Tetrahedron 70 (2014) 3276e3283

Contents lists available at ScienceDirect

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

Designing chiral derivatizing agents (CDA) for the NMR assignment

of the absolute conguration: a theoretical and experimental
approach with thiols as a case study
~ oa
, Ricardo Riguera *
Silvia Porto, Emilio Quin
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

a b s t r a c t

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

A general protocol for the design of successful chiral derivatizing agents (CDAs) for the NMR assignment
of absolute conguration is described. The design of the most efcient arylalkoxyacetic acid reagent for
the assignment of chiral thiols is taken as example. The importance of theoretical calculations in the
discovery of the conformational preference of modelled arylmethoxyacetic acid (AMAA) thioesters is
stressed, as well as NMR experiments to conrm the conformations predicted for the different CDAs and
to select for synthesis the most adequate for that substrate. The modication of the aryl moiety of the
AMAA system has shown not to provide especially good CDAs while the introduction of a sterically
hindered tert-BuO group results in a more appropriate conformation leading to 2-naphtyl-tert-butoxyacetic acid (2-NTBA) as the most efcient CDA for thiols.
2013 Elsevier Ltd. All rights reserved.

Keywords:
Chiral derivatizing agent (CDA)
Arylalkoxyacetic acid
Nuclear magnetic resonance (NMR)
Absolute conguration
Chiral thiols
Theoretical modelling
Aryl-tert-butoxyacetic acids (ATBAAs)

1. Introduction
Since the seminal works of pioneers like Mosher,1 NMR methods
for the assignment of absolute conguration have experienced
a large development in the last decades and have given solutions to
researchers in many elds of Chemistry where to know the threedimensional structure of chiral structures is a must (Natural Products, Asymmetric Synthesis, Analysis of Pharmaceuticals.).2 In the
most usual approach, the absolute conguration 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 reaction
with the two enantiomers of an appropriate chiral derivatizing
agent (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 diastereomeric derivatives obtained. To be more specic, the chemical shifts of the substituents bonded to the chiral centre of the
substrate (L1/L2) must be compared, and the absolute conguration
is determined in accordance with the signs of their differences
(DdRSL1 and DdRSL2)12 in both derivatives (Fig. 1).

* Corresponding author. E-mail address: ricardo.riguera@usc.es (R. Riguera).

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

(R)-CDA

Model

R R

NMR
Analysis

L
L

L
R
(S)-CDA

X
R R

CDA-X

L
L

O
(?)-A

(R)-CDA-(?)-A

H
HX

O
R

L
L

(S)-CDA-(?)-A

Configuration
assigned

Fig. 1. Conceptual representation of the assignment of the absolute conguration by

means of a double derivatization.

The assignment of conguration is therefore based on the

existence of a correlation between the absolute conguration at the
chiral centre of the CDA (i.e., known) and the chemical shifts of
L1/L2 in the two derivatives, what allows establishing the conguration of the chiral centre placed between L1/L2 (i.e., unknown).
These correlations are possible due to presence of groups at the
CDA, such as aryl rings that generate different and selective induced
anisotropic magnetic eld effects (shielding/deshielding) on the
L1/L2 substituents in each derivative.
More recently, methods that require the preparation of only one
derivative, instead of two, have been developed. They make use of
just one enantiomer of the CDA. In some cases, these methods

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

compare the spectrum of the free substrate and the spectrum of

the CDA-substrate derivative.13 In others, the methods are based in
the controlled manipulation of the conformational equilibrium
between the main conformers.14
Whatever method one decides to use, the choice of an adequate
CDA for the substrate whose chirality is going to be investigated is
of major importance. On numerous occasions, if the type of compound that needs to be derivatized has been studied previously
(i.e., a secondary alcohol, a primary amine), the appropriate CDA
will either be commercially available or easily prepared.
However, in other cases, researchers will need to design and
develop brand new auxiliaries to face new challenging structural
situations, such as functional groups not previously tested, new
polyfunctional compounds, complex molecular frameworks, and so
on.
In this paper, we describe a general approach and protocol to
help researchers to develop new effective and reliable CDAs
investing the minimum of experimental work. The use of theoretical calculations and modelling to predict the effect of structural
changes is stressed. The design of a 2-naphtyl-tert-butoxyacetic
acid as CDA for assignment of absolute conguration of thiols is
described as a case study.
2. Results and discussion
2.1. Chiral derivatizing agents: general characteristics
Since the rst reagents proposed by Mosher (i.e., MTPA, MPA in
Fig. 2), many other structurally different types of compounds have
been proposed as CDAs for a variety of functional groups.2
However, the use of some chiral auxiliaries has been occasional
and in many cases, the methods were just empirical lacking information on any type of conformational studies (theoretical, dynamic NMR.) to support their behaviour. Additionally, many of
those reagents were usually tested with either very few compounds
of known absolute conguration or without the required structural
diversity, so their use could not be called general.

