Título/s: | A conformational model for MTPA esters of chiral N-(2-Hydroxyalkyl)acrylamides |
Fuente: | Advances in Chemistry |
Autor/es: | Rustoy, Eduardo M.; Baldessari, Alicia; Monsalve, Leandro N. |
Editor: | Hindawi |
Palabras clave: | Ésteres; Acrilatos; Estereoquímica; Lipasas; Modelos; Computación |
Idioma: | eng |
Fecha: | 2014 |
Ver+/- Research Article
A Conformational Model for MTPA Esters of Chiral N-(2-Hydroxyalkyl)acrylamides Eduardo M. Rustoy,1 Alicia Baldessari,1 and Leandro N. Monsalve1,2 Laboratorio de Biocata´lisis, Departamento de Quı´mica Orga´nica y UMYMFOR, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabello´n , Piso , Ciudad Universitaria, CEGA Buenos Aires, Argentina INTI-CONICET, Avenida Gral. Paz , Ed. , San Mart´ın, BJKA Buenos Aires, Argentina Correspondence should be addressed to Leandro N. Monsalve; monsalve@inti.gob.ar Received May ; Revised July ; Accepted July ; Published August Academic Editor: Daniel Glossman-Mitnik Copyright © Eduardo M. Rustoy et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. e absolute stereochemistry of novel chiral N-(-hydroxylalkyl)acrylamides prepared by a lipase-catalyzed resolution was successfully determined by 1H NMR of their MTPA esters. e method was validated for this particular case by computational experiments. 1. Introduction It is well known that chiral acrylamides are useful compounds in organic synthesis [–]. e absolute stereochemistry of chiral compounds is determined by using several methods []. Among the meth- ods available, NMR spectroscopy using chiral derivatizing agents such as -methoxy--(triuoromethyl)phenylacetic acid (MTPA) has been widely used in the determination of con guration of stereogenic centers bearing either hydroxyl or amine groups. More recently, this methodology has been applied for the derivatization of chiral primary alcohols thus determining the absolute con guration of stereogenic centers at a two- and three-bond distance from the hydroxyl group [–]. Moreover, the modi ed Mosher’s method has been used to determine the absolute con guration of primary alcohols with chiral methyl groups at C- []. However, it should be noted that this modi cation of Mosher’s method seemed to be unsuccessful for determining their stereochemistry of MTPA esters of some simple C- branched primary alcohols with conjugated groups or a con- secutive chiral centre at C-. According to Tsuda et al. the dif- ference in chemical shi between diastereotopic oxymethy- lene protons is similar for both diastereomers []. We have previously performed a lipase-catalyzed synthe- sis of nonchiral and chiral N-(-hydroxyalkyl)acrylamides (Scheme ) [, ]. We employed the modi ed Mosher’s method for the determination of %ee. e absolute con guration of products was found to be (S). However, a report by Puertas et al. [] describes the enantioselective behavior of Candida antarctica lipase B (CAL B) aording the (R)-acrylamides instead of (S)- acrylamides as products, using racemic amines as starting materials. Considering the absence of a conformational model for MTPA esters of -chiral primary alcohols and the results of our experiments showing opposite selectivity to previous experience, we decided to test the reliability of the method for our case. e aim of this work was to validate the results by conformational analysis of MTPA esters and thus obtain a reasonable explanation for NMR data on a molecular basis. 2. Results and Discussion We performed the synthesis of chiral N-(-hydroxya- lkyl)acrylamides a–d and their corresponding MTPA esters a–d and a–d as described in order to assign their absolute stereochemistry and the degree of stereoselectivity achieved in each case (Scheme ). A er puri cation, the MTPA esters were analyzed by 1H NMR spectroscopy in CDCl3. e results observed for compounds (S)-b and (S)-b were taken as example and showed signi cant dierences in the chemical shi for many Hindawi Publishing Corporation Advances in Chemistry Volume 2014, Article ID 736417, 6 pages http://dx.doi.org/10.1155/2014/736417 Advances in Chemistry
O O Et HO R NH2 HN O R OH + 2 CAL B 2? = R = –CH3; 2? = R = –CH2CH3; 2? = R = –(CH2)2CH3; 2? = R = –(CH2)3CH3 S : Lipase-catalyzed synthesis of a–d. HN O (S) R OH H N (S) O R (R) O MeO Ph HbHa O H N (S) O R (S) O CF3CF3 MeO Ph HbHa O (R)-MTPA, TEA (S)-MTPA, TEA or 2 22 2 2 (S)-2? R = CH3 (S)-2? R = CH2CH3 (S)-2? R = (CH2)2CH3 (S)-2? R = (CH2)3CH3 (S)- ? R = CH3 (S)- ? R = CH2CH3 (S)- ? R = (CH2)2CH3 (S)- ? R = (CH2)3CH3 (S)- ? R = CH3 (S)- ? R = CH2CH3 (S)- ? R = (CH2)2CH3 (S)- ? R = (CH2)3CH3 S : MTPA esters (S)-a–d and (S)-a–d. signals. Particularly, signals for diastereotopic protons Ha and Hb of the (R)-MTPA amido ester (S)-b were for the major isomer at . and . ppm and for the minor isomer at . and . ppm (Figure , Spectrum A). For the (S)- MTPA ester (S)-b these signals are reversed, so that those corresponding to the major isomer are observed at . and . ppm and the signals for the minor isomer are observed at . and . ppm (Figure , Spectrum B). e integration of the above-mentioned signals in both cases gave the same % ee value for b. e same procedure was applied to study the enan- tiomeric purity of