Water-soluble xanthobilirubinic acids?

Abstract  Xanthobilirubinic acid, a model dipyrrinone for one-half of the bilirubin molecule in photochemical and metabolism studies, is more polar than bilirubin and insoluble in water and in chloroform. Replacing the β-alkyl substituents on the lactam ring of xanthobilirubinic acid with methyl-capped ethylene glycol, diethylene glycol, and triethylene glycol (PEG) groups steadily increased the water solubility of the pigment so that the last is completely soluble in both water and chloroform. Synthesized by base-catalyzed condensation of the corresponding methyl-capped 3,4-diPEG-pyrrolin-2-one with 3,5-dimethyl-4(2-ethoxycarbonylethyl)-2-formyl-1H-pyrrole, these new PEGylated analogs of xanthobilirubinic acid are yellow-colored dipyrrinones that form intermolecular hydrogen-bonded dimers in chloroform solution but are monomeric in methanol and water, as revealed by ¹H NMR spectroscopy and vapor pressure osmometry. Methyl xanthobilirubinate has served as a synthetic precursor to bilirubinoids; its amphiphilic PEGylated analogs suggest a route to water-soluble bilirubinoids and biliverdinoids. Graphical abstract        

Fluorophenyl Bilirubins: Synthesis and Stereochemistry

Summary.  Analogs of bilirubin with vinyl groups replaced by symmetrically-disposed o-fluorophenyls (1, bis-exo, and 2, bis-endo) were synthesized and characterized spectroscopically. Their ¹H NMR spectra and NOE data are consistent with an intramolecularly hydrogen-bonded ridge-tile conformation where each propionic acid group embraces an opposing dipyrrinone. Like bilirubin, 1 and 2 exhibit negative chirality induced circular dichroism (ICD) Cotton effects in chloroform containing quinine. Unlike bilirubin, however, in aqueous buffer containing human serum albumin, 2 exhibits a negative exciton chirality ICD, whereas that of 1 is positive. Received May 22, 2001. Accepted May 29, 2001     

Fluorophenyl Bilirubins: Synthesis and Stereochemistry

 Analogs of bilirubin with vinyl groups replaced by symmetrically-disposed o-fluorophenyls (1, bis-exo, and 2, bis-endo) were synthesized and characterized spectroscopically. Their ¹H NMR spectra and NOE data are consistent with an intramolecularly hydrogen-bonded ridge-tile conformation where each propionic acid group embraces an opposing dipyrrinone. Like bilirubin, 1 and 2 exhibit negative chirality induced circular dichroism (ICD) Cotton effects in chloroform containing quinine. Unlike bilirubin, however, in aqueous buffer containing human serum albumin, 2 exhibits a negative exciton chirality ICD, whereas that of 1 is positive.     

<Superscript>13</Superscript>C-labeled bilirubin: synthesis of 3<Superscript>1</Superscript>(3<Superscript>2</Superscript>),17<Superscript>1</Superscript>(17<Superscript>2</Superscript>)-di-[<Superscript>13</Superscript>C]-mesobilirubin-XIIIα

Abstract  The title compound, labeled with ¹³C in the ethyl groups was synthesized from K¹³CN and low-molecular-weight components. The synthetic relay compound was 3¹(3²)[¹³C]-xanthobilirubinic acid methyl ester in a synthetic route that leads to a label in the ethyl β-substituent of a dipyrrinone model for bilirubin. This labeled dipyrrinone was oxidatively coupled to the dimethyl ester of mesobiliverdin-XIIIα, thereby providing a route to a ¹³C-labeled mesobiliverdin and mesobilirubin, with one carbon of each ethyl being 98% ¹³C-enriched. Graphical Abstract        

自由基环化制备β-内酰胺的理论研究

使用密度泛函方法在UB3LYP/6-311＋＋G(3df, 2p)水平上对自由基环化合成β-内酰胺的四种反应途径进行理论研究. 结合Marcus理论对影响反应的热力学及动力学因素进行分析, 发现氨基甲酰基自由基4-exo环合反应是理想的动力学控制过程; 酰胺自由基的4-exo环合反应与5-endo环合反应相比是动力学有利的转化过程; 单取代的酰胺烷基自由基的4-exo环合反应是一类动力学和热力学都较为不利的反应; 羰基自由基加成亚胺N＝C双键的4-exo环合反应与5-endo环合反应相比动力学不利而热力学有利.     