MeO
H

OH

MeO
F3 C

OH

MeO
H

(R)-MPA

(R)-MTPA

MeO
H

OH

OH

(R)-1-NMA

MeO
H

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

The linker is the functional group that connects the auxiliary to

the chiral substrate through a covalent bond. So, it has to be complementary to the functionality of the substrate. The covalent bond
created should have a restricted rotation to help to x a nal
prevalent conformation on the CDA-substrate system. The coupling
reaction between the substrate and the CDA should make use of
experimental conditions as smooth as possible so it does not
modify other parts of the substrate. Also, it should render high
yields (ideally, quantitative) and, in those cases when the CDA reacts simultaneously with two enantiomers, kinetic resolution must
be avoided.
The anisotropy magnetic group generates the main induced
anisotropic magnetic eld effects (shielding/deshielding) that must
give rise to perceptible shifts in the NMR signals (1H, 13C, 19F, 31P.)
of the substrate investigated. The anisotropic effect that it is
a through-space phenomenon, must show appropriate strength
(intensity) to generate effective shifts. Also, the shape and orientation of the magnetic cone respect the substrate (its spatial selectivity) must be adequate. Typical anisotropic systems are those
with high p electron density: aromatic rings, carbonyl groups, triple bonds and so, being the rst ones the most used (aromatic
systems based on aryl rings).
The inductor is a conformation-directing group whose role is to
stabilize a certain major conformer, generating a well-dened
conformational preference. It can act mainly through polar or steric effects as well as by formation of hydrogen bonds.
The supplementary group plays a subordinate role with respect
to the other three substituents. It should collaborate with these
substituents or at least do not obstruct them.
In general, the reagents should have the smallest possible
number of NMR signals so they do not overlap with those of the
substrate or they must be in zones of the d scale where they do not
interfere. If so, this condition avoids the need to resort to complex
and expensive routes in order to synthesize deuterated reagents.

OH
O

O
(R)-2-NMA

3277

(R)-9-AMA

Fig. 2. Selection of arylmethoxyacetic acids used as CDAs for congurational assignment by NMR.

2.2. General procedure for the design of reliable and general

CDAs
The following course of action can be followed when choosing
or designing a CDA appropriate for a new class of compounds.
2.2.1. Experimental and theoretical studies with known CDAs.

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

a) NMR screening (1H, 13C) of potentially interesting CDAs that

have proven to be effective with other groups and able to make
covalent linkages with the functional group/s under study
should be performed with a selection of substrates of known
absolute conguration. Simple model compounds with easily
recognized signals should be chosen and tested in order to
appreciate if coherent DdRS signs and signicant values greater

