Studies on orally active cephalosporin esters. III. Effect of the 3-substituent on the chemical stability of pivaloyloxymethyl esters in phosphate buffer solution

The effect of substituents at the C-3 position on the degradation kinetics of the pivaloyloxymethyl (POM) ester of delta 3 cephalosporin in phosphate buffer solution (pH 6-8) was investigated. In the degradation, the isomerization process to the delta 2 ester was the rate-determining step. In this study, the logarithm of the isomerization rate to the delta 2 ester (log k12) correlated with the carbon-13 nuclear magnetic resonance chemical shift difference value at C-3 and C-4 of the delta 3 ester (delta delta (4-3)). The energy level of the lowest unoccupied molecular orbital (LUMO) of the delta 3 esters also correlated with log k12. The electronic properties at the C-2 position had no effect on the isomerization reaction. On the other hand, the logarithm of the isomerization rate back to the delta 3 ester (log k21) correlated with the van der Waals volume (MV) of the 3-substituent. These results show that the substituent at the C-3 position influences mainly the electronic structure of the conjugated pi-bond system (C3 = C4 - C4 = O) and consequently affects the feasibility of isomerization to the delta 2 ester, i.e., the stability to degradation.     

Studies on orally active cephalosporin esters. II. Chemical stability of pivaloyloxymethyl esters in phosphate buffer solution

The degradation kinetics of pivaloyloxymethyl (POM) esters of cephalosporins in phosphate buffer solution (pH 6-8) were investigated. The degradation of the starting delta 3 cephalosporin ester proceeded mainly via isomerization to the delta 2 ester and subsequent hydrolysis to the delta 2 acid. Hydrolysis to the delta 3 acid (the parent acid) was very slow. Analysis of the rate constants indicated that the isomerization rate k12 was approximately equal to the apparent degradation rate of the delta 3 ester kdeg, and slower than the hydrolysis rate of the delta 2 ester k24. The isomerization process to the delta 2 ester was found to be the rate-determining step in the degradation of cephalosporin esters. The substituent at the C-3 position of the cephalosporins affected the degradation kinetics. The degradation was accelerated by increase of pH, buffer concentration and added protein.     

Studies on orally active cephalosporin esters. V. A prodrug approach for oral delivery of 3-thiazoliomethyl cephalosporin

Oral delivery of 3-thiazoliomethyl cephalosporin 1 was attempted through a prodrug approach by applying thiamine chemistry. The 3-thiazoliomethyl group was modified to a ring-opened structure with no ionic charge, and the 4-carboxyl group was converted to pivaloyloxymethyl ester. Lipophilicity of the resulting derivatives (8-10) was suitable for passive absorption from the intestinal tract, and chemical stability in phosphate buffer solution (pH 6.86) was moderate. When administered orally to mice, these derivatives were mainly transformed to a novel 3-spiro cephalosporin 11, and desired reconversion to the 3-thiazoliomethyl cephalosporin was minor. Isomerization to delta 2-cephalosporin 14 was also observed. These results showed that the derivatives (8-10) tested in this study did not serve as orally active prodrugs of 3-thiazoliomethyl cephalosporin 1.     

Isomerisierung von Methoxy- und Carbomethoxysubstituierten Cycloalkyl- und Alken-radikalkationen

The very complex isomerization patterns of methoxy and carbomethoxy substituted cycloalkanes (3- to 7-membered rings) have been investigated using collisional activation, metastable ion characteristics and field ionization kinetics. The extent of isomerization depends on both the ring size and the substituent. Irrespective of the electronic properties of the substituent, ring opening involves exclusively the C-1? C-2 bond whereby linear alkene radical cations are formed. In the case of OCH₃- and COOCH₃ substituents the position of the resulting double bond (terminal or α,β-unsaturated) is determined more by the ring size of the precursor molecules and less by the electronic properties of the substituents. Contrary to these findings alklyl substituted cycloalkanes (3- to 5-membered rings) rearrange exclusively to terminal alkene radical cations. The barrier for double bond isomerization seems to be substantially influenced by substituents.     

