N-(2-nitrophenyl)proline: An intramolecular hydrogen bond forming reagent for the determination of the absolute configuration of primary amines

Article abstract of DOI:10.1021/ol7017455

N-(2-Nitrophenyl)proline (2-NPP) amides of primary amines have a conformational preference for intramolecular hydrogen bonding. Because of the strong and selective anisotropic effects on the amine substituents, the absolute configuration of α-chiral primary amines can be assigned by comparing the ¹H chemical shifts of diastereomeric 2-NPP amides.

Full text of DOI:10.1021/ol7017455

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3853-3855
N-(2-Nitrophenyl)proline: An
Intramolecular Hydrogen Bond Forming
Reagent for the Determination of the
Absolute Configuration of Primary
Amines
Hee Choon Ahn and Kihang Choi*
Department of Chemistry and Center for Electro- and Photo-ResponsiVe Molecules,
Korea UniVersity, Seoul 136-701, Republic of Korea
kchoi@korea.ac.kr
Received July 22, 2007
ABSTRACT
N-(2-Nitrophenyl)proline (2-NPP) amides of primary amines have a conformational preference for intramolecular hydrogen bonding. Because
of the strong and selective anisotropic effects on the amine substituents, the absolute configuration of
assigned by comparing the 1H chemical shifts of diastereomeric 2-NPP amides.
r-chiral primary amines can be
Determination of the absolute configuration of chiral mol-
ecules is a key problem in the study of natural products and
asymmetric synthesis, and one of the most convenient and
widely used methods for absolute configuration determination
is 1H NMR spectroscopy.1 In this method, the chiral substrate
is derivatized with the two enantiomers of a chiral deriva-
Here, we report that N-(2-nitrophenyl)proline (2-NPP, 3)
can be used as a new CDA for primary amines showing suffi-
ciently large ∆δRS values. Unlike MTPA and MPA, NPP
has a cyclic structure in which the aryl and carboxylic acid
groups are constrained through a five-membered ring (Figure
1). Once a primary amine is linked to the NPP carboxylic
acid group through an amide bond, a hydrogen bond is
1
tizing agent (CDA), and the H NMR spectra of the two
resulting diastereomers are compared. Interpretation of the
chemical shift difference (∆δRS ) δ(R) - δ(S)) based on
the representative conformations of the diastereomers allows
the absolute configuration of the chiral substrate to be
assigned. Several CDAs have been developed for different
classes of compounds, and for the cases of R-chiral primary
amines, Mosher’s R-methoxytrifluoromethylphenylacetic acid
(MTPA, 1)2 and Trost’s R-methoxyphenylacetic acid (MPA,
2)3 are the two most frequently used reagents. Because of
the complexity of the conformational distribution, however,
the amides derived from these reagents show small ∆δRS in
general and the development of more efficient CDAs is still
required.4
(1) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Chem. ReV. 2004, 104, 17-117.
(2) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-
519. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
(3) Trost, B. M.; Belletire, J. L.; Godleski, S.; Mcdougal, P. G.; Balkovec,
J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer,
J. P. J. Org. Chem. 1986, 51, 2370-2374.
(4) (a) Harada, K.; Shimizu, Y.; Fujii, K. Tetrahedron Lett. 1998, 39,
6245-6248. (b) Lo´pez, B.; Quin˜oa´, E.; Riguera, R. J. Am. Chem. Soc. 1999,
121, 9724-9725. (c) Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem.
1999, 64, 4669-4675. (d) Porto, S.; Duran, J.; Seco, J. M.; Quin˜oa´, E.;
Riguera, R. Org. Lett. 2003, 5, 2979-2982. (e) Garc´ıa, R.; Seco, J. M.;
Va´zquez, S. A.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 2006, 71, 1119-
1130. (f) Takeuchi, Y.; Konishi, M.; Hori, H.; Takahashi, T.; Kometani,
T.; Kirk, K. L. Chem. Commun. 1998, 365-366. (g) Takeuchi, Y.; Segawa,
M.; Fujisawa, H.; Omata, K.; Lodwig, S. N.; Unkefer, C. J. Angew. Chem.,
Int. Ed. 2006, 45, 4617-4619.
10.1021/ol7017455 CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/21/2007

