research article a conformational model for mtpa esters...

Research ArticleA Conformational Model for MTPA Esters ofChiral N-(2-Hydroxyalkyl)acrylamides

Eduardo M Rustoy1 Alicia Baldessari1 and Leandro N Monsalve12

1 Laboratorio de Biocatalisis Departamento de Quımica Organica y UMYMFOR Facultad de Ciencias Exactas y NaturalesUniversidad de Buenos Aires Pabellon 2 Piso 3 Ciudad Universitaria C1428EGA Buenos Aires Argentina

2 INTI-CONICET Avenida Gral Paz 5445 Ed 42 San Martın B1650JKA Buenos Aires Argentina

Correspondence should be addressed to Leandro N Monsalve monsalveintigobar

Received 19 May 2014 Revised 13 July 2014 Accepted 13 July 2014 Published 10 August 2014

Academic Editor Daniel Glossman-Mitnik

Copyright copy 2014 Eduardo M Rustoy et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The absolute stereochemistry of novel chiral N-(2-hydroxylalkyl)acrylamides prepared by a lipase-catalyzed resolution wassuccessfully determined by 1H NMR of their MTPA esters The method was validated for this particular case by computationalexperiments

1 Introduction

It is well known that chiral acrylamides are useful compoundsin organic synthesis [1ndash3]

The absolute stereochemistry of chiral compounds isdetermined by using several methods [4] Among the meth-ods available NMR spectroscopy using chiral derivatizingagents such as 2-methoxy-2-(trifluoromethyl)phenylaceticacid (MTPA) has been widely used in the determination ofconfiguration of stereogenic centers bearing either hydroxylor amine groups More recently this methodology has beenapplied for the derivatization of chiral primary alcohols thusdetermining the absolute configuration of stereogenic centersat a two- and three-bond distance from the hydroxyl group[5ndash8] Moreover the modified Mosherrsquos method has beenused to determine the absolute configuration of primaryalcohols with chiral methyl groups at C-2 [9]

However it should be noted that this modification ofMosherrsquos method seemed to be unsuccessful for determiningtheir stereochemistry of MTPA esters of some simple C-2branched primary alcohols with conjugated groups or a con-secutive chiral centre at C-3 According to Tsuda et al the dif-ference in chemical shift between diastereotopic oxymethy-lene protons is similar for both diastereomers [9]

We have previously performed a lipase-catalyzed synthe-sis of nonchiral and chiral N-(2-hydroxyalkyl)acrylamides(Scheme 1) [10 11]

We employed the modified Mosherrsquos method for thedetermination ofeeThe absolute configuration of productswas found to be (S) However a report by Puertas et al [12]describes the enantioselective behavior of Candida antarcticalipase B (CALB) affording the (R)-acrylamides instead of (S)-acrylamides as products using racemic amines as startingmaterials

Considering the absence of a conformational model forMTPA esters of 120573-chiral primary alcohols and the resultsof our experiments showing opposite selectivity to previousexperience we decided to test the reliability of themethod forour case The aim of this work was to validate the results byconformational analysis of MTPA esters and thus obtain areasonable explanation for NMR data on a molecular basis

2 Results and Discussion

We performed the synthesis of chiral N-(2-hydroxya-lkyl)acrylamides 2andashd and their corresponding MTPA esters3andashd and 4andashd as described in order to assign their absolutestereochemistry and the degree of stereoselectivity achievedin each case (Scheme 2)

After purification the MTPA esters were analyzed by1H NMR spectroscopy in CDCl

3 The results observed for

compounds (S)-3b and (S)-4b were taken as example andshowed significant differences in the chemical shift for many

Hindawi Publishing CorporationAdvances in ChemistryVolume 2014 Article ID 736417 6 pageshttpdxdoiorg1011552014736417

2 Advances in Chemistry

OO

EtHO

R

NH2 HN

O

R OH

+

1 2

CAL B

2a = R = ndashCH3 2b = R = ndashCH2CH3 2c = R = ndash(CH2)2CH32d = R = ndash(CH2)3CH3

