A chemical model for redox regulation of protein tyrosine phosphatase 1B (PTP1B) activity

Growing evidence indicates that endogenously produced hydrogen peroxide acts as a cellular signaling molecule that (among other things) can regulate the activity of some protein phosphatases. Recent X-ray crystallographic studies revealed an unexpected chemical transformation underlying the redox regulation of protein tyrosine phosphatase 1B, in which oxidative inactivation of the enzyme yields an intrastrand protein cross-link between the catalytic cysteine residue and its neighboring amide nitrogen. This work describes a small organic molecule that serves as an effective model for the redox-sensing assembly of functional groups at the active site of PTP1B. Findings obtained using this model system suggest that the oxidative transformation of PTP1B to its "crosslinked" inactive form can proceed directly via oxidation of the active-site cysteine to a sulfenic acid (RSOH). The remarkably facile nature of this protein cross-link-forming reaction, along with the widespread cellular occurrence of protein sulfenic acids generated via oxidation of cysteine residues, suggests that the type of oxidative protein cross-link formation first seen in the context of PTP1B represents a potentially general mechanism for redox "switching" of protein function. Thus, the chemistry characterized here could have broad relevance to both redox-regulated signal transduction and the toxic effects of oxidative stress.     

Antioxidant activity of the anti-inflammatory compound ebselen: a reversible cyclization pathway via selenenic and seleninic acid intermediates

A revised mechanism that accounts for the glutathione peroxidase (GPx)-like catalytic activity of the organoselenium compound ebselen is described. It is shown that the reaction of ebselen with H(2)O(2) yields seleninic acid as the only oxidized product. The X-ray crystal structure of the seleninic acid shows that the selenium atom is involved in a noncovalent interaction with the carbonyl oxygen atom. In the presence of excess thiol, the Se--N bond in ebselen is readily cleaved by the thiol to produce the corresponding selenenyl sulfide. The selenenyl sulfide thus produced undergoes a disproportionation in the presence of H(2)O(2) to produce the diselenide, which upon reaction with H(2)O(2), produces a mixture of selenenic and seleninic acids. The addition of thiol to the mixture containing selenenic and seleninic acids leads to the formation of the selenenyl sulfide. When the concentration of the thiol is relatively low in the reaction mixture, the selenenic acid undergoes a rapid cyclization to produce ebselen. The seleninic acid, on the other hand, reacts with the diselenide to produce ebselen as the final product. DFT calculations show that the cyclization of selenenic acids to the corresponding selenenyl amides is more favored than that of sulfenic acids to the corresponding sulfenyl amides. This indicates that the regeneration of ebselen under a variety of conditions protects the selenium moiety from irreversible inactivation, which may be responsible for the biological activities of ebselen.     

Synthesis and photochromism of novel unsymmetrical diarylethenes with an azaindole unit

A new class of unsymmetrical photochromic diarylethenes with an azaindole moiety has been firstly synthesized. Their properties, including photochromism, crystal structure, as well as fluorescence, were investigated systematically. The azaindole was connected directly to the central cyclopentene ring as a heteroaryl moiety and available to participate in the photoisomerization reaction. Each of the diarylethenes exhibited favorable photochromism, good thermal stability, remarkable fatigue resistance, and notable fluorescence switches in both solution and solid media. The substituents at the para-position of the terminal benzene ring affected evidently their properties: the electron-donating methoxy could be effective to enhance the cyclization quantum yield, while the electron-withdrawing cyano could shift the absorption maximum to a longer wavelength in both hexane and solid film. The results revealed that the introduction of azaindole moieties and different substituents played an important role in the photoisomerization process of these diarylethenes.     

