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Tetrahedron 70 (2014) 3276e3283

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Tetrahedron

journal homepage: www.elsevier .com/locate/ tet

Designing chiral derivatizing agents (CDA) for the NMR assignmentof the absolute configuration: a theoretical and experimentalapproach with thiols as a case study

Silvia Porto, Emilio Qui~no�a, Ricardo Riguera *

Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS),University of Santiago de Compostela, 15782 Santiago de Compostela, Spain

a r t i c l e i n f o

Article history:Received 17 August 2013Received in revised form 14 October 2013Accepted 23 October 2013Available online 30 October 2013

Keywords:Chiral derivatizing agent (CDA)Arylalkoxyacetic acidNuclear magnetic resonance (NMR)Absolute configurationChiral thiolsTheoretical modellingAryl-tert-butoxyacetic acids (ATBAAs)

* Corresponding author. E-mail address: ricardo.rig

0040-4020/$ e see front matter � 2013 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2013.10.077

a b s t r a c t

A general protocol for the design of successful chiral derivatizing agents (CDAs) for the NMR assignmentof absolute configuration is described. The design of the most efficient arylalkoxyacetic acid reagent forthe assignment of chiral thiols is taken as example. The importance of theoretical calculations in thediscovery of the conformational preference of modelled arylmethoxyacetic acid (AMAA) thioesters isstressed, as well as NMR experiments to confirm the conformations predicted for the different CDAs andto select for synthesis the most adequate for that substrate. The modification of the aryl moiety of theAMAA system has shown not to provide especially good CDAs while the introduction of a stericallyhindered tert-BuO group results in a more appropriate conformation leading to 2-naphtyl-tert-butoxy-acetic acid (2-NTBA) as the most efficient CDA for thiols.

� 2013 Elsevier Ltd. All rights reserved.

O

X

HL

LR

R R

O

X

HL

LR

R R

HX

HL

L

(R)-CDA

(S)-CDA

L

L

L

L

NMRAnalysis

CDA-X

HL

L

Model

(?)-A

(R)-CDA-(?)-A

(S)-CDA-(?)-AConfiguration

assigned

Fig. 1. Conceptual representation of the assignment of the absolute configuration bymeans of a double derivatization.

1. Introduction

Since the seminal works of pioneers likeMosher,1 NMRmethodsfor the assignment of absolute configuration have experienceda large development in the last decades and have given solutions toresearchers in many fields of Chemistry where to know the three-dimensional structure of chiral structures is a must (Natural Prod-ucts, Asymmetric Synthesis, Analysis of Pharmaceuticals.).2 In themost usual approach, the absolute configuration of chiral substrates(both mono- and polyfunctional compounds), such as: alcohols,2a,3

amines,2a,4 thiols,5 carboxylic acids,2a,6 cyanohydrins,7 diols,2c,8

aminoalcohols,2c,9 triols,2c,10 can be assigned by their reactionwith the two enantiomers of an appropriate chiral derivatizingagent (CDA) followed by comparison of the 1H or 13C NMR spectra11

(or other nuclei, such as 19F or 31P in some cases)2 of the two di-astereomeric derivatives obtained. To be more specific, the chem-ical shifts of the substituents bonded to the chiral centre of thesubstrate (L1/L2) must be compared, and the absolute configurationis determined in accordance with the signs of their differences(DdRSL1 and DdRSL2)12 in both derivatives (Fig. 1).

uera@usc.es (R. Riguera).

All rights reserved.

The assignment of configuration is therefore based on theexistence of a correlation between the absolute configuration at thechiral centre of the CDA (i.e., known) and the chemical shifts ofL1/L2 in the two derivatives, what allows establishing the configu-ration of the chiral centre placed between L1/L2 (i.e., unknown).These correlations are possible due to presence of groups at theCDA, such as aryl rings that generate different and selective inducedanisotropic magnetic field effects (shielding/deshielding) on theL1/L2 substituents in each derivative.

More recently, methods that require the preparation of only onederivative, instead of two, have been developed. They make use ofjust one enantiomer of the CDA. In some cases, these methods

Fig. 3. General structure of CDAs based on a phenylacetic acid moiety. MPA has beenused as model compound. Other examples of functional groups used in the differentroles played by the substituents have been included.

S. Porto et al. / Tetrahedron 70 (2014) 3276e3283 3277

compare the spectrum of the ‘free’ substrate and the spectrum ofthe CDA-substrate derivative.13 In others, the methods are based inthe controlled manipulation of the conformational equilibriumbetween the main conformers.14

Whatever method one decides to use, the choice of an adequateCDA for the substrate whose chirality is going to be investigated isof major importance. On numerous occasions, if the type of com-pound that needs to be derivatized has been studied previously(i.e., a secondary alcohol, a primary amine), the appropriate CDAwill either be commercially available or easily prepared.

However, in other cases, researchers will need to design anddevelop brand new auxiliaries to face new challenging structuralsituations, such as functional groups not previously tested, newpolyfunctional compounds, complex molecular frameworks, and soon.

In this paper, we describe a general approach and protocol tohelp researchers to develop new effective and reliable CDAsinvesting the minimum of experimental work. The use of theoret-ical calculations and modelling to predict the effect of structuralchanges is stressed. The design of a 2-naphtyl-tert-butoxyaceticacid as CDA for assignment of absolute configuration of thiols isdescribed as a case study.