Scheme 1 Lipase-catalyzed synthesis of 2andashd

HN

O

(S)

R OH

HN

(S) O

R(R)

O

MeO

PhHbHa

O

HN

(S) O

R(S)

O

CF3CF3 MeO

PhHbHa

O

(R)-MTPA TEA (S)-MTPA TEA

or

2998400

2998400

2 2 2998400

(S)-2a R = CH3

(S)-2b R = CH2CH3(S)-2c R = (CH2)2CH3(S)-2dR = (CH2)3CH3

(S)-3a R = CH3


(S)-4a R = CH3


Scheme 2 MTPA esters (S)-3andashd and (S)-4andashd

signals Particularly signals for diastereotopic protons H11015840aand H11015840b of the (R)-MTPA amido ester (S)-3b were for themajor isomer at 120575 436 and 437 ppmand for theminor isomerat 120575 433 and 444 ppm (Figure 3 Spectrum A) For the (S)-MTPA ester (S)-4b these signals are reversed so that thosecorresponding to themajor isomer are observed at 120575 433 and444 ppmand the signals for theminor isomer are observed at120575 436 and437 ppm (Figure 1 SpectrumB)The integration ofthe above-mentioned signals in both cases gave the same 35ee value for 2b

The same procedure was applied to study the enan-tiomeric purity of the other three products 2a 2c and 2dTable 1 (columns 4 and 5) shows these results

This pattern for the oxymethylene protons of chiralprimary alcohols esterified with MTPA is according to previ-ously published results on the determination of the absolutestereochemistry of a series of chiral primary alcohols witha methyl group at C-2 position [9] and chiral 13-dihidro-xyketones [7] In these works the absolute configurationof stereogenic centers was assigned by considering the Δ120575between oxymethylene protons Larger Δ120575 values of (R)-MTPA derivative were diagnosis forR stereochemistry on thecarbon vicinal to oxymethylene whereas smaller Δ120575 valuesof (R)-MTPA derivative were diagnosis for the opposite

stereochemistry (S) Accordingly (S)-MTPA derivatives of(R)-primary alcohols showed smaller Δ120575 values for theiroxymethylene proton signals than those prepared from (S)-primary alcohols

For (R)-MTPA derivatives of chiral N-(2-hydroxya-lkyl)acrylamides here reported we found Δ120575 = 001 ppm forthe major isomer and Δ120575 = 011 ppm for the minor isomerThis fact should indicate that the absolute stereochemistry ofthe major isomer is (2R21015840S) and therefore (S) is the absoluteconfiguration of the products 2andashd

On the other hand the stereoselective behavior of lipasestowards hydrolysis of esters of chiral secondary alcohols hasbeen extensively studied The Kazlauskas rule is intended topredict the behavior of lipases in such cases and according tothis rule lipases tend to hydrolyze esters of chiral secondaryalcohols having absolute configuration (R) faster than theirenantiomer [13] Lipases also showed the same stereochemi-cal preference in transesterification and aminolysis reactions[14 15]

This model takes into consideration that the substituentseniority can be correlated with substituent size which is notalways the case The enormous diversity of substrates accep-ted by lipases and reaction conditions applied showed thatthis rule is not met in some circumstances [16 17]

Advances in Chemistry 3

432434436438440442444446448

(2R2998400S)

(a)

(2S2 S) (2S2 S)

432434436438440442444446448

998400 998400

(b)

Figure 1 1HNMR signals for diastereotopic protons H11015840a andH11015840b in the (R)-MTPA amido ester (S)-3b (SpectrumA) and (S)-MTPA amidoester (S)-4b (Spectrum B)

Table 1 Conformers of both diastereomers of 3b

Compound Diastereomer Tor1 (∘) Tor2 (∘) 998779119864 (Kcalmol) P

(R)-3b (2R21015840R)