Formation of 4H-1,2-benzoxazines by intramolecular cyclization of nitroalkanes. Scope of aromatic oxygen-functionalization reaction involving a nitro oxygen atom and mechanistic insights

In this paper, we deal with the scope and mechanism of the strong Br?nsted acid-catalyzed intramolecular cyclization reaction of methyl 3-aryl-2-nitropropionates to give 4H-1,2-benzoxazines. This reaction can be regarded as an oxygen functionalization of the aromatic ring wherein the oxygen atom is derived from the nitro group in the molecule, and it is favored by the presence of electron-withdrawing groups on the benzene ring. The reaction rate is strongly influenced by the acidity of the reaction medium, and the methyl ester group on the alpha-carbon atom with respect to the nitro group facilitates deprotonation at the alpha-position to give aci-nitro species in situ. Some correlation was found between the electron-withdrawing ability of the substituents on benzene, represented in terms of Hammett's sigma p value of the substituents, and the rate of disappearance of the starting substrate leading to the product in trifluoromethanesulfonic acid (TFSA)/trifluoroacetic acid (TFA) medium. This would be because the acidity of the alpha-proton with respect to the nitro group is influenced by the substituents on the benzene ring. Experimentally, we excluded the 6pi electrocyclization mechanism involving deprotonation of the benzyl proton of the protonated aci-nitro species. Alternative cyclization mechanisms involving equilibrating monocationic aci-nitro species bearing O-protonated ester carbonyl group and O-protonated aci-nitro species were calculated to be highly energetically unfavorable. Diprotonated or protosolvative species can reduce the activation energy significantly, and this is consistent with the observed acidity-dependent nature of the cyclization.     

Total synthesis of phorboxazole B

An efficient and highly convergent total synthesis of the potent antitumor agent phorboxazole B has been achieved. The synthetic strategy of this synthesis features: 1) a highly efficient substrate-controlled hydrogenation to construct the functionalized cis-tetrahydropyrane unit; 2) iterative crotyl addition to synthesize the segment that contains alternating hydroxyl and methyl substituents; 3) Hg(OAc)2/I2-induced cyclization to establish the cis-tetrahydropyrane moiety; 4) 1,3-asymmetric induction in the Mukaiyama aldol reaction to afford the stereogenic centers at C9 and C3; and 5) the exploration of the Still-Gennari olefination reaction to complete the macrolide ring of phorboxazoloe B.     

Solid-phase synthesis of pyrroloisoquinolines via the intramolecular N-acyliminium Pictet-Spengler reaction

In the present investigation, solid-phase routes toward 1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-ones via the intramolecular N-acyliminium Pictet-Spengler reaction are established. Peptide aldehydes generated from their parent N-Boc 1,3-oxazines by acidic reaction conditions undergo intramolecular condensation reactions with the amide N of a solid-supported peptide backbone, thus forming a 1:1 epimeric mixture of a cyclic 5-hydroxylactam, which in turn is in equilibrium with the corresponding intermediate N-acyliminium ion. Provided appropriate acidic reaction conditions, a second ring may be appended via Pictet-Spengler cyclization from the aromatic ring of a neighboring phenylalanine derivative in the peptide sequence. The aromatic substitution pattern of the nucleophilic benzene ring of the phenylalanine derivative and the nature of the acidic reaction media are critically important for the course of the reaction, and both Lewis and Br?nsted acids may be employed to effect the cyclization process. This intramolecular reaction is under strict control of stereoselectivity, and only a single stereoisomer is detected in the crude products. A range of mono-, di-, and trisubstituted phenylalanines with diverse sets of electron-donating and electron-withdrawing substituents, pyrene, and naphthalenes have successfully been brought within the scope of the reaction, thus providing a unique scaffold for combinatorial library synthesis.     

Mono- and diboronates derived from tridentate ONO ligands and arylboronic acids

The syntheses of eight [4.3.0] heterobicyclic boronates containing a N → B coordinative bond are described. The monomeric compounds were prepared by reaction of arylboronic acids with a tridentate ligand having the ONO donor set of atoms. It was shown that substituents at the para-position of the B-phenyl moiety transmit electronic effects to the CN bond which in turn is polarized by formation of the N → B coordination bond. At the same time, related tridentate ligands were also reacted with 1,4-benzenediboronic acid in order to prepare benzene diboron complexes. The structure of this type of compounds was confirmed by X-ray analysis for one of the derivatives.     

