The Synthesis of Diphenyl Phosphonate Analogues of α-Amino Acids as Enzyme Inhibitors

Abstract

α-Aminoalkylphosphonic acids are analogues of natural aminoacids and as such have been the subject of much research effort over past years¹. The diphenyl esters of α- aminoalkylphosphonic acids are particularly potent and show high selectivity as irreversible inhibitors of serine proteinases. Thus far, α-aminoalkylphosphonic acid ester analogues of a number of aliphatic- and aromatic aminoacids have been prepared including valine, phenylalanine, tryptophan, and tyrosine², and the basic aminoacids ornithine, lysine. etc.³. We have now also prepared the a-diphenyl phosphonate analogues of the acidic aminoacids, aspartic and glutamic⁴. These have been examined as potential inactivators of serine proteinases exhibiting a P₁ specificity for aspartate and glutamate, e.g. S. aureus V8 protease and granzyme B.     

Internal Rotation of the Acetyl Methyl Group in Methyl Alkyl Ketones: The Microwave Spectrum of Octan-2-one

Methyl n-alkyl ketones form a class of molecules with interesting internal dynamics in the gas-phase. They contain two methyl groups undergoing internal rotations, the acetyl methyl group and the methyl group at the end of the alkyl chain. The torsional barrier of the acetyl methyl group is of special importance, since it allows for the discrimination of the conformational structures. As part of the series, the microwave spectrum of octan-2-one was recorded in the frequency range from 2 to 40 GHz, revealing two conformers, one with C₁ and one with C_s symmetry. The barriers to internal rotation of the acetyl methyl group were determined to be 233.340(28) cm⁻¹ and 185.3490(81) cm⁻¹, respectively, confirming the link between conformations and barrier heights already established for other methyl alkyl ketones. Extensive comparisons to molecules in the literature were carried out, and a small overview of general trends and rules concerning the acetyl methyl torsion is given. For the hexyl methyl group, the barrier height is 973.17(60) cm⁻¹ for the C₁ conformer and 979.62(69) cm⁻¹ for the C_s conformer.     

Vibrations de valence C?H dans les hydrocarbures et les halogénures de butyle

The valence vibrations C? H and C? D of a number of alkanes and of (CH₃)₃CX are studied using compounds deuterated in specific positions. For the methyl and the methylene groups an experimental model of group frequencies is proposed, which allows some general conclusions to be drawn concerning the assignation of the frequencies. The methyl group always shows a Fermi resonance between ν_s and 2δ_as in the region of 2930–2870 cm^?1. In consequence the unperturbed ν_sCH₃ frequency may be situated at ∽2915 cm^?1 and the absence of a coupling with other groups can be checked. The vibrations of the methylene group adjacent to a methyl group have higher frequencies than those of CH₂ groups further removed. The coupling of the methylene group with other groups is always strong and may amount to 10 cm^?1. For a chain of methylene groups, the coupling is the larger the longer the chain; being relatively small for symmetrical modes (∽3 cm^?1) for the antisymmetric mode. A correlation is found between protonated and deuterated groups which leads to isotope effects comparing well with recorded values.     

Deuteron magnetic resonance study of the mechanism of methyl group exchange between tetramethyltitanium and trimethylaluminium

The exchange of methyl groups between tetramethyltitanium and trimethylaluminium has been studied by the direct observation of a new resonance line in the ²D NMR spectrum of the reaction mixture containing perdeuterated and undeuterated organometallic compounds.The kinetics and mechanism of the exchange reaction are influenced by the ethyl ether concentration in a hexane solution of the tetramethyltitanium compound. At a molar ratio TiMe₄/Et₂0 > 1 rapid exchange occurs between unsolvated metal alkyls. Tetramethyltitanium etherate reacts with trimethylaluminium in two steps, an initial fast complexation to Me₃Ti [AlMe₄] which accounts for the transfer of a single methyl group from the titanium to the aluminium atom and a subsequent slow reverse process which leads to the transfer of methyl groups from the aluminium to the titanium atom and which results ultimately in a random equilibrium distribution of the labelled methyl groups amongst both metal atoms.Mixing the etherates of both titanium and aluminium methyl compounds led to the appearance of an extra signal downfield (τ 5.6 ppm) which is apparently due to the methyl resonance of the species [TiMe₃]⁺ in the solvent-separated ion-pair form of the complex [TiMe₃]⁺ [AlMe₄]^?.     