3278

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

than the experimental error are obtained for the L1/L2 groups
around the chiral center(s).
b) Dynamic NMR (DNMR) experiments can be carried out i.e., by
lowering the probe temperature in order to get information on
the conformational equilibrium and characteristics of the CDAsubstrate entity. Other experimental techniques, such as CD,
can also be very useful for this objective.
c) Theoretical calculations (MM, semiempirical, aromatic shielding effects, etc.) are an important tool in this context because
help to clarify the conformational scenario. Particularly important is to identify the minimum energy conformers, their
energy differences, the orientation of the anisotropic group and
the shielding effects on L1/L2 associated to each conformer. This
information should be coherent with the chemical shifts observed in the NMR spectra considering a fast equilibrium between conformers.
d) As a result of the previous points, the typical 3D spatial models
reecting the correlation between chemical shifts of L1/L2 (DdRS
signs) and their spatial location (absolute conguration) can be
hypothesized and submitted to experimental validation with
a series, as large and structurally varied as possible, of substrates of known absolute conguration.
2.2.2. Designing a new CDA: the importance of the theoretical calculations. If the use of known CDAs for the assignment of a new
class of substrate is not satisfactory (i.e., too small DdRS values or
irregular 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 to
introduce modications on known CDAs without a rational guidance, it is far better to carry out theoretical calculations on potentially interesting CDAs so that we can predict the effect of structural
modications.
A case where the protocol here outlined has proven to be particularly useful is represented by the search of CDA for the assignment of the absolute conguration of chiral secondary thiols.5
We describe here that protocol in the belief that it will be of use
for those interested in the design of CDAs.
2.3. Chiral thiols: a case study
The rst decision to be taken in the design of the CDA for thiols, is
the selection of linkage between the substrate (thiol) and the CDA.
Although there are obvious differences with carboxylic esters and
amides, thioester functionality seemed appropriate to start with.
Thus, just a few thiols of known absolute conguration and
considered as test compounds, were derivatized with the AMAAs of
Fig. 2 and the corresponding thioesters examined by NMR.5
Interestingly, the NMR spectra of those derivatives produced in
all 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 cases
the usefulness of those auxiliaries as CDAs for thiols, the lack of
NMR response when the aryl ring of the CDA is changed is surprising. In fact, the relative effectiveness of those CDAs to separate
the signals of enantiomeric alcohols and amines (carboxylic acid
ester and amide derivatives) is known to vary with the richness of
aromatic ring and the DdRS values increase in the order MPA<1NMA<2-NMA<9-AMA.4a,b,15
Obviously, the substitution of sulfur for oxygen in the linkage
between the CDA and the substrate breaks that rule probably due to
the different size, electronic, steric and conformational properties
of the thioester with respect to the carboxylic ester and amide
groups.
This stresses the need for developing a specic CDA for thiols
and following the reasoning of point 2 above, modelling studies

(DFT calculations) on a series of aryl and alkoxy modied AMAA

thioesters were carried out in order to predict, which structural
modications could lead to an effective CDA for NMR assignment of
chiral thiols.
2.3.1. Theoretical studies of CDA thioesters. The series of AMAA
thioesters (1e12), indicated in Fig. 4, and comprising variations in
the Ar, and OR groups of the CDA part and on the substrate (metanothiol, (S)-butane-2-thiol and ()-neomenthanethiol), were
submitted to DFT calculations.

(a)
1'

2'

3'
4'

MeSH
SH
Methanethiol

SH

(S)-Butane-2-thiol

(b)

(+)-Neomenthanethiol

O
R2

R1O (R)
Ar

S
H

Ar

R1

R2

Ph
2-Naphthyl

Me
Me

Me
Me

9-Anthryl

Me

Me

Ph

Me

(S)-2-butyl

2-Naphthyl

Me

(S)-2-butyl

9-Anthryl

Me

(S)-2-butyl

Ph

Me

(+)-neomenthyl

7
8

thioester

Ph

tBu

Me

2-Naphthyl

tBu

Me

9-Anthryl

tBu

Me

10

Ph

tBu

(S)-2-butyl

11

2-Naphthyl

tBu

(S)-2-butyl

12

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

For the sake of simplicity, the results of the replacement of the

aryl group (maintaining unchanged the methoxy) are discussed
rst (structures 1e7), while the combined effect of changing the
aryl and the alkoxy groups (structures 8e12) are discussed
afterwards.
2.3.2. The effect of replacement of the aryl group: the conformation of
the thioesters 1e7 by theoretical studies. The main conformers involved in the equilibra were obtained by rotation of the CaeOR1,
CaeCAr, CaeCO, and SeCa0 bonds (Fig. 5).16 Potential energy surfaces (PES) scans of 1e7 were carried out using DFT at the B3LYP/631G* level17 using Gaussian 03.18 Equilibrium geometries and energies of stable conformations identied from the PES scans were
then obtained at the B3LYP/6-31G* levels. Harmonic frequencies
were computed analytically to characterize stationary points and to
get ZPVE corrections. In addition, solvents effects were modelled
using the polarizable continuum model (PCM), employing the
chloroform parameters provided with Gaussian 03 and the singlepoint energies were computed at the PCM-B3LYP/6-31G* level as
well.19
In the case of the AMAA thioesters of methanothiol (1e3), the
calculations show that the most important conformers are obtained by rotation of CaeCO, CaeOMe and CaeCAr bonds (Fig. 5).
The potential energy proles around the CaeCO had two energy
minima: the ap conformation, in which the CaeOMe bond was
antiperiplanar with respect to the C]O bond and the sp conformation, in which these two bonds were in a synperiplanar disposition. The calculations indicated also that the ap conformation is
more stable than the sp conformation (Table 1).

