Tertiary Butyl Ester Research Articles

Peripherally “tertiary butyl ester” functionalized bipyridine cored dendrons: from synthesis and characterization to molecular dynamic simulation study

In this study, we report the design, synthesis, characterization and solvent dependent behaviour of series of new bipyridine cored poly(benzyl-ether) dendrons functionalized with tertiary butyl esters.

Method for the Preparation of N‐protected β‐Cyano L‐alanine Tertiary Butyl Esters

AbstractHere we report a simple, efficient and scalable one‐pot procedure for the synthesis of N‐protected β‐cyano L‐alanine tertiary butyl esters from N‐protected L‐asparagines. Reaction of N‐protected L‐asparagines with 2.2 equivalents of (Boc)2O and catalytic amount of N,N‐dimethylamino pyridine (DMAP) in tertiary butanol at room temperature resulted N‐protected β‐cyano L‐alanine tertiary butyl esters. We also synthesized N‐protected β‐cyano L‐alanines from the obtained crude N‐protected β‐cyano L‐alanine tertiary butyl esters without column chromatography on gram scale in good yields. Control experiments gave the corresponding nitrile acids over the tertiary butyl esters. Later, we synthesized nitrile containing dipeptides by coupling N‐Boc‐β‐cyano L‐alanine 4 a with amino acid methyl ester hydrochlorides.

DM-Dim for carboxylic acid protection

The 1,3-dithian-2-yl-methyl (Dim) and its analogous groups including dimethyl-Dim (dM-Dim) can provide a new dimension of orthogonality for carboxylic acid protection. They can be deprotected under nearly neutral oxidative conditions. In this paper, the protection of carboxylic acid with dM-Dim, deprotection of dM-Dim ester with sodium periodate, stability of dM-Dim protected carboxylic acid under acidic and basic conditions, and selective deprotection of dM-Dim protected carboxylic acids in the presence of tertiary butyl and methyl esters are presented.

A direct and sustainable synthesis of tertiary butyl esters enabled by flow microreactors

Tertiary butyl esters find large applications in synthetic organic chemistry. A straightforward method for the direct introduction of the tert-butoxycarbonyl group into a variety of organic compounds has been developed using flow microreactor systems. The resultant flow process was more efficient, versatile and sustainable compared to the batch.

ChemInform Abstract: A Mesoporous Organosilica Grafted Pd Catalyst (MOG‐Pd) for Efficient Base Free and Phosphine Free Synthesis of Tertiary Butyl Esters via Tertiary‐Butoxycarbonylation of Boronic Acid Derivatives Without Using Carbon Monoxide.

AbstractThe catalytic activity of the newly synthesized catalyst is evaluated for the synthesis of tertiary butyl esters via tert‐butoxycarbonylation of boronic acid derivatives.

A mesoporous organosilica grafted Pd catalyst (MOG-Pd) for efficient base free and phosphine free synthesis of tertiary butyl esters via tertiary-butoxycarbonylation of boronic acid derivatives without using carbon monoxide

A reusable MOG-Pd catalyst has been synthesized, characterized and it shows high efficiency in tert-butoxycarbonylation under green condition.

Synthesis and Characterization of Carboxyl Terminated Polydimethylsiloxanes

A series of hydrogen terminated polydimethylsiloxanes (PDMS-H) had been controlled synthesized via ring-opening polymerization. Then, methylmethacrylate (MMA) and tert-butyl methacrylate (tBMA) were grafted to PDMS-H via hydrosilylation reactions in the presence of Speier's catalyst, the hydrosilylation addition patterns of MMA and tBMA showed a strong preference toward β-1,2 addition, no α-1,2 addition product or 1,4-addition product was observed. Carboxyl terminated polydimethylsiloxanes were prepared by subsequent hydrolysis reaction in an aqueous NaOH/ethanol solution and under acid condition, respectively. Both methods could obtain carboxyl terminated polydimethylsiloxanes successfully. However, a significant decrease of the molecular weight of products was observed in the alkaline hydrolysis process, while the acid hydrolysis of tertiary butyl ester group terminated polydimethylsiloxanes could be conducted in a highly controlled manner. Besides, the synthesis of carboxyl terminated polydimethylsiloxanes via acid hydrolysis reaction can be conducted well only when the terminal group of polydimethylsiloxanes is tertiary butyl, this can be explained by the specificity of tertiary butyl.