取代基对有机钼化合物中α-氢转移反应势垒和产物稳定性的影响

使用B3LYP方法研究了发生在有机钼化合物R³R⁴Mo(≡CH)(CHR¹R²)和R³R⁴Mo(＝CH₂)(＝CR¹R²)之间的α-氢转移反应, 探讨了R¹, R², R³和R⁴位置上不同取代基对α-氢转移反应势垒和产物稳定性的影响. 研究发现, 金属钼有机化合物中, 发生α-氢转移的碳原子在过渡态中采用sp²杂化. R¹和R²位置上取代基对α-氢转移反应势垒的影响取决于取代基对过渡态中碳原子的未参与sp²杂化的p_z轨道上单电子的离域作用. 当R¹, R²位置是甲基时, 由于碳原子的p_z轨道与甲基的一个C—H键轨道间存在强的超共轭效应, 从而可以较大程度地降低α-氢转移反应的势垒. 研究结果还表明, 当R³, R⁴位置为SiH₃时的反应势垒较低. 所以当R¹和R² 位置为Me, R³和R⁴位置为SiH₃时, 反应势垒最低. 第一个甲基取代R¹或R²位置的H时, 反应势垒降低很大; 第二个甲基继续取代时, 反应势垒的降低约为第一个甲基的一半. 第一个SiH₃取代R³或R⁴位置的甲基时, 反应势垒降低较大; 第二个SiH₃继续取代时, 反应势垒的降低小于第一个SiH₃的一半. 对反应物和产物的相对稳定性的研究表明, 第一个甲基和第二个甲基对产物的相对能量的降低几乎相同; 第一个SiH₃降低产物的相对能量, 但是第二个SiH₃使产物的相对能量升高, 从而抵消了第一个SiH₃对产物的稳定作用.     

Spectres de vibration et conformations du propionate et de l'isobutyrate de méthyle

Infrared and Raman spectra (3600–3620cm^?1) of methyl propionate CH₃CH₂-COOCH₃, CH₃CH₂COOCD₃ and methyl isobutyrate (CH₃)₂CHCOOCH₃, (CH₃)₂CHCOOCD₃, in liquid and crystalline states, have been recorded. Rotational isomerism, by rotation around the C-C bond α to the carbonyl group, is detected and the energy difference between the conformers is 1.1 ±0.3 kcal mol^?1 for methyl propionate and 0.5 ±0.1 kcal mol^?1 for methyl isobutyrate. Vibrational assignments in terms of group frequencies are proposed for each conformer, only the more stable being present in the crystal.     

A 1H NMR and molecular modelling investigation of diastereotopic methylene hydrogen atoms

The ¹H NMR spectra of methyl 3‐bromo‐2‐methylpropionate (1a) and the corresponding chloro compound (2a) show no long‐range coupling between the methyl and methylene protons. In contrast, in the analogous dihalocompounds, methyl 2,3‐dibromo‐2‐methylpropionate (1b) and methyl 2,3‐dichloro‐2‐methylpropionate (2b), one of the methylene protons exhibits a large ⁴J_HH coupling (0.8 Hz) to the methyl group, but the other proton shows no observable splitting. This can be explained quantitatively by calculations of the conformational preferences in these compounds combined with the known orientation dependence of the ⁴J_HHcouplings. One conformer predominates in the dihalo compounds 1b and 2b, and this is responsible for the ⁴J_HH coupling. In 1a and 2a all three conformers are populated and the ⁴J_HH couplings average to zero. The technique is a potentially general method of unambiguously assigning diastereotopic methylene protons. Copyright © 2002 John Wiley & Sons, Ltd.     