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

3279

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

Table 1
Calculated relative energies (DE0, kcal/mol) for the main conformations of the AMAA
thioesters of methanethiol (1e3)
Conformer

Species
1

ap1
ap2
ap10
ap20
sp1
sp2
sp10
sp20

0.00
0.11
d
d
1.60
2.11
d
d

0.00
0.24
0.34
0.32
1.97
2.52
1.62
2.11

d
0.00
d
d
1.05
1.91
d
d

Two ap (ap1 and ap2) and two sp (sp1 and sp2) conformers are
found in the study of the rotation around the CaeOMe bond. The
difference between these two ap rotamers (or the two sp rotamers)
is the orientation of the methoxy group with respect to the carbonyl
group, that is, gauche for ap1 (or sp1) and anti for ap2 (or sp2).
Finally, the conformational preference around the CaeCAr bond
revealed a minimum energy structure, with the aryl ring and the
CaeOMe bond almost coplanar in the ap conformations (ap1 and
ap2) and the aryl ring and the CaeH bond coplanar in the sp (sp1
and sp2). For thioester 2, with a non symmetrically substituted
naphthyl group, both anti and syn orientations of the naphthyleH(2) with respect to the CaeH bond are signicative. In the
case of thioester 3, the anthryl ring and the CaeH bonds are almost
coplanar in ap and sp conformations. Both the phenyl and the
naphthyl rings are oriented with respect to the substrate part
similarly to MPA thioesters while in 3, the anthryl ring seems to be
rotated (Fig. 6).
Analysis on the AMAA thioesters of (S)-butane-2-thiol (4, 5, and
6) and () neomenthanethiol (7) produced conformations very
similar in structure and energy, to those of the AMAA thioesters of
methanothiol, suggesting that the nature of the thiol (R2) has not
much inuence on the geometry of the AMAA thioester moiety.20

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

(6) from the calculations.

In particular, rotation around the SeCa0 bond of the AMAA

thioesters of (S)-butane-2-thiol (4, 5) generated four lower energy
rotamers named as syn, cisoids (c and c), and anti (Fig. 5).21
Conformer syn has the two bonds COeS and Ca0 eH at w15 ,
conformer c has those two bonds at w30 , conformer c has
those two bonds at w30 , and conformer anti has those two
bonds at w180 . The energy data indicate that rotamers syn, c,
c are the most representative ones and their energy are very
similar.22 Again, the phenyl and the naphthyl rings point their
shielding sides to the substrate L1/L2 substituents.
For its part, when the 9-AMA thioester 6 was examined, the
calculations showed that the most stable conformer (antiperiplanar;
Fig. 6) has the anthryl group in a conformation that projects its
shielding cone well away from the substrate (L1/L2), therefore useless
as CDA, similarly to what had been observed in compound 3.
In resume, modelling of the CDA thioesters varying the aryl
groups predicts that:
a) In general, there are several conformers with signicant
population.
b) In the main conformations, the phenyl and 2-naphtyl rings are
oriented with the shielding cone approximately pointing to

3280

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

L1/L2 but the anthryl ring is badly oriented for effective

shielding of L1/L2 in the substrate.
c) The conformational composition of those AMAA thioesters
does not vary with the structure of the thiol.
While point c) is positive because it suggests that those CDA will
behave the same with any thiol, points a and b clearly indicate that
replacement of the aryl ring in thioesters is not the way to generate
effective CDA for thiols from a chiral phenylacetic acids.
2.3.3. The effect of replacement of the aryl group: experimental verication. The reliability of those predictions on thioesters 1e7 can
be experimentally demonstrated by simple NMR experiments.
Thus, in the (R)-MPA thioester of (S)-butane-2-thiol and neomenthyanethiol (4 and 7), the substituent L2 is shielded by the
phenyl ring in ap conformations while the substituent L1 is not
affected (see Fig. 7a), therefore substituent L1 is shielded in sp
conformations while the L2 remains unaffected and the opposite
situation occurs in the (S)-MPA thioester (see Fig. 7b). Given that
the ap forms are more abundant than the sp forms, L2 will be more
shielded in the (R)-MPA thioester than in the (S)-MPA thioester and
will produce negative DdRS values (see Fig. 7c), whilst L1 will be
more shielded in the (R)-MPA thioester than in the (S)-MPA thioester and will produce positive DdRS values (Table 2).23

