Tert-butyloxycarbonyl Group Research Articles

Conformational studies on substituted ε-caprolactams by X-ray crystallography and NMR spectroscopy

The synthesis and conformational analysis of e-caprolactams containing a –COOMe group at the C-6 position is described. The influence of different C-2, C-6 and N substituents on ring conformation was studied using X-ray crystallography and NMR spectroscopy. The results provide evidence that all the analysed caprolactams adopt a chair type conformation with a planar lactam. In the 6-substituted caprolactam, the –COOMe residue prefers to reside in an equatorial position, but can be induced to occupy an axial orientation by the introduction of a bulky tert-butyloxycarbonyl (BOC) group on the lactam nitrogen or by C-2/C-3 ring desaturation. The BOC protected caprolactam was found to undergo exchange between two chair forms as detected by solution NMR, one with the C-6 ester equatorial (30%) and the other with it in the axial position (70%); the latter was observed by X-ray crystallography. For the C-2 dithiocarbamate substituted C-6 methyl ester seven-membered rings, a single chair form is observed for cis-isomers with both substituents equatorial. The analogous trans-isomers, however, exist as two chair forms in a 1 : 1 equilibrium ratio of 1,NC4 and 4C1,N conformers, where either substituent can occupy axial or equatorial positions.

β-Lactamase inhibition by 7-alkylidenecephalosporin sulfones: allylic transposition and formation of an unprecedented stabilized acyl-enzyme.

The inhibition of the class A SHV-1 β-lactamase by 7-(tert-butoxycarbonyl)methylidenecephalosporin sulfone was examined kinetically, spectroscopically, and crystallographically. An 1.14 Å X-ray crystal structure shows that the stable acyl-enzyme, which incorporates an eight-membered ring, is a covalent derivative of Ser70 linked to the 7-carboxy group of 2-H-5,8-dihydro-1,1-dioxo-1,5-thiazocine-4,7-dicarboxylic acid. A cephalosporin-derived enzyme complex of this type is unprecedented, and the rearrangement leading to its formation may offer new possibilities for inhibitor design. The observed acyl-enzyme derives its stability from the resonance stabilization conveyed by the β-aminoacrylate (i.e., vinylogous urethane) functionality as there is relatively little interaction of the eight-membered ring with active site residues. Two mechanistic schemes are proposed, differing in whether, subsequent to acylation of the active site serine and opening of the β-lactam, the resultant dihydrothiazine fragments on its own or is assisted by an adjacent nucleophilic atom, in the form of the carbonyl oxygen of the C7 tert-butyloxycarbonyl group. This compound was also found to be a submicromolar inhibitor of the class C ADC-7 and PDC-3 β-lactamases.

Photoresponsive Colorimetric Change of a t-BOC-Polyaniline/Spiropyran Film Based on Conducting Pattern

Among the polymers, polyaniline (PANI) is a unique conjugated polymer in that it can be tailored for specific applications through a non-redox acid/base doping process. Unfortunately, Its poor solubility in most common organic solvents has limited the industrial application of PANI because of its high aromatic nature, strong inter-chain hydrogen bonding, and high charge delocalization. The patterning of conjugated polymers on various substrates was achieved by using a variety of techniques, such as the deposition by scanning electrochemical microscopy, screen printing, micromolding in capillaries (MIMIC), inkjet printing, photochemical patterning by photolithography, and microcontact printing through self-assembly monolayer (SAM). Recently, we reported micro-scale conducting pattern using the organic soluble PANI substituted with acid-labile tertbutyloxycarbonyl (t-BOC) group on the glass substrate and reversible photochromism between spiropyran (SP) and fluorecein molecules by photolithography. If this lightregulated reversible uptake and release of protons to SP is combined with the t-BOC-PANI, then the colorimetric change could be controlled by additional stimuli. We report here for the first time the reversible colorimetric change on patterned film of t-BOC-PANI/SP by various stimuli such as photo, thermal, acid/base.