Targeting mitochondrial transcription in fission yeast with ETB, an inhibitor of HSP60, the chaperone that binds to the mitochondrial transcription factor Mtf1

Mtf1 has been characterized as a mitochondrial transcription factor and is shown to regulat mitochondrial transcription. Mtf1 has an additional function as a transcription factor for the nuclear gene srk1 in fission yeast. Hsp60 has been linked to a variety of important cellular functions such as apoptosis and the immune response. It functions mainly as a molecular chaperone that assists correct protein folding in the mitochondrion. Epolactaene tertiary butyl ester(ETB) is an inhibitor of human Hsp60 that can inhibit Hsp60 chaperone activity. In this study,we report that in fission yeast, Mtf1 binds to Hsp60 in vivo and in vitro, ETB inhibits the binding of Mtf1 and Hsp60, and inhibits mitochondrial transcription but not nuclear transcription of srk1. We propose that Hsp60 may act as a molecular chaperone that folds mitochondrial Mtf1 into a functional form and that ETB inhibits this Hsp60 chaperone activity by disrupting Mtf1 binding to Hsp60 and thus inhibits mitochondrial transcription in fission yeast.

Vesicle-templated pH-responsive polymeric nanocapsules

We report the synthesis of pH responsive polymeric nanocapsules by templating unilamellar vesicles of dimethyldioctadecylammonium bromide (DODAB) using a RAFT-based templating approach. A short-chain living anionic copolymer containing randomly distributed acrylic acid and butyl acrylate units was first synthesized by RAFT in solution using dibenzyl trithiocarbonate (DBTTC) as the RAFT agent. The anionic copolymer chains were subsequently adsorbed onto the surface of cationic DODAB vesicles and were further chain extended to form a thick polymeric shell by feeding a monomer mixture comprising methyl methacrylate (MMA) and tertiary butyl acrylate (t-BA) in combination with the divinyl crosslinker ethylene glycol dimethacrylate (EGDMA) under starved feed conditions. CryoTEM characterization demonstrated successful formation of a thick crosslinked polymeric shell around the vesicles. Subsequent acid hydrolysis of the tertiary butyl ester groups of the crosslinked polymeric shell resulted in the formation of pH-responsive nanocapsules.

Titration syntheses of polyaminosubstituted phthalocyanines via nucleophilic aromatic substitutions on zinc(II) 1,2,3,4,8,9,10,11,15,16,17,18,22,23,24,25-hexadecafluorophthalocyanine

Primary amines, secondary amines and tertiary butyl esters of amino acids are used as nucleophiles with zinc(II) hexadecafluorophthalocyanine to provide mixtures of mono and disubstituted fluorinated phthalocyanines under mild conditions, or polyaminosubstituted phthalocyanines when using the amines as solvents. Diamines give cyclic substituted phthalocyanines, binuclear or trinuclear phthalocyanines or mixtures of both types, depending on the chain length or structure of the diamine.

Epolactaene binds human Hsp60 Cys442 resulting in the inhibition of chaperone activity

Epolactaene is a microbial metabolite isolated from Penicillium sp., from which we synthesized its derivative ETB (epolactaene tertiary butyl ester). In the present paper, we report on the identification of the binding proteins of epolactaene/ETB, and the results of our investigation into its inhibitory mechanism. Using biotin-labelled derivatives of epolactaene/ETB, human Hsp (heat-shock protein) 60 was identified as a binding protein of epolactaene/ETB in vitro as well as in situ. In addition, we found that Hsp60 pre-incubated with epolactaene/ETB lost its chaperone activity. The in vitro binding study showed that biotin-conjugated epolactaene/ETB covalently binds to Hsp60. In order to investigate the binding site, binding experiments with alanine mutants of Hsp60 cysteine residues were conducted. As a result, it was suggested that Cys442 is responsible for the covalent binding with biotin-conjugated epolactaene/ETB. Furthermore, the replacement of Hsp60 Cys442 with an alanine residue renders the chaperone activity resistant to ETB inhibition, while the alanine replacement of other cysteine residues do not. These results indicate that this cysteine residue is alkylated by ETB, leading to Hsp60 inactivation.

