Boc Group Research Articles

Deprotection of the BOC Groups in Poly(2-(tert-butoxycarbonyloxy)ethyl methacrylate) Controlled by the Incorporation of Polymerizable Thermally Latent Acids

Poly((2-tert-butoxycarbonyloxy)ethyl methacrylate) (PBHEMA) is converted to poly(2-hydroxyethyl methacrylate) (PHEMA) with the release of isobutene and CO2 by heating and this reaction is accelerated by an acid. The thermal latent acid catalysts (TLA) are useful for the control of a working temperature for the deprotection of the tert-butoxycarbonyl (BOC) groups included in PBHEMA. In this study, styrene- and methacrylate-type sulfonic esters were synthesized and copolymerized with BHEMA in order to investigate the effect of the TLAs incorporated into the polymer chains. Thermogravimetric analysis (TGA) and differential thermal analysis (DTA) were carried out for the copolymers of BHEMA with the polymerizable TLAs in order to discuss the deprotection features of the BOC group in comparison with the results for the systems of PBHEMA blended with the low-molecular-weight TLAs.

Solid‐Phase Synthesis of Peptidols via Reductive Cleavage Through a Benzotriazole Linker

AbstractPeptidols were prepared through the reductive cleavage of benzotriazole intermediates obtained from the on‐bead activation of 3,4‐diaminobenzoyl linkers. Remarkably, this method used commercially available amino acid residues and resins without further modification. Pure peptidols were collected with only filtration in 49%–87% yield. Only the derivatives with aspartic acid as the first C‐terminal residue required sophisticated chromatography purification. Esters and carboxylic acids were identified as side products and were suppressed by additional reduction or reduction in DMF. Remarkably, the reduction of peptides with the first aspartic acid residue at the C‐terminal afforded a C‐terminal lactone, which could be reduced by deprotection at 0 °C. For the synthesis of branched peptidols, the bulky wedge structures of the branched peptides resulted in low total yields, which were improved to 23%–28% by using peripheral Boc groups and SPPS on the Tental gel resin. In addition, this method gave two peptaibols, SPF‐5506‐A4 and Ac‐Gramicidin A, in 11% and 46% yields, respectively.

Constructing Dual-State Emissive Fluorophores via Boc Protection and Discovering a High-Fidelity Imaging Probe for Lipid Droplets.

Dual-state emissive (DSE) materials exhibit fluorescence in both solid and solution states and have become an emerging material in the fields of materials science and sensing in recent years. However, due to the lack of effective and universal preparation methods, DSE materials, especially those with long emission wavelengths, are still scarce. Developing an effective method for constructing such DSE molecules is urgently needed. In this study, we constructed three DSE molecules (NRP-Boc, DCIP-Boc, and DCMP-Boc) with far-red to near-infrared fluorescence by simply modifying three traditional aggregation-caused quenching (ACQ) fluorophores with tert-butyloxycarbonyl (Boc) groups. Density functional theory (DFT) calculations and crystal data revealed the reasons for the bright fluorescence of these three molecules in solution and solid, demonstrating that this Boc protection method is a simple and effective strategy for constructing DSE molecules. We also found that these three DSE molecules have the potential to target and visualize lipid droplets (LDs). Among them, DCIP-Boc shows advantages of a large Stokes shift, long emission wavelength, low fluorescence background, and good photostability in cells, providing a powerful new molecular tool with DSE property for high-fidelity imaging of LDs.

