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A total conformational analysis of diastereomeric esters and calculation of their conformational shielding models
Abstract
A total conformational analysis of diastereomeric esters was performed and the conformational shielding models (CSM) of the esters necessary for the NMR spectroscopic stereochemical assignment of carboxylic acids or alcohols were calculated. The esters of (R)-2-butanol and both enantiomers of O-methylphenylacetic acid (MPA), 2-phenoxypropanoic, 2-(2-formylphenoxy)propanoic, 2-methoxy-3-phenyl-propanoic and 2-methoxy-2-methyl-3-phenylpropanoic acids were investigated. The calculation method used was DFT B3LYP/6-31+G∗ (at the highest level in the optimization cascade). The Boltzmann weighting of individual conformers, covering an energy range of 2kcal/mol, was used to evaluate the ring current effects of the aromatic group on the basis of a classical Pople point-dipole model describing anisotropy. The results afforded a CSM for the pairs of diastereomeric esters. The calculated CSM coincides with an empirical CSM of MPA and 2-phenoxycarboxylic acid esters and is in accordance with the experimental stereochemical results obtained for 2-methoxy-3-phenylpropanoic acid esters. The low values observed for the differential shieldings (ΔδRS) of 2-methoxy-2-methyl-3-phenylpropanoic acid esters were confirmed by their complex conformational equilibrium.
... Having previously followed such guidelines in the total conformational analysis of several esters with up to 11 dihedrals in their structure, the initial optimization of thousands of conformers all together have afforded reliable sets of conformers. The following higher level optimization of the selected conformers has led to the results that, in turn, have allowed calculation of the molecular shielding models in exceptional accordance with differential shielding effects in the NMR spectra [8]. ...
... DFT and the hybrid B3LYP functional have allowed accurate computation of the geometries concerning the type of molecules under study [8]. This, in turn, has allowed calculating NMR and IR spectral characteristics in very good agreement with the experimental data [8,11,12]. ...
... DFT and the hybrid B3LYP functional have allowed accurate computation of the geometries concerning the type of molecules under study [8]. This, in turn, has allowed calculating NMR and IR spectral characteristics in very good agreement with the experimental data [8,11,12]. The DF method using the B3LYP hybrid functional has been proven to give a good estimate of the electron correlation for some molecules, in particular, in conformational studies, when it is used with the 6-31G * or 6-311++G * * basis set [13,14]. ...
Critical assessment of performance of alternative molecular modeling methods depending on a specific object and goal of the investigation is a question of continuous interest. This prompted us to demonstrate the origin of the guidelines we have used for a rational choice and use of a proper low level calculation method (LLM) for an initial geometry optimization of generated conformers, with the aim of selecting a set for further optimization. What was performed herein was a comparison of LLMs: MM3, MM+, UFF, Dreiding, AM1, PM3, and PM6 on the optimization of conformers’ geometry of
α
-methoxyphenylacetic acid (MPA) 2-butyl esters as a set of typical diastereomeric esters of a chiral derivatizing agent. This set of esters calculated represents only compounds of this certain type in the current work. The LLM conformer energies were correlated with benchmark energies found by using higher level reference method B3LYP/6-311++G** on the geometries gained previously by optimization with LLMs. In an alternative treatment, the energy range to be covered and corresponding number of LLM optimized conformers obligatory for submitting to further optimization using a high level optimization cascade were considered on the basis of determination of the cut-off conformer (COFC).
... Having previously followed such guidelines in the total conformational analysis of several esters with up to 11 dihedrals in their structure, the initial optimization of thousands of conformers all together have afforded reliable sets of conformers. The following higher level optimization of the selected conformers has led to the results that, in turn, have allowed calculation of the molecular shielding models in exceptional accordance with differential shielding effects in the NMR spectra [8]. ...
... DFT and the hybrid B3LYP functional have allowed accurate computation of the geometries concerning the type of molecules under study [8]. This, in turn, has allowed calculating NMR and IR spectral characteristics in very good agreement with the experimental data [8,11,12]. ...
... DFT and the hybrid B3LYP functional have allowed accurate computation of the geometries concerning the type of molecules under study [8]. This, in turn, has allowed calculating NMR and IR spectral characteristics in very good agreement with the experimental data [8,11,12]. The DF method using the B3LYP hybrid functional has been proven to give a good estimate of the electron correlation for some molecules, in particular, in conformational studies, when it is used with the 6-31G * or 6-311++G * * basis set [13,14]. ...