Thermal rearrangement of 1,3-thiazolidine sulfoxides: Thiolsulfinate and thioaldehyde intermediates

Stereospecific ring opening of the sulfoxides cis- 13 and trans- 14 in refluxing toluene gave the corre sponding sulfenic acids 9 , 10 intermediates respectively. The sulfenic acid 9 dimerized to the thiolsulfinate 17 by dual function of the sulfenic acid as S-nucleophile/S-electrophile with loss of water while the sulfenic acid 10 was unchanged. The stereospecific recyclization of 10 to the parent sulfoxide 14 increases the higher pi-electron density of the double. The thermolysis of the thiolsulfinate 17 gave the transient sulfenic acid 9 , which dimerized again to repeat the process and unisolable thioaldehyde 21 . The thioaldehyde 21 was con verted to either pyrrole 15 by the action of a sulfinic acid 20 catalyst formed inevitably by hydrolysis of 17 under the reaction conditions, or thiazole 18 under neutral conditions. In these rearrangements, the amide carbonyl group facilitated the elimination of a neighboring hydrogen.     

Theoretical Analysis of Structural Characteristics of Morin Rearrangement for Cephalosporins Prepared from Penicillin Sulfoxide

The structure of penicillin sulfoxide is rearranged to cephalosporins by the Morin rearrangement. It is a unit reaction for the preparation of various types of cephalosporins. In order to make better use of the reaction and in view of the shortage of the reaction theory, this study used m062x/6-311++G(d, p) to explore the possible ring-opening reaction of the penicillin sulfoxide. It is found that the isomer of(S)-sulfoxide is a necessary structure. At the same time, the intramolecular hydrogen bonding effect between the side-chain amide proton(-CONH-) and the sulfinyl oxygen(-SO) is the decisive structure factor for the formation of alkenyl in ring-opening reaction, and the best reaction path is S0- TS2- IN1 channel. The main effect of acid catalysis is to catalyze the dehydration reaction of sulfenic acid to form sulfur cations for subsequently ring closing reaction.     

Photoreactive polyamides having m- or 1-type dimer moiety derived from 4-(3-oxo-3-phenyl-1-propenyl)benzoic acid derivatives

Photoreactive polyamides having m- or 1 -type cyclobutane moiety were prepared via a topochemical photodimerization of 4-(3-oxo-3-phenyl-1-propenyl)benzoic derivatives,⁴ followed by polycondensation of cyclobutane dicarboxylate derivatives with diamines. From the spectral studies of resulted polyamides compared with the corresponding reference diamides, it was concluded that both types of polyamides were depolymerized photochemically to give the same type of amide derivative having chalcone moiety with a small amount of undefined side reaction. The cyclobutane ring of the m-dimer from 4-(3-oxo-3-phenyl-1-propenyl)benzoic acid in crystal is severely twisted presumably because of the enhanced steric repulsions between two pairs of adjacent substituents. The higher quantum yield of the m-dimer for the photocleavege, compared with that of the 1 -dimer, has been interpreted in terms of such steric repulsions by the strained structure of the m-dimer.     

Efficient Synthesis of Conformationally Restricted Apoptosis Inhibitors Bearing a Triazole Moiety

Apoptosis is a biological process relevant to different human diseases that is regulated through protein–protein interactions and complex formation. Peptidomimetic compounds based on linear peptoids and cyclic analogues with different ring sizes have been previously reported as potent apoptotic inhibitors. Among them, the presence of cis/trans conformers of an exocyclic tertiary amide bond in slow exchange has been characterized. This information encouraged us to perform an isosteric replacement of the amide bond by a 1,2,3‐triazole moiety, in which different substitution patterns would mimic different amide rotamers. The syntheses of these restricted analogues have been carried out through an Ugi multicomponent reaction followed by an intramolecular cyclization. The unexpected formation of a β‐lactam scaffold prompted us to study the course of the intramolecular cyclization of the Ugi adducts. In order to modulate this cyclization, a small library of compounds bearing both heterocyclic scaffolds has been synthesized and their activities as apoptosis inhibitors have been evaluated.     

