N-arylcarbonylpseudoprolines as tunable chiral derivatizing agents for the determination of the absolute configuration of secondary alcohols

Article abstract of DOI:10.1002/ejoc.201100209

New chiral derivatizing agents, 3-arylcarbonyl-2,2-dimethyloxazolidine-4- carboxylic acids (N-arylcarbonylpseudoprolines), were prepared through a simple, short-step synthesis. The absolute configuration of secondary alcohols can be assigned on the basis of the NMR spectroscopic chemical shift difference between diastereomeric pseudoproline esters. Preparation of more efficient agents was achieved simply by using aromatic groups with stronger anisotropic effect. New chiral derivatizing agents, N-arylcarbonylpseudoprolines, were prepared and used to determine the absolute configuration of secondary alcohols. Preparation of more efficient agents was achieved simply by using aromatic groups with stronger anisotropic effect.

Full text of DOI:10.1002/ejoc.201100209

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100209
N-Arylcarbonylpseudoprolines as Tunable Chiral Derivatizing Agents for the
Determination of the Absolute Configuration of Secondary Alcohols
So-Yeong Han[a] and Kihang Choi*[a]
Keywords: Configuration determination / Chirality / Conformation analysis
New chiral derivatizing agents, 3-arylcarbonyl-2,2-dimethyl-
signed on the basis of the NMR spectroscopic chemical shift
oxazolidine-4-carboxylic acids (N-arylcarbonylpseudoprol- difference between diastereomeric pseudoproline esters.
ines), were prepared through a simple, short-step synthesis.
The absolute configuration of secondary alcohols can be as-
Preparation of more efficient agents was achieved simply by
using aromatic groups with stronger anisotropic effect.
configuration of secondary alcohols. In our design, the aro-
matic group is attached to a carbonyl group, and the chiral
center is derived from chiral starting materials. Because of
this modular and chiral pool approach, manipulation of the
anisotropic effect by switching aromatic groups could easily
be accomplished.
Introduction
Since the advent of asymmetric synthesis, there is a grow-
ing demand for the development of simple and efficient
methods for the assignment of the absolute configuration
of stereogenic centers. One of the traditional approaches
especially useful for noncrystalline compounds is the NMR
anisotropy method,[1] in which the chiral compound is deri-
vatized with two enantiomers of a chiral derivatizing agent
(CDA) and the NMR spectra are compared to obtain the
chemical shift difference [ΔδRS = δ(R) – δ(S)] between the
two resulting diastereomers. Proper analysis of the ΔδRS
values based on the diastereomer conformations and the
anisotropic shielding effect produced by the CDA can lead
to the assignment of the absolute configuration of the chiral
compound.
Figure 1. Structures of MTPA, MPA, and ΨPro reagents. The
ΨPro amide bond is drawn in the cis conformation.
Several CDAs have been developed for different classes
of compounds, and Mosher’s α-methoxytrifluoromethyl-
phenylacetic acid (MTPA, 1)[2] and Trost’s α-methoxyphen-
ylacetic acid (MPA, 2)[3] are the two most widely used
agents for secondary alcohols. Although successfully used
for the structure determination of many chiral alcohols and
natural products, these agents often produce small ΔδRS val-
ues, because of the weak anisotropic effect of the phenyl
group and the conformational flexibility of the resulting es-
ters. There have been continuous efforts[4] to develop more
efficient agents affording larger ΔδRS values, and most of
these agents are based on chiral carboxylic acids with an
aromatic group directly attached to a chiral center. In a
continuing effort to develop tunable CDAs,[5] we report here
that N-arylcarbonylpseudoprolines (3, Figure 1) could be
used as new CDAs for the determination of the absolute
Results and Discussion
Pseudoprolines (ΨPros) are cyclic amino acids obtained
by condensation of aldehydes or ketones with serine, threo-
nine, and cysteine. It is well known that the incorporation
of these proline surrogates into a peptide sequence induces
the cis conformation at the amide bond N-terminal to the
ΨPro residue.[6] The cis/trans ratio of this ΨPro amide bond
is strongly affected by local structures, and it has been re-
ported that compound 3a, the N-benzoyl ΨPro derived
from serine, adapts predominantly the cis amide conforma-
1
tion (Figure 1) and shows only one set of H NMR signals
in CDCl3.[7] We envisioned that this conformational prefer-
ence could be retained in the corresponding esters also, and,
because the anisotropic aromatic group would be posi-
tioned close to the attached alcohol in the cis conformation,
compound 3a might be used as a new CDA for chiral
alcohols.