Integrated engineering at distal site and active center regulates stereoselectivity and activity of carbonyl reductase towards N-Boc-pyrrolidone

Green and efficient biosynthesis of two enantiomeric products of N-Boc-pyrrolidinol (NPBL) as key pharmaceutical blocks for treatment of cancer and HIV has received much attention. The precursor, N-Boc-pyrrolidone (NPBO), is considered as a difficult-to-reduce ketone by carbonyl reductases, because it has a bulky Boc group and sterically similar substitutions on either side of the carbonyl group resulting in low stereoselectivity and conversion. Moreover, activity enhancement concomitant with reversal of stereoselectivity is challenging. Carbonyl reductase (CpCR) from Candida parapsilosis shows 90 %ee for (S)-NBPL, but low catalytic efficiency. In this study, we considered both activity and selectivity, and proposed an integrated engineering strategy. The distal site was introduced from an activity perspective and the active pocket sites were introduced by virtual saturation mutagenesis from a stereoselectivity perspective. Mutants L34A/W116A (95 %ee (S)) and L34A/W116T/F285C/W286S (94 %ee (R)) were obtained with 26.8-fold and 2.9-fold higher catalytic efficiencies, respectively. Molecular dynamics simulations revealed the mechanism of stereoselective flip-flop and activity enhancement; mutation altered the substrate-binding mode and changed the shape and size of the cavities, thus contributing to the change in the ratio of active conformations in the pre-reactive state. This study, which differs from the traditional method of exchanging large and small pockets, provides a viable approach for the rational design of carbonyl reductases with high stereoselectivity for target substrates.

Cu-Catalyzed Direct Enantioselective Vinylogous Mannich Reaction between β,γ-Unsaturated Pyrazoleamides and Ketimines.

A catalytic asymmetric vinylogous Mannich-type reaction between β,γ-unsaturated amides and ketimines has been developed in excellent regio-, diastereo-, and enantioselectivities. The methodology provides an efficient approach to construct chiral homoallylic amines with a 3-amino-2-oxindole scaffold. Moreover, the transformations of the chiral products, including the removal of the pyrazole group or Boc group, the reduction of the C-C double bond, and Suzuki coupling, have been investigated.

Visible light-driven photocatalytic sulfonative oxidation of benzyl secondary amines.

A method for the α-oxidation and sulfonation of benzyl secondary amines was developed utilizing Ir(III) or Eosin Y as the photocatalyst in the presence of O2 as a green oxidant. Using commercial substrates, 37 products from cyclic and acyclic benzylamines were achieved with good functional group compatibility in 48-87% yields. Furthermore, tetrahydroisoquinoline protected by an Ac or a Boc group was oxidized under standard conditions.

Acid-Modulated Peptide Synthesis for Application on Oxide Biosensor Interfaces.

In this paper we report an acid-modulated strategy for novel peptide microarray production on biosensor interfaces. We initially selected a controlled pore glass (CPG) as a support for solid-phase peptide synthesis (SPPS) to implement a chemistry that can be performed at the interface of multiple field effect transistor (FET) sensors, eventually to generate label-free peptide microarrays for protein screening. Our chemistry uses a temporary protection of the N-terminal amino function of each amino acid building block with a tert-butyloxycarbonyl (Boc) group that can be removed after each SPPS cycle, in combination with semi-permanent protection of the side chains of trifunctional amino acid residues. Such a protection scheme with a well-proven record of application in conventional, batchwise SPPS has been fine-tuned for optimal performance on CPG and, from there, translated to SPR chips that allow layer-by-layer monitoring of amino acid coupling. Our results validate this acid-modulated synthesis as a feasible approach for producing peptides in high yields and purity on flat glass surfaces, such as those in bio-FETs.

Chemo-Enzymatic Synthesis of Isomeric I-branched Polylactosamines Using Traceless Blocking Groups.

Poly-N-acetyl lactosamines (polyLacNAc) are common structural motifs of N- and O-linked glycan, glycosphingolipids and human milk oligosaccharides. They can be branched by the addition of β1,6-linked N-acetyl-glucosamine (GlcNAc) moieties to internal galactoside (Gal) residues by the I-branching enzyme beta-1,6-N-acetylglucosaminyltransferase 2 (GCNT2). I-branching has been implicated in many biological processes and is also associated with various diseases such as cancer progression. Currently, there is a lack of methods that can install, in a regioselective manner, I-branches and allows the preparation of isomeric poly-LacNAc derivatives. Here, we described a chemo-enzymatic strategy that addresses this deficiency and is based on the enzymatic assembly of an oligo-LacNAc chain that at specific positions is modified by a GlcNTFA moiety. Replacement of the trifluoroacetyl (TFA) moiety by tert-butyloxycarbonyl (Boc) gives compounds in which the galactoside at the proximal site is blocked from modification by GCNT2. After elaboration of the antennae, the Boc group can be removed, and the resulting amine acetylated to give natural I-branched structures. It is also shown that fucosides can function as a traceless blocking group that can provide complementary I-branched structures from a single precursor. The methodology made it possible to synthesize a library of polyLacNAc chains having various topologies.