Structure—Activity Relationships of Epolactaene Derivatives: Structural Requirements for Inhibition of Hsp60 Chaperone Activity.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Structure–activity relationships of epolactaene derivatives: structural requirements for inhibition of Hsp60 chaperone activity

Epolactaene is a microbial metabolite isolated from the fungal strain Penicillium sp. It arrests the cell cycle at the G 0/G 1 phase and induces the outgrowth of neurites in human neuroblastoma SH-SY5Y cells. In this communication, we report the structure–activity relationships (SARs) of new epolactaene derivatives, including those lacking the epoxylactam moiety and having various side chains. These derivatives were evaluated for their ability to inhibit the growth of human cancer cell lines. They were also analyzed for their ability to affect human heat shock protein 60 (Hsp60), which we have already identified as a protein that binds to epolactaene. We also identified the important structural framework of epolactaene/ETB (epolactaene tertiary butyl ester) for not only binding to Hsp60 but also inhibiting Hsp60 chaperone activity.

Species-Specific Detoxification Metabolism of Fenpyroximate, a Potent Acaricide

Abstract The mode of selective toxicity of fenpyroximate ( tert -butyl ( E )-α-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxy)- p -toluate), a potent acaricide, was studied with respect to its detoxification metabolism. Among its metabolites examined, only ester hydrolyzed metabolites completely lost the inhibitory activity toward NADH–ubiquinone oxidoreductase, which suggested that ester hydrolysis was the key step in detoxification. After a single oral administration of fenpyroximate to rats, two labile intermediates (metabolites A and B) as well as ester hydrolyzed metabolites were found in the liver and plasma as the major metabolites. These intermediates were also observed in an in vitro metabolism system employing rat liver S-9 (9000 g supernatant) fraction under the presence of diisopropyl fluorophosphate, a carboxyesterase inhibitor. Metabolites A and B were isolated and identified as 1-hydroxymethyl-1-methylethyl ( E )-α-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxy)- p -toluate and 2-hydroxy-2-methylpropyl ( E )-α-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxy)- p -toluate, respectively. Under slightly basic conditions or in rat plasma, metabolite A was stoichiometrically and nonenzymatically converted to metabolite B most likely via intramolecular transesterification. The rate of in vitro metabolite A production was approximately 10 times greater than that of direct carboxyesterase hydrolysis of fenpyroximate; metabolite B was hydrolyzed approximately 100 times faster than fenpyroximate by carboxyesterase. Therefore, it is presumed that fenpyroximate is hydrolyzed principally via hydroxylation of fenpyroximate to metabolite A followed by transesterification to metabolite B in the rat. Hydroxylation of fenpyroximate to metabolite A was observed not only in rat liver, but also in mouse, rabbit, crab-eating monkey, carp, quail liver, and Spodoptera litula mid gut. Neither tertiary butyl ester hydrolysis nor metabolite A formation was detected in Tetranychus urticae Koch (two spotted spider mites), a fenpyroximate-sensitive organism in vivo and in vitro . Consequently, selectivity of fenpyroximate between spider mites and non-target organisms, especially mammals, would be attributable to the species-specific detoxification, ester hydrolysis via microsomal hydroxylation followed by intramolecular transesterification.

An improved synthesis of corrole

Reaction of two equivalents of 5-iodo-3,4-dialkylpyrrole, in situ-generated from the corresponding tertiary butyl ester, with 5,5′-diformyldipyrromethane afforded corrole macrocycle in 20% yield. Utilization of readily available tertiary butyl 5-iodo-3,4-dialkylpyrrole-2-carboxylate and 5,5′-diformyldipyrromethane opens a simple route to corrole.

Progress in 193 nm Positive Resists.

We used the tertiary butyl ester protecting group for the construction of our 193-nm resists. [1] This paper describes an investigation of the impact of acid-cleavable protecting group structure on the properties of a series of model acrylic polymers. In this investigation, factors such as thermochemical stability, reactivity to photogenerated acid, and dissolution properties of exposed films as a function of dose were examined. The impact of photo-acid structure and its role in the dissolution properties of exposed films will also be discussed. Additionally, we will introduce a new cycloaliphatic polymer family (polynorbomenes) with superior etch resistance, significantly broadening the polymer chemistry available for the construction of new 193-nm photoresists. [2]

Thiol levels in rat bronchio-alveolar lavage fluid after administration of cysteine esters.