... (The glycoconjugates of bile acids itself have long been a subject of interest to researchers from different fields [18].)˛-Methoxyphenylacetic acid (MPA) was involved because of its role of the chiral derivatizing agent allowing to determine the absolute stereochemistry of the ester diastereomers by measuring of differential shielding effects in the NMR spectra of diastereomers [19,20]. As an extension of the synthetic approach two N-Boc-protected -amino acids, viz. ...
... Step 2. The diastereomeric mixture of each of the hemiacetal esters (9)(10)(11)(12)(13)(14) was further enzymatically acetylated in stereoselective manner affording one diastereomer of trans-hemiacetal acetate (15)(16)(17)(18)(19)(20), which was easily separated by column chromatography over silica. ...
... For the "one-pot synthesis" the overall yield of the pyranose deoxy sugar ester of N-Boc-Tyr (14) was higher than that of corresponding furanose deoxy sugar ester (12) but notably lower than that of corresponding N-Boc-Phe esters (11) and (13). In the lipase-catalyzed kinetic resolution of diastereomers the yield of N-Boc-Tyr esters (18) and (20) was lower than that observed for N-Boc-Phe esters (17) and (19). At the same time, there was no great difference between the yield of acetylated furanose and pyranose deoxy sugar esters in case of both of the N-Boc protected amino acid esters. ...
An extension of the scope of the chemoenzymatic strategy for the synthesis of stereochemically pure pyranose deoxy sugar esters of different carboxylic acids has been achieved. The objective of the work was to extend the strategy to the synthesis of furanose deoxy sugar derivatives and additionally, to N-Boc-protected amino acid esters. With all used carboxylic acids (deoxycholic acid, α-methoxyphenylacetic acid, N-Boc-l-phenylalanine and N-Boc-l-tyrosine) the lipase-catalyzed stereoselective acetylation of furanose or pyranose hemiacetal moiety as a key step afforded one desired stereochemically pure acetylated hemiacetal deoxy sugar ester in high de.Graphical abstractResearch highlights▶ Stereochemically pure furanose and pyranose deoxy sugar esters were synthesized. ▶ Different carboxylic acids were used to synthesize deoxy sugar esters. ▶ Diastereomeric deoxy sugar esters were resolved by lipase-catalyzed acetylation.
... The most stable conformers found were further explored with a VEGA [10,11] implemented conformational search; the force field SP4 [12] implemented therein was used. The output of the latter was subjected to the ab initio calculation procedure described in [13,14]. The maximum method and basic set used were M06/6-31G [15] for reaction path calculations and M06/6-31+G⁄ for conformational analysis. ...
... The ordering of twenty conformers in Lipnick's original scheme [41] is ultimately correct, yet placing them in a wheel model [42][43][44][45][46][47][48][49] is so confusing that no correlation can be inferred to help one categorize them into groups. ...
... like methoxyphenylacetic acid [33,34] or mandelic acid [35] can be used to derivatize all hydroxyl groups of a diol or polyol compound. Named derivatization would allow NMR spectroscopic determination of stereoisomeric homogeneity and absolute configuration of the stereogenic centres by the differential shielding effects in NMR spectra [35,36]. A regioselective tosylation of the primary OH group of 1,2-diols for HPLC analysis over chiral stationary phase has been proposed [37]. ...
... The determination of absolute configuration of chiral compounds is an essential process not only in the field of asymmetric chemistry but also in all fields of science that involve such compounds. [1][2][3][4][5][6][7] 1 H NMR analysis of diastereomers formed by reactions of chiral samples with chiral derivatizing agents (CDAs) is one of the most commonly used methods for noncrystalizable compounds and complex natural products. [8][9][10][11][12][13][14] In this method, arylacetic acid-type CDAs have been widely used for chiral secondary alcohols and primary amines. ...