Epoxidation of Bicyclo[2.2.1]hept-5-ene-2,3-endo- and Exodicarboxylic Acid N-Arylimides

Epoxidation of endo- and exo-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid N-arylimides with a solution of peracetic acid in anhydrous dioxane affords 5,6-exo-epoxybicycloheptanedicarboxylic acid N-arylimides. The epoxidation reaction is not sensitive to the configuration of the imide fragment, to the character and position of the substituent in the aromatic ring. The reaction is determined only by oxidation conditions.     

A Photoelectron-spectroscopic investigation of the Homoconjugative Interaction between π- and Walsh-Orbitals in endo- and exo-Cyclopropano-norbornene

Photoelectron spectra of endo- and exo-cyclopropano-norbornene ( = endo- and exo-tricyclo[3.2.1.0^2.4]octa-6-ene) show that a significant homoconjugation exists between the π-orbital of the double bond and the symmetric Walsh-es-orbital of the cyclopropane ring in the exo-isomer, whereas the interaction is negligeable in the endo-derivative.     

Secondary α-deuterium kinetic isotope effects in [2+4] cycloaddition of (E)-2-phenylnitroethene to cyclopentadiene

Abstract  

Secondary α-deuterium kinetic isotope effects confirm that [2+4] cycloaddition between (E)-2-phenylnitroethene and cyclopentadiene occurs in concerted manner, on both the pathway leading to 6-endo-phenyl-5-exo-nitronorbornene and the pathway leading to the corresponding 6-exo-phenyl-5-endo-nitro isomer. According to Hammond terminology the transition states on competitive pathways should be considered in terms of symmetrical early states.     

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.     

Selective Hydrogen Chloride Elimination from Primary Chlorides Induced by the Fluoride Anion. Anchimeric participation of the chloromethyl group in the heterolytic opening of an epoxide. Stereospecific syntheses of 5,6-bis (methylidene)-syn-2-norbornen-7-ol and 5,6-bis (methylidene)-endo-3-chloro-exo-2-norbornanol

Syntheses of the alcohols 10 and 18 , and the corresponding ketones 11 and 19 are presented. Endo-5, exo-6-bis (chloromethyl)-endo-3-chloro-exo-2-norbornanol ( 16 ) and endo-5-(bromomethyl)-exo-6-(chloromethyl)-endo-3-chloro-exo-2-norbornanol ( 17 ) were obtained by HCl- and, respectively, HBr-addition to endo-5, exo-6-bis (chloromethyl)-exo-2, 3-epoxynorbornane ( 5 ). The Wagner-Meerwein rearrangement was precluded in these reactions probably because of the formation of a relatively stable chloronium ion 15 arising from the participation of the 1,4-chlorine atom of the endo-5-chloromethyl group in the heterolytic ring opening of the epoxide 5 . The ‘naked’ fluoride anion (excess CsF in DMF or KF in DMF with 18-crown-6-ether) permitted the selective elimination of 2 equivalents of HCl from 16 and yielded the chlorohydrin-diene 18 .     

Synthesis and Trapping of Some Substituted 1-Bromocyclopropenes

Summary. Treatment of a number of 2-substituted 1,1,2-tribromocyclopropanes with MeLi at −78°C gave the corresponding 1-bromocyclopropenes, which were reacted with three cyclic dienes to yield the [4 + 2]-cycloadducts. Cycloaddition with 1,3-diphenylisobenzofuran (DPIBF) gave the exo adducts, in most cases in excellent yield, whereas cyclopentadiene afforded endo adducts only, but in moderate yield. In most reactions with furan no adduct was formed, but two 1-bromocyclopropenes derivatives with an aromatic side chain were exceptions and furnished mixtures of exo and endo adducts in moderate yields.     