N,N'-Diisopropyl-O-Diphenylmethyl Isourea: A Mild and Convenient Alkylating Agent for the Formation of Cephalosporin Derivatives

N,N-Diisopropyl-O-diphenylmethyl isourea reacts with cephalosporin-4-carboxylic acid in tetrahydrofuran at room temperature to give the diphenylmethyl (DPM) ester in good yields without isomerization of the double bond from C-3 to C-2.     

On the isomerization of ent-kaurenic acid

Kaurenic acid (1a) is a tetracyclic diterpene that has an exocyclic double bond at delta16. Isokaurenic acid (2a) has an endocyclic delta15double bond. This compound has been isolated from Espeletia tenore (Espeletinae), a resinous plant from the Venezuelan Andes, but its occurrence is rare. In order to obtain a larger amount of 2a, the isomerization of la, which is easily obtained from other Espeletinae, was tried. Kaurenic acid methyl ester (1b) was treated with dil. HCl in CH3Cl/EtOH, after 6 h under reflux a yield of 41.5% isokaurenic acid methyl ester (2b) was obtained but 35.7% 16alpha-ethoxy-kauran-19-oic acid methyl ester (3b) had formed as a byproduct. Treating 1b with CF3COOH in refluxing CH2Cl2 permitted to obtain a yield of 66.6% of 2b in 4 h and only traces of 16alpha-hydroxy-kauran-19-oic acid methyl ester (3a) as a byproduct. Both isomers were separated on a silica gel column impregnated with 20% AgNO3. Treating 2b with KOH in refluxing DMSO yielded pure isokaurenic acid, no back isomerization was observed.     

Migration of the exocyclic double bond in terpenoid coumarins of the iresane series

In terpenoid coumarins of the iresane series with an exocyclic double bond, migration of the double bond into the ring with the retention of the configuration of the substituent in position 1 is observed in an acid medium. The reaction has been performed in CF₃COOH and has been monitored by the PMR method. Badrakemin has yielded conferol, badrakemone has yielded conferone, badrakemin acetate has yielded conferol acetate, colladonin has yielded moschatol, and farnesiferol A and gummosin have yielded the corresponding isomers with endocyclic double bonds. The rate of the reaction is affected by the nature of the substituent at C-6. The presence of a keto group increases the time of isomerization to 1.5 h as compared with the 5–10 min for compounds with an OH group at C-6. The increase in the time of the reaction leads to the formation of byproducts. The reaction does not take place in CH₃COOH.     

Transmission of substituent effects through unsaturated systems. I—relative magnitudes of proton and carbon substituent chemical shifts in ethylenes,butadienes, α-enones and benzenes

The carbon-13 shifts of C-1, C-2 and C-3 are determined in a series of 1-cyclohexen-3-ones substituted in position 1. Linear relationships are demonstrated between the substituent chemical shifts of corresponding carbons in substituted ethylenes, butadienes, α-enones and benzenes. The substituent chemical shifts of proton H-2 are also reported and correlated with those of corresponding protons in ethylenes and benzenes. The slopes of the lines for the carbons directly linked to the substituent are close to unity, showing a relative independence of the substituent effect for this nucleus from the variation of the unsaturated framework. In contrast to this, the transmission of the substituent effect through one double bond (nuclei β to the substituents) decreases as the number of conjugated π bonds in the whole structure increases. This relationship is interpreted as being due to the ability of an unsaturated system to spread the variation of π electron density induced by the substituent.     