2,6‐Dimethoxy‐7,9‐dimethylpurinium iodide hemihydrate

In the title compound, C₉H₁₃N₄O₂⁺·I⁻·0.5H₂O, the non‐H atoms of the ionic components lie on a mirror plane in Cmca, with the O atom of the partial water molecule lying on a twofold rotation axis. Whereas one of the methoxy methyl groups is directed away from the adjacent N‐methyl group, the other methoxy methyl group is directed towards its adjacent N‐methyl group. The conformation of the methoxy methyl groups provides an explanation for the outcomes of intramolecular thermal rearrangements of 2,6‐dialkoxy‐7,9‐dimethylpurinium salts.     

Long range 13C shift effects (δ and ϵ) in methylcyclohexanes

¹³C n.m.r. spectra of a number of methyl substituted cyclohexanes, some of them conformationally homogeneous, have been recorded in CDCl₃ and used to determine shift effects engendered by the introduction of methyl groups on carbon atoms remote from the site of substitution. Sizeable changes in shifts are found, including a substantial effect of an equatorial methyl group on an axial methyl group δ to it (+0.6₇ ppm, ‘δ_ea’). The effects reported are of consequence in investigations of conformational problems by ¹³C n.m.r. techniques.     

Stereochemistry of the Methyl Group in (R)‐3‐Methylitaconate Derived by Rearrangement of 2‐Methylideneglutarate Catalysed by a Coenzyme B12‐Dependent Mutase

2‐Methylideneglutarate mutase is an adenosylcobalamin (coenzyme B₁₂)‐dependent enzyme that catalyses the equilibration of 2‐methylideneglutarate with (R)‐3‐methylitaconate. This reaction is believed to occur via protein‐bound free radicals derived from substrate and product. The stereochemistry of the formation of the methyl group of 3‐methylitaconate has been probed using a `chiral methyl group'. The methyl group in 3‐([²H₁,³H]methyl)itaconate derived from either (R)‐ or (S)‐2‐methylidene[3‐²H₁,3‐³H₁]glutarate was a 50 : 50 mixture of (R)‐ and (S)‐forms. It is concluded that the barrier to rotation about the C−C bond between the methylene radical centre and adjacent C‐atom in the product‐related radical [^.CH₂CH(⁻O₂CC=CH₂)CO₂⁻] is relatively low, and that the interaction of the radical with cob(II)alamin is minimal. Hence, cob(II)alamin is a spectator of the molecular rearrangement of the substrate radical to product radical.     

Sensing the Molecular Structures of Hexan-2-one by Internal Rotation and Microwave Spectroscopy

Using two molecular jet Fourier transform spectrometers, the microwave spectrum of hexan-2-one, also called methyl n-butyl ketone, was recorded in the frequency range from 2 to 40 GHz. Three conformers were assigned and fine splittings caused by the internal rotations of the two terminal methyl groups were analyzed. For the acetyl methyl group CH₃ COC₃H₆CH₃, the torsional barrier is 186.9198(50) cm⁻¹, 233.5913(97) cm⁻¹, and 182.2481(25) cm⁻¹ for the three observed conformers, respectively. The value of this parameter could be linked to the structure of the individual conformer, which enabled us to create a rule for predicting the barrier height of the acetyl methyl torsion in ketones. The very small splittings arising from the internal rotation of the butyl methyl group CH₃COC₃H₆ CH₃ could be resolved as well, yielding the respective torsional barriers of 979.99(88) cm⁻¹, 1016.30(77) cm⁻¹, and 961.9(32) cm⁻¹.     

Microwave spectrum,conformational preference,barrier to internal rotation,and centrifugal distortion of 1-amino-2-propanol

The microwave spectrum of CH₃CH(OH)CH₂NH₂ has been investigated in the 26.5–39.7 GHz region. One rotamer with an intramolecular hydrogen bond formed between hydroxyl and ammo groups was assigned. This conformation is also characterized by having the methyl group anti to the amino group. Other forms, if they exist, must be at least 1 kcal mole^?1 less stable. Four vibrationally excited states belonging to three different normal modes were assigned and the barrier to internal rotation of the methyl group was found to be 3173 ± 100 cal mole^?1.     