2. Results and discussion

2.1. Chiral derivatizing agents: general characteristics

Since the first reagents proposed by Mosher (i.e., MTPA, MPA inFig. 2), many other structurally different types of compounds havebeen proposed as CDAs for a variety of functional groups.2

However, the use of some chiral auxiliaries has been occasionaland in many cases, the methods were just empirical lacking in-formation on any type of conformational studies (theoretical, dy-namic NMR.) to support their behaviour. Additionally, many ofthose reagentswere usually testedwith either very few compoundsof known absolute configuration or without the required structuraldiversity, so their use could not be called ‘general’.

O

OHH

MeO

(R)-MPA

O

OHF3C

MeO

(R)-MTPA

O

OHH

MeO

(R)-1-NMA

O

OHH

MeO

(R)-2-NMA

O

OHH

MeO

(R)-9-AMA

α

Fig. 2. Selection of arylmethoxyacetic acids used as CDAs for configurational assign-ment by NMR.

The most successful CDAs without doubt have been those de-rived or closely related to a-chiral phenylacetic acid. The generalstructure of this kind of auxiliaries is depicted in Fig. 3. It includesan asymmetric atom, usually carbon (Ca), and directly bonded to it:1) a linker group, 2) an anisotropy magnetic group, 3) an inductorgroup (a main conformation-inducing group) and 4) a supplemen-tary group.

The linker is the functional group that connects the auxiliary tothe chiral substrate through a covalent bond. So, it has to be com-plementary to the functionality of the substrate. The covalent bondcreated should have a restricted rotation to help to fix a finalprevalent conformation on the CDA-substrate system. The couplingreaction between the substrate and the CDA should make use ofexperimental conditions as smooth as possible so it does notmodify other parts of the substrate. Also, it should render highyields (ideally, quantitative) and, in those cases when the CDA re-acts simultaneously with two enantiomers, kinetic resolution mustbe avoided.

The anisotropy magnetic group generates the main inducedanisotropic magnetic field effects (shielding/deshielding) that mustgive rise to perceptible shifts in the NMR signals (1H, 13C, 19F, 31P.)of the substrate investigated. The anisotropic effect that it isa through-space phenomenon, must show appropriate strength(intensity) to generate effective shifts. Also, the shape and orien-tation of the ‘magnetic cone’ respect the substrate (its spatial se-lectivity) must be adequate. Typical anisotropic systems are thosewith high p electron density: aromatic rings, carbonyl groups, tri-ple bonds and so, being the first ones the most used (aromaticsystems based on aryl rings).

The inductor is a conformation-directing group whose role is tostabilize a certain major conformer, generating a well-definedconformational preference. It can act mainly through polar or ste-ric effects as well as by formation of hydrogen bonds.

The supplementary group plays a subordinate role with respectto the other three substituents. It should collaborate with thesesubstituents or at least do not obstruct them.

In general, the reagents should have the smallest possiblenumber of NMR signals so they do not overlap with those of thesubstrate or they must be in zones of the d scale where they do notinterfere. If so, this condition avoids the need to resort to complexand expensive routes in order to synthesize deuterated reagents.

2.2. General procedure for the design of reliable and generalCDAs

The following course of action can be followed when choosingor designing a CDA appropriate for a new class of compounds.

2.2.1. Experimental and theoretical studies with known CDAs.

a) NMR screening (1H, 13C) of potentially interesting CDAs thathave proven to be effective with other groups and able to makecovalent linkages with the functional group/s under studyshould be performed with a selection of substrates of knownabsolute configuration. Simple model compounds with easilyrecognized signals should be chosen and tested in order toappreciate if coherent DdRS signs and significant values greater

R2R1OS

O

Ar H

SH

(S)-Butane-2-thiol

SH

R1Ar R2 thioester

Me Me 1PhMe Me 22-NaphthylMe Me 39-Anthryl

tBu Me 8PhtBu Me 92-NaphthyltBu Me 109-Anthryl

Me (S)-2-butyl 4PhMe (S)-2-butyl 52-Naphthyl

Me (S)-2-butyl 69-Anthryl

tBu (S)-2-butyl 11PhtBu (S)-2-butyl 122-Naphthyl

Me (+)-neomenthyl 7Ph

1'2'

3'4'

(+)-Neomenthanethiol

(R)

MeSH

(a)

(b)

Methanethiol

Fig. 4. (a) Structure of the thiols used in this study. (b) AMAA and ATBAA thioestersselected for the calculations (1e12).