Migration of the exocyclic double bond in terpenoid coumarins of the iresane series

In terpenoid coumarins of the iresane series with an exocyclic double bond, migration of the double bond into the ring with the retention of the configuration of the substituent in position 1 is observed in an acid medium. The reaction has been performed in CF₃COOH and has been monitored by the PMR method. Badrakemin has yielded conferol, badrakemone has yielded conferone, badrakemin acetate has yielded conferol acetate, colladonin has yielded moschatol, and farnesiferol A and gummosin have yielded the corresponding isomers with endocyclic double bonds. The rate of the reaction is affected by the nature of the substituent at C-6. The presence of a keto group increases the time of isomerization to 1.5 h as compared with the 5–10 min for compounds with an OH group at C-6. The increase in the time of the reaction leads to the formation of byproducts. The reaction does not take place in CH₃COOH.All-Union Scientific-Research Institute of Medicinal Plants, Moscow. Translated from Khimiya Prirodnykh Soedinenii, No. 5, pp. 630–637, September–October, 1979.     

Novel approach for the conversion of natural Δ3 cephalosporin derivatives into corresponding Δ2 cephalosporin derivatives

A simple one pot synthetic method for the isomerization of cephem double bond from the natural 3‐position to 2‐cephem positions is affected by silylation. Thus cephalosporin acids are treated with Ntrimethylsilylacetamide (MSA) or N,O‐bis(trimethylsilyl)acetamide (BSA) and the resulting silyl esters are treated with triethylamine at ambient temperature in the same pot to afford Δ²‐cephalosporins, which are potentially related compounds in cephalosporin antibacterial compounds.     

Investigation on the regioselectivities of intramolecular oxidation of unactivated C-H bonds by dioxiranes generated in situ

We found that dioxiranes generated in situ from ketones 1-6 and Oxone underwent intramolecular oxidation of unactivated C-H bonds at delta sites of ketones to yield tetrahydropyrans. From the trans/cis ratio of oxidation products 1a and 2a as well as the retention of the configuration at the delta site of ketone 5, we proposed that the oxidation reaction proceeds through a concerted pathway under a spiro transition state. The intramolecular oxidation of ketone 6 showed the preference for a tertiary delta C-H bond over a secondary one. This intramolecular oxidation method can be extended to the oxidation of the tertiary gamma' C-H bond of ketones 9 and 10. For ketone 11 with two delta C-H bonds and one gamma' C-H bond linked respectively by a sp(3) hydrocarbon tether and a sp(2) ester tether, the oxidation took place exclusively at the delta C-H bonds. Finally, by introducing proper tethers, regioselective hydroxylation of steroid ketones 12-14 have been achieved at the C-17, C-16, C-3, and C-5 positions.     

胆二烯a、b的光异构化

取胆二烯a、b的模型化合物,中胆紫素,放在一些不含氧的溶剂中进行光照,根据光照前后的吸收光谱和核磁共振氢谱分析,在光照达到平衡以后,其构型可能由比较关闭的螺环型变成比较张开的伸展型,C-10位上的双键由Z型变成E型。     

Studies on penem and carbapenem. I. Syntheses and oral absorption of ester-type prodrugs of sodium (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3-c arboxylat e

Acyloxyalkyl esters (2a-d), alkyloxycarbonyloxyalkyl esters (2e-g) and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (2h) of (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3- carboxylic acid (1) were synthesized. Enhanced oral absorption was observed in mice reflecting increased lipophilicity, compared with the parent 1 itself. Among them, the ester 2h showed a prolonged plasma level and a large area under the blood concentration-time curve (AUC) in rats. These ester-type prodrugs of penem 1 in phosphate buffer (pH 6.86) were much more stable than those of cephalosporins which easily degraded via isomerization to delta 2 cephalosporins.     