All the tested compounds showed the same trend in their
proton chemical shift differences. If the general structure of
an R-chiral primary amine is represented as in Figure 3, the
Figure 1. Structures of MTPA, MPA, and NPP reagents.
expected to be formed between the amide hydrogen and
proline nitrogen (NPro) atoms. Both the cyclic structure and
the intramolecular hydrogen bond can help to reduce the
molecule’s conformational flexibility and stabilize a repre-
sentative conformation where the substrate and the NPP
phenyl ring with an anisotropic effect are in close proximity.
To investigate the utility of NPP reagents, we prepared
diastereomeric NPP amides of R-chiral amines with diverse
structures. (S)- and (R)-2-NPP were synthesized from L- and
D-proline, respectively, by a nucleophilic aromatic substitu-
tion reaction with 1-fluoro-2-nitrobenzene. The acids were
then coupled with chiral primary amines 5-14 (R ) H) of
known absolute configuration. The 1H signals from the amine
substrate were assigned by using COSY and other NMR
spectroscopic methods and the chemical shifts were com-
pared for both diastereomers to obtain the ∆δRS values
(Figure 2).
Figure 3. Representative conformations of (R)- and (S)-NPP
amides. Intramolecular hydrogen bonds are indicated by dashed
lines. In the Newman projection, the amide bond is omitted for
clarity.
∆δRS values of the NPP amides are always positive for the
R1 substituent and negative for the R2 substituent. This con-
sistent and uniform distribution of the chemical shift differ-
ences could be explained on the basis of the amide confor-
mation shown in Figure 3. In this model conformation, the
CR-H, N-H, and CdO bonds adopt an all-anti arrangement
as in MTPA and MPA amides,1 and the CdO and C-NPro
bonds are also depicted in an anti relationship because this
conformation can be stabilized by the intramolecular hydro-
gen bond between the amide hydrogen and proline nitrogen
atoms. In (R)-NPP amides, the aryl group and the R2
substituent are located on the same side of the amide plane
so the anisotropic shielding of the R2 substituent is expected.
In (S)-NPP amides, the aryl group is on the opposite side of
the plane and the R1 substituent is under the shielding effect.
Thus, the ∆δRS values should be positive for the protons on
the R1 group and negative for the protons on the R2 group.
In general, the ∆δRS absolute values of the 2-NPP amides
are considerably larger than the values reported for the
corresponding MTPA and MPA amides (Table 1), suggesting
that 2-NPP can be used as a more error-free reagent for
assigning the absolute configuration of chiral amines.
The conformational preference of 2-NPP amides was
further investigated by using conformational search and ab
initio calculations.5 In the lowest energy conformation of
the (S)-2-NPP amide of isopropylamine (Figure 4), the
(CR-H)-(N-H) and (CdO)-(C-NPro) bonds are in anti
arrangements and the amide hydrogen and the proline
nitrogen atoms are separated by 2.3 Å. The two methyl
groups from the amine substrate are located on the opposite
sides of the amide plane and the one corresponding to the
Figure 2. ∆δRS values of 2-NPP diastereomeric amides (R )
2-NPP) of chiral amines 5-14. 1H NMR spectra were recorded in
CDCl3.
(5) Spartan’06 (Wavefunction, Inc.) was used for the calculations. A
Monte Carlo conformation search was performed by using the MMFF force
field to find the lowest energy conformation, which was then used as an
initial structure for the ab initio geometry optimization (RTH/6-31G**).
3854
Org. Lett., Vol. 9, No. 19, 2007