S. Porto et al. / Tetrahedron 70 (2014) 3276e32833278

than the experimental error are obtained for the L1/L2 groupsaround the chiral center(s).

b) Dynamic NMR (DNMR) experiments can be carried out i.e., bylowering the probe temperature in order to get information onthe conformational equilibrium and characteristics of the CDA-substrate entity. Other experimental techniques, such as CD,can also be very useful for this objective.

c) Theoretical calculations (MM, semiempirical, aromatic shield-ing effects, etc.) are an important tool in this context becausehelp to clarify the conformational scenario. Particularly im-portant is to identify the minimum energy conformers, theirenergy differences, the orientation of the anisotropic group andthe shielding effects on L1/L2 associated to each conformer. Thisinformation should be coherent with the chemical shifts ob-served in the NMR spectra considering a fast equilibrium be-tween conformers.

d) As a result of the previous points, the typical ‘3D spatial models’reflecting the correlation between chemical shifts of L1/L2 (DdRS

signs) and their spatial location (absolute configuration) can behypothesized and submitted to experimental validation witha series, as large and structurally varied as possible, of sub-strates of known absolute configuration.

2.2.2. Designing a new CDA: the importance of the theoretical cal-culations. If the use of known CDAs for the assignment of a newclass of substrate is not satisfactory (i.e., too small DdRS values orirregular distribution of signs), then a new CDA should be designed,synthesized and tested experimentally as outlined above.

In our experience, instead of proceeding to a ‘blind search’ or tointroduce modifications on known CDAs without a rational guid-ance, it is far better to carry out theoretical calculations on poten-tially interesting CDAs so that we can predict the effect of structuralmodifications.

A case where the protocol here outlined has proven to be par-ticularly useful is represented by the search of CDA for the as-signment of the absolute configuration of chiral secondary thiols.5

We describe here that protocol in the belief that it will be of usefor those interested in the design of CDAs.

2.3. Chiral thiols: a case study

The first decision to be taken in the design of the CDA for thiols, isthe selection of linkage between the substrate (thiol) and the CDA.Although there are obvious differences with carboxylic esters andamides, thioester functionality seemed appropriate to start with.

Thus, just a few thiols of known absolute configuration andconsidered as test compounds, were derivatized with the AMAAs ofFig. 2 and the corresponding thioesters examined by NMR.5

Interestingly, the NMR spectra of those derivatives produced inall cases essentially the same chemical shifts and small DdRS values,independently of the aromatic ring present in the auxiliary.

Apart from the small DdRS values that may limit in some casesthe usefulness of those auxiliaries as CDAs for thiols, the lack ofNMR response when the aryl ring of the CDA is changed is sur-prising. In fact, the relative effectiveness of those CDAs to separatethe signals of enantiomeric alcohols and amines (carboxylic acidester and amide derivatives) is known to vary with the richness ofaromatic ring and the DdRS values increase in the order MPA<1-NMA<2-NMA<9-AMA.4a,b,15

Obviously, the substitution of sulfur for oxygen in the linkagebetween the CDA and the substrate breaks that rule probably due tothe different size, electronic, steric and conformational propertiesof the thioester with respect to the carboxylic ester and amidegroups.

This stresses the need for developing a specific CDA for thiolsand following the reasoning of point 2 above, modelling studies

(DFT calculations) on a series of aryl and alkoxy modified AMAAthioesters were carried out in order to predict, which structuralmodifications could lead to an effective CDA for NMR assignment ofchiral thiols.

2.3.1. Theoretical studies of CDA thioesters. The series of AMAAthioesters (1e12), indicated in Fig. 4, and comprising variations inthe Ar, and OR groups of the CDA part and on the substrate (met-anothiol, (S)-butane-2-thiol and (þ)-neomenthanethiol), weresubmitted to DFT calculations.

For the sake of simplicity, the results of the replacement of thearyl group (maintaining unchanged the methoxy) are discussedfirst (structures 1e7), while the combined effect of changing thearyl and the alkoxy groups (structures 8e12) are discussedafterwards.

2.3.2. The effect of replacement of the aryl group: the conformation ofthe thioesters 1e7 by theoretical studies. The main conformers in-volved in the equilibra were obtained by rotation of the CaeOR1,CaeCAr, CaeCO, and SeCa0 bonds (Fig. 5).16 Potential energy sur-faces (PES) scans of 1e7were carried out using DFT at the B3LYP/6-31G* level17 using Gaussian 03.18 Equilibrium geometries and en-ergies of stable conformations identified from the PES scans werethen obtained at the B3LYP/6-31G* levels. Harmonic frequencieswere computed analytically to characterize stationary points and toget ZPVE corrections. In addition, solvents effects were modelledusing the polarizable continuum model (PCM), employing thechloroform parameters provided with Gaussian 03 and the single-point energies were computed at the PCM-B3LYP/6-31G* level aswell.19

In the case of the AMAA thioesters of methanothiol (1e3), thecalculations show that the most important conformers are ob-tained by rotation of CaeCO, CaeOMe and CaeCAr bonds (Fig. 5).The potential energy profiles around the CaeCO had two energyminima: the ap conformation, in which the CaeOMe bond wasantiperiplanar with respect to the C]O bond and the sp confor-mation, in which these two bonds were in a synperiplanar dispo-sition. The calculations indicated also that the ap conformation ismore stable than the sp conformation (Table 1).

Fig. 5. Main conformers of the AMAA thioesters by rotation around the highlighted bonds from theoretical calculations.

Fig. 6. Main orientation of the anthryl ring in 9-AMA thioester of (S)-butane-2-thiol(6) from the calculations.