Fabrication of a BOC-Protected 2-Hydroxyethyl Methacrylate Brush and Deprotection of the BOC Group to Control the Surface Hydrophilicity.

Fabrication of functional surfaces with designed patterns of different hydrophilicity has potential applications in active control of water droplets and water harvesting. For practical applications, the fabrication process needs to be applied to a large area in a cost-effective manner. Herein, we report the fabrication of a polymer brush of 2-(tert-butoxycarbonyloxy)ethyl methacrylate having a BOC-protected hydroxy group. The deprotection of the BOC group converts poly(2-(tert-butoxycarbonyloxy)ethyl methacrylate) (PBHEMA) into poly(2-hydroxyethyl methacrylate) (PHEMA) and hence changes the hydrophilicity. The chemical transformation changes the refractive index and thickness of the brush. This simple chemistry enables easy formation of the boundary of different hydrophilicity. Last, we demonstrate that the shape of the water droplet can be manipulated on the designed surface having different hydrophilicity.

Synthetic copolymers with natural product side‐chain pendents

AbstractDehydroabietic acid is a natural product in the class of rosins. Here we report the design, synthesis and characterization of copolymers containing dehydroabietate side‐chain pendents, derived from homologated dehydroabietic ethyl methacrylate and tert‐butoxy carbonyl (Boc) l‐alanine methacryloyloxyethyl ester with varying comonomer proportions by reversible addition fragmentation chain transfer polymerization. The cleavage of Boc groups from the copolymers resulted in water‐soluble copolymers with cationic surface charge. Since proper hydrophobic−hydrophilic balance in a single polymer chain is maintained, the copolymers self‐assembled in aqueous media with a critical aggregation concentration of 2.8–3.0 mg L−1, confirmed by fluorescence spectroscopy. 1H NMR spectroscopy, dynamic light scattering, SEM and AFM were used to further investigate the aqueous solution self‐assembly of random copolymers. The collective findings from 1H NMR, dynamic light scattering, SEM and AFM clearly revealed the existence of micellar particles in water with alanine units on the surface of the nanoaggregates and homologated dehydroabietate pendents along with the hydrophobic main‐chain backbone in the core. In addition, to get a clear insight into the nanoaggregates' potential for drug encapsulation in aqueous medium, Nile Red was incorporated as a model hydrophobic dye. © 2023 Society of Industrial Chemistry.

Carbamate-Protected (BOC and O-NB) 2-Aminopyrimidinedione-Based Janus G-C Nucleobase Motifs as Building Blocks for Supramolecular Assembly and Smart Polymers.

In this paper, we report "carbamate protected" 2-aminopyrimidinedione-based Janus G-C nucleobases (2-APD Janus G-C nucleobases) featuring polymerizable groups and self-complementary triple H-bonding motifs DDA and AAD as building blocks for developing smart polymers and self-healing materials. The carbamate-masked H-bonding motif, cleavable under acidic (BOC group) or photocleavable (O-nitrobenzyl group) conditions, would facilitate the synthesis of smart polymers by alleviating aggregation during polymerization which in turn would exclude self-assembly-assisted solubility issues. Ready accessibility in excellent yields coupled with the possibility for facile introduction of polymerizable groups would make these building blocks excellent candidates for diverse polymerization applications.