178 1 154 42minus66 2 054 226minus70 5 000 56566 2 072 167

(S)-3b (2R21015840S)

73 minus5 059 174minus49 minus4 170 2669 1 034 266minus76 4 188 20minus177 7 000 473168 4 160 31165 0 244 08162 minus2 302 03minus54 1 164 29156 minus108 299 03minus62 minus140 172 26

For this reason we considered that this primary conclu-sion should be submitted to further analysis since this resultseems difficult to be interpreted in terms of the Kazlauskasrule that predicted (R)-configurationTherefore the stereoch-emical outcome of the enzymatic aminolysis of ethyl acrylatewas not confirmed Previous results on the enzyme-catalyzedtransesterification of acrylates [18] derivatives of such com-pounds showed enantioselectivity towards (R)-enantiomer

Furthermore some authors reported that enzyme-catalyzed hydrolysis and transesterification of alcohols [14]and hydrolysis of amide [19] derivatives of such compoundsshowed enantioselectivity towards (R)- or (S)-enantiomerdepending on the catalyst and the reaction conditions

Moreover we could not establish precisely if the reason-ing from previously published results could also be appliedin the determination of absolute stereochemistry of the chiralprimary alcohols belonging to products 2andashd bymeans of 1HNMR analysis of their MTPA derivatives Besides the experi-mental fact that the configuration of the chiral products wasknown no clear evidence was found that could be inter-preted or generalized on a molecular basis (ie evidence ofconformational restrictions) For this reason we decided toperform some experiments in silico in order to provide anindependent explanation for experimental results

Conformational search experiments were performedwithMTPAderivatives (S)-3b (2S21015840S) and (R)-3b (2R21015840S) Inthese experiments the torsion angles OndashC11015840ndashC21015840ndashC31015840 (Tor1)andMeOndashC2ndashC1=O (Tor2) (Figure 2) were varied in order toobtain the most stable conformers of both compounds andthus interpret the chemical shift differences observed bet-ween their oxymethylene protons and H21015840 in 1H NMRexperiments

As it can be observed in Table 1 up to nine stable con-formers were found for (S)-3b within 3Kcalmol above theglobalminimumMost conformers had theirmethoxyl groupsynperiplanar to their carbonyl ester which is accordingto previous calculations on other MTPA esters by DFTmethods However many rotamers alongOndashC11015840 and C11015840ndashC21015840bond were found to be stable enough to be importantcontributions to conformer populationThis fact explains thebroader signals and lower Δ120575 values between oxymethyleneprotons for (S)-3b isomer It was observed that signals at 120575436 and 437 ppm are broad (more than 6Hz wide) and notcompletely resolved

On the other hand only four stable conformers werefound for the diastereomer (R)-3b All of them had theirmethoxyl group synperiplanar to their carbonyl ester Majorcontributions to the conformational population were the H21015840


OMe

F3C Ph

O

CH2CH3

HN

O

Tor1

Tor2

O

Figure 2 Torsion angles Tor1 (red and bold) and Tor2 (blue and bold) employed for conformational search of compound (S)-3b

Ph

OMe

CF3Ha

OHb

NH(C=O)ndashCH=CH2

H3 C H2C

H

O

0

054

072

154

ndash minus70∘

5∘

ΔE (kcalmol)

(a)

23 A

(b)

Figure 3 (a) Newman projections along the axes C1ndashC2 (up) and C11015840ndashC21015840 (down) for the most stable conformer of (R)-3b Torsion anglesTor1 and Tor2 are indicated Major contributions to this type of conformation are highlighted in the energy level diagram on the right (b)Picture of a 3D molecular render of the same conformer showing intramolecular hydrogen bonding between amide hydrogen and a fluorineatom (HndashF distance 23 angstrom)

antiperiplanar to oxygen attached to C11015840 (Figure 3) Twostable conformers have this conformation and they con-tribute to 791 of the total conformer population Moreoverthese conformers show one oxymethylene hydrogen (H11015840b)synperiplanar to the aromatic ring and the other (H11015840a)synperiplanar to the C=O bond These observations couldexplain the large difference of chemical shifts between bothoxymethylene protons (011 ppm) and the coupling con-stants observed for H11015840a-H21015840 and H11015840b-H21015840 (41 Hz) Theoccurrence of intramolecular hydrogen bonding between theamide hydrogen and a fluorine atom was also confirmed forboth conformers We assume that this hydrogen bond plays akey role in conformer stability