Photoreactive Polynorbornene Bearing 4-(Diphenylamino)benzoate Groups: Synthesis and Application in Electroluminescent Devices

Summary. A new fluorescent and photoreactive polymer, poly-(endo,exo-bis(4-(4-(diphenylamino)benzoyloxy)benzyl)bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate), was prepared by ring opening metathesis polymerization. This polymer combines the photoreactivity of aryl esters with the fluorescence properties of derivatives of 4-(diphenylamino)benzoic acid. The polymer exhibits blue photo- and electroluminescence and can be used as active layer in organic light emitting devices (OLED). Upon irradiation with UV light (254 nm) the aromatic ester groups undergo decarboxylation, which is accompanied by the loss of photoluminescence. Photolithographic patterning of the polymer surface was used to obtain structured fluorescent surfaces and patterned OLEDs.     

Conformation and hydrogen bonding for the bicyclic compound 3‐thiabicyclo[3.2.0]heptane‐6,7‐dicarboxylic acid 3,3‐dioxide

The initial goal of this work was to verify the geometry of the product of a photochemical reaction, viz. the title compound, C₈H₁₀O₆S, (II). Our crystallographic study firmly establishes the cis–anti–cis nature of the substituents on the cyclobutane ring. The geometry is also designated as exo, where exo signifies that the five‐membered ring is on the opposite side of the central cyclobutane ring from the carboxylic acid substituents. The structure determination reveals two molecules, A and B, in the asymmetric unit that display substantially different conformations of the bicyclic core: the cyclobutane ring puckering angles are 22 and 3°, and the sulfolane ring conformations are twist (S‐exo) and envelope (S‐endo). Intrigued by this variation, we then compared the conformations of other molecules in the Cambridge Structural Database that have sulfolane rings fused to cyclobutane rings. In this class of compound, there are five examples of saturated cyclobutane rings, with ring puckering angles ranging from 3 to 35°. The sulfolane rings were more similar: four of the six molecules exhibit envelope conformations with S‐endo, as in molecule B of (II). Despite the conformational differences, the hydrogen‐bonding scheme for both molecules is similar: carboxyl –OH groups form hydrogen bonds with carboxyl and sulfone O atoms. Alternating A and B molecules joined by hydrogen bonds between sulfone O atoms and carboxyl –OH groups form parallel chains that extend in the ac plane. Other hydrogen bonds between the carboxyl groups link the chains along the b axis.     

Addition copolymerization of norbornene lactone catalyzed by Pd complexes

The addition copolymerization of norbornene (NB) with functionalized monomers can lead to the modification of physical properties of poly(NB). Herein, the synthesis of new copolymer of NB with exo-norbornene lactone (exo-NBL) is reported. The copolymerization proceeded by four Pd catalytic systems, and of these, Pd(allyl)IDippCl/AgSbF₆ (IDipp = 1,3-bis[2,6-diisopropylphenyl]imidazolin-2-ylidene)) was the most effective for the incorporation of exo-NBL. Specifically, the copolymerization with exo-NBL/NB feed ratio of 50/50 at r.t. by 0.1 mol% of the Pd catalyst produced poly(NB-co-exo-NBL) with M_n of 87,000, and M_w/M_n of 1.2 in 40% yield, incorporating exo-NBL of 18 mol%. The time–conversion plots and ¹H diffusion ordered spectroscopy (DOSY) NMR analysis of the copolymer suggest that it has a random sequence. In contrast, no copolymer was formed from endo-NBL. This is because of steric hindrance of the endo-lactone moiety by considering the (co)polymerization of endo-5-norbornene-2-carboxylic acid methyl ester (endo-NBCO₂Me). The incorporation of exo-NBL improves the solubility of poly(NB-co-exo-NBL) in several chlorinated solvents and gives high thermal stability with 10% weight loss at a temperature of more than 400°C. Two amorphous halos corresponding to intra- and interchain distances were observed in the WAXD patterns, allowing to calculate d-spacing values, which are higher than that of poly(NB).     