[a] Department of Chemistry and Research Institute for Natural
Sciences, Korea University,
Seoul 136-701, Republic of Korea
Fax: +82-2-3290-3121
To investigate the utility of ΨPro 3a, we prepared the
corresponding esters of α-chiral secondary alcohols of
known absolute configuration. First, (S)- and (R)-3a were
E-mail: kchoi@korea.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100209.
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Eur. J. Org. Chem. 2011, 2920–2923

N-Arylcarbonylpseudoprolines as Tunable Chiral Derivatizing Agents
prepared by a simple, three-step synthesis starting from l- (R)-ΨPro esters, the aryl group is on the opposite side of
and d-serine methyl esters, respectively, and then they were the plane, and it is the R1 substituent that is under the
coupled with chiral alcohols. As expected, only one set of shielding effect. Thus, according to the representative con-
NMR signals was observed for each ester, showing that formation predicted by the modeling study, the ΔδRS values
ΨPro 3a and its esters have similar amide isomer equilib- should be positive for the R2 substituent and negative for
rium properties. The 1H NMR signals were assigned by the R1 substituent, and this is in good agreement with the
using the COSY and NOESY spectroscopic methods, and experimental result.
the chemical shifts were compared between the dia-
stereomeric esters to obtain the ΔδRS values (Figure 2).
Figure 4. Representative conformations of (R)- and (S)-ΨPro es-
ters. In the extended Newman projection, the ester group is omitted
for clarity.
Figure 2. ΔδRS values of ΨPro 3a esters of chiral alcohols. 1H
NMR spectra were recorded in CDCl3.
All the tested compounds showed the same trend in their
Because of the modular structure of N-arylcarbonyl
ΨPro, preparation of a similar CDA with enhanced aniso-
tropic effect was simple and straightforward. Compound
ΔδRS values; if structures of secondary alcohols are drawn
as in Figure 2, the ΔδRS values of the ΨPro esters are always
positive for the Cα substituent on the right and negative for
3b, a second version of the ΨPro agent, was synthesized in
the substituent on the left. Although detailed studies are
a similar way by using 2-naphthoyl chloride instead of ben-
required to fully understand this consistent distribution of
zoyl chloride. The ΔδRS values obtained with a new set of
diastereomeric esters of ΨPro 3b have the same signs as
those obtained with ΨPro 3a esters, suggesting that these
esters have similar conformational preference. As expected,
the ΔδRS values, the result of conformational search calcula-
tions is informative.[8] In the lowest energy conformation of
the (S)-3a ester of 2-propanol (Figure 3), the amide bond is
in the cis conformation in which the steric interaction with
the ΔδRS values are significantly larger for the ΨPro 3b es-
the oxazolidine geminal dimethyl group is minimized. The
ters than those for the corresponding esters of MTPA,
(H–Cα)–(O–CO) and (Cα–O)–(C=O) bonds adopt syn-per-
MPA, and ΨPro 3a (Table 1). We also prepared another
iplanar arrangements similar to those in the representative
ΨPro agent by using 1-naphthoyl chloride, and the ΔδRS
values with this N-(1-naphthoyl) ΨPro turned out to be
much smaller than those with ΨPro 3b and rather close to
conformations of MTPA and MPA esters.[1a] The ΨPro Cα–
N bond and the ester group C=O bond are also arranged
in a syn relationship, presumably because this conformation
the values observed with ΨPro 3a (data not shown). This
can be stabilized by the intramolecular interaction between
result suggests that the proper orientation as well as the
the amide carbonyl C with partial positive charge and the
ester carbonyl O with partial negative charge (Figure 4). In
Table 1. ΔδRS values of chiral alcohols A–D obtained with different
CDAs in CDCl3.
