by a precise quantification method using 13C nuclear magnetic resonance spectroscopy. The resulting degrees of substitution show in most of the cases a stochiometric reaction between anhydrides and amines of chitooligosaccharides, and around 70 % of efficiency for O-acylation, proving the promising potential of such modifications. To the best of our knowledge, we describe here the first example of selective acylation of chitooligosaccharides using anhydrides, and most of all the first example of 13C quantitative NMR spectroscopy performed on chitooligosaccharides and its derivatives. These innovative structures are the gateway to the creation of new biosourced and/or biodegradable surfactants.

Preparation of von Hippel-Lindau (VHL) E3 ubiquitin ligase ligands exploiting constitutive hydroxyproline for benzylic amine protection.

The von Hippel-Lindau (VHL) protein serves as the substrate recognition subunit of the multi-subunit Cullin-2 RING E3 ubiquitin ligase (CRL2VHL), which regulates intracellular concentrations of hypoxia inducible factors (HIFs) through a ubiquitin proteasome system (UPS) cascade. Strategic recruitment of CRL2VHL by bi- or trifunctional targeted protein degraders (e.g., PROTACs®) offers the prospect of promoting aberrant polyubiquitination and ensuing proteasomal degradation of disease-related proteins. Non-peptidic, l-hydroxyproline-bearing VHL ligands such as VH032 (1) and its chiral benzylic amine analog Me-VH032 (2), are functional components of targeted protein degraders commonly employed for this purpose. Herein, we compare two approaches for the preparation of 1 and 2 primarily highlighting performance differences between Pd(OAc)2 and Pd-PEPPSI-IPr for the key C-H arylation of 4-methylthiazole. Results from this comparison prompted the development of a unified, five-step route for the preparation of either VH032 (1) or Me-VH032 (2) in multigram quantities, resulting in yields of 56% and 61% for 1 and 2, respectively. Application of N-Boc-l-4-hydroxyproline rather than N-tert-butoxycarbonyl to shield the benzylic amine during the coupling step enhances step economy. Additionally, we identified previously undisclosed minor byproducts generated during arylation steps along with observations from amine deprotection and amidation reaction steps that may prove helpful not only for the preparation of 1 and 2, but for other VHL recruiting ligands, as well.

A new entrant in ketene family: Generation of 2‐(3‐Oxo‐allyl)‐isoindole‐1,3‐dione and their [4+2] Cycloadditions with 1,3‐Diazabuta‐1,3‐dienes

AbstractThe manuscript describes a synthetic route for the formation of 5‐(methylisoindole‐1,3‐dione) pyrimidinones by [4+2] cycloaddition reactions of functionalized 1,3‐diazabuta‐1,3‐dienes with 2‐(3‐Oxo‐allyl)‐isoindole‐1,3‐dione generated in situ from phthaloylalanine and tosyl chloride using triethylamine as a base. The functionalized 5‐(methylisoindole‐1,3‐dione) pyrimidinones were further explored in the deprotection of amines to afford a variety of 5‐methylamino pyrimidinones. The synthesis of such functionalized pyrimidinones is significant as they have a wide range of pharmacological profiles and are valuable as organic synthons. Mechanistic insights are also proposed for the given synthetic methodology.

Graphene oxide bifunctionalized with NH2/NH3+ and their outstanding-performance against corrosion

Graphene oxide bifunctionalized with NH2/NH3+ (BFGO) is presented here. Further, its potential application to produce smart nanocomposite coatings (Epoxy Resin-BFGO) with hydrophobic and dual corrosion protection (active-passive) is demonstrated. The underlying bifunctionalization mechanisms were disclosed for the first time, in which graphene oxide was covalently functionalized using N-isopropylidene-3-aminopropyl-triethoxysilane (ITES) by microwave irradiation. The bifunctionalization is produced when the imine is protonated (amine deprotection) under acidic conditions, leading to BFGO with NH2:NH3+ groups (atomic ratio = 43:57) confirmed by XPS. Nanocomposites based on Epoxy Resin/BFGO exhibited hydrophobic contact angles (θ = 105°) and outstanding passive-active protection against corrosion for A36 mild steel (A36MS) in a saline solution (1 M ≅ 58.4 g/L). These smart nanocomposite coatings exhibited a corrosion current density (icorr) diminished in around 5 orders of magnitude (icorr = 3.89 E−08 mA/cm2) compared to A36MS coated with neat Epoxy Resin (icorr = 2.34 E−03 mA/cm2). Furthermore, Epoxy Resin-BFGO showed a more noble corrosion potential value (Ecorr = −158 mV) and the lowest corrosion rate (CR = 4.57 E−07 mm/year).