Effect of vinylene and 1,4-phenylene spacers on efficiency of the ground-state intramolecular charge-transfer in enlarged 4-dimethylamino-1-methylpyridinium cations

¹⁵N NMR chemical shifts of the exo- and endocyclic nitrogen atoms show how efficient is the ground-state intramolecular charge transfer between these sites in 4-dimethylamino-1-methylpyridinium cation (increased contribution of the quinoid resonance form results in a shielding and deshielding effect of their NMR signals, respectively). As it was anticipated, insertion of vinylene and/or 1,4-phenylene spacers to the cation considerably hinders the ground-state charge transfer. This hypothesis is further supported by an analysis of the C–NMe₂ bond lengths (X-ray data show that spacers elongate this bond). The selected valence angles in the compounds studied are also linearly dependent on δ(¹⁵N_endo) and δ(¹⁵N_exo) values. Although the correlation coefficient for the δ(¹⁵N_endo) versus δ(¹⁵N_exo) dependence is equal to 0.983, decrease of the net charge on one nitrogen atom is not compensated entirely by its increase on another nitrogen atom. This shows that exocyclic nitrogen atom is not the only acceptor of the positive charge in the molecule. The natural population analysis shows that the positive charge is transferred not only to the exocyclic N but also to, e.g., 1- and N-methyl C as well as to C3 and C5 atoms in pyridine ring. Ground-state charge transfer through the p-phenylene moiety was found to be less effective than through the trans-vinylene bridge. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Carbon-13 NMR spectra of some epoxides derived from dicyclopentadiene

The ¹³C NMR spectra of a series of epoxides derived from endo- and exo-dicyclopentadiene and their partially hydrogenated compounds were determined to examine the substituent effects arising from the introduction of the oxirane ring in comparison with those found in other ring systems. The ¹³C signals of some epoxides were assigned by using lanthanide shift reagents. Characteristic substituent effects exerted by an oxirane ring were demonstrated. Marked steric γ-effects of ?8—13 ppm were observed at the bridge carbon signal in the bicyclo[2.2.1]heptane skeleton. Differences were found in the substituent effects between endo- and exo-dicyclopentadiene epoxides, and have been discussed in relation to the molecular geometry.     

Amphiphilic Dipyrrinones

Summary. Replacing the typical lactam β-alkyl substituents of xanthobilirubinic acid and kryptopyrromethenone, two bilirubin analogs long used as model compounds in studies of its photochemistry and metabolism, leads to increased amphiphilicity. Synthesized by base-catalyzed condensation of 3,4-dimethoxypyrrolin-2-one with the appropriate pyrrole α-aldehyde, the 2,3-dimethoxyl analogs of xanthobilirubinic acid and kryptopyrromethenone are yellow-colored dipyrrinones that form intermolecular hydrogen-bonded dimers in the solid, as determined by X-ray crystallography, and in CHCl₃, as revealed by ¹H NMR and vapor pressure osmometry. These two new dipyrrinones are approximately ten times more soluble in water than their parent dipyrrinones.     

Mass spectrometry in stereochemical problems. 6 — The case of mono and di-substituted norbornanes

The mass spectrometric behaviour of pairs of stereoisomeric mono- and di-substituted norbornanes, namely bicyclo[2.2.1]heptane-2-endo- and -exo-carboxylic acid, methyl bicyclo[2.2.1]heptane-2-endo- and -exo-carboxylate, 2-exo-acetamidobicyclo[2.2.1]heptane-2-endo- and 2-endo-acetamidobicyclo[2.2.1]heptane-2-exo-carboxylic acid and methyl 2-exo-acetamidobicyclo[2.2.1]heptane-2-endo- and 2-endo-acetamido-bicyclo[2.2.1]heptane-2-exo-carboxylate was studied in detail with particular emphasis on characterization of the stereoisomers. The fragmentation patterns, studied with the aid of mass-analysed ion kinetic energy spectrometry, were supported by semi-empirical MO–SFC calculations, performed using the AM1 method included in the AMPAC program.     