In connection with study of chiral derivatizing agents (CDAs) for NMR determination of absolute configuration of organic compounds, factors controlling the conformational preference between syn- and anti-forms in α-substituted α-fluorophenylacetic acid methyl ester (FC(X)(Ph)COOMe) model systems were theoretically investigated. Substituents X at the stereogenic carbon atom were X = H, CCH and CH3, the electronic and steric properties of which were significantly different from each other. The model system with X = CCH and that with X = CH3 were found to be possible candidates for fluorine-containing CDAs. The syn conformation is stable compared with the anti one by 0.7 kcal mol−1 for the ester with X = CCH. On the other hand, the anti conformation is stable compared with the syn one by 0.5 kcal mol−1 for the ester with X = CH3. Both natural bond orbital (NBO) analysis and deletion of selected orbitals based on the donor–acceptor NBO scheme were adopted for semi-quantitative estimation of factors responsible for the conformational preference as well as a qualitative inspection of occupied canonical molecular orbitals (MOs). It was shown that [σ–(σ* + π*)(CO)] and [σ–σ*(Ph) and π(Ph)–σ*] hyperconjugations are the main factors controlling the conformational preferences between the syn and anti conformations. Other types of effects such as electrostatic effects were also investigated. The role of the fluorine atom was also clarified. Copyright © 2009 John Wiley & Sons, Ltd.
Scalable protocols of straightforward synthesis of enantiomeric γ‐(acyloxy)carboxylic acids and γ‐lactones are presented. The key step is lipase‐catalyzed stereoselective acylation of γ‐hydroxycarboxylic acid sodium salt in organic solvent followed by acidification of the product, extraction and acidic relactonization of the unreacted enantiomer. The mixture of γ‐(acyloxy)carboxylic acid and γ‐lactone is separated either by extraction with solution of sodium bicarbonate or by distillation. A switch of enantioinduction of Candida antarctica lipase B along homologous nucleophiles from R configuration of γ‐hydroxyhexanoic acid salt to S configuration of the C7 and longer‐chain homologues has been disclosed. Both enantiomers of γ‐(acyloxy)pentanoic acids; γ‐(acetyloxy)octanoic and ‐nonanoic acids with S configuration; [(1S,5R)‐5‐(chloroacetyloxy)cyclopent‐2‐en‐1‐yl]acetic acid and enantiomeric γ‐lactones derived from them were prepared with e. r. >98.5/1.5. The rates of acylation of C5 to C9 homologous salts differ by three orders of magnitude but remain applicable for preparative synthesis by variation of the enzyme loading and reaction time.
A stereochemically safe high-yielding procedure for linking unprotected as well as protected hydroxycarboxylic acids to chiral secondary alcohols via glycolic acid linker is proposed. L-menthol has been linked with both enantiomers of mandelic, malic, and methoxyphenylacetic acid using bromo- or iodoacetyl group as a precursor of the glycolic acid linker. High-field nuclear magnetic resonance (NMR) and chiral high-performance liquid chromatography (HPLC) determination of high diastereomeric ratio (dr) (>99%) of the products bearing remote stereocenters was explored. Chiral HPLC allowed quantitation of the diastereomers up to dr 99.9/0.1. High-field NMR quantitation of the diastereomeric and parent alcoholic impurities in esters was demonstrated at the molar 0.3% and 0.03% levels, respectively. These analyses were done via comparison of integral intensities from major component (13) C satellites in (1) H or even in (13) C spectra to the (1) H or (13) C signals of impurities. Despite lower sensitivity, the last option generally has much better selectivity. In this way the dynamic resolution is brought down by two orders. Chirality 00:000-000, 2013. © 2013 Wiley Periodicals, Inc.
Direct confirmation of the preferred conformation of diastereomeric esters derived from a chiral secondary alcohol and a chiral derivatizing agent in solution, which is crucial for reliable NMR-based assignment of absolute stereochemistry of the alcohol, has been attained for the first time by examination of IR spectra of the CFTA esters.
This study has focused on the synthesis of truncated analogues of the hydroxyethylene dipeptide isosteres, such as Ritonavir®, currently in clinical use as HIV-1 protease inhibitors. The reactions of pyridine-2- and quinoline-2-carbaldehydes with methyl acrylate, in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) or 3- hydroxyquinuclidine (3-HQ) as nucleophilic catalysts, have afforded a series of Baylis-Hillman adducts, acetylation and cyclisation of which have provided access to a series of indolizine-2-carboxylate esters. The carboxylic acids, obtained by base-catalyzed hydrolysis of these esters, have been coupled with various protected (and unprotected) amino compounds using the peptide coupling agent, 1,1’-carbonyldiimidazole (CDI), to afford a series of indolizine-2-carboxamides as indolizine-based truncated Ritonavir® analogues in quantitative yield. Aza-Michael reactions of pyridine-3-carbaldehydederived Baylis-Hillman adducts with various amino compounds have provided access to a range of pyridine-based products as mixtures of diastereomeric aza-Michael products.