Efficient, continuous N-Boc deprotection of amines using solid acid catalysts

Rapid, catalytic N-Boc deprotection of aromatic and aliphatic amines is achieved using readily-available porous inorganic solid acids in flow.

Rational Chemical Multifunctionalization of Graphene Interface Enhances Targeted Cancer Therapy.

The synthesis of a drug delivery platform based on graphene was achieved through a step-by-step strategy of selective amine deprotection and functionalization. The multifunctional graphene platform, functionalized with indocyanine green, folic acid, and doxorubicin showed an enhanced anticancer activity. The remarkable targeting capacity for cancer cells in combination with the synergistic effect of drug release and photothermal properties prove the great advantage of a combined chemo- and phototherapy based on graphene against cancer, opening the doors to future therapeutic applications of this type of material.

Rational Chemical Multifunctionalization of Graphene Interface Enhances Targeted Cancer Therapy

AbstractThe synthesis of a drug delivery platform based on graphene was achieved through a step‐by‐step strategy of selective amine deprotection and functionalization. The multifunctional graphene platform, functionalized with indocyanine green, folic acid, and doxorubicin showed an enhanced anticancer activity. The remarkable targeting capacity for cancer cells in combination with the synergistic effect of drug release and photothermal properties prove the great advantage of a combined chemo‐ and phototherapy based on graphene against cancer, opening the doors to future therapeutic applications of this type of material.

High yielding self-assembly favored by preorganization.

A series of macrocyclic molecules were self-assembled via imine condensation. In order to overcome the insolubility and lability of the amino precursors, amine deprotection and imine condensation are performed in a one-pot manner. Conformation preorganization of the precursors leads to high-yielding self-assembly of the cage products.

Photomediated post-fabrication modification of azlactone-functionalized gels for the development of hydrogel actuators.

We report an approach for the photomediated post-fabrication modification of reactive, azlactone-containing gels using light-initiated deprotection of amines caged with 2-(nitrophenyl)propyloxycarbonyl (NPPOC). Photomediated modification of these gels can be used to generate a gradient in chemical functionality. When functionalized with tertiary amine groups, these gradient gels exhibit rapid and reversible shape deformations in response to changes in pH.

Selective and clean synthesis of aminoalkyl-H-phosphinic acids from hypophosphorous acid by phospha-Mannich reaction.

Aminoalkyl-H-phosphinic acids, also called aminoalkylphosphonous acids, are investigated as biologically active analogues of carboxylic amino acids and/or as valuable intermediates for synthesis of other aminoalkylphosphorus acids. Their synthesis has been mostly accomplished by phospha-Mannich reaction of a P–H precursor, an aldehyde and an amine. The reaction is rarely clean and high-yielding. Here, reaction of H3PO2 with secondary amines and formaldehyde in wet AcOH led to aminomethyl-H-phosphinic acids in nearly quantitative yields and with almost no by-products. Surprisingly, the reaction outcome depended on the basicity of the amines. Amines with pKa > 7–8 gave the desired products. For less basic amines, reductive N-methylation coupled with oxidation of H3PO2 to H3PO3 became a relevant side reaction. Primary amines reacted less clearly and amino-bis(methyl-H-phosphinic acids) were obtained only for very basic amines. Reaction yields with higher aldehydes were lower. Unique carboxylic–phosphinic–phosphonic acids as well as poly(H-phosphinic acids) derived from polyamines were obtained. Synthetic usefulness of the aminoalkyl-H-phosphinic was illustrated in P–H bond oxidation and its addition to double bonds, and in selective amine deprotection. Compounds with an ethylene-diamine fragment, e.g. most common polyazamacrocycles, are not suitable substrates. The X-ray solid-state structures of seventeen aminoalkyl-phosphinic acids were determined. In the reaction mechanism, N-hydroxyalkyl species R2NCH2OH and [R2N(CH2OH)2]+, probably stabilized as acetate esters, are suggested as the reactive intermediates. This mechanism is an alternative one to the known phospha-Mannich reaction mechanisms. The conditions can be utilized in syntheses of various aminoalkylphosphorus compounds.

Sub-10 nm Resolution Patterning of Pockets for Enzyme Immobilization with Independent Density and Quasi-3D Topography Control.