In the case of the 2-NMA thioesters (5), the shielding effects are
similar to those with the MPA because the conformational equilibra
are analogous, and the same distributions of DdRS signs are observed (Table 2). The change of the aromatic ring (2-naphtyl instead
of phenyl ring) increases slightly the DdRS values.
For its part, the introduction of the anthryl ring as in 9-AMA
thioesters (6) produced only very small DdRS in accordance with
the bad orientation of the anthryl group with respect to L1/L2
(Fig. 6).
Further experimental evidence on the reliability of the calculations to predict the energies and conformations can be obtained
from low temperature, solvent polarity and NOESY NMR
experiments.5
Thus, in accordance with the difference of energy between the
ap and sp main conformers (1.6 kcal/mol for MPA thioesters), the 1H
NMR 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 attributed
to the interconversion between syn, c and c forms.

Fig. 8. Partial 1H NMR spectra of the (R)-MPA thioester of (S)-butane-2-thiol in 4:1

CS2/CD2Cl2 at different temperatures.

Similarly, as DFT calculations revealed that the ap and sp forms

present quite similar dipole moments (e.g., m for 1 are 1.0, 1.6, 1.4
and 1.9 D for ap1, ap2, sp1 and sp2 forms, respectively), the use of
solvents of different polarity should not modify signicantly neither 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), produced
similar DdRS values and the same distribution of signs regardless of
the polarity.
Table 3
DdRS values (ppm) obtained for MPA thioesters of (S)-octane-2-thiol (13) in different
deuterated solvents

1'
Fig. 7. Equilibria between the ap and sp rotamers of (a) (R)-MPA thioester of (S)-butane-2-thiol [(R)-4] and (b) (S)-MPA thioester of (S)-butane-2-thiol [(S)-4]. Red arrows
indicate the shielding effect caused by the aromatic system. (c) Distribution of DdRS
signs for MPA thioesters from the 1H NMR spectra.

Table 2
DdRS 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-NTBA
thioesters of (S)-butane-2-thiol (12)a
Compound

CH3(10 )

CH2(30 )

CH3(40 )

4
5
11
12

0.07
0.08
0.10
0.12

0.05
d
0.09
0.10

0.06
0.07
0.10
0.12

In CDCl3.

3'

SMPA
0

4'

5'

13

Solvent

CH3(1 )

CH2(30 )

[CH2]4(40 )

CH3(50 )

CS2/CD2Cl2 (4:1)
CDCl3
CD3CN
MeOD
(CD3)2CO

0.08
0.07
0.08
0.08
0.06

0.05
0.04
0.03
0.04
0.04

0.06
0.05
0.04
0.07
0.06

0.03
0.03
0.02
0.03
0.03

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

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

phenyl or 2-naphthyl rings and an unfavourable orientation of the

anthryl ring. This leads to small DdRS values and therefore neither
compounds 1e7 are good CDAs for thiols. Those results suggest that
in order to gain higher DdRS values, the introduction of sterically
demanding alkoxy groups instead of the methoxy group, as in 1e7,
could lead to restrictions in the conformational equilibrium, and
therefore to the existence of a dominant conformer. Next, we
present the results of the DFT calculations and NMR results obtained by replacement of the methoxy group of 1e7 by tert-butoxy
as in 8e12.
Thus, DFT calculations on the thioesters 8 and 11, containing
phenyl and tert-butoxy group, showed a conformational composition qualitatively similar to those of MPA thioesters 1 and 4, with
rotation around CaeCO, CaeOtBu leading to three main rotamers in
equilibrium: ap2, sp1 and sp2, the ap rotamers being the most
stable one. Nevertheless, the energy data indicates that the DE
between the ap and sp conformers is higher in the tert-butoxy
containing thioesters (8 and 11) than in MPA thioesters 1 and 4
(Fig. 9a). From the conformational standpoint, this should lead an
increase of the DdRS values due to a rise of populations of the ap
conformers in equilibrium, induced by an increment of the energy
difference between the sp and ap forms.