NMR studies on bridged polycyclic compounds: Spin system transitions due to induced solvent shifts

An NMR study of some bridged bicyclo and tricyclo compounds yielded unusual spectra with respect to solvent effects and virtual coupling. As is the general case for most large polycyclic systems a complete analysis of the spectrum is not possible and the structural details derived from NMR are based on a partial analysis of the spectrum. If the accessible resonances correspond to protons adjacent to methylene groups, the resonance patterns and the chemical shifts may be strongly dependent upon solvent. For 6-endo-hydroxy, bicyclo[2.2.1]heptane-2,endo-carboxylic acid lactone (1), 6-endo-hydroxy, 2-exo-methyl-bicyclo[2.2.2]octane-2-endo-carboxylic acid lactone (2), and exo-3,4,exo-8,9-diepoxy, endo-tricyclo[5,2,1,0^2,6]decane (3), resonances for each fall in this class and the change induced by solvent are attributed to virtual coupling as well as a change in the overall splitting pattern.     

Extensive hydrogen and halogen bonding,and absence of intramolecular hydrogen bonding between alcohol and nitro groups in a series of endo‐nitronorbornanol compounds

The influence of the substituent at the C2 position on the hydrogen‐bonding patterns is compared for a series of five related compounds, namely (±)‐3‐exo,6‐exo‐dibromo‐5‐endo‐hydroxy‐3‐endo‐nitrobicyclo[2.2.1]heptane‐2‐exo‐carbonitrile, C₈H₈Br₂N₂O₃, (II), (±)‐3‐exo,6‐exo‐dibromo‐6‐endo‐nitro‐5‐exo‐phenylbicyclo[2.2.1]heptan‐2‐endo‐ol, C₁₃H₁₃Br₂NO₃, (III), (±)‐methyl 3‐exo,6‐exo‐dibromo‐5‐endo‐hydroxy‐3‐endo‐nitrobicyclo[2.2.1]heptane‐2‐exo‐carboxylate, C₉H₁₁Br₂NO₅, (IV), (±)‐methyl 3‐exo,6‐exo‐dibromo‐7‐diphenylmethylidene‐5‐endo‐hydroxy‐3‐endo‐nitrobicyclo[2.2.1]heptane‐2‐exo‐carboxylate, C₂₂H₁₉Br₂NO₅, (V), and (±)‐methyl 3‐exo,6‐exo‐dibromo‐5‐endo‐hydroxy‐3‐endo‐nitro‐7‐oxabicyclo[2.2.1]heptane‐2‐exo‐carboxylate, C₈H₉Br₂NO₆, (VI). The hydrogen‐bonding motif in all five compounds is a chain, formed by O—H...O hydrogen bonds in (III), (IV), (V) and (VI), and by O—H...N hydrogen bonds in (II). All compounds except (III) contain a number of Br...Br and Br...O halogen bonds that connect the chains to each other to form two‐dimensional sheets or three‐dimensional networks. None of the compounds features intramolecular hydrogen bonding between the alcohol and nitro functional groups, as was found in the related compound (±)‐methyl 3‐exo,6‐exo‐dichloro‐5‐endo‐hydroxy‐3‐endo‐nitrobicyclo[2.2.1]heptane‐2‐exo‐carboxylate, (I) [Boeyens, Denner & Michael (1984b). J. Chem. Soc. Perkin Trans. 2, pp. 767–770]. The crystal structure of (V) exhibits whole‐molecule disorder.