Practical Route to the Left Wing of CTX1B and Total Syntheses of CTX1B and 54‐deoxyCTX1B

Ciguatoxins, the principal causative agents of ciguatera seafood poisoning, are extremely large polycyclic ethers. We report herein a reliable route for constructing the left wing of CTX1B, which possesses the acid/base/oxidant‐sensitive bisallylic ether moiety, by a 6‐exo radical cyclization/ring‐closing metathesis strategy. This new route enabled us to achieve the second‐generation total synthesis of CTX1B and the first synthesis of 54‐deoxyCTX1B.     

Stereoselective Cascade Cyclizations with Samarium Diiodide to Tetracyclic Indolines: Precursors of Fluorostrychnines and Brucine

A series of γ-indolylketones with fluorine, cyano or alkoxy substituents at the benzene moiety was prepared and subjected to samarium diiodide-promoted cyclization reactions. The desired dearomatizing ketyl cascade reaction forming two new rings proceeded in all cases with high diastereoselectivity, but with differing product distribution. In most cases, the desired annulated tetracyclic compounds were obtained in moderate to good yields, but as second product tetracyclic spirolactones were isolated in up to 29 % yield. The reaction rate was influenced by the substituents at the benzene moiety of the substrate as expected, with electron-accepting groups accelerating and electron-donating groups decelerating the cyclization process. In case of a difluoro-substituted γ-indolylketone a partial defluorination was observed. The intermediate samarium enolate of the tetracyclic products could be trapped by adding reactive alkylating agents as electrophiles delivering products with quarternary carbons. In the case of a dimethoxy-substituted tetracyclic cyclization product a subsequent reductive amination stereoselectively provided a pentacyclic compound that was subsequently N-protected and subjected to a regioselective elimination. The obtained functionalized pentacyclic product should be convertible into the alkaloid brucine by four well-established steps. Overall, the presented report shows that functionalized tetracyclic compounds with different substituents are rapidly available with the samarium diiodide cascade cyclization as crucial step. Hence, analogues of the landmark alkaloid strychnine, for example, with specific fluorine substitutions, should be easily accessible.     

New approach for two chromene carboxylic acids having a fully substituted benzene ring

Two chromene carboxylic acids having a fully substituted benzene ring, 8-chlorocannabiorcichromenic acid (1) and mycochromenic acid (2), were synthesized via thermal cyclization of the corresponding four substituted phenyl propargyl ethers.     

Intramolecular Diels-Alder reaction of N-allyl 2-furoyl amides: effect of steric strain and amide rotational isomerism

Intramolecular Diels-Alder reactions of various N-allyl 2-furoyl amides with different substituents on the nitrogen atom were investigated. The reaction of amides having bulky substituents proceeded at a faster rate than the analogs whose substituents were of less bulkiness. From the systematic experimental survey of the substituent effects and the energetic evaluation based on the DFT calculations at the B3LYP/6-31G(d) level, the enhanced reactivity was ascribed to the relief of steric strain upon cyclization rather than the amide rotational isomerism governed by the bulky substituents.     

A novel approach to synthesis of the cinnoline ring system via organoiron(cyclopentadienyl) complexes

An efficient synthesis of 3-mono or 3,4-disubstituted cinnolines from (o-dichlorobenzene)(cyclopentadienyl)iron hexafluorophosphate in three or four steps has been achieved. o-Chlorophenyl-alkyl or alkylaryl ketone complexes obtained from the o-dichlorobenzene complex upon treatment with enolate anions, react with hydrazine forming 3-mono or 3,4-disubstituted 1,4-dihydrocinnoline complexes. Treatment of the later with sodium amide leads to an aromatization-demetallation reaction resulting in formation of cinnolines, i.e. 3-methyl-, 3-phenyl- and 3,4-dimethylcinnoline. The influence of substituents bonded to the carbon atom adjacent to the complexed benzene ring in o-chlorophenyl -alkyl or -alkylaryl ketone prior to cyclization on the cyclization reaction is discussed.     