(a)

sp
H OMe

ap
H
Ph

L2

L1
OMe

L2

L1
Ph

population
ap
H NMR

L (ap)

population
sp

In summary, the calculations predict that anthryl substituted

alkoxyacetic acid cannot be considered potentially efcient CDA for
thiols. For their part, the phenyl and 2-naphtyl substituted compounds show a good orientation of the aryl ring to shield the
substrate, while the presence of a bulky tert-butoxy favours the ap
conformers over the sp ones. These two factors point to the phenyl
and 2-naphtyl tert-butoxyacetic acids as the most potentially interesting CDAs for congurational assignment of chiral thiols.
2.3.5. The effect of replacement of the inductor group: experimental
verication. When NMR spectra of thioesters 4, 5, 11 and 12 are
compared, the DdRS values of the tert-butoxy substituted ones follow the order expected from the richness of the aromatic system
leading 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 was
obtained by recording the NMR spectra thioesters of a series of
thiols of known absolute conguration and varied structures.26

Me
Me

L (sp)

E= 1.6 Kcal/mol

ap

H
Ph

L2

L1
OtBu

L2

L1
Ph

population
ap
H NMR

Me H

OH
O

Me H
Me
O
Me

OH
O

(S)-2-NTBA

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

L
population
sp

L (ap)

L (sp)

E= 2.4 Kcal/mol
(ppm)

(b)
AE (kcal/mol)

(R)-2-NTBA

(ppm)

sp
H OtBu

3281

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

Dihedral C-Ar (deg)

Fig. 9. (a) Conformational equilibrium between ap and sp forms in MPA thioesters and
PTBA 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 angles
calculated with the B3LYP/6-31G* approximation.

For their part, calculations on model thioesters 9 and 12,

(2-naphtyl and tert-butoxy) indicated also a conformational composition qualitatively similar to that of 8 and 11 (2-naphtyl and
methoxy) with two ap conformers (ap2, ap20 ) and four sp conformers (sp1, sp10, sp2, sp20 ) that differ in the orientation of the
asymmetrically substituted 2-naphtyleH(2) with respect to the
CaeH bond.24 Nevertheless, the energy barrier to rotation around
CaeCAr shows a clear increase when the methoxy group is replaced
by the bulkier tert-butoxy group (Fig. 9b) and this should lead an
increase 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 shielding
cone with respect to substituents L1/L2, that is, not compensated by
the increased DE.

3. Conclusion
A general protocol for the design of reliable Chiral Derivatizing
Agents (CDAs) for the NMR assignment of absolute conguration of
organic compounds is presented using as example the development of a new arylalkoxyacetic acid based reagent for the
assignment of chiral thiols.
In this protocol, theoretical calculations play a central role to
predict the conformational composition of virtually modied arylalkoxyacetic acid reagents. Those predictions are then checked by
different NMR experiments identifying the substituents leading to
an optimal CDA.
In this way, energy calculations on modelled thioester derivatives predict that the modication of the aryl system of an
arylmethoxyacetic acid is not sufcient to provide a good CDA,
while the introduction of a sterically hindered tert-BuO group instead results in a more appropriate conformational composition.
Combination of both substitutions eventually led to 2-naphtyl-tertbutoxyacetic acid as the best suited CDA for thiols. The reliability of
this reagent has been checked with a number of chiral thiols of
known absolute conguration.

4. Experimental section
4.1. General procedures
The thioesters (4e7 and 11e13) were prepared by treatment of
the thiol (1 equiv; 0.150 mmol) with the corresponding arylmethoxyacetic acid or aryl-tert-butoxyacetic acid (1.2 equiv;
0.180 mmol) in the presence of EDCHCl (1.2 equiv; 0.180 mmol) and
DMAP (catalytic) in dry CH2Cl2 (2.5 mL), and under argon atmosphere (EDCHCl1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,

3282

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

DMAP4-dimethylaminopyridine). The mixtures were stirred at

room temperature for 2e4 h approximately. The organic layers were
washed with water, HCl (1 M), water, NaHCO3 (sat) and water, then
dried (anhydrous Na2SO4) and concentrated under reduced pressure
to obtain the thioesters. Final purications were achieved by ash
column chromatography on silica gel 230e400 mesh (elution with
hexane/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
1
H NMR spectra of samples in 4:1 CS2/CD2Cl2 (5 mg in 0.6 mL) at
different temperatures were recorded at 500 MHz. 1H NMR spectra
of (R)- and (S)-13 in CDCl3, CD3CN, MeOD and (CD3)2CO were
recorded at 250 MHz. Chemical shifts (parts per million) are internally referenced to the TMS signal (0.00 ppm) in all cases. J
values are recorded in Hertz.