Phagocytic uptake and ROS‐mediated cytotoxicity in human hepatic cell line of amphiphilic polyphosphazene nanoparticles

The pH-responsive amphiphilic polyphosphazenes bearing N,N-diisopropylethylenediamine (DPA) have been proven to be promising nanovehicles for drug antitumor therapy. To further modify these amphiphilic polyphosphazenes with fluorescent labeling agent or other biochemical functional groups, serine methyl ester containing active chemical group NH(2) was chosen to be introduced to get a novel polymer [NP(PEG)(0.24) (DPA)(0.5)(SME)(1.26) (n) (PDS-NH(2) ). Considering the possible toxic effect of -NH(2) group, the biocompatibility in bloodstream and nanotoxicity on human normal hepatic L-02 cells was evaluated in this study. The polymer [NP(PEG)(0.24)(DPA)(0.5)(SME-BOC)(1.26)](n) (PDS-BOC) linked with tert-butyloxycarbonyl groups to protect and hide -NH(2) group was applied as the comparison. First, the bovine serum albumin (BSA) adsorption and phagocytic uptake behavior in human THP-1 macrophages were performed. The results suggested that only a minor percentage of the nanoparticles were involved in BSA binding and phagocytic uptake as the result of PEGylation on the particulate surface. To determine the nanotoxicity on human normal hepatic L-02 cells, we measured cell viability, apoptosis and necrosis, reactive oxygen species generation, the loss of mitochondrial membrane potential, and the levels of the apoptotic signaling proteins in L-02 cells after the cells being exposed to nanoparticles of different concentrations (0.1, 0.2, and 0.5 mg/mL) for 24 h. Our data indicated that the two nanoparticles induced cytotoxicity in a dose-dependent manner; PDS-NH(2) caused more cytotoxicity than PDS-BOC as a result of -NH(2) exposure. The increased expression of caspase-3 and caspase-9 suggested that they triggered apoptosis through mitochondria-dependent pathways in L-02 cells.

From Molecular to Macroscopic Engineering: Shaping Hydrogen‐Bonded Organic Nanomaterials

The self-assembly and self-organization behavior of chromophoric acetylenic scaffolds bearing 2,6-bis(acetylamino)pyridine (1, 2) or uracyl-type (3-9) terminal groups has been investigated by photophysical and microscopic methods. Systematic absorption and luminescence studies show that 1 and 2, thanks to a combination of solvophilic/solvophobic forces and π-π stacking interactions, undergo self-organization in apolar solvents (i.e., cyclohexane) and form spherical nanoparticles, as evidenced by wide-field optical microscopy, TEM, and AFM analysis. For the longer molecular module, 2, a more uniform size distribution is found (80-200 nm) compared to 1 (20-1000 nm). Temperature scans in the range 283-353 K show that the self-organized nanoparticles are reversibly formed and destroyed, being stable at lower temperatures. Molecular modules 1 and 2 were then thoroughly mixed with the complementary triply hydrogen-bonding units 3-9. Depending on the specific geometrical structure of 3-9, different nanostructures are evidenced by microscopic investigations. Combination of modules 1 or 2 with 3, which bears only one terminal uracyl unit, leads to the formation of vesicular structures; instead, when 1 is combined with bis-uracyl derivative 4 or 5, a structural evolution from nanoparticles to nanowires is observed. The length of the wires obtained by mixing 1 and 4 or 1 and 5 can be controlled by addition of 3, which prompts transformation of the wires into shorter rods. The replacement of linear system 5 with the related angular modules 6 and 7 enables formation of helical nanostructures, unambiguously evidenced by AFM. Finally, thermally induced self-assembly was studied in parallel with modules 8 and 9, in which the uracyl recognition sites are protected with tert-butyloxycarbonyl (BOC) groups. This strategy allows further control of the self-assembly/self-organization process by temperature, since the BOC group is completely removed on heating. Microscopy studies show that the BOC-protected ditopic modules 8 self-assemble and self-organize with 1 into ordered linear nanostructures, whereas BOC-protected tritopic system 9 gives rise to extended domains of circular nano-objects in combination with 1.

New Potent Bisubstrate Inhibitors of Histone Acetyltransferase p300: Design, Synthesis and Biological Evaluation

Bisubstrate-type compound Lys-CoA has been shown to inhibit the p300 histone acetyl transferase activity efficiently and may constitute a lead compound for a novel class of anticancer therapeutics. Based on this strategy, we synthesized a series of CoA derivatives and evaluated these molecules for their activity as p300 histone acetyltransferases inhibitor. The best activity was obtained with compound 3 bearing a C-5 spacing linker that connects the CoA moiety to a tert-butyloxycarbonyl (Boc) group. Based on docking simulations, this inhibitor exhibits favorable interactions with two binding areas, namely pockets P1 and P2, within the active site.