(S)-ΨPro esters, the aryl group and the R2 substituent are
located on the same side of the ester carbonyl plane, so
anisotropic shielding of the R2 substituent is expected. In
Alcohol
MTPA 1[a] MPA 2[b] ΨPro 3a
ΨPro 3b
A
1-CH3
0.08
–0.13
0.15
0.33
3-CH2
4-CH3
1-CH3
3-CH2
4-CH2
5-CH3
β-CH3
OCH3
CH3
–0.05/–0.04 0.11
–0.11
–0.08
–0.12
0.18
–0.19
–0.31
0.25
0.23
–0.14
0.15
0.25
B
0.08
[c]
–0.10/–0.01 –0.21
[c]
–0.15
–0.03
0.14
–0.02
0.13
–0.40
–0.27
0.36
–0.18
0.27
–0.07
0.07
–0.04
0.06
0.14
[c]
C
[c]
D
–0.08
[c]
o-CH
–0.03
–0.12
–0.23
Figure 3. The calculated structure of the (S)-3a ester of 2-propanol:
a front view (left) and a side view (right with depth cues) onto the
oxazolidine ring (C, gray; H, light gray; O, red; N, blue).
[a] From ref.[4b] and ref.[9] The originally reported values are ΔδSR
rather than ΔδRS values. [b] From ref.[1a] and references cited
therein. [c] Not available.
Eur. J. Org. Chem. 2011, 2920–2923
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S.-Y. Han, K. Choi
SHORT COMMUNICATION
size of the aromatic ring are of importance in the enhanced
anisotropic effect of ΨPro 3b.
Conclusions
We have presented pseudoproline-based CDAs for the
determination of the absolute configuration of secondary
alcohols. The agents were prepared by an efficient, short-
step synthesis. Especially, manipulation of the anisotropic
group was accomplished by using different arylcarbonyl ha-
lides, so that the preparation of more efficient CDAs was
easy and straightforward. The esters of ΨPro 3b showed
significantly large ΔδRS values in various solvents, suggest-
ing that this series of compounds could provide a reliable
NMR spectroscopic method to determine the absolute con-
figuration of chiral alcohols.
We tested the solvent dependence of ΔδRS values to find
out whether the ΨPro agents could be used as effective
CDAs in a wide range of solvents. The ΔδRS values of ΨPro
esters of (S)-sec-butyl alcohol (A) were compared in com-
monly used NMR spectroscopic solvents (Table 2). All
these values have the same signs as those obtained in
CDCl3, which indicates that the esters retain the same con-
formational preference in the tested solvents. Moreover, the
overall anisotropic effect increases with the solvent polarity,
affording the largest ΔδRS values in [D4]MeOH and [D6]-
DMSO. The results obtained in [D6]DMSO with diverse
alcohols (Figure 5) show that ΨPro 3b can be used as a
reliable CDA even in polar NMR spectroscopic solvents.
Experimental Section
(R)-3-Benzoyl-2,2-dimethyloxazolidine-4-carboxylic Acid [(R)-3a]:
d-Serine methyl ester hydrochloride (0.50 g, 3.2 mmol) and N,N-
diisopropylethylamine (DIEA, 1.1 mL, 2.0 equiv.) were dissolved in
THF (10 mL), and benzoyl chloride (0.40 mL, 1.1 equiv.) was
added. After stirring for 2 h, the solution was diluted with EtOAc
and washed with brine. The organic layer was dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by SiO2 chromatography to give N-benzoyl-d-serine
methyl ester (0.66 g, 92%). [α]2D2 = –20 (c = 0.4 in MeOH). 1H
NMR (400 MHz, CDCl3, TMS): δ = 7.83–7.86 (m, 2 H), 7.52–7.56
(m, 1 H), 7.44–7.48 (m, 2 H), 7.11 (br. s, 1 H, NH), 4.87–4.90 (m,
1 H, α-CH), 4.06–4.11 (m, 2 H, β-CH2), 3.84 (s, 3 H, OCH3) ppm.
13C NMR (100 MHz, CDCl3, TMS): δ = 177.1, 167.7, 133.4, 132.0,
Table 2. ΔδRS values of chiral alcohol A obtained with ΨPro 3 in
various NMR spectroscopic solvents.
Solvent
ε[a]
ΨPro 3a
ΨPro 3b
1-CH3
4-CH3
1-CH3
4-CH3
CDCl3
4.8
2.4
20.7
32.7
0.15
0.08
0.17
0.18
0.16
0.18
–0.12
–0.08
–0.15
–0.16
–0.14
–0.17
0.33
0.28
0.31
0.38
0.32
0.35
–0.31
–0.24
–0.38
–0.46
–0.38
–0.42
[D8]toluene
[D6]acetone
[D4]MeOH
[D3]acetonitrile 37.5
[D6]DMSO 46.7
[a] Solvent dielectric constant from ref.[10]
128.6, 127.1, 63.4, 55.1, 52.8 ppm. MS(ESI): m/z
= 224.4
[M + H]+.
