Unusual Orthogonality in the Cleavage Process of Closely Related Chelating Protecting Groups for Carboxylic Acids by Using Different Metal Ions

Three structurally related relay protecting groups for carboxylic acids that are based on chelating amines have been developed. These protecting groups can easily be introduced by coupling the carboxylic acid and the corresponding amine in the presence of 2‐(1H‐benzotriazole‐1‐yl)‐1,1,3,3‐tetramethyluronium tetrafluoroborate (TBTU). In addition to being stable to a whole array of reaction conditions, these protecting groups are also stable under acidic and basic conditions, allowing them to be used in combination with the ester protection of carboxylic acids. The cleavage of these protecting groups is activated by the chelation of metal ions, involving an unusual coordination of the amide nitrogen. Despite their similarity, cleavage of these protecting groups is possible in both a stepwise and an orthogonal fashion by applying different metal salts.     

Synthesis of Novel 2‐Vinylcyclopropane Phosphonic Acids

2‐Vinylcyclopropane‐1‐phosphonic acid diesters 1a–d were synthesized by the reaction of trans‐1,4‐dibromo‐2‐butene with α‐substituted phosphonic acid diesters. Esterification of 1‐ethoxycarbonyl‐2‐vinylcyclopropane‐1‐carboxylic acid with dimethyl 2‐hydroxyethyl‐phosphonate gave the 2‐vinylcyclopropane phosphonic acid dimethylester 1e. The silylation of phosphonic acid diesters 1a–e by halotrimethylsilanes followed by solvolysis with methanol or water resulted in the formation of phosphonic acids 2a–e. In the case of steric hinderance of the phosphoryl group, monoesters 3c,d were also formed. Furthermore, ethyl carboxylate 1b could be chemoselectively cleaved by aqueous potassium hydroxide to carboxylic acid 4.     

Difference between Extra‐ and Intracellular T1 Values of Carboxylic Acids Affects the Quantitative Analysis of Cellular Kinetics by Hyperpolarized NMR

Incomplete knowledge of the longitudinal relaxation time constant (T₁) leads to incorrect assumptions in quantitative kinetic models of cellular systems, studied by hyperpolarized real‐time NMR. Using an assay that measures the intracellular signal of small carboxylic acids in living cells, the intracellular T₁ of the carboxylic acid moiety of acetate, keto‐isocaproate, pyruvate, and butyrate was determined. The intracellular T₁ is shown to be up to four‐fold shorter than the extracellular T₁. Such a large difference in T₁ values between the inside and the outside of the cell has significant influence on the quantification of intracellular metabolic activity. It is expected that the significantly shorter T₁ value of the carboxylic moieties inside cells is a result of macromolecular crowding. An artificial cytosol has been prepared and applied to predict the T₁ of other carboxylic acids. We demonstrate the value of this prediction tool.     

Improved Routes for the Preparation of Pentaerythritol Mono‐O‐benzyl Ether

Two new efficient routes for the synthesis of pentaerythritol monobenzyl ether are described. In one route, the known mono‐O‐benzylidenepentaerythritol (5) is selectively benzylated via its dibutylstannylene acetal and then the benzylidene acetal is hydrolized. In the other route, compound 5 is reduced directly to the monobenzyl ether using EtAlCl₂‐Et₃SiH.     

A Straightforward Synthesis of Six‐Membered‐Ring Heterocyclic α‐Aminophosphonic Acids from N‐Acyliminium Ions

A convenient synthesis of phosphonic analogues of pipecolic acid and its heterocyclic analogues is reported. The major step of the elaborated procedure is the introduction of the phosphonate group into the skeleton of the appropriate cyclic amide through N‐acyliminium ions. The former ones were obtained by preparation of the hemiaminals or their methyl ethers from the N‐protected cyclic amides. Finally, the reaction with trimethyl phosphite in the presence of BF₃·OEt₂ afforded the desired phosphonates, which were converted into phosphonic acids by the hydrolysis of phosphonate moiety with simultaneous cleavage of the nitrogen protecting groups.     

Enantioselective,Desymmetrizing, Bromolactonization Reactions of Symmetric Olefinic Dicarboxylic Acids

The results of studies leading to the development of enantioselective desymmetrizing, bromolactonization reactions of symmetric olefinic dicarboxylic acids, which are promoted by a C₃‐symmetric trisimidazoline catalyst, are described. These processes generated carboxylic‐acid‐containing bromolactones in moderately high enantiomeric excesses. The results of optimization studies showed that reactions in a mixed solvent system of toluene and acetone proceeded with the highest levels of enantioselectivity. NMR studies probing the interactions between the catalyst and dicarboxylic acid substrates, as well as the effect of acetone on the stereochemistry of the process, are also described.     