Efficient Preparation of 2-Aminomethylbiphenyls via Suzuki-Miyaura Reactions

We prepared four 2-(aminomethyl)arylboronic acids and studied their reactivity in the Suzuki―Miyaura coupling reaction with different aryl halides. We observed significant increases in yields and shorter reaction times when the amine adjacent to the boronic acid was protected by a tert-butyloxycarbonyl (t-Boc) group. We then investigated the origin of the greater reactivity of N-t-Boc-protected substrates with regard to the potential role of an N―B bond.

ChemInform Abstract: Safety-Catch Anchoring Linkage for Synthesis of Peptide Amides by Boc/ Fmoc Strategy.

Summary: 2-Methoxy-4,4’-bis(methylthio)benzhydrylamine (10) and the corresponding disulfoxide were prepared and tested as a model amide protecting groups for their stability toward acidic conditions. Subsequently, the novel 4-[4,4’-bis(methylsulfinyl)-2-o~-(9-fluorenylmethylo~c~bonyl) benzhydrylami- nolbutanoic acid (SCAL) handle (9) has been prepared and applied to solid-phase peptide synthesis of C-terminal peptide amide using both 9-fluorenylmethyloxycarbonyl (Fmoc) and tert-butyloxycarbonyl (Boc) groups for Na-amino protection. A range of naturally occurring peptides, especially hormones such as oxytocin, secretin, LHRH, and calcitonin, contain a C-terminal amide function. Synthesis of peptide amides is best carried out by application of appropriate handles, which are quantitatively coupled in a single step onto amino-functionalized supports to provide ageneral starting point for peptide chain assembly. Surprisingly, the development of amide-anchor groups which can be cleaved by relatively mild procedures (e.g., TFA), were established only recently.’ Considerable attention has been focused on preparation of benzylamine1’2 and benzhydrylamine1’3 deriva- tives substituted with electron-donating alkoxy groups. Earlier we have examined some benzhydrylamines containingp-methylsulfinyl orp-methylthio groups as a model amrde protecting groups4 We have found that 4,4’-bis(methylsulfinyl)benzhydryl protecting group for amides is fully compatible with Fmoc and/or Boc protecting groups. We now describe the synthesis and application of anew type of safety-catch acid labile5 (SCAL) handle9 derived from 2-alkoxy-4,4’-bis(methyl- thio)benzhydrylamine, which extends the orthogonalit$ of currently

An alkoxide anion-triggered tert-butyloxycarbonyl group migration. Mechanism and application

We report a fast N→O tert-butyloxycarbonyl (Boc) migration of the imide (3R,4R)-tert-butyl 3-((6-(bis(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (2) via a base-generated alkoxide. The mechanism of the migration is intramolecular, involving an unusual nine-membered cyclic transition state.

Thiomaleic Anhydride: A Convenient Building Block for the Synthesis of α-Substituted γ- and δ-Lactones through Free-Radical Addition, Nucleophilic Ring Opening, and Subsequent Thiocarboxylate Manipulation

Iodoalkyl tert-butyl carbonates and carbamates undergo clean free-radical addition to thiomaleic anhydride to give substituted thiosuccinic anhydrides in high yield on treatment with tris(trimethylsilyl)silane and a radical initiator. After removal of the tert-butyloxycarbonyl group, cyclization then affords lactones or lactams substituted in the alpha-position by a thiocarboxylic acid residue. This group is converted to amides through reaction with electron-deficient sulfonamides or to aldehydes and/or ketones by the reaction of derived thioesters with either thiophenol, an electron-deficient allyl phenyl sulfide, or phenylboronic acid.

One-Pot Synthesis of a Novel Ladder Polymer of Calixarene via Condensation Reaction of Resorcinol and Alkanedial Based on Dynamic Covalent Chemistry

Reaction of resorcinol and 1,4-butanedial [(CH2)2(CHO)2] in the presence of concentrated HCl in ethanol at 80 °C for 48 h afforded a soluble polymer (CRA−polymer) in quantitative yield under thermodynamic control. Single X-ray crystal analysis revealed that the precursor product had cyclic structure, and TOF mass spectroscopy of CRA−polymer revealed a ladder structure with calixresorcinarene moieties in the main chain. The photoinduced deprotection reaction of CRA−polymer derivative (CRA−polymer−BOC) containing tert-butyloxycarbonyl groups were examined in the film state in the presence of photoacid generator to produce the alkaline developable CRA−polymer with release of isobutylene and carbon dioxide.