Regulating Steric Hindrance of Porous Organic Polymers in Composite Solid-State Electrolytes to Induce the Formation of LiF-Rich SEI in Li-Ion Batteries

Lithium fluoride (LiF) at the solid electrolyte interface (SEI) contributes to the stable operation of polymer-based solid-state lithium metal batteries. Currently, most of the methods for constructing lithium fluoride SEI are based on the design of polar groups of fillers. However, the mechanism behind how steric hindrance of fillers impacts LiF formation remains unclear. This study synthesizes three kinds of porous polyacetal amides (PAN-X, X=NH₂, NH-CH₃, N-(CH₃)₂) with varying steric hindrances by regulating the number of methyl substitutions of nitrogen atoms on the reaction monomer, which are incorporated into polymer composite solid electrolytes, to investigate the regulation mechanism of steric hindrance on the content of lithium fluoride in SEI. The results show that bis(trifluoromethanesulfonyl)imide (TFSI⁻) will compete for the charge without steric effect, while excessive steric hindrance hinders the interaction between TFSI⁻ and polar groups, reducing charge acquisition. Only when one hydrogen atom on the amino group is replaced by a methyl group, steric hindrance from the methyl group prevents TFSI⁻ from capturing charge in that direction, thereby facilitating the transfer of charge from the polar group to a separate TFSI⁻ and promoting maximum LiF formation. This work provides a novel perspective on constructing LiF-rich SEI.     

Effect of aminoacids on the surface free energy of nitrofurantoin

Changes in nitrofurantoin surface free energy components, Lifshitz-van der Waals, _s ^LW , electron donor, _s ^– , and electron acceptor, _s ⁺ , due to adsorption of the aminoacids: lysine, alanine and glutamic acid, were determined by means of the thin-layer wicking technique. It was found that the aminoacids slightly increase the _s ^– component already at 10^–4 M concentration. They reduce the _s ⁺ component practically to zero, and a very sharp increase of _s ^– was observed when the nitrofurantoin surface was precovered from the solutions at concentrations larger tan 10^–4 M. It is concluded that the adsorption of the aminoacids takes place via hydrogen bonding and electrostatic interactions between nitrofurantoin surface and aminoacid molecules. The increase in the _s ^– parameter is probably caused by the presence of carboxyl groups in the aminoacid molecules.     

Conformational analysis and x-ray crystal structure of [(η5-C5H5)Fe(CO)(PPh3)CH2CH3]

The complex [(η⁵-C₅H₅)Fe(CO)(PPh₃)CH₂CH₃] is shown by ¹H NMR spectroscopy and an X-ray crystal structure analysis to adopt a single conformation with the methyl group residing between the cyclopentadienyl and carbon monoxide ligands.     

Carbon-13 NMR. The analysis of the relaxation times T1 of benzofuran and of a series of its methyl derivatives. Correlations between molecular motions and structural properties

Carbon-13 relaxation times (T₁) and nuclear Overhauser enhancements (η) have been measured for benzofuran and a series of its methyl derivatives. The contributions of dipolar (T₁ ^DD) and spin rotation (T₁^SR) mechanisms have both been determined. The temperature dependence of T₁ has been studied. The relationships between molecular motions and structural properties have been emphasized. The overall motional anisotropy of the benzofuran molecule is increased by substitution in positions 2 and 5. The internal rotation of a methyl group may change depending on its position in the molecule and on the influence of other methyl groups in its close neighbourhood.     