Rapid Synthesis of Novel and Known Coumarin‐3‐carboxylic Acids Using Stannous Chloride Dihydrate under Solvent‐Free Conditions

Various coumarin‐3‐carboxylic acid (=2‐oxo‐2H‐1‐benzopyran‐3‐carboxylic acid; CcaH) derivatives have been synthesized in good yields using catalytic amounts of SnCl₂?2 H₂O under solvent‐free conditions. This inexpensive, nontoxic, and readily available catalytic system (10 mol‐%) efficiently catalyzes the Knoevenagel condensation and intramolecular cyclization of various 2‐hydroxybenzaldehydes or acetophenones with Meldrum's acid. High product yields, use of inexpensive and safe catalyst, and solvent‐free conditions display both economic and environmental advantages.     

Esterification‐nitration of Ortho‐hydroxyphenyl Carboxylic Acids and Benzoic Acids with Cerium(IV) Ammonium Nitrate (CAN)

A convenient and useful esterification was realized, and this reaction proceeded without a dehydrating reagent or water removal equipment. A series of ortho‐hydroxyphenyl carboxylic acids and benzoic acids were transformed to their corresponding methyl esters under CAN/CH₃OH reaction conditions. Whereas in an aprotic solvent, acetonitrile, sp³‐C tethered ortho‐hydroxyphenyl carboxylic acids undergo simultaneous o,p‐dinitration and intramolecular esterification reactions in good yields. Also, 2‐((1 E)‐2‐nitrovinyl)‐4‐nitro‐phenol ( 3e ) showed selective cytotoxicities toward MCF‐7, HEP G2, and HEP 3B cell lines with IC₅₀ values of 23.50, 7.33, and 7.59 ug/mL, respectively.     

Chemoenzymatic Syntheses of Sialylated Oligosaccharides Containing C5‐Modified Neuraminic Acids for Dual Inhibition of Hemagglutinins and Neuraminidases

A fast chemoenzymatic synthesis of sialylated oligosaccharides containing C5‐modified neuraminic acids is reported. Analogues of GM₃ and GM₂ ganglioside saccharidic portions where the acetyl group of NeuNAc has been replaced by a phenylacetyl (PhAc) or a propanoyl (Prop) moiety have been efficiently prepared with metabolically engineered E. coli bacteria. GM₃ analogues were either obtained by chemoselective modification of biosynthetic N‐acetyl‐sialyllactoside (GM₃NAc) or by direct bacterial synthesis using C5‐modified neuraminic acid precursors. The latter strategy proved to be very versatile as it led to an efficient synthesis of GM₂ analogues. These glycomimetics were assessed against hemagglutinins and sialidases. In particular, the GM₃NPhAc displayed a binding affinity for Maackia amurensis agglutinin (MAA) similar to that of GM₃NAc, while being resistant to hydrolysis by Vibrio cholerae (VC) neuraminidase. A preliminary study with influenza viruses also confirmed a selective inhibition of N1 neuraminidase by GM₃NPhAc, suggesting potential developments for the detection of flu viruses and for fighting them.     

Thermodynamic Estimate of pKa Values of the Carboxylic Acids in Aqueous Solution with the Density Functional Theory

The 96 pK_a values of 85 carboxylic acids in aqueous solution were calculated with the density functional theory method at the level of B3LYP/6‐31+G(d,p) and the polarizable continuum model (PCM) was used to describe the solvent. In the calculations of pK_a values, the dissociation Gibbs free energies were directly calculated using carboxylic acid dissociation reactions in aqueous solution, i. e., no thermodynamic cycle was employed, which is different from the previous literatures. A highly significant correlation of R²=0.95 with a standard deviation (SD) of 0.36 between the experimental pK_a values and the calculated dissociation Gibbs free energies [ΔG(calc.)] was found. The slope of pK_a vs. (G(calc.)/(20303RT) is only 47.6% of the theoretically expected value, which implies that the ΔG(calc.) value from the theoretical calculation is larger than the actual one for all 85 carboxylic acids studied. Thus, by adding the 0.476 scaling‐factor into the slope, we can derive a reliably procedure that can reproduce the experimental pK_a values of carboxylic acids. The pK_a values furnished by this procedure are in good agreement with the experimental results for carboxylic acids in aqueous solution.     