Benzyl 2-{[2-(tert-butoxycarbonylamino)-4-methylpentanoyl]methylamino}-4-methylpentanoate

The title compound, C25H40N2O5, was synthesized in 55.9% yield by condensation of N-methyl-l-leucine benzyl ester toluene sulfonic acid with tert-butoxy­carbonyl-l-leucine at 273 K and its crystal structure determined. The dipeptide derivative conjugates through the amide linkage and includes two protecting groups, a tert-butyloxycarbonyl group at the C-tip and a benzyl group at the N-tip.

EPR study of copper(II) complexes of hydroxysalen derivatives in order to be used in the DNA cleavage

Two series of functionalised hydroxy-salen-copper(II) complexes with various side chain lengths have been synthesized. The first one is characterised by amino side chain protected by the tert-butyloxycarbonyl group (Boc) whereas, the second series is obtained by removal of the Boc-protecting group under acidic conditions and formation instead of it an ammonium salt. EPR studies were carried out on the copper(II) complexes. EPR signals attributed to monomers and dimers of Cu 2+ species were evidenced. Determination of the copper(II) environment in each complex was attempted using all the experimental results. Square planar and tetrahedral symmetries were found for the copper(II) monomers. From the fine structure observed for the pair signal, the distance between the Cu 2+ ions in the pair has been calculated (3.9–4.3 Å). From these values, it seems that the formation of pairs is obtained by a face-to-face bimolecular association.

Design and Synthesis of 12‐Aza‐Epothilones (Azathilones)—“Non‐Natural” Natural Products with Potent Anticancer Activity

Design and Synthesis of 12‐Aza‐Epothilones (Azathilones)—“Non‐Natural” Natural Products with Potent Anticancer Activity

Synthesis of tritium-labeled Semax

The tert-butyloxycarbonyl derivative of Met-Glu-His-Phe-Pro-Gly was prepared and condensed with either unsaturated or labeled proline. The unsaturated peptide protected by the tert-butyloxycarbonyl group was hydrogenated with gaseous tritium in the presence of a catalyst. The Semax analog labeled in the proline fragment was deprotected by acid hydrolysis. The molar radioactivity of the product (PBq mol−1) reached 0.93 in the route via labeled proline and 0.37 in the route via unsaturated Semax analog.

Patterned Fluorescence Images Using a Photocleavable NVOC‐Protected Quinizarin.

AbstractFor Abstract see ChemInform Abstract in Full Text.

New PFOS Free Photoresist Systems for EUV Lithography

New photoresist compositions containing tert-butyloxycarbonyl group protected C-4-hydroxyphenyl calix [4] resorcinarene molecular glasses and perfluorooctylsulfonate (PFOS) free photoacid generators (PAG) composed of a triphenylsulfonium aryloxyperfluoroalkylsulfonate was developed. The patterning performance of PFOS free photoresist compositions was examined using extreme ultraviolet (EUV or 13.4 nm) lithography and compared with photoresist compositions containing conventional perfluorobutanesulfonate (PFBS) PAGs. Features as small as 30 nm with low line edge roughness (LER) were readily obtained for both formulations. The non-PFOS photoacid generator forms acid that contains fewer fluorine atom than found in PFOS or in PFBS. The newly developed non-PFOS PAGs may find application in chemically amplified resists that address the environmental concerns raised by the widely used PFOS containing PAGs.

Patterned Fluorescence Images Using a Photocleavable NVOC-Protected Quinizarin

Photolabile protecting groups have widely been used in the fundamental and applied research areas. Among various photocleavable protecting groups reported, 6-nitroveratroyloxycarbonyl (NVOC) group, an o-nitrobenzyl derivative, has gained much attention due to efficient removal upon UV irradiation. Accordingly, the NVOC protecting strategy has been employed in a variety of solution and solid-phase chemistry. Generation of patterned color images in the polymer film using a photolabile a-methylnitroveratryloxycarbonyl (α-MNVOC) protecting group was reported. In this note, we report the first application of the NVOC protecting group to the direct generation of patterned fluorescent images. Previously, we and other groups described ‘precursor approach’ for the patterned functional images in the polymer film without employing wet-developing processes. The concept of the ‘precursor approach’ is to use different electronic properties between the protected and unprotected forms (Figure 1). Thus, a dye molecule is nonfluorescent when the key functional group of the dye molecule is protected with a protecting group (PG). If the protecting group is removed under photoinduced chemical transformation, the fluorescence can be regenerated, allowing patterned fluorescent images in the polymer film by selective removal of the protecting group in the exposed areas. The protecting group investigated in our previous research was tert-butyloxycarbonyl (t-Boc) group which required a photoacid generator to cleave the protecting group in the exposed areas. The NVOC group, however, does not require acidic conditions for deprotection. Thus, the NVOCprotecting strategy should be a useful alternative for patterned images in polymer film where acidic conditions could not be employed. In order to test the feasibility of generation of patterned images with a photolabile protecting group-containg precursor molecule, the NVOC-protected compound 2 was readily prepared from quinizarin (1) and 4,5-dimethoxy-5nitrobenzyl chloroformate as shown in Scheme 1. The NVOC-protected quinizarin 2 was found to have a maximum absorption wavelength in the UV region (350 nm) and was observed to show no fluorescence, similar to the t-Bocprotected quinizarin. In order to investigate the feasibility of generating quinizarin moieties by direct photolysis from NVOC-protected precursor 2, a thin PMMA film containing the precursor 2 (20 wt%) on a quartz substrate was irradiated with 360 nm UV light.

