Assignment of absolute configuration on the basis of the conformational effects induced by chiral derivatizing agents: The 2-arylpyrrolidine case

Article abstract of DOI:10.1021/ol701502e

A novel approach for determining the absolute configuration of a chiral compound is proposed. The methodology is based on the distinct conformational effects imposed on a chiral substrate by each enantiomer of a chiral derivatizing agent. As a proof of co

Full text of DOI:10.1021/ol701502e

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4123-4126
Assignment of Absolute Configuration
on the Basis of the Conformational
Effects Induced by Chiral Derivatizing
Agents: The 2-Arylpyrrolidine Case
Paloma Vidal,* Concepcio´n Pedregal, Nuria D´ıaz, Howard Broughton,
Jose´ L. Acen˜a, Alma Jime´nez, and Juan F. Espinosa*
Centro de InVestigacio´n Lilly, AVenida de la Industria 30, 28108 Alcobendas,
Madrid, Spain
Vidal_paloma@lilly.com; jfespinosa@lilly.com
Received June 29, 2007
ABSTRACT
A novel approach for determining the absolute configuration of a chiral compound is proposed. The methodology is based on the distinct
conformational effects imposed on a chiral substrate by each enantiomer of a chiral derivatizing agent. As a proof of concept, it is shown that
the absolute configuration of 2-arylpyrrolidines can easily be determined by inspection of the multiplicity of the NMR signal of the methine
proton of the pyrrolidine ring in the corresponding Mosher’s amides.
Since its description more than 30 years ago, the so-called
“Mosher’s method” has been successfully applied to a great
variety of chiral alcohols and amines.1 The method involves
derivatization of the chiral substrate with the two enantiomers
of the chiral reagent R-methoxy-R-(trifluoromethyl)phenyl-
acetic acid (MTPA), followed by the comparative analysis
by the substituents from the phenyl group of the chiral
auxiliary in each diastereoisomer.
Although the conformational aspects of the MTPA deriva-
tives have been studied in great detail,2 such studies have
focused more on the conformational composition of the
MTPA moietysmainly on the rotation around the CR-CO
and CR-Ph bondssthan on the conformational properties
of the substrate upon ester or amide formation. In general,
it is assumed that the conformation of the substrate moiety
is similar in both diastereomers and it is generally treated as
a rigid unit in the conformational correlation models.
Nevertheless, one can envisage that each enantiomer of the
chiral auxiliary may induce the chiral substrate to adopt
different conformations in the resulting diastereomers. If this
1
of the H NMR spectra of the resulting diastereoisomers.
The sign of the chemical shift differences of the substituents
attached to the asymmetric carbon can then be correlated
with the absolute configuration by using an empirical model.
It is well-known that such chemical shift differences are a
consequence of the different anisotropic effect experienced
(1) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1968, 90, 3732. (b)
Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2453. (c)
Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(2) Seco, J. M.; Latypov, S. K.; Quin˜oa, E.; Riguera, R. J. Org. Chem.
1997, 62, 7569.
10.1021/ol701502e CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/21/2007