Second generation light-driven molecular motors. Unidirectional rotation controlled by a single stereogenic center with near-perfect photoequilibria and acceleration of the speed of rotation by structural modification

Nine new molecular motors, consisting of a 2,3-dihydro-2-methylnaphtho[2,1-b]thiopyran or 2,3-dihydro-3-methylphenanthrene upper part and a (thio)xanthene, 10,10-dimethylanthracene, or dibenzocycloheptene lower part, connected by a central double bond, were synthesized. A single stereogenic center, bearing a methyl substituent, is present in each of the motors. MOPAC93-AM1 calculations, NMR studies, and X-ray analysis revealed that these compounds have stable isomers with pseudoaxial orientation of the methyl substituent and less-stable isomers with pseudoequatorial orientation of the methyl substituent. The photochemical and thermal isomerization processes of the motors were studied by NMR and CD spectroscopy. The new molecular motors all show two cis-trans isomerizations upon irradiation, each followed by a thermal helix inversion, resulting in a 360 degrees rotation around the central double bond of the upper part with respect to the lower part. The direction of rotation is controlled by a single stereogenic center created by the methyl substituent at the upper part. The speed of rotation, governed by the two thermal steps, was adjusted to a great extent by structural modifications, with half-lives for the thermal isomerization steps ranging from t(1/2)(theta) 233-0.67 h. The photochemical conversions of two new motors proceeded with near-perfect photoequilibria of 1:99.     

Evidence of substituent-induced electronic interplay. Effect of the remote aromatic ring substituent of phenyl benzoates on the sensitivity of the carbonyl unit to electronic effects of phenyl or benzoyl ring substituents

Carbonyl carbon (13)C NMR chemical shifts delta(C)(C[double bond]O) measured in this work for a wide set of substituted phenyl benzoates p-Y-C(6)H(4)CO(2)C(6)H(4)-p-X (X = NO(2), CN, Cl, Br, H, Me, or MeO; Y = NO(2), Cl, H, Me, MeO, or NMe(2) ) have been used as a tool to study substituent effects on the carbonyl unit. The goal of the work was to study the cross-interaction between X and Y in that respect. Both the phenyl substituents X and the benzoyl substituents Y have a reverse effect on delta(C)(C[double bond]O). Electron-withdrawing substituents cause shielding while electron-donating ones have an opposite influence, with both inductive and resonance effects being significant. The presence of cross-interaction between X and Y could be clearly verified. Electronic effects of the remote aromatic ring substituents systematically modify the sensitivity of the C[double bond]O group to the electronic effects of the phenyl or benzoyl ring substituents. Electron-withdrawing substituents in one ring decrease the sensitivity of delta(C)(C[double bond]O) to the substitution of another ring, while electron-donating substituents inversely affect the sensitivity. It is suggested that the results can be explained by substituent-sensitive balance of the contributions of different resonance structures (electron delocalization, Scheme 1).     

新型弯曲形双偶氮苯类液晶合成及光致异构性能研究

弯曲形偶氮苯液晶由于其偶氮键独特的光致可逆异构化性能,已成为光电子信息材料研究的热门课题,但光响应速度慢已成为制约其发展的关键因素.目前报道的弯曲型偶氮类液晶化合物的偶氮键都距离中心核较远的位置,光致异构的响应时间较长,大都在分钟以上,不利于光敏器件应用研究.本工作试图以2-甲基-1,3-间苯二胺为中心核,将偶氮键紧挨中心核两边,末端为直链烷基,设计合成了一系列新型弯曲形双偶氮苯类液晶化合物,以期缩短光响应时间.通过IR, 1H NMR, 13C NMR和ICP-MS光谱鉴定这些化合物的分子结构,经差示扫描量热仪(DSC)和偏光显微镜(POM)测定其液晶相变温度和相态织构;并通过测定2-甲基-1,3-双(4-((4-庚基苯基)酯基)-1-(E)-偶氮苯基)苯(2c)的紫外-可见光的吸收光谱研究其光致异构化性能,通过UV-Vis光谱仪和偏光显微镜(POM)测定其液晶化合物以及掺杂向列相液晶材料的光致异构现象和响应时间.实验结果表明,所有设计合成的弯曲形双偶氮苯类液晶化合物均具有近晶相相态,且相态温度范围较宽,当近晶相态化合物2c掺杂到向列相混合液晶中时,其光致异构响应时间为2~3 s,在日光下液晶态恢复时间为3~4s,在乙酸乙酯稀溶液中时10s可达到光稳态.说明这类弯曲形双偶氮液晶化合物具有较快的光致异构响应速度.     