Table 1Calculated relative energies (DE0, kcal/mol) for themain conformations of the AMAAthioesters of methanethiol (1e3)

Conformer Species

1 2 3

ap1 0.00 0.00 d

ap2 0.11 0.24 0.00ap10 d 0.34 d

ap20 d 0.32 d

sp1 1.60 1.97 1.05sp2 2.11 2.52 1.91sp10 d 1.62 d

sp20 d 2.11 d

S. Porto et al. / Tetrahedron 70 (2014) 3276e3283 3279

Two ap (ap1 and ap2) and two sp (sp1 and sp2) conformers arefound in the study of the rotation around the CaeOMe bond. Thedifference between these two ap rotamers (or the two sp rotamers)is the orientation of themethoxy groupwith respect to the carbonylgroup, that is, gauche for ap1 (or sp1) and anti for ap2 (or sp2).

Finally, the conformational preference around the CaeCAr bondrevealed a minimum energy structure, with the aryl ring and theCaeOMe bond almost coplanar in the ap conformations (ap1 andap2) and the aryl ring and the CaeH bond coplanar in the sp (sp1and sp2). For thioester 2, with a non symmetrically substitutednaphthyl group, both anti and syn orientations of the naph-thyleH(2) with respect to the CaeH bond are significative. In thecase of thioester 3, the anthryl ring and the CaeH bonds are almostcoplanar in ap and sp conformations. Both the phenyl and thenaphthyl rings are oriented with respect to the substrate partsimilarly to MPA thioesters while in 3, the anthryl ring seems to berotated (Fig. 6).

Analysis on the AMAA thioesters of (S)-butane-2-thiol (4, 5, and6) and (þ) neomenthanethiol (7) produced conformations verysimilar in structure and energy, to those of the AMAA thioesters ofmethanothiol, suggesting that the nature of the thiol (R2) has notmuch influence on the geometry of the AMAA thioester moiety.20

In particular, rotation around the SeCa0 bond of the AMAAthioesters of (S)-butane-2-thiol (4, 5) generated four lower energyrotamers named as syn, cisoids (cþ and c�), and anti (Fig. 5).21

Conformer syn has the two bonds COeS and Ca0eH at wþ15�,conformer cþ has those two bonds at wþ30�, conformer c� hasthose two bonds at w�30�, and conformer anti has those twobonds at wþ180�. The energy data indicate that rotamers syn, cþ,c� are the most representative ones and their energy are verysimilar.22 Again, the phenyl and the naphthyl rings point theirshielding sides to the substrate L1/L2 substituents.

For its part, when the 9-AMA thioester 6 was examined, thecalculations showed that the most stable conformer (antiperiplanar;Fig. 6) has the anthryl group in a conformation that projects itsshielding conewell away from the substrate (L1/L2), therefore uselessas CDA, similarly to what had been observed in compound 3.

In resume, modelling of the CDA thioesters varying the arylgroups predicts that:

a) In general, there are several conformers with significantpopulation.

b) In the main conformations, the phenyl and 2-naphtyl rings areoriented with the shielding cone approximately pointing to

S. Porto et al. / Tetrahedron 70 (2014) 3276e32833280

L1/L2 but the anthryl ring is badly oriented for effectiveshielding of L1/L2 in the substrate.

c) The conformational composition of those AMAA thioestersdoes not vary with the structure of the thiol.

While point c) is positive because it suggests that those CDAwillbehave the same with any thiol, points a and b clearly indicate thatreplacement of the aryl ring in thioesters is not the way to generateeffective CDA for thiols from a chiral phenylacetic acids.

2.3.3. The effect of replacement of the aryl group: experimental ver-ification. The reliability of those predictions on thioesters 1e7 canbe experimentally demonstrated by simple NMR experiments.

Thus, in the (R)-MPA thioester of (S)-butane-2-thiol and neo-menthyanethiol (4 and 7), the substituent L2 is shielded by thephenyl ring in ap conformations while the substituent L1 is notaffected (see Fig. 7a), therefore substituent L1 is shielded in spconformations while the L2 remains unaffected and the oppositesituation occurs in the (S)-MPA thioester (see Fig. 7b). Given thatthe ap forms are more abundant than the sp forms, L2 will be moreshielded in the (R)-MPA thioester than in the (S)-MPA thioester andwill produce negative DdRS values (see Fig. 7c), whilst L1 will bemore shielded in the (R)-MPA thioester than in the (S)-MPA thio-ester and will produce positive DdRS values (Table 2).23

Fig. 7. Equilibria between the ap and sp rotamers of (a) (R)-MPA thioester of (S)-bu-tane-2-thiol [(R)-4] and (b) (S)-MPA thioester of (S)-butane-2-thiol [(S)-4]. Red arrowsindicate the shielding effect caused by the aromatic system. (c) Distribution of DdRS

signs for MPA thioesters from the 1H NMR spectra.

Table 2DdRS values (ppm) for MPA thioesters of (S)-butane-2-thiol (4), 2-NMA thioesters of(S)-butane-2-thiol (5), PTBA thioesters of (S)-butane-2-thiol (11), and 2-NTBAthioesters of (S)-butane-2-thiol (12)a

Compound CH3(10) CH2(30) CH3(40)

4 þ0.07 �0.05 �0.065 þ0.08 d �0.0711 þ0.10 �0.09 �0.1012 þ0.12 �0.10 �0.12

a In CDCl3.