the other three products a, c, and d. Table (columns and ) shows these results. is pattern for the oxymethylene protons of chiral primary alcohols esteri ed with MTPA is according to previ- ously published results on the determination of the absolute stereochemistry of a series of chiral primary alcohols with a methyl group at C- position [] and chiral ,-dihidro- xyketones []. In these works the absolute con guration of stereogenic centers was assigned by considering the between oxymethylene protons. Larger values of (R)- MTPA derivative were diagnosis for R stereochemistry on the carbon vicinal to oxymethylene whereas smaller values of (R)-MTPA derivative were diagnosis for the opposite stereochemistry (S). Accordingly, (S)-MTPA derivatives of (R)-primary alcohols showed smaller values for their oxymethylene proton signals than those prepared from (S)- primary alcohols. For (R)-MTPA derivatives of chiral N-(-hydroxya- lkyl)acrylamides here reported, we found = 0.01 ppm for the major isomer and = 0.11 ppm for the minor isomer. is fact should indicate that the absolute stereochemistry of the major isomer is (R,S) and therefore (S) is the absolute con guration of the products a–d. On the other hand the stereoselective behavior of lipases towards hydrolysis of esters of chiral secondary alcohols has been extensively studied. e Kazlauskas rule is intended to predict the behavior of lipases in such cases and, according to this rule, lipases tend to hydrolyze esters of chiral secondary alcohols having absolute con guration (R) faster than their enantiomer []. Lipases also showed the same stereochemi- cal preference in transesteri cation and aminolysis reactions [, ]. is model takes into consideration that the substituent seniority can be correlated with substituent size, which is not always the case. e enormous diversity of substrates accep- ted by lipases and reaction conditions applied showed that this rule is not met in some circumstances [, ]. Advances in Chemistry
4.324.344.364.384.404.424.444.464.48 (2R,2S) (a) (2S,2 S) (2S,2 S) 4.324.344.364.384.404.424.444.464.48 (b) F : 1H NMR signals for diastereotopic protons Ha and Hb in the (R)-MTPA amido ester (S)-b (Spectrum A) and (S)-MTPA amido ester (S)-b (Spectrum B). T : Conformers of both diastereomers of b. Compound Diastereomer Tor () Tor () (Kcal/mol) %P (R)-b (R,R) . . − . . − . . . . (S)-b (R,S) − . . − − . . . . − . . − . . . . . . − . . − . . − . . − − . . For this reason, we considered that this primary conclu- sion should be submitted to further analysis, since this result seems dicult to be interpreted in terms of the Kazlauskas rule that predicted (R)-con guration. erefore the stereoch- emical outcome of the enzymatic aminolysis of ethyl acrylate was not con rmed. Previous results on the enzyme-catalyzed transesteri cation of acrylates [] derivatives of such com- pounds showed enantioselectivity towards (R)-enantiomer. Furthermore, some authors reported that enzyme- catalyzed hydrolysis and transesteri cation of alcohols [] and hydrolysis of amide [] derivatives of such compounds showed enantioselectivity towards (R)- or (S)-enantiomer depending on the catalyst and the reaction conditions. Moreover, we could not establish precisely if the reason- ing from previously published results could also be applied in the determination of absolute stereochemistry of the chiral primary alcohols belonging to products a–d, by means of 1H NMR analysis of their MTPA derivatives. Besides the experi- mental fact that the con guration of the chiral products was known, no clear evidence was found that could be inter- preted or generalized on a molecular basis (i.e., evidence of conformational restrictions). For this reason, we decided to perform some experiments in silico in order to provide an independent explanation for experimental results. Conformational search experiments were performed with MTPA derivatives (S)-b (S,S) and (R)-b (R,S). In these experiments the torsion angles O–C–C–C (Tor) and MeO–C–C=O (Tor) (Figure ) were varied in order to obtain the most stable conformers of both compounds and thus interpret the chemical shi dierences observed bet- ween their oxymethylene protons and H in 1H NMR experiments. As it can be observed in Table , up to nine stable con- formers were found for (S)-b within Kcal/mol above the global minimum. Most conformers had their methoxyl group synperiplanar to their carbonyl ester, which is according to previous calculations on other MTPA esters by DFT methods. However, many rotamers along O–C and C–C bond were found to be stable enough to be important contributions to conformer population. is fact explains the broader signals and lower values between oxymethylene protons for (S)-b isomer. It was observed that signals at . and . ppm are broad (more than Hz wide) and not completely resolved. On the other hand, only four stable conformers were found for the diastereomer (R)-b. All of them had their methoxyl group synperiplanar to their carbonyl ester. Major contributions to the conformational population were the H Advances in Chemistry