These results are difficult to assimilate to those predictedin Kazlauskas rule based on the size of the substituents in thestereocenter and designed to predict which enantiomer of asecondary alcohol reacts faster in enzyme catalyzed reactionsThe rule is reliable with substrates having substituents whichdiffer significantly in size

In the acylation reaction of every chiral alkanolamineused in this work the enzyme showed an enantioselectivebehavior opposite to that described by Kazlauskas rulepreferably getting the product by reaction of alkanolaminewith (S) configuration instead of the (R) predicted by the ruleIn 1a the fact could be explained considering that the hydrox-ymethyl group is clearly larger than the methyl group butin 1b ethyl and hydroxymethyl substituents are about thesame size and compounds 1c and 1d have their alkyl sub-stituent larger than their hydroxyalkyl substituent In these

two compounds theKazlauskas rule could be applied in termsof substituent size

The opposite configuration observed between the exper-imental results and that predicted by the rule could beattributed more likely to electronic effects than to steric hin-drance For instance Maraite et al showed that Pseudomonasstutzeri lipase stereoselectivity for benzoin acylation couldbe explained by hydrogen bonding between Tyr-54 hydroxylgroup and carbonyl oxygen of the substrate [20] A similareffect could be attained by hydrogen bonding betweenhydroxylmoiety of alkanolamine and the threonine-rich loopof residues 39ndash44 of CAL B Therefore it could be suggestedthat the chemo- and enantioselectivity of the lipase-catalyzedN-acylation of chiral alkanolamines must be driven by thepresence of the hydroxyl group in one substituent rather thanthe difference in the substituent size

3 Conclusions

In this work we have proposed a conformational model forMTPAesters of chiralN-(2-hydroxyalkyl)acrylamidesThe insilico conformational analysis of the corresponding diastere-omers (R)-3b and (S)-3b showed that the differences inconformational restrictions and consequently 1H NMR sig-nal splitting for oxymethylene protons arose from specificintramolecular interactions rather than nonspecific sterichindrance This analysis was also useful for explaining thechemical shift differences for both diastereomers and served


for the validation of the stereochemical determination ofchiral N-(2-hydroxyalkyl)acrylamides obtained by lipase-catalyzed resolution

4 Experimental

41 General Remarks 1H NMR spectra were recorded inCDCl

3as solvent using a Bruker Avance II 500 spectrometer

operating at 500MHz Chemical shifts are reported in 120575 units(ppm) relative to tetramethylsilane (TMS) set at 0 ppm andcoupling constants are given in hertz The synthesis of N-(2-hydroxyalkyl)acrylamides 2andashd and their correspondingMTPA derivatives 3andashd and 4andashd were performed as des-cribed previously [11]

42 Molecular Modeling The structures of (2R21015840R)-21015840-(acr-yloylamino)butyl 333-trifluoro-2-methoxy-2-phenylpropa-noate (R)-3b and (2R21015840S)-21015840-(acryloylamino)butyl 333-trifluoro-2-methoxy-2-phenylpropanoate (S)-3b were subm-itted to conformational search using the molecular mechan-ics method MM+ and a conformational search algorithmintegrated on HyperChem 80 The selected torsions to varywere OndashC11015840ndashC21015840ndashC31015840 (Tor1) and MeOndashC2ndashC1=O (Tor2)and conformations of energies below 6Kcalmol over theglobal minimum were submitted to geometry optimizationusing Gamess [21] Energies were minimized employing DFTmethod B3LYP using 6ndash31 g basis function Solvent effectwas simulated using the PCM method with the standardparameters for chloroform included in the software packageOptimized structures for each isomer were visualized usingChemBio3D Ultra 110 and overlaid in order to discardrepeated structures