In the case of the 2-NMA thioesters (5), the shielding effects aresimilar to those with the MPA because the conformational equilibraare analogous, and the same distributions of DdRS signs are ob-served (Table 2). The change of the aromatic ring (2-naphtyl insteadof phenyl ring) increases slightly the DdRS values.

For its part, the introduction of the anthryl ring as in 9-AMAthioesters (6) produced only very small DdRS in accordance withthe bad orientation of the anthryl group with respect to L1/L2(Fig. 6).

Further experimental evidence on the reliability of the calcula-tions to predict the energies and conformations can be obtainedfrom low temperature, solvent polarity and NOESY NMRexperiments.5

Thus, in accordance with the difference of energy between theap and spmain conformers (1.6 kcal/mol forMPA thioesters), the 1HNMR spectra of these thioesters taken at different temperatures(from 298 to 183 K) showed no changes on the L1/L2 chemical shifts(Fig. 8). The only change observed, concerns H(20) and is attributedto the interconversion between syn, c� and cþ forms.

Fig. 8. Partial 1H NMR spectra of the (R)-MPA thioester of (S)-butane-2-thiol in 4:1CS2/CD2Cl2 at different temperatures.

Similarly, as DFT calculations revealed that the ap and sp formspresent quite similar dipole moments (e.g., m for 1 are 1.0, 1.6, 1.4and 1.9 D for ap1, ap2, sp1 and sp2 forms, respectively), the use ofsolvents of different polarity should not modify significantly nei-ther the ratio of the ap/sp populations nor the NMR spectra.

In fact, the NMR spectra of (R)- and (S)-MPA thioesters of (S)-octane-2-thiol (13) recorded in several solvents (Table 3), producedsimilar DdRS values and the same distribution of signs regardless ofthe polarity.

Table 3DdRS values (ppm) obtained for MPA thioesters of (S)-octane-2-thiol (13) in differentdeuterated solvents

SMPA

1' 3' 5'4'

13

Solvent CH3(10) CH2(30) [CH2]4(40) CH3(50)

CS2/CD2Cl2 (4:1) 0.08 �0.05 �0.06 �0.03CDCl3 0.07 �0.04 �0.05 �0.03CD3CN 0.08 �0.03 �0.04 �0.02MeOD 0.08 �0.04 �0.07 �0.03(CD3)2CO 0.06 �0.04 �0.06 �0.03

2.3.4. The effect of replacement of the inductor group: the confor-mation of thioesters 8e12 by theoretical studies. Calculations in-dicated that substitution of the aryl ring, as in 1e7, leads to theexistence of several main conformations with a fairly oriented

S. Porto et al. / Tetrahedron 70 (2014) 3276e3283 3281

phenyl or 2-naphthyl rings and an unfavourable orientation of theanthryl ring. This leads to small DdRS values and therefore neithercompounds 1e7 are good CDAs for thiols. Those results suggest thatin order to gain higher DdRS values, the introduction of stericallydemanding alkoxy groups instead of the methoxy group, as in 1e7,could lead to restrictions in the conformational equilibrium, andtherefore to the existence of a dominant conformer. Next, wepresent the results of the DFT calculations and NMR results ob-tained by replacement of the methoxy group of 1e7 by tert-butoxyas in 8e12.

Thus, DFT calculations on the thioesters 8 and 11, containingphenyl and tert-butoxy group, showed a conformational composi-tion qualitatively similar to those of MPA thioesters 1 and 4, withrotation around CaeCO, CaeOtBu leading to three main rotamers inequilibrium: ap2, sp1 and sp2, the ap rotamers being the moststable one. Nevertheless, the energy data indicates that the DEbetween the ap and sp conformers is higher in the tert-butoxycontaining thioesters (8 and 11) than in MPA thioesters 1 and 4(Fig. 9a). From the conformational standpoint, this should lead anincrease of the DdRS values due to a rise of populations of the apconformers in equilibrium, induced by an increment of the energydifference between the sp and ap forms.

H

L1L2OMe

Ph H L2

H

L1

OMe

PhH

apsp

ΔE= 1.6 Kcal/mol

δL (ap)δL (sp)

δL

δ (ppm)

populationsp

populationap

H NMR

H

L1L2OtBu

Ph HL2

H

L1

OtBu

PhHap

sp

ΔE= 2.4 Kcal/mol

H NMRδL (ap)

δL (sp)

δL

δ (ppm)

populationsp

populationap

(a)

(b)

Dihedral Cα-Ar (deg)

AE (k

cal/m

ol)

(R)-MPASMe (1)(R)-2NMASMe (2)(R)-PTBASMe (8)(R)-2NTBASMe (9)

Fig. 9. (a) Conformational equilibrium between ap and sp forms in MPA thioesters andPTBA thioesters. (b) Potential energy curves for AMAA thioesters of methanothiol (1, 2)and ATBAA thioesters of methanothiol (8, 9) as a function of the CaeAr dihedral anglescalculated with the B3LYP/6-31G* approximation.