The assignment of the relative stereochemistry of the aza-Michael products has been established using 1-D and 2-NOESY experiments and computer modelling techniques.
Computer modelling studies have also been conducted on selected aza-Michael products using ACCELRYS Cerius2 software, followed by interactive docking into the HIV-1
protease receptor site, using AUTODOCK 4.0. The docking studies have revealed hydrogen-bonding interactions between the enzyme and the synthetic ligands. Saturation Transfer Difference (STD) NMR experiments have also indicated binding of some of the aza-Michael products to the HIV-1 protease subtype C enzyme, thus indicating their binding and possible inhibitory potential.
Molecular mechanics, semiempirical (AM1), and aromatic shielding effect calculations and DNMR experiments show that MTPA esters are constituted by three main conformers in close populations due to restricted rotation around the Cα−CO and Cα−Ph bonds. The small predominance of one conformer and the simultaneous operation of aromatic shielding and deshielding effects on the alcohol part, due to the orientation of the Ph ring, explains the small ΔδRS values observed. A graphical description of the aromatic magnetic field distribution in the conformers of MTPA and MPA esters and its use to correlate the average chemical shifts with the absolute stereochemistry is presented. Comparison of MTPA with MPA (two conformers) as reagents for determination by NMR of absolute stereochemistry indicates that MTPA esters are intrinsically limited by the greater complexity of their conformational composition, yield very small ΔδRS values, and are consequently less reliable for configurations assignment of chiral alcohols than MPA or other arylmethoxyacetic acid reagents such as (R)- and (S)-α-methoxy-α-(9-anthryl)acetic acids.
Both theoretical and experimental evidences prove that the absolute configuration of an α-chiral carboxylic acid can be safely assigned by comparison of the 1H NMR spectra of its esters with (R)- and (S)-ethyl 2-(9-anthryl)-2-hydroxyacetate (5, AHA). A simplified conformational model, based on the dominance of the ap over the sp conformer and the selective effect of the anthryl group, allows the (R/S) assignment directly from the NMR chemical shifts.
Diastereometric esters of O-arylated (R)-lactic acids have been studied by 1 H NMR spectroscopy with respect to their potential application as reagents for chiral analysis. The substitution pattern of the acid moiety of the ester was found to have a decisive influence on the magnitude of the resolution of the signals from the diastereoisomers
The use of 1H- 13C and 1H- 1H 2D COSY correlation experiments substantially enhances the potential of the NMR procedure for determining the absolute configuration of chiral secondary alcohols via their diastereomeric MPA and/or MTPA esters. Phenyl ring current effects are observed over remarkably long distances and comparable effects are seen for both 13C and 1H chemical shifts. The use of 13C chemical shifts to aid configurational assignment is particularly valuable.
The prediction of the absolute configuration of a-chiral carboxylic acids from the H-1 NMR spectra of their esters with (R)- and (S)-ethyl 2-hydroxy-2-(9-anthryl) acetate [(R)- and (S)-g-AHA, 5] is discussed. Low-temperature NMR experiments, MM, semiempirical, and aromatic shielding effect calculations allowed the identification of the main conformers and showed that, in all esters studied, conformer crp is the most stable. A simple model for the assignment of the absolute configuration from NMR data is presented, and its reliability is corroborated with acids 6-31 of known absolute configuration. In addition to 5, other auxiliary reagents with open (32-38) and cyclic (39-42) structures have also been studied, trans-(+)- and (-)-2-phenyl-1-cyclohexanol (41) was found to be particularly efficient and produced Delta delta(RS) values similar to those of 5.
For a 1,3-dimethylated model compound (1), (3)J(CC) coupling constants were calculated by a density functional (SOS-DFPT/IGLO) method using molecular mechanics as well as ab initio optimized geometries. Boltzmann averaging of the calculated coupling constants for individual conformers resulted in good agreement with the experimental data. The comparison to calculated values allows a more quantitative interpretation of the experimental coupling constants for the conformational analysis of open chain compounds.