is the case, we propose that such conformational differences
can be exploited for the assignment of the absolute config-
uration of the chiral compound, provided the conformational
preferences are interpreted in terms of a structural model.
This approach differs from, and complements, current NMR
methodologies that are based on the assessment of the
chemical shift differences between the protons of the
Mosher’s derivatives.3
arranges the amide carbonyl synperiplanar to the trifluo-
methyl group, in agreement with previous studies of MTPA
amides that showed that the synperiplanar arrangement is
predominant over the antiperiplanar disposition.2 Regarding
the pyrrolidine moiety, the ring adopts a slightly distorted
envelope conformation that places N1, C2, C3, and C5 on
the plane and C4 at the flap of the envelope. Two confor-
mational families, represented by conformers A and B,
coexist in solution (Figure 2). The conformers differ in the
This novel concept has been explored with chiral 2-phenyl-
pyrrolidine 1 of known (S)-configuration4 (Figure 1). This
Figure 2. Representation of conformers A and B. The atom
numbering is shown in conformer A.
Figure 1. Structure of the 2-arylpyrrolidines and their correspond-
ing MTPA amides.
orientation of the flap of the envelope relative to the phenyl
substituent (located on the same side in conformer A and
on opposite sides in conformer B). Remarkably, the calcula-
tions predict that A is the most abundant conformer in the
SR isomer, whereas B is the preferred conformer in SS
(Figure 3), indicating that the configuration of the deriva-
substrate has been selected because (i) the conformational
behavior of five-membered rings is usually highly influenced
by the nature of the substituents5 so that each enantiomer of
the chiral auxiliary may have a distinct effect on the
conformational preferences of the pyrrolidine ring, (ii) the
application of standard Mosher’s technology to these com-
pounds is complicated by the coexistence of two unequally
populated syn and anti rotamers around the C-N amide
bond,6 and (iii) 2-arylpyrrolidines are important compounds
in organic and medicinal chemistry and the development of
a rapid procedure for the determination of their absolute
configuration would be highly beneficial.
To investigate the conformational properties of the pyr-
rolidine ring in the two diastereomeric Mosher’s amides, we
resorted to molecular mechanics calculations using the MMX
force field within PCModel program.7 A conformational
search was performed for the diastereomeric amides SR and
SS of amine 1, where the first character refers to the
configuration of the pyrrolidine carbon and the second to
the configuration of the MTPA auxiliary. Rotation around
the amide bond was allowed to take into account syn and
anti orientations. The calculations predict that the syn rotamer
is higher in energy than the corresponding anti form, in which
steric interactions between the MTPA R-carbon substituents
and the aryl ring are largely avoided. The MTPA moiety
Figure 3. Conformational preference of diastereoisomers 1a and
1b according to the MMX force field.
tizing agent has an influence on the conformational behavior
of the pyrrolidine ring as desired.
The computational results were evaluated by NMR studies
of amides 1a (SR) and 1b (SS). The 1H spectra of both amides
showed two sets of signals in 90:10 (1a) and 96:4 (1b) ratios
as a consequence of slow rotation around the amide bond,
as reported for other cyclic amides.6 The major peaks were
attributed to the most stable anti rotamer and assigned with
the assistance of a HSQC experiment. The 1H spectra of both
amides showed an isolated signal at about 5.1 ppm corre-
sponding to the methine proton (H2) of the pyrrolidine ring.
In both amides, selective excitation of H2 in a 1D-NOESY
(3) Seco, J. M.; Quin˜oa, E.; Riguera, R. Chem. ReV. 2004, 104, 17.
(4) Matteson, D. S.; Youn, Kim, G. Org. Lett. 2002, 4, 2153.
(5) Eliel, E. E.; Wilen, S. H. Stereochemistry of Organic Compounds;
Eliel, E. E., Wilen, S. H., Eds.; Wiley-Interscience: New York, 1994;
Chapter 11, p 758.
(6) (a) Hoye, T. R.; Rener, M. K. J. Org. Chem. 1996, 61, 2056. (b)
Hoye, T. R.; Rener, M. K. J. Org. Chem. 1996, 61, 8489.
(7) PCModel for Windows, Version 8.5; Serena Software: Bloomington,
IN, 2003.
4124
Org. Lett., Vol. 9, No. 21, 2007

experiment8 produced NOEs to the vicinal protons (H3 and
H3′) and to the ortho protons of the phenyl substituent on
the pyrrolidine ring. Interestingly, a NOE between H2 and
one of the protons at C4 is clearly observed in 1b, whereas
this NOE is weaker in 1a (Figure 4), indicating a distinct
Figure 5. Experimental (top spectra) and calculated H2 signal for
amides 1a and 1b.
Figure 4. 1D-DPFGSE NOESY spectra of Mosher’s amides 1a
and 1b in DMSO-d6. H2 resonance was inverted by using a
Gaussian-shaped pulse.
of doublets, whereas in 1b both coupling constants are
similar, leading to a pseudo-triplet with an apparent coupling
constant of 7.6 Hz.
The coupling constants between H2 and the C3 protons
in conformers A and B were calculated by using the well-
established Karplus-Altona relationship9 in order to simulate
the shape of the H2 signal that would be expected for each
conformer. Figure 5 shows that neither A nor B reproduce
the experimental H2 signal for any of the amides, indicating
the presence of an equilibrium between both conformers that
results in average coupling constant values. We have
estimated the conformer ratio that provides the best fit to
the experimental signal as depicted in Figure 5. Such analysis
reveals that conformer A is the most populated geometry in
1a whereas conformer B is the preferred geometry in 1b, as
previously concluded from NOE studies.
conformational behavior of the pyrrolidine ring in each
diastereomeric amide.
The intensity of the H2-H4 NOE is sensitive to the
population of conformer B because in this conformer H2 is
close to H4, whereas in conformer A these protons are too
far away from each other to give rise to a NOE (Figure 3).
Therefore, the fact that the H2-H4 NOE is stronger in 1b
than in 1a agrees with the predominance of conformer B in
the former, and of conformer A in the latter, as predicted by
the molecular mechanics calculations. In addition, the
orientation of the MTPA moiety relative to the pyrrolidine
ring can also be inferred from the NOEs between the H2
and the protons of the chiral auxiliary (Figure 4). While a
NOE between H2 and the methoxy protons was observed in
1a, this NOE was absent in 1b, where a NOE between H2
and the ortho protons of the MTPA phenyl ring was detected.
This NOE pattern is consistent with the calculated structures
that show that H2 is located on the same side as the methoxy
group of the MTPA with respect to the plane of the envelope
in 1a and on the same side as the phenyl group of MTPA in
1b (Figure 3).
The combination of NMR and theoretical calculations
therefore demonstrates that the conformational behavior of
the pyrrolidine moiety in the Mosher’s amides of 1 is
influenced by the chirality of the MTPA auxiliary and, as a
consequence, the NOEs and the proton-proton coupling
constants of the pyrrolidine protons in Mosher’s amides SR
(or in its enantiomer RS) differ from those in the diastereo-
meric Mosher’s amide SS (or in RR), and they can be utilized
as diagnostic parameters for configurational assignment of
2-arylpyrrolidines. Conveniently, the absolute configuration
of this type of compounds can be simply derived from the
multiplicity of the H2 signal as follows: if the configuration
of the MTPA moiety in the Mosher’s amide is R and the H2
signal is a doublet of doublets (one of the couplings is
roughly twice the other) the absolute configuration of the
amine under examination is S, whereas if this signal is an
apparent triplet (both couplings are similar) the absolute
The differences in the conformational behavior of the
pyrrolidine ring in each diastereomeric amide are also
1
reflected in the vicinal H-1H coupling constants between
1
the pyrrolidine protons. Specifically, in comparing the H
spectrum of 1a with that of 1b (Figure 5), we noticed a
significant difference in the multiplicity of the H2 signal. In
1a, H2 is coupled to the vicinal protons at C3 with different
coupling constants (7.9 and 3.7 Hz), resulting in a doublet
(8) Stott, K.; Stonehouse, J.; Keeler, J.; Hwang, T. L.; Shaka, A. J. J.
Am. Chem. Soc. 1995, 4, 123.
(9) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C. Tetrahedron
1980, 36, 2783.
Org. Lett., Vol. 9, No. 21, 2007
4125