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors thank UBA X010 CONICET PIP 112-200801-0080109 andANPCyTPICT 2005-32735 for partial financialsupport Eduardo M Rustoy Alicia Baldessari and LeandroN Monsalve are research members of CONICET

References

[1] M Nyerges D Bendell A Arany et al ldquoSilver acetate-catalysedasymmetric 13-dipolar cycloadditions of imines and chiralacrylamidesrdquo Tetrahedron vol 61 no 15 pp 3745ndash3753 2005

[2] Y Tian W Lu Y Che L B Shen L M Jiang and Z Q ShenldquoSynthesis and characterization of macroporous silica modifiedwith optically active poly[N-(oxazolinylphenyl)acrylamide]derivatives for potential application as chiral stationary phasesrdquoJournal of Applied Polymer Science vol 115 no 2 pp 999ndash10072010

[3] J Tobis Y Thomann and J C Tiller ldquoSynthesis and charac-terization of chiral and thermo responsive amphiphilic conet-worksrdquo Polymer vol 51 no 1 pp 35ndash45 2010

[4] J M Seco E Quinoa and R Riguera ldquoThe assignment of abso-lute configuration by NMRrdquo Chemical Reviews vol 104 no 1pp 17ndash118 2004

[5] T Pehk E LippmaamM Lopp A Paju B C Borer and R J KTaylor ldquoDetermination of the absolute configuration of chiralsecondary alcohols new advances using 13C- and 2D-NMRspectroscopyrdquo Tetrahedron Asymm vol 4 no 7 pp 1527ndash15321993

[6] K Akiyama S Kawamoto H Fujimoto andM Ishibashi ldquoAbs-olute stereochemistry of TT-1 (rasfonin) an 120572-pyrone-contain-ing natural product from a fungus Trichurus terrophilusrdquo Tet-rahedron Letters vol 44 no 46 pp 8427ndash8431 2003

[7] J L Galman and H C Hailes ldquoApplication of a modifiedMosherrsquos method for the determination of enantiomeric ratioand absolute configuration at C-3 of chiral 13-dihydroxyketonesrdquo Tetrahedron Asymmetry vol 20 no 15 pp 1828ndash18312009

[8] L V Parfenova T V Berestova T V Tyumkina et al ldquoEnantios-electivity of chiral zirconocenes as catalysts in alkene hydro-carbo- and cycloalumination reactionsrdquo Tetrahedron Asymme-try vol 21 no 3 pp 299ndash310 2010

[9] M Tsuda Y Toriyabe T Endo and J Kobayashi ldquoApplication ofmodified Mosherrsquos method for primary alcohols with a methylgroup at C2 positionrdquo Chemical amp Pharmaceutical Bulletin vol51 no 4 pp 448ndash451 2003

[10] EMRustoy andA Baldessari ldquoChemoselective enzymatic pre-paration of N-hydroxyalkylacrylamides monomers for hydro-philic polymer matricesrdquo Journal of Molecular Catalysis BEnzymatic vol 39 no 1ndash4 pp 50ndash54 2006

[11] L N Monsalve E M Rustoy and A Baldessari ldquoBiocatalyticsynthesis of chiral N-(2-hydroxyalkyl)-acrylamidesrdquo Biocataly-sis and Biotransformation vol 29 no 2-3 pp 87ndash95 2011

[12] S Puertas R Brieva F Rebolledo and V Gotor ldquoLipase cat-alyzed aminolysis of ethyl propiolate and acrylic esters Synthe-sis of chiral acrylamidesrdquo Tetrahedron vol 49 no 19 pp 4007ndash4014 1993