The Fries rearrangement of resorcinol monobenzoate and orcinol monobenzoate was studied by using various molecular modelling approaches. The conformational analysis of the reactants and products was accomplished. The methods used were the molecular mechanical MM+ approach, the Hartree–Fock method with an STO-3G basis set and the density functional method B3LYP with basis sets 3-21G, 6-31G and 6-31+G*. The results obtained by using the B3LYP/6-31+G* method, unlike those obtained by using the lower-level methods, allowed calculation of the values of the thermodynamic distribution of isomeric components in equilibrium mixtures (monobenzoate/benzophenone) that appeared to be in good accordance with the experimental results.
The conformational analysis of 1-acetyl-2-methylhydrazine was performed using DNMR spectroscopy and quantum chemical calculations (B3LYP/6-31+G*, AM1 and PM3). Activation barrier for interconversion of Z and E conformers was measured to be 16.1kcal/mol by DNMR. DFT calculations indicate that there are four minima on the 1-acetyl-2-methylhydrazine potential energy surface and the most stabile is Z conformer with the hydrogen bond between carbonyl group oxygen and hydrogen at non-amide nitrogen. The amide nitrogen was found to be close to planar in minima but strongly pyramidalized in TS. The activation barriers calculated at B3LYP/6-31+G* level of theory were in good agreement with experimentally measured one. AM1 method with molecular mechanics correction gave potential energy surface in reasonable agreement with DFT results, but the activation energies were strongly underestimated. PM3 method was found to give unsatisfactory results for conformational analysis of 1-acetyl-2-methylhydrazine.
It is shown that the cheap and easily prepared mandelic acid esters (or their OAc analogues) are best suited than the expensive, although usually employed, OMe mandelic acid esters to assess both the enantiomeric excesses and absolute configurations of secondary alcohols.
The propanamide and methoxyacetamide derivatives of (S)-4-benzyl-2,2,5,5-tetramethyloxazolidine, a new chirality controlling auxiliary based on the restricted rotation around amide bond, generate chiral lithium Z-enolates by lithiation. They undergo highly lk-1,4 and ul-1,4-inductive alkylations with a variety of alkylating reagents, respectively. The diastereotopic face participated in the reactions is that remote from the 4-shielding substituent of oxazolidine in the syn-conformations. Coplanarity between the enolate double bond and the oxazolidine plane in the transition state can be a major factor for the observed excellent selectivities.
Different approaches for determining the problem of absolute configuration based on nuclear magnetic resonance (NMR) spectroscopy were studied. The first approach involves those procedures where derivatization of the substrate whose absolute configuration was studied was not necessary. A pure enantiomer was analyzed by NMR in a chiral environment, provided by a chiral solvent or by the addition of a chiral solvating agent (CSA) to a nonchiral standard NMR solvent. Several instrumental methods for the determination of absolute configuration which include X-ray crystallography, chiro-optical methods, optical rotatory dispersion (ORD) or specific optical rotation were also described.
Diastereomeric esters and amides have been prepared from o-methoxy-o-trifluoromethylphenylacetyl chloride and various secondary alcohols and amines. The nmr spectra of the R,R and S,S vs. the R,S and S,R diastereomers show significantly different chemical shifts: 0.03-0.13 ppm in the proton region and 0.11-0.71 ppm in the fluorine region. By measuring the intensities of the nmr signals of the diastereomerically situated groups of esters and amides prepared from this enantiomerically pure reagent, satisfactory determinations of the enantiomeric composition of a number of alcohols and amines have been made. The use of the α-methoxy-α-trifluoromethylphenylacetyl derivative offers the distinct advantage, over other reagents having only proton resonances, that determinations of enantiomeric composition based upon fluorine resonances are usually more reliable, since the fluorine signals are simple and in an uncongested region. This is a absolute method, independent of optical rotation; accurate determinations can be made on 20-mg samples. Thus this reagent extends the application of this nmr technique. Furthermore, the reagent shows complete stability to racemization under prolonged reaction conditions. A practical synthesis and convenient resolution of the reagent have been developed.