O

OHH

O

(R)-2-NTBA

Me

MeMe

O

OHO

H

(S)-2-NTBA

Me

MeMe

Fig. 10. Structure of the CDAs of choice for the NMR assignment of the absoluteconfiguration of chiral thiols [(R)- and (S)-2-naphtyl tert-butoxyacetic acids].

For their part, calculations on model thioesters 9 and 12,(2-naphtyl and tert-butoxy) indicated also a conformational com-position qualitatively similar to that of 8 and 11 (2-naphtyl andmethoxy) with two ap conformers (ap2, ap20) and four sp con-formers (sp1, sp10, sp2, sp20) that differ in the orientation of theasymmetrically substituted 2-naphtyleH(2) with respect to theCaeH bond.24 Nevertheless, the energy barrier to rotation aroundCaeCAr shows a clear increase when the methoxy group is replacedby the bulkier tert-butoxy group (Fig. 9b) and this should lead anincrease of the DdRS values, too.

Finally, calculations on thioester 10 (9-anthryl and tert-butoxy)indicated, as before in 3 and 6, a bad orientation of the shieldingcone with respect to substituents L1/L2, that is, not compensated bythe increased DE.

In summary, the calculations predict that anthryl substitutedalkoxyacetic acid cannot be considered potentially efficient CDA forthiols. For their part, the phenyl and 2-naphtyl substituted com-pounds show a good orientation of the aryl ring to shield thesubstrate, while the presence of a bulky tert-butoxy favours the apconformers over the sp ones. These two factors point to the phenyland 2-naphtyl tert-butoxyacetic acids as the most potentially in-teresting CDAs for configurational assignment of chiral thiols.

2.3.5. The effect of replacement of the inductor group: experimentalverification. When NMR spectra of thioesters 4, 5, 11 and 12 arecompared, the DdRS values of the tert-butoxy substituted ones fol-low the order expected from the richness of the aromatic systemleading to choose (R)- and (S)-2-naphtyl tert-butoxyacetic acids(Fig. 10)25 as the best CDAs for thiols (Table 2).

Experimental demonstration of the accuracy of this choice wasobtained by recording the NMR spectra thioesters of a series ofthiols of known absolute configuration and varied structures.26

3. Conclusion

A general protocol for the design of reliable Chiral DerivatizingAgents (CDAs) for the NMR assignment of absolute configuration oforganic compounds is presented using as example the de-velopment of a new arylalkoxyacetic acid based reagent for theassignment of chiral thiols.

In this protocol, theoretical calculations play a central role topredict the conformational composition of virtually modified ary-lalkoxyacetic acid reagents. Those predictions are then checked bydifferent NMR experiments identifying the substituents leading toan optimal CDA.

In this way, energy calculations on modelled thioester de-rivatives predict that the modification of the aryl system of anarylmethoxyacetic acid is not sufficient to provide a good CDA,while the introduction of a sterically hindered tert-BuO group in-stead results in a more appropriate conformational composition.Combination of both substitutions eventually led to 2-naphtyl-tert-butoxyacetic acid as the best suited CDA for thiols. The reliability ofthis reagent has been checked with a number of chiral thiols ofknown absolute configuration.

4. Experimental section

4.1. General procedures

The thioesters (4e7 and 11e13) were prepared by treatment ofthe thiol (1 equiv; 0.150 mmol) with the corresponding arylme-thoxyacetic acid or aryl-tert-butoxyacetic acid (1.2 equiv;0.180 mmol) in the presence of EDCHCl (1.2 equiv; 0.180 mmol) andDMAP (catalytic) in dry CH2Cl2 (2.5 mL), and under argon atmo-sphere (EDCHCl¼1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,

S. Porto et al. / Tetrahedron 70 (2014) 3276e32833282

DMAP¼4-dimethylaminopyridine). The mixtures were stirred atroom temperature for 2e4 h approximately. The organic layers werewashed with water, HCl (1 M), water, NaHCO3 (sat) and water, thendried (anhydrous Na2SO4) and concentrated under reduced pressureto obtain the thioesters. Final purifications were achieved by flashcolumn chromatography on silica gel 230e400 mesh (elution withhexane/ethyl acetate mixtures). Yields ranging from 80 to 95 %.

4.2. Theoretical calculations

See detailed description in Section 2.3.2 and references within.

4.3. NMR spectroscopy

1H NMR spectra of samples in 4:1 CS2/CD2Cl2 (5 mg in 0.6 mL) atdifferent temperatures were recorded at 500 MHz. 1H NMR spectraof (R)- and (S)-13 in CDCl3, CD3CN, MeOD and (CD3)2CO wererecorded at 250 MHz. Chemical shifts (parts per million) are in-ternally referenced to the TMS signal (0.00 ppm) in all cases. Jvalues are recorded in Hertz.

4.3.1. [298 K] (R)-MPA thioester of (S)-butane-2-thiol [(R)-4]. 1HNMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.85 (t, J¼7.3 Hz, 3H), 1.24(d, J¼6.9 Hz, 3H), 1.47e1.52 (m, 2H), 3.29e3.35 (m,1H), 3.40 (s, 3H),4.56 (s, 1H), 7.23e7.30 (m, 5H).