[13] R J Kazlauskas A N E Weissfloch A T Rappaport and L ACuccia ldquoA rule to predict which enantiomer of a secondaryalcohol reacts faster in reactions catalyzed by cholesterolesterase lipase from Pseudomonas cepacia and lipase fromCandida rugosardquo Journal of Organic Chemistry vol 56 no 8pp 2656ndash2665 1991

[14] F Francalanci P Cesti W Cabri D Bianchi T Martinengoand M Foa ldquoLipase-catalyzed resolution of chiral 2-amino 1-alcoholsrdquo Journal of Organic Chemistry vol 52 no 23 pp 5079ndash5082 1987

[15] J Gonzalez-Sabın V Gotor and F Rebolledo ldquoEnantioselec-tive acylation of rac-2-phenylcycloalkanamines catalyzed bylipasesrdquo Tetrahedron Asymmetry vol 16 no 18 pp 3070ndash30762005

[16] X Xia Y-H Wang B Yang and X Wang ldquoWheat germ lipasecatalyzed kinetic resolution of secondary alcohols in non-aqueous mediardquo Biotechnology Letters vol 31 no 1 pp 83ndash872009

[17] P Hoyos V Pace J V Sinisterra and A R Alcantara ldquoChem-oenzymatic synthesis of chiral unsymmetrical benzoin estersrdquoTetrahedron vol 67 no 38 pp 7321ndash7329 2011

[18] S Akai T Naka S Omura et al ldquoLipase-catalyzed dominokinetic resolutionintramolecular Diels-Alder reaction one-potsynthesis of optically active 7-oxabicyclo[221]heptenes fromfurfuryl alcohols and 120573-substituted acrylic acidsrdquo Chemistry AEuropean Journal vol 8 pp 4255ndash4264 2002


[19] N W Fadnavis M Sharfuddin and S K Vadivel ldquoResolutionof racemic 2-amino-1-butanol with immobilised penicillin GacylaserdquoTetrahedron Asymmetry vol 10 no 23 pp 4495ndash45001999

[20] A Maraite P Hoyos J D Carballeira A C Cabrera M BAnsorge-Schumacher and A R Alcantara ldquoLipase from Pseu-domonas stutzeri purification homology modelling and ratio-nal explanation of the substrate binding moderdquo Journal ofMolecular Catalysis B Enzymatic vol 87 pp 88ndash98 2013

[21] M W Schmidt K K Baldridge J A Boatz et al ldquoGeneralatomic and molecular electronic structure systemrdquo Journal ofComputational Chemistry vol 14 no 11 pp 1347ndash1363 1993

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

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International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

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Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

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Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


OO

EtHO

R

NH2 HN

O

R OH

+

1 2

CAL B

2a = R = ndashCH3 2b = R = ndashCH2CH3 2c = R = ndash(CH2)2CH32d = R = ndash(CH2)3CH3

Scheme 1 Lipase-catalyzed synthesis of 2andashd

HN

O

(S)

R OH

HN

(S) O

R(R)

O

MeO

PhHbHa

O

HN

(S) O

R(S)

O

CF3CF3 MeO

PhHbHa

O

(R)-MTPA TEA (S)-MTPA TEA

or

2998400

2998400

2 2 2998400

(S)-2a R = CH3


(S)-3a R = CH3


(S)-4a R = CH3


Scheme 2 MTPA esters (S)-3andashd and (S)-4andashd

signals Particularly signals for diastereotopic protons H11015840aand H11015840b of the (R)-MTPA amido ester (S)-3b were for themajor isomer at 120575 436 and 437 ppmand for theminor isomerat 120575 433 and 444 ppm (Figure 3 Spectrum A) For the (S)-MTPA ester (S)-4b these signals are reversed so that thosecorresponding to themajor isomer are observed at 120575 433 and444 ppmand the signals for theminor isomer are observed at120575 436 and437 ppm (Figure 1 SpectrumB)The integration ofthe above-mentioned signals in both cases gave the same 35ee value for 2b