Synthesis of Isoindolo[2,1‐a]quinazoline‐5,11‐dione Derivatives via the Reductive One‐Pot Reaction of N‐Substituted 2‐Nitrobenzamides and 2‐Formylbenzoic Acids

Various isoindolo[2,1‐a]quinazoline‐5,11‐dione derivatives 3 were synthesized in good yields by means of the reductive reaction of N‐substituted 2‐nitrobenzamides 1 and 2‐formylbenzoic acids 2 in the presence of SnCl₂?2 H₂O under reflux in EtOH (Scheme, Table). The procedure needed two steps, the reduction of the nitro group of the 2‐nitrobenzamide and ring closure by nucleophilic addition of the NH₂ group to both the formyl and carboxylic acid C?O groups.     

Directly Bridging Indoles to 3,3′‐Bisindolylmethanes by Using Carboxylic Acids and Hydrosilanes under Mild Conditions

A straightforward Lewis acid‐promoted protocol for 3,3′‐bisindolylmethanes (BIMs) synthesis by reductive alkylation of indoles at the C3 position with carboxylic acids in the presence of hydrosilane was developed for the first time. Instead of aldehydes, more readily available, stable, and easy‐to‐handle carboxylic acids have been employed as alternative alkylating agents. As an efficient organocatalyst, B(C₆F₅)₃ enables the reductive alkylation of various substituted indole derivatives with carboxylic acids with up to 98 % yield at room temperature and under neat conditions. This metal‐free strategy offers an alternative approach for the direct functionalization of indoles to BIMs with carboxylic acids and such protocol allows selective reduction of carboxylic acid to aldehyde in combination with C−C bond formation.     

From Alkanes to Carboxylic Acids: Terminal Oxygenation by a Fungal Peroxygenase

A new heme–thiolate peroxidase catalyzes the hydroxylation of n‐alkanes at the terminal position—a challenging reaction in organic chemistry—with H₂O₂ as the only cosubstrate. Besides the primary product, 1‐dodecanol, the conversion of dodecane yielded dodecanoic, 12‐hydroxydodecanoic, and 1,12‐dodecanedioic acids, as identified by GC–MS. Dodecanal could be detected only in trace amounts, and 1,12‐dodecanediol was not observed, thus suggesting that dodecanoic acid is the branch point between mono‐ and diterminal hydroxylation. Simultaneously, oxygenation was observed at other hydrocarbon chain positions (preferentially C2 and C11). Similar results were observed in reactions of tetradecane. The pattern of products formed, together with data on the incorporation of ¹⁸O from the cosubstrate H₂¹⁸O₂, demonstrate that the enzyme acts as a peroxygenase that is able to catalyze a cascade of mono‐ and diterminal oxidation reactions of long‐chain n‐alkanes to give carboxylic acids.     

A Study on the Diastereoselective Synthesis of α‐Fluorinated β3‐Amino Acids by α‐Fluorination

The treatment of a β³‐amino acid methyl ester with 2.2 equiv. of lithium diisopropylamide (LDA), followed by reaction with 5 equiv. of N‐fluorobenzenesulfonimide (NFSI) at ?78° for 2.5 h and then 2 h at 0°, gives syn‐fluorination with high diastereoisomeric excess (de). The de and yield in these reactions are somewhat influenced by both the size of the amino acid side chain and the nature of the amine protecting group. In particular, fluorination of N‐Boc‐protected β³‐homophenylalanine, β³‐homoleucine, β³‐homovaline, and β³‐homoalanine methyl esters, 5 and 9 – 11 , respectively, all proceeded with high de (>86% of the syn‐isomer). However, fluorination of N‐Boc‐protected β³‐homophenylglycine methyl ester ( 16 ) occurred with a significantly reduced de. The use of a Cbz or Bz amine‐protecting group (see 3 and 15 ) did not improve the de of fluorination. However, an N‐Ac protecting group (see 17 ) gave a reduced de of 26%. Thus, a large N‐protecting group should be employed in order to maximize selectivity for the syn‐isomer in these fluorination reactions.     

Synthesis of Unsymmetrically Substituted Phosphane Oxides (R1R2P(O)H) and Phosphinous Acids (R1R2POH)

This paper describes the synthesis of unsymmetrically substituted phosphinous acids and phosphane oxides featuring at least one electron‐withdrawing pentafluoroethyl group. The presence of a diethylamino function as a protecting group allows a selective reaction of RClPNEt₂ (R=CF₃, C₆F₅, C₆H₅) with LiC₂F₅. On treatment with para‐toluenesulfonic acid the isolated aminophosphanes R(C₂F₅)PNEt₂ are readily converted into the corresponding phosphinous acids or phosphane oxides, respectively. Investigation of the tautomeric equilibrium between oxide and acid tautomer revealed (CF₃)(C₂F₅)POH as a stable phosphinous acid, whereas the pentafluorophenyl and phenyl derivatives constitute a solvent dependent equilibrium between the acid and the oxide tautomer.     