4.3.2. [183 K] (R)-MPA thioester of (S)-butane-2-thiol [(R)-4]. 1HNMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.85 (t, J¼7.3 Hz, 3H), 1.25(d, J¼6.8 Hz, 3H), 1.47e1.55 (m, 2H), 3.19e3.23 (m, 1H), 3.38 (s, 3H),4.61 (s, 1H), 7.28e7.31 (m, 5H).

4.3.3. [298 K] (S)-MPA thioester of (S)-butane-2-thiol [(S)-4]. 1HNMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.92 (t, J¼7.4 Hz, 3H), 1.16(d, J¼6.9 Hz, 3H), 1.53e1.59 (m, 2H), 3.30e3.34 (m,1H), 3.40 (s, 3H),4.56 (s, 1H), 7.23e7.30 (m, 5H).

4.3.4. [183 K] (S)-MPA thioester of (S)-butane-2-thiol [(S)-4]. 1HNMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.94 (t, J¼7.1 Hz, 3H), 1.15(d, J¼6.7 Hz, 3H), 1.51e1.59 (m, 2H), 3.23e3.27 (m, 1H), 3.39 (s, 3H),4.61 (s, 1H), 7.28e7.33 (m, 5H).

4.3.5. [298 K] (R)-MPA thioester of (þ)-neomenthanethiol [(R)-7]. 1HNMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.57 (d, J¼6.5 Hz, 3H), 0.81(d, J¼6.6 Hz, 3H), 0.85 (d, J¼6.5 Hz, 3H), 0.87e0.99 (m, 2H),1.04e1.12 (m, 1H), 1.18e1.30 (m, 2H), 1.56e1.62 (m, 1H), 1.70e1.80(m, 3H), 3.38 (s, 3H), 3.87e3.90 (m, 1H), 4.58 (s, 1H), 7.23e7.30 (m,5H).

4.3.6. [183 K] (R)-MPA thioester of (þ)-neomenthanethiol [(R)-7]. 1HNMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.51 (d, J¼6.0 Hz, 3H), 0.86(d, J¼6.1 Hz, 6H), 0.88e0.96 (m, 2H), 1.05e1.09 (m, 1H), 1.18e1.28(m, 2H), 1.54e1.61 (m, 1H), 1.67e1.72 (m, 2H), 1.83e1.86 (m, 1H),3.33 (s, 3H), 3.76 (br s, 1H), 4.59 (s, 1H), 7.26e7.31 (m, 5H).

4.3.7. [298 K] (S)-MPA thioester of (þ)-neomenthanethiol [(S)-7]. 1HNMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.75 (d, J¼6.5 Hz, 3H), 0.78(d, J¼6.3 Hz, 3H), 0.86 (d, J¼6.5 Hz, 3H), 0.88e0.99 (m, 2H),1.07e1.11 (m, 1H), 1.18e1.24 (m, 1H), 1.32e1.39 (m, 1H), 1.45e1.58(m, 2H), 1.68e1.70 (m, 1H), 1.77e1.81 (m, 1H), 3.39 (s, 3H),3.92e3.95 (m, 1H), 4.57 (s, 1H), 7.22e7.30 (m, 5H).

4.3.8. [183 K] (S)-MPA thioester of (þ)-neomenthanethiol [(S)-7]. 1HNMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.73 (d, J¼6.5 Hz, 3H), 0.79(d, J¼5.9 Hz, 3H), 0.86e0.94 (m, 5H), 1.07e1.11 (m, 1H), 1.19e1.24(m, 1H), 1.30e1.37 (m, 1H), 1.45e1.47 (m, 2H), 1.68e1.73 (m, 1H),

1.81e1.85 (m,1H), 3.36 (s, 3H), 3.88 (br s, 1H), 4.61 (s,1H), 7.27e7.33(m, 5H).

4.3.9. (R)-MPA thioester of (S)-octane-2-thiol [(R)-13]. 1H NMR(500.13 MHz, CS2/CD2Cl2) d (ppm): 0.84 (t, J¼7.0 Hz, 3H), 1.18 (br s,8H), 1.24 (d, J¼6.8 Hz, 3H), 1.42e1.46 (m, 2H), 3.33e3.37 (m, 1H),3.39 (s, 3H), 4.55 (s, 1H), 7.22e7.30 (m, 5H).

1H NMR (250.13MHz, CDCl3) d (ppm): 0.84 (t, J¼6.7 Hz, 3H), 1.20(br s, 8H), 1.29 (d, J¼6.9 Hz, 3H), 1.46e1.56 (m, 2H), 3.46 (s, 3H),3.46e3.57 (m, 1H), 4.71 (s, 1H), 7.32e7.45 (m, 5H).

1H NMR (250.13 MHz, CD3CN) d (ppm): 0.84 (t, J¼6.9 Hz, 3H),1.21 (br s, 8H), 1.26 (d, J¼6.9 Hz, 3H), 1.46e1.54 (m, 2H), 3.40 (s, 3H),3.41e3.47 (m, 1H), 4.78 (s, 1H), 7.36e7.41 (m, 5H).

1H NMR (250.13 MHz, MeOD) d (ppm): 0.86 (t, J¼6.8 Hz, 3H),1.22 (br s, 8H), 1.27 (d, J¼6.9 Hz, 3H), 1.46e1.55 (m, 2H), 3.43 (s, 3H),3.44e3.50 (m, 1H), 4.78 (s, 1H), 7.32e7.42 (m, 5H).