The ability to precisely control the localization of enzymes on a surface is critical for several applications including biosensing, bionanoreactors, and single molecule studies. Despite recent advances, fabrication of enzyme patterns with resolution at the single enzyme level is limited by the lack of lithography methods that combine high resolution, compatibility with soft, polymeric structures, ease of fabrication, and high throughput. Here, a method to generate enzyme nanopatterns (using thermolysin as a model system) on a polymer surface is demonstrated using thermochemical scanning probe lithography (tc-SPL). Electrostatic immobilization of negatively charged sulfonated enzymes occurs selectively at positively charged amine nanopatterns produced by thermal deprotection of amines along the side-chain of a methacrylate-based copolymer film via tc-SPL. This process occurs simultaneously with local thermal quasi-3D topographical patterning of the same polymer, offering lateral sub-10 nm resolution, and vertical 1 nm resolution, as well as high throughput (5.2 × 104 μm2/h). The obtained single-enzyme resolution patterns are characterized by atomic force microscopy (AFM) and fluorescence microscopy. The enzyme density, the surface passivation, and the quasi-3D arbitrary geometry of these patterned pockets are directly controlled during the tc-SPL process in a single step without the need of markers or masks. Other unique features of this patterning approach include the combined single-enzyme resolution over mm2 areas and the possibility of fabricating enzymes nanogradients.

Glutarimide Alkaloids Through Multicomponent Reaction Chemistry

A concise four step synthetic route for glutarimide alkaloids of high biological interest is presented. The scaffold is accessed via an Ugi four component reaction, hereby introducing two points of variation. This is followed by a hydrolysis, a cyclization under mild conditions, and an amine deprotection. The diastereomers of the cyclized intermediate can be easily separated, thus leading to optically pure alkaloids. By this route, four natural products and ten derivatives were synthesized. The scope and limitations of the synthetic methodology were investigated.

Accelerated tert-butyloxycarbonyl deprotection of amines in microdroplets produced by a pneumatic spray

Protection and deprotection of organic compounds in multistep reactions using functional groups such as tert-butoxycarbonyl (Boc), is widely performed in synthetic organic chemistry. Reaction rate acceleration studies in spray-based ionization methods (electrosonic spray, paper spray, nanospray) have become increasingly common. Here, we demonstrate reaction rate acceleration of Boc deprotection using easy ambient sonic-spray ionization (EASI), a pneumatic technique which does not involve an applied voltage, in a teaching laboratory setting. The goal of this laboratory exercise was to explore acceleration in a previously unexplored spray-based reaction, while emphasizing in a pedagogic setting the importance of protecting groups for multistep synthesis. Rate acceleration factors of more than an order of magnitude were observed in the uncharged micron-sized droplets generated by EASI. The effect of reaction conditions on reaction acceleration was examined including changes in the type of acid, reagent concentration ratios and syringe pump flow rates. Student knowledge was assessed by pre-laboratory assignments, post-laboratory reports and oral interviews.

Unlocking the Potential of Phenacyl Protecting Groups: CO2-Based Formation and Photocatalytic Release of Caged Amines.

Orthogonal protection and deprotection of amines remain important tools in synthetic design as well as in chemical biology and material research applications. A robust, highly efficient, and sustainable method for the formation of phenacyl-based carbamate esters was developed using CO2 for the in situ preparation of the intermediate carbamates. Our mild and broadly applicable protocol allows for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary amines in high to excellent yields. Moreover, we demonstrate the utility by a mild and convenient photocatalytic deprotection protocol using visible light. A key feature of the [Ru(bpy)3](PF6)2-catalyzed method is the use of ascorbic acid as reductive quencher in a neutral, buffered, two-phase acetonitrile/water mixture, granting fast and highly selective deprotection for all presented examples.

ChemInform Abstract: In situ Protection and Deprotection of Amines for Iron Catalyzed Oxidative Amidation of Aldehydes.

AbstractCarbon dioxide is found to be the ideal protecting group for the in situ protection and deprotection of amines for the oxidative amination of aldehydes.

In situ protection and deprotection of amines for iron catalyzed oxidative amidation of aldehydes

An environmentally friendly synthetic route by the application of CO2 to synthesize amides via in situ protection and deprotection of amines for iron catalyzed oxidative amidation of aldehydes was developed. Various secondary and tertiary amides have been synthesized in moderate to good yields under mild and neutral reaction conditions. The use of amine hydrochloride salts and hence base for neutralization step is totally avoided in this protocol.

Chemoselective deprotection of N-allylic amines using DDQ

A highly chemoselective and simple method for the deprotection of N-allylic amines using DDQ has been developed. The use of DDQ in dichloromethane–water provides a mild and efficient one-step deallylation of a wide variety of orthogonally protected tertiary amine derivatives.

Total synthesis and antibacterial testing of the A54556 cyclic acyldepsipeptides isolated from Streptomyces hawaiiensis.