Fabrication of a reusable electrochemical platform based on acid-responsive host-guest interaction with β- cyclodextrin

A reusable electrochemical glassy carbon electrode (GCE) platform based on the acid-responsive host-guest interaction between β-cyclodextrin (β-CD) and benzimidazole (BM) derivatives was developed. The β-CD can specifically recognize the BM derivative through the acid -responsive host-guest interaction. The electrode was first modified by eletrografting to immobilize a diamine linker (Boc-EDA), resulting in GCEBoc-EDA in which one amine was used for covalent immobilization to the electrode and another Boc protected amine was used to solid-phase synthesis on following step-by-step modifications on the electrode. After deprotection of the Boc group on the GCEBoc-EDA, carbonyldiimidazole (CDI)-activated β-CD was coupled with –NH2 on the electrode to result in GCEβ-CD. Due to the nonspecific interaction, we further improved the GCEβ-CD electrode by introducing immobilized poly(ethylene glycol) methyl ether (PEG-Me) to result in GCEβ-CD/PEG-Me, along with optimized procedures. CV, DPV, and EIS methods were applied for recording the electrochemistry signals. We utilized GCEβ-CD/PEG-Me to investigate the host-guest interaction and found the electrochemical signal exhibited dynamic behavior. The GCEβ-CD/PEG-Me was able to regenerate the β-CD surface more than 20 times after HCl acidic washes. We further investigated the interaction of carbendazim (CBZ), a commonly used fungicide in the agriculture and food industry, and observed a positive electrochemical response. The sensor design has potential applications in ensuring food safety.

Designing functionalized polymers through post-polymerization modification of side chain leucine-based polymer

The opportunity to modify the chemical functionality of the incorporated amino acid moiety in side chain amino acid-based polymers provides access to tailor their optical, mechanical, and biological properties. Methacrylate monomers from C-terminus modified amino acids and their subsequent polymerization leads to the formation of polymethacrylate polymers with pendant amine (-NH2) groups. To this end, the post-polymerization reactions on the amine groups offer a facile route to prepare functionalized side chain amino acid-based polymeric materials. Herein, we synthesized side chain L-leucine pendant homopolymer using reversible addition-fragmentation chain transfer (RAFT) polymerization of Boc-L-leucine methacryloyloxyethyl ester (Boc-leu-HEMA) and subsequently the Boc group is deprotected to prepare P(H3N+-leu-HEMA). Post-polymerization modifications on the pendant amine groups were performed to incorporate fluorescent probe, propargyl group, methacrylic moiety, hydrophobic fatty acid, anionic pendant, and hydrophilic polyethylene glycol (PEG) units; which demonstrates an efficient platform to build a library of functionalized polymers from a single polymeric backbone. We have studied the solvatochromic behavior of fluorescence probe bearing polymers using fluorescence spectroscopy. The ability of the pendent methacrylic unit containing polymers to undergo crosslinking and the mechanical properties of the synthesized gel are investigated by the rheological study.

New synthesis of β-aryl-GABA drugs

A new synthetic method for the preparation of β-aryl-GABA drugs is reported. The key step for the construction of α,β-unsaturated-β-aryl-γ-lactam derivatives relies on a novel cascade radical reaction. An N-propargyl aryl amide was rapidly constructed starting from an aryl carboxylic acid and propargyl amine. Protection of the amide N–H with a Boc group, followed by a cascade radical aryl migration reaction, produced the key intermediate, an unsaturated β-aryl-γ-lactam. Further catalytic hydrogenation and deprotection gave rolipram. Meanwhile, coupling of the glycine methyl ester and propargyl bromide, followed by benzoylation gave the radical precursor. The radical reaction resulted in the production of the unsaturated β-aryl-γ-lactam with the glycine moiety. After aminolysis reactions, phenylpiracetam and phenylpiracetam hydrazide were produced, respectively. This synthetic protocol provides a general and simple approach for preparing racemates or chiral forms of β-aryl-GABA drugs and analogues.