Synthesis, enantiomeric resolution, F-18 labeling and biodistribution of reboxetine analogs: promising radioligands for imaging the norepinephrine transporter with positron emission tomography

Racemic and enantiomerically pure (( S, S) and ( R, R)) 2-[α-(2-(2-[ 18F]fluoroethoxy)phenoxy)benzyl]morpholine ([ 18F]FRB) and its tetradeuterated form [ 18F]FRB-D 4, analogs of the highly selective norepinephrine reuptake inhibitor reboxetine (2-[α-(2-ethoxyphenoxy)benzyl]morpholine, RB), have been synthesized for studies of norepinephrine transporter (NET) system with positron emission tomography (PET). The [ 18F]fluorinated precursor, ( S, S)/( R, R)- N- tert-butyloxycarbonyl-2-[α-(2-hydroxyphenoxy)benzyl]morpholine (( S, S)/( R, R)- N-Boc-desethylRB), was prepared by the N-protection of ( S, S)/( R, R)-2-[α-(2-hydroxyphenoxy)benzyl]morpholine (( S, S)/( R, R)-desethylRB) with a tert-butyloxycarbonyl (Boc) group followed by enantiomeric resolution with chiral HPLC to provide both ( S, S) and ( R, R) enantiomers with >99% enantiomeric purity. These compounds were then used for radiosynthesis to prepare enantiomerically pure [ 18F]FRB and [ 18F]FRB-D 4 via the following three-step procedure: (1) formation of 1-bromo-2-[ 18F]fluoroethane ([ 18F]BFE or [ 18F]BFE-D 4) by nucleophilic displacement of 2-bromoethyl triflate (or D 4 analog) with no-carrier added [ 18F]F − in THF; (2) reaction of [ 18F]BFE (or [ 18F]BFE-D 4) with N-Boc-desethylRB in DMF in the presence of excess base; and (3) deprotection with trifluoroacetic acid. The racemates, ( S, S) and ( R, R) enantiomers of [ 18F]FRB and [ 18F]FRB-D 4 were obtained in 11–27% (decay corrected to the end of bombardment, EOB) in 120-min synthesis time with a radiochemical purity of >98% and specific activities of 21–48 GBq/μmol (EOB). The results of the whole-body biodistribution studies with ( S, S)-[ 18F]FRB-D 4 were similar to those with ( S, S)-[ 18F]FRB but showed relatively faster blood clearance and no significant in vivo defluorination. Positron emission tomography studies in baboon brain also showed that ( S, S)-[ 18F]FRB-D 4 may be a potentially useful ligand for imaging NET with PET.

No Auxiliary, No Byproduct Strategy for Water-Soluble Prodrugs of Taxoids: Scope and Limitation of O−N Intramolecular Acyl and Acyloxy Migration Reactions

Since numerous new taxoids active against multidrug resistant (MDR) tumors have been developed and their poor water-solubility is a very real problem in intravenous administration, we have designed and synthesized a series of novel water-soluble taxoid prodrugs (isotaxoids). These prodrugs, a 2'-O-isoform of taxoids, showed promising results with higher water solubility (0.8-1.1 mg/mL) and proper kinetics for parent drug release by a simple pH-dependent chemical mechanism via O-N intramolecular acyl migration. No additional functional auxiliaries are released during the conversion to parent drugs, which would be an advantage in toxicology and general pharmacology, and the cost for the evaluations of auxiliary units in these fields could be saved in prodrug development. In addition, we demonstrate for the first time the successful application of the O-N intramolecular acyloxy migration reaction in the prodrug design, with the exception of the tert-butyloxycarbonyl group, and that this reaction can be provided with no organic solvent and no side products.