The first total synthesis of all six known A54556 acyldepsipeptide (ADEP) antibiotics from Streptomyces hawaiiensis is reported. This family of compounds has a unique mechanism of antibacterial action, acting as activators of caseinolytic protease (ClpP). Assembly of the 16-membered depsipeptide core was accomplished via a pentafluorophenyl ester-based macrolactamization strategy. Late stage amine deprotection was carried out under neutral conditions by employing a mild hydrogenolysis strategy, which avoids the formation of undesired ring-opened depsipeptide side products encountered during deprotection of acid-labile protecting groups. The free amines were found to be significantly more reactive toward late stage amide bond formation as compared to the corresponding ammonium salts, giving final products in excellent yields. A thorough NMR spectroscopic analysis of these compounds was carried out to formally assign the structures and to aid with the spectroscopic assignment of ADEP analogues. The identity of two of the structures was confirmed by comparison with biologically produced samples from S. hawaiiensis. An X-ray crystallographic analysis of an ADEP analogue reveals a conformation similar to that found in cocrystal structures of ADEPs with ClpP protease. The degree of antibacterial activity of the different compounds was evaluated in vitro using MIC assays employing both Gram-positive and Gram-negative strains and a fluorescence-based biochemical assay.

Lanthanide-Containing Polycations for Monitoring Polyplex Dynamics via Lanthanide Resonance Energy Transfer

Theranostic nanomaterials have emerged in the past decade that combine therapeutic delivery and diagnostic imaging into one package. Such materials offer the opportunity to aid diagnosis, track therapeutic biodistribution, and monitor drug release. We have developed a series of nucleic acid delivery polymers containing oligoethylene amines that are able to be protonated at physiological pH (for binding/compacting pDNA) and a lanthanide-chelating domain, which imparts diagnostic functionality. Diamine monomers (containing between 3 and 6 Boc-protected ethyleneamines) were prepared via a multistep procedure involving the selective protection and deprotection of primary and secondary amines. The polymer structures were then synthesized by step-growth polymerization of the oligoethylene diamines with a bisanhydride of diethylenetriamine pentaacetic acid (DTPA-BA), yielding degrees of polymerization between 18 and 24. Chelation of the polymers with gadolinium and terbium was performed to offer MRI contrast agent and luminescence properties, respectively. All of the polymer chelates were found to house approximately one water coordination site, as calculated by the Horrock's equation and possess longitudinal relaxivities (r1, on a per Gd basis) at least twice that of Magnevist, a clinical contrast agent. All the structures formed polyplexes with pDNA with highly positive zeta potentials and hydrodynamic diameters around 50-80 nm. Lanthanide resonance energy transfer (LRET) was used to monitor polyplex association and dissociation. Polyplexes were formed using the donor-acceptor pair comprising of terbium-chelated polymer with five ethyleneamines within the repeat unit (6c-Tb) and tetramethyl rhodamine (TMR)-labeled pDNA. Association/dissociation in the presence of heparin and NaCl was monitored. The effect of amine number along the polymer backbone on transfection efficiency and cytotoxicity was also investigated. None of the polymers revealed cytotoxic effects with cultured cells; however, the polymer with six ethyleneamines clearly offered the highest transfection efficiency. This preliminary study offers insight into the development of materials with the ability to monitor polyplex unpackaging over time within the cellular environment.

Neuron‐like PC12 cell patterning on a photoactive self‐assembled monolayer

A new approach to pattern cells using photochemistry and self-assembled monolayer (SAM) was described in this study. Photocleavable 4,5-dimethoxy-2-nitrobenzyl chloroformate (NVOC) protected amine on an alkanethiol-gold SAM was developed for cell patterning. The cleavage of NVOC and the deprotection of amines on the SAM were controlled spatially by two sequential UV exposures with a photomask. Biomolecule patterning was achieved by introducing cell nonadhesive poly(ethylene glycol) after the first exposure and subsequently cell adhesive protein laminin after the second exposure to create surface cell adhesiveness differential for cell patterning. UV-Vis spectrophotometry was used to determine the photolysis of caged self-assembled molecules; in addition, water contact angle, atomic force microscopy, cyclic voltammetry, and X-ray photoelectron spectroscopy were used to characterize properties of different surfaces. To test the efficacy of resulting surfaces in patterning cells, a neuron-like cell line, PC12 cell line, was used. The in vitro cell studies showed successful PC12 cell patterns on the photoactive SAM surfaces. This patterning technique is unique in that it does not rely on cell adhesive or nonadhesive properties of the starting base material as both cell adhesive and cell nonadhesive molecules were individually introduced onto the base material surface through photo-uncaging at preselected regions for the ultimate cell patterning.