Theoretical Study on Cooperation Catalysis of Chiral Guanidine/ Copper(I) in Asymmetric Azide-Alkyne Cycloaddition/[2 + 2] Cascade Reaction.

Density functional theory (DFT) calculations with BP86-D3(BJ) functionals were employed to reveal the mechanism and stereoselectivity of chiral guanidine/copper(I) salt-catalyzed stereoselective three-component reaction among N-sulfonyl azide, terminal alkyne, and isatin-imine for spiroazetidinimines that was first reported by Feng and Liu (Angew. Chem. Int. Ed. 2018, 57, 16852-16856). For the noncatalytic cascade reaction, the denitrogenation to generate ketenimine species was the rate-determining step, with an activation barrier of 25.8-34.8 kcal mol-1. Chiral guanidine-amide promoted the deprotonation of phenylacetylene, generating guanidine-Cu(I) acetylide complexes as active species. In azide-alkyne cycloaddition, copper acetylene coordinated to the O atom of the amide moiety in guanidium, and TsN3 was activated by hydrogen bonding, affording the Cu(I)-ketenimine species with an energy barrier of 3.5∼9.4 kcal mol-1. The optically active spiroazetidinimine oxindole was constructed via a stepwise four-membered ring formation, followed by deprotonation of guanidium moieties for C-H bonding in a stereoselective way. The steric effect of the bulky CHPh2 group and chiral backbone in the guanidine, combined with the coordination between the Boc group in isatin-imine with a copper center, played important roles in controlling the stereoselectivity of the reaction. The major spiroazetidinimine oxindole product with an SS configuration was formed in a kinetically more favored way, which was consistent with the experimental observation.

The Coupling of Dihydroxybenzene Derivatives to MWCNT and Electrochemical NADH Oxidation

3,4 and 2,5- dihydroxybenzene compounds were separately and covalently coupled to the multiwalled carbon nanotube (MWCNT) deposited on the surface of glassy carbon electrode through electrochemical reduction of diazonium compound of benzylamine bearing Boc protecting group (tert-butyloxycarbonyl). Following the removal of the Boc group, an amide bond was formed between the amine-terminated surface and the acyl group of the dihydroxybenzene derivatives. The electrochemical properties of dihydroxybenzene-modified MWCNT and the influence of the sweep rate on the voltammogram were elucidated by cyclic voltammetry (CV). Electron transfer kinetics of modified MWCNT by dihydroxybenzene derivatives was also studied using Laviron’s theory. As evidenced by an improvement in the anodic peak current and a negative shift in the overpotential of NADH oxidation when compared to the bare MWCNT, 3,4 and 2,5- dihydroxybenzene modified MWCNT electrodes were shown to possess catalytic activity toward NADH oxidation.

One-Step Transformations from ACQ Luminogens to DSEgens via the Boc Protection Process.

Dual-state emission luminogens (DSEgens), as a new type of luminescent materials that can effectively emit light in solution and solid state, have attracted tremendous attention due to their potential application in chemical sensing, biological imaging, organic electronic devices, etc. In this study, two new rofecoxib derivatives ROIN and ROIN-B have been synthesized, and their photophysical properties are fully investigated by experimental studies and theoretical calculations. The key intermediate ROIN, resulting from one-step conjugation of rofecoxib with an indole unit, shows the classical aggregation-caused quenching (ACQ) effect. Meanwhile, by introducing a tert-butoxycarbonyl (Boc) group on the basis of ROIN without enlarging the π conjugation system, ROIN-B was successfully developed with an obvious DSE property. In addition, both fluorescent behaviors and their transformation from ACQ to DSE were elucidated clearly by going through the analysis of their single X-ray data. Moreover, the target ROIN-B, as a new DSEgens, also displays reversible mechanofluorochromism and lipid droplet-specific imaging ability in HeLa cells. Taken together, this work proposes a precise molecular design strategy to afford a new DSEgens, which may provide guidance for the future exploration of new DSEgens.

