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.
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Org. Lett., Vol. 9, No. 21, 2007