Synthetic studies on psiguadial B: Construction of bicyclo[4.3.1]decane skeleton via double cyclization reaction of alkyne dicobalt complex

A new method for constructing the polycyclic skeleton of psiguadial B (1), a meroterpenoid isolated from an evergreen shrub of Myrtaceae, was developed. The terpenoid substructure of 1 was constructed on the basis of a cascade double cyclization reaction of an alkyne dicobalt complex, which afforded the bicyclo[4.3.1]decane derivative having a benzyl group with the correct configuration. The substituted aromatic ring was introduced to the bridgehead position of the intermediate, and bromination under radical conditions followed by intramolecular cyclization reaction resulted in formation of the benzopyran moiety in a stereoselective manner.     

7-Decarboxymethyl-cobyrinates: vitamin B12-derivatives that lack the c-side chain

The synthesis of cobyrinic acid derivatives by reduction of dehydrocobyrinates is largely unexplored. It is, however, a rational path to B(12) analogues that lack specific substituents of the corrin moiety of natural B(12) derivatives. The partial syntheses of four epimeric 7-decarboxymethyl-cobyrinates is described, which is achieved by reduction of Δ7-dehydro-7-de[carboxymethyl]-cobyrinate with zinc or with the 'prebiotic' reducing agent formic acid. A direct and remarkably efficient route was found to 7-decarboxymethyl-cobyrinates, which are cobyrinic acid derivatives in which the c-side chain at ring B of vitamin B(12) is missing. The structures of the hexamethyl-7-decarboxymethyl-cobyrinates were characterized and the stereochemical and conformational properties at their newly saturated ring B were analyzed. The stereochemical outcome of the reduction was found to depend strongly on the reaction conditions. In 7-decarboxymethyl-cobyrinates, both peripheral carbon centres of ring B carry a hydrogen atom, and the characteristic quaternary carbon centre at C7 of the cobyrinic acid moiety of vitamin B(12) is lacking. The still highly substituted 7-decarboxymethyl-cobyrinates are readily dehydrogenated in the presence of dioxygen, furnishing 7-de[carboxymethyl]-Δ(7)-dehydro-cobyrinate as the common, unsaturated oxidation product. The noted stability of vitamin B(12) and of other Co(III)-cobyrinates in the presence of air is a consequence of their highly substituted corrin macrocycle, a finding of interest in the context of chemical rationalizations of the B(12) structure.     

Acid-promoted sequential cationic cyclizations for the synthesis of (±)-taiwaniaquinol B

A formal total synthesis of (±)-taiwaniaquinol B starting from (E/Z)-citral has been accomplished by sequential cationic cyclizations promoted by acids. The cyclization to an α-cyclogeranyl ketone derivative is promoted by Lewis acid, whereas the use of Brønsted acid promotes an olefin isomerization leading to undesired cyclizations. The final ring formation to give the hydrofluorenone skeleton is promoted by Brønsted acid. Thus, the choice of the acid in each step critically determined the cationic reaction pathways and cyclization outcome.     

Atom-economic and stereoselective syntheses of the ring a and B subunits of the bryostatins

This article describes chemoselective and atom-economic methods for the stereoselective assembly of the ring A and B subunits of bryostatins. A Ru-catalyzed tandem alkene-alkyne coupling/Michael addition reaction was developed and applied to the synthesis of bryostatin ring B. We explored an acetylide-mediated epoxide-opening/6-exo-dig cyclization route to access the bryostatin ring A, although ring A was eventually furnished through an acid-catalyzed tandem transketalization/ketalization sequence. In addition, a dinuclear zinc-catalyzed methyl vinyl ketone (MVK) aldol strategy was evaluated for the construction of the polyacetate moiety. Utilization of these methods ultimately led to the rapid assembly of the northern bryostatin fragment containing both the ring A and B subunits.