1. The intraperitoneal administration of cysteine, N-acetylcysteine, the methyl, isopropyl, cyclo pentyl, neo pentyl, cyclo hexyl and tertiary butyl esters of cysteine and of cystine dimethyl ester increased the levels of total non-protein sulphydryls and cysteine in the bronchioalveolar lavage fluid and plasma of rats. In all cases the non-protein sulphydryl levels reflected the increased cysteine levels. 2. Cysteine, N-acetylcysteine, the cysteine esters and cystine dimethyl ester raised the levels of non-protein sulphydryls and hence cysteine in the bronchioalveolar lining fluid as follows: CIPE > CCPE > CME > CDME > CneoPE > CCHE > Nac > CySH > CTBE. 3. Plasma levels of NPSH were increased as follows: Nac > CySH > CCPE > CCHE > CneoPE > CIPE > CME > CDME > CTBE. 4. All except CTBE have been shown to protect against the lethal effects of inhaled perfluoroisobutene, a pyrolysis product of polytetrafluoroethene which induces a fulminating pulmonary oedema. 5. This study showed that by raising the levels of thiols in the bronchioalveolar lavage fluid (BALF), the epithelial cells lining the bronchiolar, alveolar regions of the lung could be protected against inhaled toxicants. 6. It is proposed that increased thiol levels in the BALF may contribute to the overall protection induced by these compounds by reacting with inhaled electrophiles to prevent or reduce damage to tissue in close proximity to the airways.

Structure-activity relationships of cysteine esters and their effects on thiol levels in rat lung in vitro

Pretreatment with cysteine esters increases cysteine (CySH) levels in rat lung and protects against the lethal effects of inhaled perfluoroisobutene in vivo. There are marked differences in the duration of protection achieved with different cysteine esters. In this study we have compared the uptake and metabolism of CySH, N-acetyl cysteine (NAc), cysteine esters and cystine esters in vitro using rat lung and liver homogenates and lung slices. Liver homogenates metabolized CySH and cysteine esters faster than lung homogenates. The half life (T 1 2 ) of CySH in lung was 58.8 ± 17.3 min and in liver was 14.0 ± 1.6 min (mean ± SEM). T 1 2 of the esters in lung ranged between 6.5 and 12.1 min and in liver between 1.9 and 5.3 min. Cysteine tertiary butyl ester, which does not protect in vivo, was not hydrolysed to CySH by lung or liver homogenates. All esters increased and prolonged intracellular CySH concentrations in lung slices to a much greater extent than CySH itself. NAc did not raise intracellular CySH above that of the controls and no NAc appeared within the slice. After CySH incubation intracellular CySH was 0.9±0.1 nmol/mg wet wt at 10 min whereas after incubation with the esters it ranged between 2.60 and 3.65 mol/mg wet wt. Cysteine cyclohexyl ester prolonged the increase of CySH the longest and cysteine methyl ester the shortest. CySH levels with cysteine cyclohexyl ester were 2.74 ± 0.15 and 4.13 ± 0.37 nmol/mg wet wt at 10 and 60 min, respectively, whereas with cysteine methyl ester, CySH levels were 2.60 ± 0.5 and 1.25 ± 0.08 solnmol mg wet wt at similar times. Cystine esters increased intracellular concentrations of both cystine and CySH. CySH concentrations ranged between 2.92 and 3.19 nmol/mg wet wt and cystine between 1.39 and 1.47 nmol/mg wet wt at 60 min. The elevation and duration of CySH in lung slices is well correlated with the duration of protection against perfluoroisobutene achieved in vivo.

Development of lipophilic anticancer agents for the treatment of brain tumors by the esterification of water-soluble chlorambucil

The lipophilic derivatives of the anticancer alkylating agent chlorambucil, chlorambucil-methyl, -isopropyl and -tertiary butyl esters, were synthesized and administered i.v. to anesthetized rats. Plasma and brain concentrations of these agents and of their active metabolites, chlorambucil and phenylacetic mustard, then were determined by high-performance liquid chromatography between 5 and 60 min. Whereas large amounts of chlorambucil-tertiary butyl ester entered and were maintained in brain, lower amounts of chlorambucil-isopropyl ester and no chlorambucil-methyl ester were found in brain. The comparative brain/plasma concentration-time integral ratios of the total active agents generated from chlorambucil-tertiary butyl, -isopropyl and -methyl esters were 0.85, 0.12 and 0.06, respectively, compared to a ratio of 0.02 for chlorambucil. In vitro alkylating activity of each ester was compared to that of equimolar chlorambucil, by reaction with 4-(p-nitrobenzyl)pyridine. Each ester possessed high intrinsic alkylating activity, equal to 38.4, 57.0 and 69.9% of chlorambucil activity, for the -tertiary butyl, -isopropyl and -methyl esters, respectively. Therefore each is an active antineoplastic agent irrespective of whether or not chlorambucil is regenerated. The rates of ester hydrolysis of these derivatives to chlorambucil were measured in fresh rat blood and in liver and brain homogenates at 37 degrees C. Chlorambucil-methyl and -isopropyl esters were hydrolysed quickly within 30 s in blood and liver, whereas chlorambucil-tertiary butyl ester was more stable with half-lives of approximately 7 h and 2 h, respectively. All proved to be relatively stable in brain homogenate. Steric hindrance around the ester linkage of chlorambucil-tertiary butyl ester reduces its affinity to and rate of hydrolysis by plasma and liver esterases, and allows it to accumulate within the brain. Chlorambucil-tertiary butyl ester maintains high levels in brain despite rapidly declining plasma concentrations and, due to these favorable pharmacokinetics and to its intrinsic anticancer activity, it possess promising characteristics for the treatment of malignant brain tumors.