Conformational models covering an energy range of 3 kcal/mol were calculated for (13S)-tetradecano-13-lactone (3), (12S)-12-methyltridecano-13-lactone (4), and (12S,13R)-12-methyltetradecano-13-lactone (8), starting from a semiempirical Monte-Carlo search with AM1 parametrization, and subsequent optimization of the 100 best conformers at the 6-31G*/B3LYP and then the TZVP/B3LYP level of density-functional theory. CD Spectra for these models were calculated by the time-dependent DFT method with the same functional and basis sets as for the ground-state calculations and Boltzmann weighting of the individual conformers. The good correlation of the calculated and experimental spectra substantiates the interpretation of these conformational models for the structure–odor correlation of musks. Furthermore, the application of the quadrant rule in the estimation of the Cotton effect for macrolide conformers is critically discussed.
(S)-2-Methoxy-2-(1-naphthyl)propionic acid (MαNP acid 1) is used for enantioseparation of many secondary alcohols and for determining the stereogenic centers. In the liquid state, based on the 1H NMR anisotropy effect and reported results, it was shown that the MαNP ester preferred a coplanar relation between the methyl and naphthyl groups and a synperiplanar relation between the Cα–OMe and CO groups. In the case of 1,2,3,4-tetrahydro-4-phenanthrenol, which is a secondary alcohol, the stereogenic center was determined by X-ray analysis. It was shown that MαNP ester adopted similar arrangements in the solid state. However, it was presumed that the strong repulsion between oxygen atoms may be disadvantageous in the solid state. Therefore, we carried out conformational analysis using the simplest MαNP methyl ester to clarify this unique relationship. From detailed results based on the energy surface determined using the RHF/STO-3G basis set, the synperiplanar positional relation was the most stable, and the calculated results agreed with many reported experimental results. At the same time, all conformational isomers of the MαNP methyl ester were used to clarify the internal conversion pathways.Graphical abstractThe most stable isomers and other isomers of MαNP methyl ester are obtained from the energy surfaces.
Parameters that allow prediction of the sense of NMR nonequivalence in N-(alkoxymethyl)-2-pyrrolidinone derivatives (2−8) are identified. These derivatives are prepared by the reaction of chiral racemic and chiral nonracemic alcohols with 1-(chloromethyl)-5(R)-methyl-2-pyrrolidinone, 1. The factors governing NMR nonequivalence (Δδ) in 2−8 were first established. The NMR parameters were then determined and compared with those derived from calculated conformations for 2−8. This information was used to establish the absolute stereochemistry of the alcohol adducts.
An empirically derived correlation of configuration of diastereomeric α-methoxy-α-trifluoromethylphenylacetic (MTPA) esters and amides with the 19F chemical shifts has been developed. The data have been rationalized in terms of a configuration-correlation model 5. The inherently large 19F chemical shifts (CDCU3 solvent, external trifluoroacetic acid) and their location in an otherwise uncongested region of the nmr spectrum makes this correlation of considerable value in connection with stereochemical studies involving chiral secondary alcohols and primary amines. Of the 25 examples studied, 19 MTPA esters and 6 MTPA amides, 18 clearly group themselves in a general pattern which is discussed in terms of the configuration-correlation model. Three MTPA esters showed no significant chemical shift nonequivalence for the 19F α-CF3 signals between R,R-S,S vs. R,S-S,R diastereomers. Of the four cases which might be considered exceptions to this nmr configurational correlation model, namely isobutyl-tert-butylcarbinol, n-butyl-tert-butylcarbinol, trifluoromethyl-tert-butylcarbinol, and borneol, the first three can be rationalized while only borneol stands as a clear exception to the model. All of the 6 MTPA diastereomeric amides studied conform to the same model.
Nuclear magnetic resonance (nmr) spectra have been determined for a series of diastereomeric esters of α-substituted phenylacetic acids with various dissymmetric secondary carbinols. In nearly all cases, the nmr spectra of the R,R and S,S diastereomers were significantly different from those of the S,R and R,S diastereomers. The effects upon the spectra of α-methoxy, α-methyl, α-t-butyl, α-trifluoromethyl, α-hydroxy, and α-chloro groups were explored. Chemical shift differences were observed for all epimerically related groups except phenyl in the diastereomeric esters such as R,S and R,R methyltrifluoromethylcarbinyl O-methylmandelate. These chemical shift differences between diastereomers were used to determine enantiomeric purities of chiral secondary carbinols. Enantiomeric purities within 1% of the polarimetrically determined values were obtained readily with an HR-100 instrument. However, racemization and/or kinetic resolution was encountered during the synthesis of some esters, particularly when the alcohol was sterically hindered. Therefore, if this method is to be used with confidence in a specific case, it will always be necessary to establish the quantitative validity of the chemical procedure by control experiments. The presence of a trifluoromethyl group in the alcohol or acid moiety of the ester was quite advantageous since the fluorine nuclear magnetic signals are then of high intensity, occur in a region uncomplicated by overlapping signals, and show generally large chemical shift differences (0.1-0.29 ppm) between diastereomers. Furthermore, the enhanced volatility of these compounds facilitates their purification. Preliminary observations of solvent and temperature effects have been made also.