Design,Synthesis, EPR‐Studies and Conformational Bias of Novel Spin‐Labeled DCC‐Analogues for the Highly Regioselective Labeling of Aliphatic and Aromatic Carboxylic Acids

Novel types of spin‐labeled N,N′‐dicyclohexylcarbodiimides (DCC) are reported that bear a 2,2,6,6‐tetramethylpiperidinyloxyl (TEMPO) residue on one side and different aromatic and aliphatic cyclohexyl analogues on the other side of the diimide core. These readily available novel reagents add efficiently to aliphatic and aromatic carboxylic acids, forming two possible spin‐labeled amide derivatives with different radical distances of the resulting amide. The addition of aromatic DCC analogues proceeds with excellent selectivity, giving amides where the carboxylic acid is exclusively connected to the aromatic residue, while little or no selectivity was observed for the aliphatic congeners. The usefulness of these adducts in structural studies was demonstrated by EPR (electron paramagnetic resonance) measurements of biradical adducts of biphenyl‐4,4′‐dicarboxylic acids. These analyses also reveal high degrees of conformational bias for aromatic DCC derivatives, which further underlines the powerfulness of these novel reagents. This observation was further corroborated by quantum chemical calculations, giving a detailed understanding of the structural dynamics, while detailed information on the solid state structure of all novel reagents was obtained by X‐ray structure analyses.     

Electronic structure,novel synthesis,and O—H...O and C—H...O interactions in two 6‐oxopiperidine‐2‐carboxylic acid derivatives

Molecules of (S)‐6‐oxo‐1‐(thiophen‐2‐ylmethyl)piperidine‐2‐carboxylic acid, C₁₁H₁₃NO₃S, crystallize as single enantiomers in the space group P2₁ and the thiophene ring is disordered over two positions, while (S)‐6‐oxo‐1‐(thiophen‐3‐ylmethyl)piperidine‐2‐carboxylic acid, C₁₁H₁₃NO₃S, crystallizes as a single enantiomer in the space group P2₁2₁2₁. Their absolute configurations were confirmed by anomalous dispersion effects in diffraction measurements on the crystals. The molecules of each compound are linked by a combination of strong O—H...O hydrogen bonds and weak C—H...O interactions, resulting in two‐ and three‐dimensional networks, respectively, in the crystal structures.     

Synthesis of Components for the Generation of Constitutional Dynamic Analogues of Nucleic Acids

The introduction of dynamic covalent polymers, in which the monomer units are linked by reversible covalent bonds and can undergo component exchange, opens up new possibilities for the generation of functional materials. Extending this approach to the generation of dynamic biopolymers in aqueous media, which are able to adapt constitution (sequence, length) to external factors (e.g., environment, medium, template), would provide an alternative approach to the de novo design of functional dynamic bio‐macromolecules. As a first step towards this goal, various mono‐ and bifunctionalised (hetero‐ and homotopic) nucleic acid‐derived building blocks of type I – X have been synthesised for the generation of dynamic main‐chain and side‐chain reversible nucleic acid analogues. Hydrazide‐ and/or acetal (protected carbonyl)‐functionalised components were selected, which differ in terms of flexibility, length, net formal charge, and hydrazide/acetal substituents, in order to explore how such factors may affect the properties (structure, solubility, molecular recognition features) of the polymer products that may be generated by polycondensation.     

Metal Complexes of Biologically Important Ligands,CLXXVII. Dichlorido Platinum(II) and Palladium(II) Complexes with Long Chain Amino Acids and Amino Acid Amides

The synthesis of Cl₂Pt[NH₂(CH₂)_nCOOH]₂ (n = 5, 10) and the reactions of their carboxylic groups with H₂N(CH₂)₁₇CH₃, d ‐glucosamine, and (R,R)‐1,2‐diaminocyclohexane to give complexes with amino acid amides as ligands, are reported. Cl₂Pd(histidine) is coupled with amino alcohols to give Cl₂Pd(histidineamide) complexes.     

Controlled Release of Covalently Bound Organic Molecules by Slow Hydrolysis for Potential Biocide Applications†

A study of the slow hydrolysis of labile acetal groups by low concentrations of lactic acid to release the active molecules is reported. A prototype molecule containing cyclic acetal groups, dimethyl‐2,3‐O‐benzylidene‐L‐tartrate (DMTAc) and the same molecule incorporated as a pendant group in a polyamide were studied for their hydrolysis by low concentrations of lactic acid. The release of benzaldehyde during slow hydrolysis is monitored by UV‐vis and ¹H‐NMR spectroscopy. This study is very useful to ultimately design and synthesize a polymer with covalently bound insecticidal/anti‐microbial/anti‐fungal materials for the development of controlled release formulations.