The same procedure was applied to study the enan-tiomeric purity of the other three products 2a 2c and 2dTable 1 (columns 4 and 5) shows these results

This pattern for the oxymethylene protons of chiralprimary alcohols esterified with MTPA is according to previ-ously published results on the determination of the absolutestereochemistry of a series of chiral primary alcohols witha methyl group at C-2 position [9] and chiral 13-dihidro-xyketones [7] In these works the absolute configurationof stereogenic centers was assigned by considering the Δ120575between oxymethylene protons Larger Δ120575 values of (R)-MTPA derivative were diagnosis forR stereochemistry on thecarbon vicinal to oxymethylene whereas smaller Δ120575 valuesof (R)-MTPA derivative were diagnosis for the opposite

stereochemistry (S) Accordingly (S)-MTPA derivatives of(R)-primary alcohols showed smaller Δ120575 values for theiroxymethylene proton signals than those prepared from (S)-primary alcohols

For (R)-MTPA derivatives of chiral N-(2-hydroxya-lkyl)acrylamides here reported we found Δ120575 = 001 ppm forthe major isomer and Δ120575 = 011 ppm for the minor isomerThis fact should indicate that the absolute stereochemistry ofthe major isomer is (2R21015840S) and therefore (S) is the absoluteconfiguration of the products 2andashd

On the other hand the stereoselective behavior of lipasestowards hydrolysis of esters of chiral secondary alcohols hasbeen extensively studied The Kazlauskas rule is intended topredict the behavior of lipases in such cases and according tothis rule lipases tend to hydrolyze esters of chiral secondaryalcohols having absolute configuration (R) faster than theirenantiomer [13] Lipases also showed the same stereochemi-cal preference in transesterification and aminolysis reactions[14 15]

This model takes into consideration that the substituentseniority can be correlated with substituent size which is notalways the case The enormous diversity of substrates accep-ted by lipases and reaction conditions applied showed thatthis rule is not met in some circumstances [16 17]


432434436438440442444446448

(2R2998400S)

(a)

(2S2 S) (2S2 S)

432434436438440442444446448

998400 998400

(b)




(R)-3b (2R21015840R)

178 1 154 42minus66 2 054 226minus70 5 000 56566 2 072 167

(S)-3b (2R21015840S)









OMe

F3C Ph

O

CH2CH3

HN

O

Tor1

Tor2

O


Ph

OMe

CF3Ha

OHb

NH(C=O)ndashCH=CH2

H3 C H2C

H

O

0

054

072

154

ndash minus70∘

5∘

ΔE (kcalmol)

(a)

23 A

(b)







3 Conclusions




4 Experimental







Acknowledgments


References
































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


432434436438440442444446448

(2R2998400S)

(a)

(2S2 S) (2S2 S)

432434436438440442444446448

998400 998400

(b)




(R)-3b (2R21015840R)

178 1 154 42minus66 2 054 226minus70 5 000 56566 2 072 167

(S)-3b (2R21015840S)









OMe

F3C Ph

O

CH2CH3

HN

O

Tor1

Tor2

O


Ph

OMe

CF3Ha

OHb

NH(C=O)ndashCH=CH2

H3 C H2C

H

O

0

054

072

154

ndash minus70∘

5∘

ΔE (kcalmol)

(a)

23 A

(b)







3 Conclusions




4 Experimental







Acknowledgments


References
































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


OMe

F3C Ph

O

CH2CH3

HN

O

Tor1

Tor2

O


Ph

OMe

CF3Ha

OHb

NH(C=O)ndashCH=CH2

H3 C H2C

H

O

0

054

072

154

ndash minus70∘

5∘

ΔE (kcalmol)

(a)

23 A

(b)







3 Conclusions




4 Experimental







Acknowledgments


References
































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



4 Experimental







Acknowledgments


References
































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of














Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

research article a conformational model for mtpa esters...

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