An empirically derived correlation of configuration and nmr chemical shifts for diastereomeric mandelate, O-methylmandelate and α-methoxy-α-trifluoromethylphenylacetate (MTPA) esters has been developed and rationalized in terms of useful models 4 and 5. These models have been successfully applied to well over 40 examples as given in Table I. The correlations involve the relative chemical shifts of the proton resonances from the groups attached to the carbinyl carbon of these diastereomeric esters. This nmr-configurational correlation should prove to be widely applicable in assigning the configuration of additional secondary carbinols, as well as other chiral α-substituted carboxylic acid derivatives.
An internal coordinate, random-search method for finding the low-energy conformations of organic molecules is described. The search is biased toward the low-energy regions of conformational space by choosing starting geometries for each step in the conformational search from among previously stored low-energy conformers. Tendencies of the search method to concentrate in certain regions of conformational space at the expense of others are reduced by uniform usage of stored structures as starting geometries and by using varying numbers or torsional rotations in each step. Tests of the procedure's ability to find all low-energy conformations of several acrylic, medium- and large-ring molecules are described. Direct comparisons of the method with Cartesian coordinate random methods and systematic internal coordinate grid searches are carried out with symmetrical and unsymmetrical molecules. The method makes it possible to carry out global conformational searches on symmetrical and unsymmetrical molecules having up to a dozen variable torsion angles.
A computational method is described that permits reliable searching for different molecular conformations. A Monte Carlo type routine is employed to randomly search the potential energy surface for a given molecule, and Allinger's MM2 force field is employed for energy calculations and minimizations. The method has two modes of operation: conformational search (by torsional or energetic criterion) and global minimum location. The Monte Carlo type routine, called random incremental pulse search (RIPS), logically couples the benefits of random searching with those of analytical minimization. The method has been tested by searching conformational space for a series of cycloalkanes. All conformational families and minimum-energy structures are reliably located in each case.
Modifications to the distance geometry algorithm as embodied in the program DGEOM have been made to improve sampling capabilities. Specifically, torsion angle sampling replaces distance sampling for 1,4 atomic relationships and correlated distance sampling is disabled. The effects of these modifications are illustrated by comparing the different sets of conformations produced for butane. In addition, these changes are shown to increase the conformational sampling of two medium-sized rings, cycloheptadecane and caprylolactam. The current results for these molecules are compared to those of other conformational searching methods.
A simple synthesis of (2R)-2-phenyl-2-[(2S)-tetrahydro-2-pyranyloxy]ethanoic acid, a versatile chiral derivatising agent (CDA), is proposed. The derivatisation of secondary alcohols aimed at the absolute configurational assignment, determination of enantiomeric purity as well as semipreparative resolution is described.
The structure of the N-2-fluorobenzoyl-N′-2-methoxyphenyl thiourea (C15H13FN2O2S, Mr=304.34) derived from X-ray diffraction on single crystal has been presented. The crystal is triclinic, space group: P−1 (#2), a=7.058(4), b=9.067(5), c=11.907(8) Å, α=89.00(2), β=86.59(2), γ=69.02(1)°, V=710.2(8) Å3, Z=2. FTIR, NMR and X-ray diffraction determination give the existence of hydrogen bond interactions. Density functional theory (DFT) using Becke's three-parameter hybrid method with the Lee, Yang, and Parr correlation functional (B3LYP) methods have been used to determine the structure and energies of stable conformers. The optimized geometry corresponding to crystal structure is the most stable conformation. This has partly been attributed to multi six-tempered and five-tempered ring formation resulting from the N(2)–H(2)⋯(1), N–(1) H(1)⋯F(1), N(2)–H(2)⋯O(2) and C(6)–H(6)⋯O(2) intra-molecular hydrogen bonds, respectively. With the basis sets of the 6-311G** quality, the DFT calculated bond parameters, harmonic vibrations and nuclear magnetic resonance values are in a very good agreement with experimental results.