Phosphol-3-ene 1-oxides and -sulfides. A systematic investigation via carbon-13 nuclear magnetic resonance spectroscopy

¹³C NMR chemical shifts and ¹³C? ³¹P couplings are reported for 18 phosphol-3-ene 1-oxides and 18 corresponding sulfides. The effects of methyl substitution at positions 3 and 4 on the carbon shifts have been systematically explored and substituent parameters derived. One bond couplings from phosphorus to C-2 and C-5 have been related to the sum of the exocyclic substituent group electronegativities (covalent boundary potential values).     

Synthesis of substituted phenols by using the ring-closing metathesis/isoaromatization approach

Ring-closing olefin metathesis (RCM) of 4-methylene-1,7-octadien-3-ones 2, followed by isomerization of the carbon--carbon double bond of 6-methylene-2-cyclohexenones 3 from exo to endo, produced various phenols 4. As an application of the method, the RCM/Mizoroki-Heck reaction of 2 was proven to be also effective for the synthesis of phenols having an additional substituent at ortho-benzylic position.     

Regiochemical Control and Suppression of Double Bond Isomerization in the Heck Arylation of 1-(Methoxycarbonyl)-2,5-dihydropyrrole

Arylation of 1-(methoxycarbonyl)-2,5-dihydropyrrole under standard Heck reaction conditions produces a mixture of compounds. The olefin undergoes two types of palladium-catalyzed reactions: (a) arylation to provide C-3 arylated derivatives and (b) competing double bond isomerization. Addition of silver carbonate and thallium acetate fully suppressed the isomerization, and good yields of C-3 substituted compounds were achieved after arylation with aryl halides. With regard to aryl triflates as arylating agents, addition of lithium chloride was necessary to promote the Heck reaction. This additive excluded the use of silver and thallium salts, but high regioselectivity and good yields could be obtained by employing tri-2-furylphosphine as ligand. Arylation was rendered both regioselective and enantioselective (58% ee) with 1-naphthyl triflate as substrate utilizing a (R)-BINAP/thallium acetate combination. The C-3 arylated enamides were converted further into the corresponding 3-arylpyrrolidines.     

Carbon-13 n.m.r. spectra of 2,3-dimethylenebicyclo[2.2.1]heptanes and 2,3-dimethylene-7-oxabicyclo[2.2.1]heptanes

The ¹³C n.m.r. spectra of 11 derivatives of 2,3-dimethylenenorbornane, 1–11, of 5 derivatives of 2,3-dimethylene-7-oxanorbornane, 12–16, and of 2,3,5,6-tetramethylene-7-oxanorbornane (17) have been measured and the chemical shifts have been assigned. The effects of 1-methyl, 5-hydroxy, 5-acetoxy, 5-para-bromobenzenesulphonyloxy and 5-keto substituents on the olefinic carbons of the s-cis-butadiene group are compared with the same substituent effects reported for model compounds. Apparent linear correlations between the reciprocals of the V←N transition energies of the butadiene chromophores and the differences of the chemical shifts ΔδC between the quaternary and methylene olefinic carbons are found for the dienes 1–3, 12–14, butadiene and 2,3-dimethylbutadiene. The ΔδC of the olefinic carbons of the tetraene 17 also falls on the correlation line if the average of the two absorption hands at 250 and 228 nm is taken for the V←N transition energy of this compound. The chemical shift of the carbon of the methano bridge H₂C-7 is almost insensitive to the presence of one or two methylene groups at C-2,3, in contrast with the downfield shift of 10–14 ppm observed when an endocyclic double bond is introduced into the norbornane skeleton.