Synthesis of N,N′-Unsymmetrical 9-Amino-5,7-dimethyl-bispidines

A new approach to the preparation of N,N'-unsymmetrically substituted 9-aminobispidines through aminal bridge removal reaction has been developed, the principal feature of which is the ability to selectively functionalize all three nitrogen atoms. The intermediates of 1,3-diazaadamantane's aminal bridge removal reaction are characterized, and the mechanism of this reaction is proposed based on the analysis of their structures. Representatives of the previously unknown saturated heterocyclic 1,5,9-triazatricyclo[5.3.1.03,8]undecane system were obtained and structurally characterized. Thus, it was possible for the first time to obtain 3,7,9-trisubstituted bispidines containing acetyl, Boc, and benzyl groups at nitrogen atoms, which can be independently removed (orthogonal protective groups).

Amino Acid-Based Polymer-Coated Silver Nanoparticles as Insulin Fibril Inhibitors

To explore the impact of polymer-coated silver nanoparticles (PC-AgNPs) on the extent of the insulin aggregation process, herein, we have synthesized three copolymers comprising poly(ethylene glycol) methyl ether methacrylate (PEGMA) and tert-butoxycarbonyl (Boc)-protected amino acid (alanine, leucine, and phenylalanine) containing methacrylate monomers, via reversible addition-fragmentation chain transfer (RAFT) polymerization. After deprotection of the Boc groups, the as-prepared water-soluble copolymers were coated on silver nanoparticles (Ag NPs), and the role of these NPs on insulin aggregation pathways was examined by multifarious spectroscopic and microscopic techniques. The extent of the inhibitory effect against the insulin fibrillation process was found to be related to the surface properties of the NPs, with the highest inhibitory effect detected for phenylalanine-based polymer-coated Ag NPs (PPhe-AgNPs). Using circular dichroism (CD) spectroscopy and Nile red (NR) fluorescence spectroscopy, we investigated the conformational changes and examined the role of hydrophobic interaction in inhibiting the aggregation properties of insulin upon treatment with PC-AgNPs. Furthermore, PC-AgNPs were also able to disintegrate the matured insulin fibrils and efficiently decreased the fibril-induced cytotoxicity, as confirmed by transmission electron microscopy (TEM) and the hemolysis study, respectively. Together, our findings established the novel amino acid-based PC-AgNPs as potent nanomaterials with 77–96% insulin fibril inhibition and marked disaggregation of matured insulin fibrils.

Novel pseudonucleosides and sulfamoyl-oxazolidinone β-D-glucosamine derivative as anti-COVID-19: design, synthesis, and in silico study

New pseudonucleosides containing cyclic sulfamide moiety and sulfamoyl β-D-glucosamine derivative are described. These pseudonucleosides are synthesized in good yields starting from chlorosulfonyl isocyanate and β-D-glucosamine hydrochloride in five steps; (protection, acetylation, removal of the Boc group, sulfamoylation, and cyclization). Further, novel glycosylated sulfamoyloxazolidin-2-one is prepared in three steps; carbamoylation, sulfamoylation, and intramolecular cyclization. The structures of the synthesized compounds were confirmed by usual spectroscopic and spectrometric methods NMR, IR, MS, and EA. Interesting molecular docking of the prepared pseudonucleosides and (Beclabuvir, Remdesivir) drugs with SARS-CoV-2/Mpro (PDB:5R80) was conducted using the same parameters for a fair comparison. A low binding affinity of the synthesized compounds compared to the Beclabuvir and other analysis showed that pseudonucleosides have the ability to inhibit SARS-CoV-2. After the motivating results of molecular docking study, the complex between the SARS-CoV-2 Mpro and compound 7 was subjected to 100 ns molecular dynamics (MD) simulation using Desmond module of Schrodinger suite, during which the receptor-ligand complex showed substantial stability after 10 ns of MD simulation. Also, we studied the prediction of absorption, distribution, properties of metabolism, excretion, and toxicity (ADMET) of the synthesized compounds. Communicated by Ramaswamy H. Sarma