An examination into the derivatization of various natural products using newly developed α-fluorination methodology is disclosed. An activated ketene enolate, generated from an acid chloride, is allowed to react with an electrophilic fluorine source (NFSi). Quenching the reaction with a nucleophilic natural product produces biologically relevant α-fluorinated carbonyl derivatives of select chemotherapeutics, antibiotics, and other pharmaceuticals.
The subcellular sites of branched-chain amino acid metabolism in plants have been controversial, particularly with respect to valine catabolism. Potential enzymes for some steps in the valine catabolic pathway are clearly present in both mitochondria and peroxisomes, but the metabolic functions of these isoforms are not clear. The present study examined the possible function of these enzymes in metabolism of isobutyryl-CoA and propionyl-CoA, intermediates in the metabolism of valine and of odd-chain and branched-chain fatty acids. Using 13 C NMR, accumulation of -hydroxypropionate from [2-13 C]propionate was observed in seedlings of Arabidopsis thaliana and a range of other plants, including both monocots and dicots. Examination of coding sequences and subcellular targeting elements indicated that the completed genome of A. thaliana likely codes for all the enzymes necessary to convert valine to propionyl-CoA in mitochondria. However, Arabidopsis mitochondria may lack some of the key enzymes for metabolism of propionyl-CoA. Known peroxisomal enzymes may convert propionyl-CoA to -hydroxypropionate by a modified -oxidation pathway. The chy1-3 mutation, creating a defect in a peroxisomal hydroxyacyl-CoA hydrolase, abolished the accumulation of -hydroxyisobutyrate from exogenous isobutyrate, but not the accumulation of -hydroxypropionate from exogenous propionate. The chy1-3 mutant also displayed a dramatically increased sensitivity to the toxic effects of excess propionate and isobutyrate but not of valine.13 C NMR analysis of Arabidopsis seedlings exposed to [U-13 C]valine did not show an accumulation of -hydroxypropionate. No evidence was observed for a modified -oxidation of valine.13 C NMR analysis showed that valine was converted to leucine through the production of ␣-ketoisovalerate and isopropylmalate. These data suggest that peroxisomal enzymes for a modified -oxidation of isobutyryl-CoA and propionyl-CoA could function for metabolism of substrates other than valine.Propionate, in the form of propionyl-CoA, is produced from a number of metabolic precursors in higher eukaryotes. It is the final product of odd-chain fatty acid -oxidation (1). It is also produced during the catabolism of several amino acids, including isoleucine, methionine, and valine (1, 2). Propionyl-CoA is also a final product of metabolism of the branched acid, phytanic acid, derived from the degradation of chlorophyll (3). Aside from a basic understanding of metabolic biochemistry, the anabolic and catabolic pathways for propionyl-CoA are also of considerable importance in metabolic engineering of polyhydroxyalkanoates in plants, especially in the production of mixed polyhydroxyalkanoate polymers that have relied on the use of propionyl-CoA as a metabolic intermediate (4, 5). Several pathways have been confirmed for the catabolism of propionylCoA (6 -8). Bacteria and yeast utilize a 2-methylcitrate pathway with reactions analogous to those of the tricarboxylic acid cycle and glyoxylate cycle (6). Mammals use a well established b...
We report in full detail our studies on the catalytic, asymmetric α-fluorination of acid chlorides, a practical method that produces an array of α-fluorocarboxylic acid derivatives in which improved yield and virtually complete enantioselectivity are controlled through electrophilic fluorination of a ketene enolate intermediate. We discovered, for the first time, that a third catalyst, a Lewis acidic lithium salt, could be introduced into a dually-activated system to amplify yields of aliphatic products, primarily through activation of the fluorinating agent. Through our mechanistic studies (based on kinetic data, isotopic labeling, spectroscopic measurements, and theoretical calculations) we were able to utilize our understanding of this “trifunctional” reaction to optimize the conditions and obtain new products in good yield and excellent enantioselectivity.
We designed and prepared a spacious and gated basket of type 2 (V = 318 Å(3)) in ten synthetic steps. With the assistance of (1)H NMR spectroscopy, we found that the pyridine gates at the rim of 2 form a seam of N-H∙∙∙N hydrogen bonds, thereby adopting right- (P) and left-handed (M) helical arrangements. The recognition characteristics of the smaller basket 1 (V = 226 Å(3)) and the larger 2 for various solvents as guests were quantified by (1)H NMR spectroscopy in CD2Cl2 (61 Å(3)), CDCl3 (75 Å(3)), CFCl3 (81 Å(3)) and CCl4 (89 Å(3)); the apparent guest binding equilibria Ka were found to be inversely proportional to the affinity of bulk solvents KS for populating each host. The rate of the P/M racemization (krac, s(-1)) was, for both 1 and 2, studied in all four solvents using dynamic NMR spectroscopy. From these experiments, two isokinetic relationships (ΔS++P/M vs. ΔH++P/M) were identified with each one corresponding to a different mechanism of P/M racemization. A computational study (B3LYP/6-31+G**//PM6) of 1 and 2 in the gas phase indicates two competing racemization pathways: (a) RM1-2 describes a pivoting of a single gate followed by the rotation of the remaining two gates, while (b) RM3 depicts simultaneous (geared) rotation of all three gates. The racemization of the larger basket 2, in all four solvents (packing coefficient, PC = 0.19-0.28), conformed to one isokinetic relationship, which also coincided with the operation of the smaller basket 1 in CD2Cl2 (PC = 0.27). However, in CDCl3, CFCl3 and CCl4 (PC = 0.33-0.39), the mode of action of 1 appears to correlate with a different isokinetic relationship. Thus, we propose that the population of the basket's inner space (PC) determines the mechanism of P/M racemization. When PC < 0.3, the mechanism of operation is RM1-2, whereas, a greater packing, represented when PC > 0.3, enforces the geared RM3 mechanistic alternative.