Humicola lanuginosa lipase was used for enantioselective hydrolyses of a series of homologous 2-phenoxyalkanoic acid ethyl esters. The enantioselectivity (E-value) of the enzyme changed from an (R)-enantiomer preference for the smallest substrate, 2-phenoxypropanoic acid ester, to an (S)-enantiomer preference for the homologous esters with longer acyl moieties. The E-values span the range from E=13 (R) to E=56 (S). A molecular modeling study identified two different substrate-binding modes for each enantiomer. We found that the enantiomers favored different modes. This discovery provided a model that offered a rational explanation for the observed switch in enantioselectivity.
In any theoretical approach to large molecules, one faces the problem of how to find the most stable conformers. It is extremely difficult to predict them, because of the large number of high energy conformers, which in general cannot be excluded from a priori consideration. In the present article, this problem is discussed and the theoretical methods designed to find the global minimum of the conformational energy are reviewed.
A new algorithm, complementarity, is developed for conformational search of macrocyclic molecules. The algorithm scans a large number of candidate conformations and energy-minimizes only the promising ones. These candidates can be generated by two operators that construct new conformations from known minima. The candidates have similar bonded-interaction energy as the known minima and possibly lower nonbonded interaction energy. This algorithm is 9 to 11 times faster than the existing methods when tested on two large rings, cycloheptadecane and rifamycin SV. © 1997 by John Wiley & Sons, Inc.
The geometry optimization using natural internal coordinates was applied for transition metal complexes. The original definitions were extended here for the skeletal degrees of freedom which are related to the translational and rotational displacements of the ηn-bonded ligands. We suggest definitions for skeletal coordinates of ηn-bonded small unsaturated rings and chains. The performance of geometry optimizations using the suggested coordinates were tested on various conformers of 14 complexes. Consideration was given to alternative representations of the skeletal internal coordinates, and the performance of optimization is compared. Using the skeletal internal coordinates presented here, most transition metal complexes were optimized between 10 and 20 geometry optimization cycles in spite of the usually poor starting geometry and crude approximation for the Hessian. We also optimized the geometry of some complexes in Cartesian coordinates using the Hessian from a parametrized redundant force field. We found that it took between two and three times as many iterations to reach convergence in Cartesian coordinates than using natural internal coordinates. © 1997 by John Wiley & Sons, Inc.
Despite the remarkable thermochemical accuracy of Kohn–Sham density-functional theories with gradient corrections for exchange-correlation [see, for example, A. D. Becke, J. Chem. Phys. 96, 2155 (1992)], we believe that further improvements are unlikely unless exact-exchange information is considered. Arguments to support this view are presented, and a semiempirical exchange-correlation functional containing local-spin-density, gradient, and exact-exchange terms is tested on 56 atomization energies, 42 ionization potentials, 8 proton affinities, and 10 total atomic energies of first- and second-row systems. This functional performs significantly better than previous functionals with gradient corrections only, and fits experimental atomization energies with an impressively small average absolute deviation of 2.4 kcal/mol.
A comparison between three different methods commonly used to estimate ring current effects on chemical shifts is presented. Haigh-Mallion, Johnson-Bovey, and classical point-dipole approximations were used to estimate the ring current contribution to chemical shifts for protons in several proteins for which both detailed X-ray crystal structures and chemical shift assignments were available. For the classical point-dipole model, new proportionality constants were calculated by fitting to ring current estimations from both the quantum-mechanical Haigh-Mallion and semiclassical Johnson-Bovey methods and compared with the previously used point-dipole constant of Perkins and Dwek. Statistical analysis of the predictions obtained by all methods indicates that the point-dipole approximation parametrized against quantum-mechanical data is superior to the previously used classical model, comparable to Johnson-Bovey calculations, and slightly poorer than predictions from the Haigh-Mallion theory. The implementation of a pseudoenergy penalty term for use in structure refinement from chemical shift data based on the classical point-dipole model is described, and its usefulness in cases where other NMR information is limited is discussed with a specific example.
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