(Table 1), suggesting that 4-NPP and 2-NPP amides adopt
similar conformations. However, the ∆δRS absolute values
are significantly larger for the 2-NPP amides than for the
corresponding 4-NPP amides, in which the nitro group is
located at the para position of the phenyl ring and therefore
cannot form a hydrogen bond with the amide group.6
Although detailed calculation studies are required to fully
understand the relationship between the ∆δRS values and the
position of the electron-withdrawing substituent, the large
∆δRS value of the 2-NPP amides is presumably due to the
hydrogen bonding between the 2-nitro and the amide groups.
Formation of this additional hydrogen bond increases the
energy barrier for the (CdO)-(C-NPro) bond rotation and
therefore stabilizes the anti conformation further. The
hydrogen bond also restricts the rotation of the phenyl ring
and stabilizes the rotamer in which the aromatic ring faces
toward the amine substrate (Figure 4). These two factors can
contribute together to increase the population of the con-
former in which one of the amine substituents is located in
the shielding region of the anisotropic group, resulting in
the large ∆δRS values of the 2-NPP amides.
Table 1. Selected ∆δRS Values of the Diastereomeric Amides
5-8 Obtained with Different CDAs
R )
MTPAa
MPAb
2-NPP
4-NPP
5
6
7
OCH3
γ-CH
δ-CH3
OCH3
δ-CH
ú′-CH
OCH3
δ-CH
-0.02
0.23
0.10/0.08
-0.02
0.40
0.02
-0.03
0.25
0.13
0.07
0.07
0.07
c
-0.06
c
0.26
-0.59
0.07
-0.14
0.13/0.08 -0.31/-0.30 -0.13/-0.07
-0.06
0.23
0.10
-0.07
0.19
0.09
0.02
0.11
0.08
0.24
-0.60
-0.15
0.23
-0.46
-0.39
-0.23
-0.40
-0.15
0.68
0.03
-0.29
-0.05
0.06
-0.24
-0.20
-0.08
-0.12
-0.03
0.28
ꢀ-CH
ú-CH
8
3-CHendo
CHexo
6-CHendo
CHexo
10-CH3
-0.06
-0.07
-0.19
c
0.44
0.32
0.19
0.07
-0.08
a From ref 7. The values originally reported in ref 7a are ∆δSR rather
than ∆δRS values. b From ref 8. c Not available.
In conclusion, we have presented an NMR spectroscopic
method for the determination of the absolute configuration
of R-chiral primary amines that is based on 2-NPP, a new
CDA readily prepared by a single-step synthesis. Unlike
MTPA and MPA amides, 2-NPP amides have a conforma-
tional preference for intramolecular hydrogen bonding
between the chiral auxiliary and the amide group. As a result,
significantly large ∆δRS values were obtained with 2-NPP
diastereomeric amides, providing a more reliable way to
assign the absolute configuration of the amines.
R1 group is located on the same side with the 2-nitrophenyl
group. Interestingly, the nitro group is located in close
proximity to the amide group enabling additional intramo-
lecular hydrogen bonding between the nitro oxygen and the
amide hydrogen atoms; the calculated distance between the
two atoms is 2.2 Å and the N-H‚‚‚O bond angle is 173°.
To investigate the effect of this additional hydrogen bond,
we prepared a new set of diastereomeric amides from N-(4-
nitrophenyl)proline (4-NPP, 4), which in turn was synthesize
from 1-fluoro-4-nitrobenzene. The ∆δRS values obtained with
4-NPP have the same signs as those obtained with 2-NPP
Acknowledgment. This work was supported by a Korea
University Grant and the Korea Science and Engineering
Foundation through CRM of Korea University.
Supporting Information Available: Synthetic details and
characterization data for compounds 3-14. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL7017455
(6) For the 4-NPP amides, the chemical shift of the amide NH proton is
0.6-0.8 ppm smaller and the N-H stretching frequency is 16-34 cm-1
higher than the corresponding 2-NPP amides. See the Supporting Informa-
tion for the spectral data.
(7) (a) Kusumi, T.; Fukushima, T.; Ohtani, I.; Kakisawa, H. Tetrahedron
Lett. 1991, 32, 2939-2942. (b) Seco, J. M.; Latypov, S. K.; Quin˜oa´, E.;
Riguera, R. J. Org. Chem. 1997, 62, 7569-7574.
(8) Latypov, S. K.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem.
1995, 60, 1538-1545.
Figure 4. The calculated structure of the (S)-2-NPP amide of
isopropylamine: a side view onto the amide plane (left) and a front
view onto the proline ring (right). Progressively darker shades of
gray represent H, C, O, and N, respectively.
Org. Lett., Vol. 9, No. 19, 2007
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