The selective α,α-difluorination of carbonyl compounds remains a challenge in modern organic synthesis; current methods often incorporate stepwise processes and/or harsh conditions, providing unsatisfactory mixtures of mono- and difluorinated products. In this communication, a practical, mild, and one-pot method for the selective α,α-difluorination of readily available acid chlorides is reported in which three separate catalysts act synergistically to form products in outstanding selectivity and fair to excellent yields.
Anion photoelectron spectroscopy (PES) and electron energy-loss spectroscopy (EELS) probe different regions of the anionic potential energy surface. These complementary techniques provided information about anionic states of acetoacetic acid (AA). Electronic structure calculations facilitated the identification of the most stable tautomers and conformers for both neutral and anionic AA and determined their relative stabilities and excess electron binding energies. The most stable conformers of the neutral keto and enol tautomers differ by less than 1 kcal/mol in terms of electronic energies corrected for zero-point vibrations. Thermal effects favor these conformers of the keto tautomer, which do not support an intramolecular hydrogen bond between the keto and the carboxylic groups. The valence anion displays a distinct minimum which results from proton transfer from the carboxylic to the keto group; thus, we name it an ol structure. The minimum is characterized by a short intramolecular hydrogen bond, a significant electron vertical detachment energy of 2.38 eV, but a modest adiabatic electron affinity of 0.33 eV. The valence anion was identified in the anion PES experiments, and the measured electron vertical detachment energy of 2.30 eV is in good agreement with our computational prediction. We conclude that binding an excess electron in a π* valence orbital changes the localization of a proton in the fully relaxed structure of the AA − anion. The results of EELS experiments do not provide evidence for an ultrarapid proton transfer in the lowest π* resonance of AA − , which would be capable of competing with electron autodetachment. This observation is consistent with our computational results, indicating that major gas-phase conformers and tautomers of neutral AA do not support the intramolecular hydrogen bond that would facilitate ultrarapid proton transfer and formation of the ol valence anion. This is confirmed by our vibrational EELS spectrum. Anions formed by vertical electron attachment to dominant neutrals undergo electron autodetachment with or without vibrational excitations but are unable to relax to the ol structure on a time scale fast enough to compete with autodetachment.
Quinol esters 2b, 2c, and 3b and sulfonamide 4c were investigated as possible precursors to 4-alkylaryloxenium ions, reactive intermediates that have not been previously detected. These compounds exhibit a variety of interesting reactions, but with one possible exception, they do not generate oxenium ions. The 4-isopropyl ester 2b predominantly undergoes ordinary acid- and base-catalyzed ester hydrolysis. The 4-tert-butyl ester 2c decomposes under both acidic and neutral conditions to generate tert-butanol and 1-acetyl-1,4-hydroquinone, 8, apparently by an SN1 mechanism. This is also a minor decomposition pathway for 2b, but the mechanism in that case is not likely to be SN1. Decomposition of 2c in the presence of N3- leads to formation of the explosive 2,3,5,6-tetraazido-1,4-benzoquinone, 14, produced by N3--induced hydrolysis of 8, followed by a series of oxidations and nucleophilic additions by N3-. No products suggestive of N3--trapping of an oxenium ion were detected. The 4-isopropyl dichloroacetic acid ester 3b reacts with N3- to generate the two adducts 2-azido-4-isopropylphenol, 5b, and 3-azido-4-isopropylphenol, 11b. Although 5b is the expected product of N3- trapping of the oxenium ion, kinetic analysis shows that it is produced by a kinetically bimolecular reaction of N3- with 3b. No oxenium ion is involved. The sulfonamide 4c predominantly undergoes a rearrangement reaction under acidic and neutral conditions, but a minor component of the reaction yields 4-tert-butylcresol, 17, and 2-azido-4-tert-butylphenol, 5c, in the presence of N3-. These products may indicate that 4c generates the oxenium ion 1c, but they are generated in very low yields (ca. 10%) so it is not possible to definitively conclude that 1c has been produced. If 1c has been generated, the N3--trapping data indicate that it is a very short-lived and reactive species in H2O. Comparisons with similarly reactive nitrenium ions indicate that the lifetime of 1c is ca. 20-200 ps if it is generated, so it must react by a preassociation process. Density functional theory calculations at the B3LYP/6-31G*//HF/6-31G* level coupled with kinetic correlations also indicate that the aqueous solution lifetimes of 1a-c are in the picosecond range.
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