1H NMR (250.13 MHz, (CD3)2CO) d (ppm): 0.84 (t, J¼6.8 Hz, 3H),1.21 (br s, 8H), 1.27 (d, J¼6.9 Hz, 3H), 1.47e1.55 (m, 2H), 3.41e3.50(m, 4H), 4.82 (s, 1H), 7.33e7.45 (m, 5H).

4.3.10. (S)-MPA thioester of (S)-octane-2-thiol [(S)-13]. 1H NMR(500.13 MHz, CS2/CD2Cl2) d (ppm): 0.87 (t, J¼6.8 Hz, 3H), 1.15 (d,J¼6.9 Hz, 3H), 1.24 (br s, 8H), 1.47e1.53 (m, 2H), 3.34e3.38 (m, 1H),3.39 (s, 3H), 4.55 (s, 1H), 7.22e7.29 (m, 5H).

1H NMR (250.13MHz, CDCl3) d (ppm): 0.87 (t, J¼6.5 Hz, 3H), 1.22(d, J¼6.9 Hz, 3H), 1.25 (br s, 8H), 1.50e1.60 (m, 2H), 3.46 (s, 3H),3.47e3.52 (m, 1H), 4.71 (s, 1H), 7.32e7.45 (m, 5H).

1H NMR (250.13 MHz, CD3CN) d (ppm): 0.87 (t, J¼6.7 Hz, 3H),1.19 (d, J¼6.9 Hz, 3H), 1.26 (br s, 8H), 1.51e1.58 (m, 2H), 3.40 (s, 3H),3.41e3.48 (m, 1H), 4.79 (s, 1H), 7.36e7.41 (m, 5H).

1H NMR (250.13MHz,MeOD) d (ppm): 0.89 (t, J¼6.7 Hz, 3H),1.21(d, J¼6.9 Hz, 3H), 1.27 (br s, 8H), 1.51e1.58 (m, 2H), 3.43 (s, 3H),3.44e3.51 (m, 1H), 4.79 (s, 1H), 7.32e7.42 (m, 5H).

1H NMR (250.13 MHz, (CD3)2CO) d (ppm): 0.88 (t, J¼6.7 Hz, 3H),1.20 (d, J¼6.9 Hz, 3H), 1.29 (br s, 8H), 1.53e1.61 (m, 2H), 3.41e3.48(m, 4H), 4.82 (s, 1H), 7.33e7.45 (m, 5H).

Acknowledgements

This workwas supportedwith grants fromMinisterios de Cienciae Innovaci�on y de Economía y Competitividad (CTQ2009-08632,CTQ2012-33436) and Xunta de Galicia (PGIDIT09CSA029209PR,CN2011/037). We also thank Prof. Federico Gago (Universidad deAlcal�a de Henares) and Dr. Armando Navarro (Universidad de Vigo)for their assistance with the computational work, and the Centro deSupercomputaci�on de Galicia (CESGA) for granting computer timeused in the quantum chemical calculations.

References and notes

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16. The rotation around the COeS bond on thioesters has been previously studiedand it shows that the cis planar form is the most stable. See: (a) Deerfield, D. W.II; Pedersen, L. G. J. Mol. Stuct. (Theochem) 1995, 358, 99e106; (b) Nagy, P. I.;Tejada, F. R.; Sarver, J. G.; Messer, W. S. J. Chem. Phys. A 2004, 108, 10173e10185;

(c) Erben, M. F.; Boese, R.; Della V�edova, C. O.; Oberhammer, H.; Willner, H. J.Org. Chem. 2006, 71, 616e622.

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18. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;Cheeseman, J. R.; Montgomery, J. A. Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.;Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian03, Re-vision C.02; Gaussian: Wallingford, CT, 2004.

19. Tomasi, J.; Persico, M. Chem. Rev. 1994, 94, 2027e2094.20. When the solvent effects (CHCl3) were taken into account by using a PCM

model, we found that the relative energies of these conformations did not varysubstantially (around 0.5 kcal/mol).

21. West, R.; Michl, J. Acc. Chem. Res. 2000, 33, 821e823.22. When we studied the rotation of the SeCa0 bond of thioester 7 (with a cyclic

thiol moiety), we found only two conformers (syn and anti). The syn form is themost relevant one

23. As the phenyl group in ap conformations occupies the same relative positionwith respect to L1/L2, all ap conformations are equivalent from the NMR pointof view, and the same occurs with the sp conformations.

24. Conformers ap2, sp1 and sp2 have the CAreH(2) bond syn to CaeH and con-formers ap20 , sp10 and sp20 have the CAreH(2) bond anti to CaeH.

25. Synthesis of (R)- and (S)-2-naphthyl-tert-butoxyacetic acid and other aryl-tert-butoxyacetic acids can be found at the SI in Ref. 5.

26. The 1H NMR spectra (R)- and (S)-MPA and 2-NTBA thioesters of the diversethiols tested showed the same distribution of DdRS signs for the protons of theside chains L1 and L2 as (R)- and (S)-4. See Ref. 5.