Site of gas-phase methylation of l-phenyl-2-aminopropane

The regioselectivity of methyl cation transfer from (CH₃)₂F⁺, (CH₃)₂Cl⁺ and (CH₃)₃O⁺ to 1-phenyl-2-aminopropane was studied by Fourier transform ion cyclotron resonance in combination with collision-induced dissociation and neutralization-reionization mass spectrometry of the stable [M + CH₃]⁺ ions formed in a chemical ionization source. The (CH₃)₂F⁺ ion transfers a methyl cation to the NH₂ group and the phenyl ring with almost equal probability. Predominant CH₃⁺ transfer to the NH₂ group is observed for the (CH₃)₂Cl⁺ ion whereas the (CH₃)₃O⁺ ion reacts almost exclusively at the amino group. The preference for methylation at NH₂ is discussed in terms of a lower methyl cation affinity of the phenyl ring than of the amino group and the existence of an energy barrier for methylation of the phenyl moiety.     

Strong effect of methyl group on the strength of ionic hydrogen bond between C2H2 and H3O+

The effect of methyl group on the strength of the ionic hydrogen bond between C₂H₂ and H₃O⁺ has been studied with quantum chemical calculations at the UMP2/6‐311++G(d,p) level. The presence of a methyl group in the proton acceptor results in an energetic increase of 6.02 kcal/mol, increased by about 39%, whereas that in the proton donor leads to an energetic decrease of 2.18 kcal/mol, decreased by 14%. The charge analyses indicate that the methyl group in the proton acceptor is electron‐donating and that in the proton donor is electron‐withdrawing. The former plays a positive contribution to the formation of ionic hydrogen bond and the latter plays a negative contribution to the formation of ionic hydrogen bond. The weakening effect of solvent on the role of methyl group in the ionic hydrogen bond has also been studied at the UB3LYP/6‐311++G(d,p) level. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2009     

Headspace gas chromatographic separation of toxic organic impurities from air

Summary To determine toxic organic compounds (methanol, ethanol, n-propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone) in air a method was developed for their headspace gas chromatographic analysis with preconcentration in n-butanol (alcohols) and in n-pentanol (ketones). The distribution coefficients of analytes in the air-absorbent system have been measured: 1051 (MeOH), 5630 (EtOH), 6773 (n-PrOH), 307 (Me₂CO), 580 (MeCOEt), 1035 (MeCOBu-i). The minimum detectable level (mg m⁻³) was determined as low as 0.9 (MeOH), 4.0 (EtOH), 0.9 (n-PrOH), 0.2 (Me₂CO), 0.1 (MeCOEt), 0.4 (MeCOBu-i). The method was effectively used for gas effluent air control in the workplace and in the atmosphere. Presented at the 21^st ISC held in Stuttgart, Germany, 15^th–20^th September, 1996     

S-alkyl and S-alkylaryl cysteine complexes with platinum(II) and their interactions with nucleosides

The reactions of K₂PtCl₄ with the aminoacids, S-methyl-L-cysteine, S-ethyl-L-cysteine, S-benzyl-L-cysteine, S-para-nitro-benzyl-L-cysteine, S-diphenyl-methyl-L-cysteine, S-tribenzyl-L-cysteine and S-4′,4′-dimethoxy-diphenylmethyl-L-cysteine were studied in neutral or acidic aqueous solutions. Complexes of the formulae PtLCl₂, [PtL₂]Cl₂ and Pt(L-H⁺)₂, where L = aminoacid, were isolated in the solid state and their structures investigated with elemental analysis, conductivity measurements, IR, ¹H NMR and ¹³CNMR spectra. The results show that the coordination sites of Pt(II) with the amino-acids are the N and S atoms, producing two diastereoisomers around the chiral sulphur atom, which were identified in the ¹H NMR and ¹³CNMR spectra. The complexes PtLCl₂ further react with the nucleosides guanosine and inosine. The complexes [PtL(nucl)₂]Cl₂ were isolated from these reactions and studied with the same methods. They showed a PtN₇ bonding with the nucleosides and retained the N, S bondings with the aminoacids. As a result of the higher trans influence of S than N, the nucleoside molecule coordinated to the metal through N₇ and trans to S has a weaker bond strength than the other, as it is revealed from the ¹H NMR and ¹³C NMR spectra of these complexes.