OMe F3C Ph O CH2CH3 H N O Tor1 Tor2 O F : Torsion angles Tor (red and bold) and Tor (blue and bold) employed for conformational search of compound (S)-b. Ph OMe CF3 Ha OHb NH(C=O)–CH=CH2 H3 C H2C H O 0 0.54 0.72 1.54 – −70 5 E (kcal/mol) (a) 2.3 A˚ (b) F : (a) Newman projections along the axes C–C (up) and C–C (down) for the most stable conformer of (R)-b. Torsion angles Tor and Tor are indicated. Major contributions to this type of conformation are highlighted in the energy level diagram on the right. (b) Picture of a D molecular render of the same conformer showing intramolecular hydrogen bonding between amide hydrogen and a uorine atom (H–F distance: . angstrom). antiperiplanar to oxygen attached to C (Figure ). Two stable conformers have this conformation and they con- tribute to .% of the total conformer population. Moreover, these conformers show one oxymethylene hydrogen (Hb) synperiplanar to the aromatic ring and the other (Ha) synperiplanar to the C=O bond. ese observations could explain the large dierence of chemical shi s between both oxymethylene protons (. ppm) and the coupling con- stants observed for Ha-H and Hb-H (. Hz). e occurrence of intramolecular hydrogen bonding between the amide hydrogen and a uorine atom was also con rmed for both conformers. We assume that this hydrogen bond plays a key role in conformer stability. ese results are dicult to assimilate to those predicted in Kazlauskas rule based on the size of the substituents in the stereocenter and designed to predict which enantiomer of a secondary alcohol reacts faster in enzyme catalyzed reactions. e rule is reliable with substrates having substituents which dier signi cantly in size. In the acylation reaction of every chiral alkanolamine used in this work the enzyme showed an enantioselective behavior opposite to that described by Kazlauskas rule, preferably getting the product by reaction of alkanolamine with (S) con guration instead of the (R) predicted by the rule. In a the fact could be explained considering that the hydrox- ymethyl group is clearly larger than the methyl group, but in b ethyl and hydroxymethyl substituents are about the same size and compounds c and d have their alkyl sub- stituent larger than their hydroxyalkyl substituent. In these two compounds the Kazlauskas rule could be applied in terms of substituent size. e opposite con guration observed between the exper- imental results and that predicted by the rule could be attributed more likely to electronic eects than to steric hin- drance. For instance, Maraite et al. showed that Pseudomonas stutzeri lipase stereoselectivity for benzoin acylation could be explained by hydrogen bonding between Tyr- hydroxyl group and carbonyl oxygen of the substrate []. A similar eect could be attained by hydrogen bonding between hydroxyl moiety of alkanolamine and the threonine-rich loop of residues – of CAL B. erefore it could be suggested that the chemo- and enantioselectivity of the lipase-catalyzed N-acylation of chiral alkanolamines must be driven by the presence of the hydroxyl group in one substituent rather than the dierence in the substituent size. 3. Conclusions In this work we have proposed a conformational model for MTPA esters of chiral N-(-hydroxyalkyl)acrylamides. e in silico conformational analysis of the corresponding diastere- omers (R)-b and (S)-b showed that the dierences in conformational restrictions, and consequently 1H NMR sig- nal splitting for oxymethylene protons, arose from speci c intramolecular interactions rather than nonspeci c steric hindrance. is analysis was also useful for explaining the chemical shi dierences for both diastereomers and served Advances in Chemistry
for the validation of the stereochemical determination of chiral N-(-hydroxyalkyl)acrylamides obtained by lipase- catalyzed resolution. 4. Experimental .. General Remarks. 1H NMR spectra were recorded in CDCl3 as solvent using a Bruker Avance II spectrometer operating at MHz. Chemical shi s are reported in units (ppm) relative to tetramethylsilane (TMS) set at ppm, and coupling constants are given in hertz. e synthesis of N- (-hydroxyalkyl)acrylamides a–d and their corresponding MTPA derivatives a–d and a–d were performed as des- cribed previously []. .. Molecular Modeling. e structures of (R,R)--(acr- yloylamino)butyl ,,-triuoro--methoxy--phenylpropa- noate (R)-b and (R,S)--(acryloylamino)butyl ,,- triuoro--methoxy--phenylpropanoate (S)-b were subm- itted to conformational search using the molecular mechan- ics method MM+ and a conformational search algorithm integrated on HyperChem .. e selected torsions to vary were O–C–C–C (Tor) and MeO–C–C=O (Tor) and conformations of energies below Kcal/mol over the global minimum were submitted to geometry optimization using Gamess []. Energies were minimized employing DFT method BLYP using – g basis function. Solvent eect was simulated using the PCM method with the standard parameters for chloroform included in the so ware package. Optimized structures for each isomer were visualized using ChemBioD Ultra . and overlaid in order to discard repeated structures. Conflict of Interests e authors declare that there is no conict of interests regarding the publication of this paper. 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