4.3.1. [298 K] (R)-MPA thioester of (S)-butane-2-thiol [(R)-4]. 1H

NMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.85 (t, J7.3 Hz, 3H), 1.24
(d, J6.9 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]. 1H
NMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.85 (t, J7.3 Hz, 3H), 1.25
(d, J6.8 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]. 1H
NMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.92 (t, J7.4 Hz, 3H), 1.16
(d, J6.9 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]. 1H
NMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.94 (t, J7.1 Hz, 3H), 1.15
(d, J6.7 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 ()-neomenthanethiol [(R)-7]. 1H
NMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.57 (d, J6.5 Hz, 3H), 0.81
(d, J6.6 Hz, 3H), 0.85 (d, J6.5 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).

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, J7.0 Hz, 3H), 1.18 (br s,
8H), 1.24 (d, J6.8 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).
1
H NMR (250.13 MHz, CDCl3) d (ppm): 0.84 (t, J6.7 Hz, 3H), 1.20
(br s, 8H), 1.29 (d, J6.9 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).
1
H NMR (250.13 MHz, CD3CN) d (ppm): 0.84 (t, J6.9 Hz, 3H),
1.21 (br s, 8H), 1.26 (d, J6.9 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).
1
H NMR (250.13 MHz, MeOD) d (ppm): 0.86 (t, J6.8 Hz, 3H),
1.22 (br s, 8H), 1.27 (d, J6.9 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).
1
H NMR (250.13 MHz, (CD3)2CO) d (ppm): 0.84 (t, J6.8 Hz, 3H),
1.21 (br s, 8H), 1.27 (d, J6.9 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, J6.8 Hz, 3H), 1.15 (d,
J6.9 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).
1
H NMR (250.13 MHz, CDCl3) d (ppm): 0.87 (t, J6.5 Hz, 3H), 1.22
(d, J6.9 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).
1
H NMR (250.13 MHz, CD3CN) d (ppm): 0.87 (t, J6.7 Hz, 3H),
1.19 (d, J6.9 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).
1
H NMR (250.13 MHz, MeOD) d (ppm): 0.89 (t, J6.7 Hz, 3H), 1.21
(d, J6.9 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).
1
H NMR (250.13 MHz, (CD3)2CO) d (ppm): 0.88 (t, J6.7 Hz, 3H),
1.20 (d, J6.9 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 work was supported with grants from Ministerios de Ciencia
n y de Economa y Competitividad (CTQ2009-08632,
e Innovacio
CTQ2012-33436) and Xunta de Galicia (PGIDIT09CSA029209PR,
CN2011/037). We also thank Prof. Federico Gago (Universidad de
 de Henares) and Dr. Armando Navarro (Universidad de Vigo)
Alcala
for their assistance with the computational work, and the Centro de
n de Galicia (CESGA) for granting computer time
Supercomputacio
used in the quantum chemical calculations.
References and notes

4.3.6. [183 K] (R)-MPA thioester of ()-neomenthanethiol [(R)-7]. 1H

NMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.51 (d, J6.0 Hz, 3H), 0.86
(d, J6.1 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 ()-neomenthanethiol [(S)-7]. 1H
NMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.75 (d, J6.5 Hz, 3H), 0.78
(d, J6.3 Hz, 3H), 0.86 (d, J6.5 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 ()-neomenthanethiol [(S)-7]. 1H
NMR (500.13 MHz, CS2/CD2Cl2) d (ppm): 0.73 (d, J6.5 Hz, 3H), 0.79
(d, J5.9 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),

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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 vary
substantially (around 0.5 kcal/mol).
West, R.; Michl, J. Acc. Chem. Res. 2000, 33, 821e823.
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 the
most relevant one
As the phenyl group in ap conformations occupies the same relative position
with respect to L1/L2, all ap conformations are equivalent from the NMR point
of view, and the same occurs with the sp conformations.
Conformers ap2, sp1 and sp2 have the CAreH(2) bond syn to CaeH and conformers ap20 , sp10 and sp20 have the CAreH(2) bond anti to CaeH.
Synthesis of (R)- and (S)-2-naphthyl-tert-butoxyacetic acid and other aryl-tertbutoxyacetic acids can be found at the SI in Ref. 5.
The 1H NMR spectra (R)- and (S)-MPA and 2-NTBA thioesters of the diverse
thiols tested showed the same distribution of DdRS signs for the protons of the
side chains L1 and L2 as (R)- and (S)-4. See Ref. 5.