Heterochiral N‐formyl methionyl peptides

Crystal and molecular structures for the heterochiral sequence N‐formyl‐l‐methionine‐d‐phenylalanine, 1, and its tertiary butyl ester, 2, are reported. The solid‐state peptide conformation is compared to that observed in solution by n.m.r. techniques. For N‐f‐Met‐d‐Phe, 1, the crystal was orthorhombic, space group P21 2121 with a cell of dimensions a = 5.061(3), b = 16.575(5) and c = 19.656(6) Å at ambient temperature of 293K; V = 1649(2)Å3, Z = 4, Dm= 1.31(2)gcm−3, Dx= 1.307gcm−3, μ(Mokx) = 2.047cm−1. For N‐f‐Met‐d‐Phe‐OtBu. 2, the crystal was monoclinic, space group P21 with a cell of dimensions a = 9.963(2), b = 11.147(2), c = 19.166(3)Å. β= 102.31(1) at 273K; V = 2080(2) Å3 Z = 4, Dm= 1.22(2)gcm−3, Dx= 1.215gcm−3μ(MoKx) = 1.714cm−1. The structures were solved from diffractometer data and refined to conventional final R = 0.046, Rw= 0.053 for F‐Met‐d‐Phe (1301 observations. I ≥ 3σ(I)) and to R = 0.056, Rw= 0.064 for the t‐butylester (2411 observations. I ≥ 3σ(I)). The l‐d acid, 1, crystallizes in an extended β‐sheet conformation with trans‐planar peptide bond; the principal torsion angle values are φ1=– 141.2(4).Ψ1= 149.6(4)3, φ2= 157.4(4)°. The methionine side chain adopts a common coiled conformation with x11= ‐ 58.0(5).x21= 175.1(4), x31= 76.5(5). The Phe side chain adopts the statistically least favored g orientation in contrast to the most populated rotamer in solution. The crystal structure is composed of parallel β‐sheets held together by four weak intermolecular contacts including two C‐H O contacts from the alpha carbons to the formyl and peptide carbonyl oxygens. Sheet layers are joined in a head‐to‐tail fashion through a very short (2.569(4) Å) contact between the carboxyl OH and the formyl oxygen and may be further stabilized by a C‐H—O interaction between the formyl proton and the carboxyl OH. Two crystallographically independent molecules are observed in the crystal structure of N‐f‐l‐Met‐d‐Phe‐OtBu, 2. These are distinct conformational isomers differing principally at both the N and C termini. Particularly noteworthy is the synplanar orientation of the ester C = O with respect to the peptide nitrogen in molecule A. which contrasts to the antiplanar orientation in molecule B. Additionally, the formyl group is coiled more towards the C‐terminus in molecule B. Principal torsion angles are φ1(A) = ‐ 120.6(5), Ψ1(A) = 102.0(6)°, φ2(A) = 128.1(6), φ1(B) = ‐ 94.6(5), Ψ1(B) = 91.9(6)°. 121.7(6)°. The peptide bond is trans‐planar in both molecules. Side chain dispositions are essentially identical in both structures. The Met side chain adopts the zig‐zag trans‐planar conformation while the Phe residue adopts an orientation near + 60° in agreement with rotamer populations observed by solution n.m.r. Typical peptide intermolecular H‐bonding is observed in the ester crystal structure; both the peptide and formyl groups participate in the proposed H‐bonding scheme.