configuration is R. Conversely, if the configuration of the
MTPA auxiliary is S, H2 appears as a triplet in the (S)-2-
arylpyrrolidine and as a doublet of doublets in the (R)-2-
arylpyrrolidine.
ability of the approach. Furthermore, the methodology was
applied to a compound of unknown configuration, 2-aryl-
pyrrolidine 4. Both Mosher’s derivatives were prepared, 4a
and 4b, in which the configuration of the MTPA stereogenic
carbon atom is R and S, respectively. The H2 signal of the
anti rotamer appears as a pseudotriplet (J ) 7.3 Hz) in 4a
and as a doublets of doublets (J ) 8.2 and 4.0 Hz) in 4b,
revealing that the configuration of 4 is R.
The validity of the procedure was verified for 2-aryl-
pyrrolidines 2 and 3 whose absolute configurations were also
known (S and R, respectively).10,11 Both compounds were
converted into the corresponding Mosher’s amides 2a and
3a, in which the configuration of the chiral auxiliary is R,
and 2b and 3b in which the configuration is S. Again, the
1H spectra of all the amides show splitting of signals arising
from the anti and syn rotamers. The diagnostic H2 signal of
the most abundant anti rotamer appears between 5.0 and 5.2
ppm as a doublet of doublets in two derivatives (2a and 3b)
and as a pseudotriplet in the other two (2b and 3a) as shown
in Figure 6. According to the aforementioned rule the
In short, we have introduced a novel concept for the
assignment of the absolute configuration of a chiral amine
that takes advantage of the conformational differences
exhibited by the chiral substrate in the corresponding
Mosher’s amides, and demonstrated its usefulness for the
determination of the absolute configuration of 2-arylpyrro-
lidines. To the best of our knowledge, this is the first example
in which the absolute configuration of a chiral compound is
determined from proton-proton coupling constants rather
than from comparison of proton chemical shifts,3 opening
new avenues for the configurational assignment of chiral
compounds. It is worth emphasizing the fact that, although
both Mosher’s amides are needed to ascertain the existence
of conformational differences between diastereoisomers and
identify a diagnostic NMR parameter that can be correlated
with the absolute configuration, only a single Mosher’s amide
is required for application of the method in related com-
pounds. The approach is advantageous over the standard
Mosher’s procedure described by Hoye et al. for cyclic
amines that involves the identification of the resonances of
both the anti and syn rotamers.6 Further work to extend this
novel approach to 2-alkyl and 3-substituted pyrrolidines is
in progress and it will be reported in due course.
Acknowledgment. The authors thank Mar´ıa de los Santos
Sanchez from Centro de Investigacio´n Lilly for technical
support.
Figure 6. H2 signal for amides 2a-4a and 2b-4b.
absolute configuration is S for 2 and R for 3. Hence, the
correct configuration was elucidated, confirming the reli-
Supporting Information Available: Experimental pro-
cedures and spectroscopy data for 1a-4a and 1b-4b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Chelucci, G.; Falorni, M.; Giacomelli, G. Synthesis 1990, 1121.
(11) Felpin, F.-X.; Girard, S.; Vo-Thanh, G.; Robins, R. J.; Villie´ras, J.;
Lebreton, J. J. Org. Chem. 2001, 66, 6305.
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