The methyl ester (0.60 g, 2.7 mmol) was dissolved in toluene
(10 mL)/CHCl3 (5 mL), and p-toluenesulfonic acid (5 mg,
0.01 equiv.) and 2,2-dimethoxypropane (0.66 mL, 2.0 equiv.) were
added. The solution was heated at reflux for 3 h to slowly remove
MeOH by distillation. After cooling down to room temperature,
the solution was diluted with CH2Cl2 and washed with saturated
NaHCO3 solution and brine. The organic layer was dried with an-
hydrous Na2SO4 and concentrated under reduced pressure. The res-
idue was purified by SiO2 chromatography to give (R)-3a methyl
ester (0.66 g, 93%). [α]2D2 = +151 (c = 0.5 in MeOH). 1H NMR
(400 MHz, CDCl3): δ = 7.36–7.38 (m, 5 H), 4.42 (br. s, 1 H, α-
CH), 4.22 [dd, 2J(H,H) = 9.2, 3J(H,H) = 6.7 Hz, 1 H, β-CH], 4.08–
2
3
4.09 [dd, J(H,H) = 9.2, J(H,H) = 3.1 Hz, 1 H, β-CH], 3.59 (s, 3
H, OCH3), 1.83 (s, 3 H, gem-CH3), 1.73 (s, 3 H, gem-CH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 171.1, 168.7, 137.7, 129.9, 128.7,
126.2, 97.0, 67.3, 61.4, 52.8, 24.9, 24.4 ppm. MS(ESI): m/z = 264.5
[M + H]+.
The above methyl ester (0.57 g, 2.2 mmol) was added to THF
(5 mL)/H2O (5 mL), and then NaOH (0.17 g, 2.0 equiv.) was added
to this mixture. After stirring for 3 h, the mixture was extracted
with diethyl ether, and the aqueous layer was acidified with aque-
ous HCl (1 n). The resulting mixture was extracted with EtOAc,
and the organic layer was washed with brine and dried with anhy-
drous Na2SO4. The mixture was concentrated to obtain (R)-3a as
a white solid (0.50 g, 93%). M.p. 140–142 °C. [α]2D1 = +121 (c = 0.5
1
in MeOH). H NMR (400 MHz, [D6]DMSO): δ = 7.38–7.41 (m, 5
2
3
H), 4.47–4.46 (m, 1 H, α-CH), 4.23 [dd, J(H,H) = 9.0, J(H,H) =
2
3
7.0 Hz, 1 H, β-CH], 3.99 [dd, J(H,H) = 9.0, J(H,H) = 2.6 Hz, 1
H, β-CH], 1.67 (s, 3 H, gem-CH3), 1.60 (s, 3 H, gem-CH3) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 171.9, 167.6, 137.7, 129.4,
Figure 5. ΔδRS values of ΨPro 3b esters of chiral alcohols. 1H
NMR spectra were recorded in [D6]DMSO.
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N-Arylcarbonylpseudoprolines as Tunable Chiral Derivatizing Agents
128.2, 126.2, 95.5, 66.8, 60.6, 24.7, 23.8 ppm. HRMS(FAB): calcd.
for C13H16NO4 [M + H]+ 250.1079; found 250.1078.
Acknowledgments
(S)-3-Benzoyl-2,2-dimethyloxazolidine-4-carboxylic Acid [(S)-3a]:[7]
The procedure described for (R)-3a was followed, except that l-
serine methyl ester hydrochloride was used instead of d-serine
methyl ester hydrochloride. The spectroscopic data were virtually
identical to those of (R)-3a except [α]2D1 = –118 (c = 0.5, in MeOH).
This work was supported by the Ministry of Education, Science
and Technology/National Research Foundation of Korea (grant
no. 2010–0000176) and the Priority Research Centers Program
(grant no. 2010–0020209).
(R)-3-(2-Naphthoyl)-2,2-dimethyloxazolidine-4-carboxylic
[(R)-3b]: The procedure described for (R)-3a was followed except
Acid
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N-(2-Naphthoyl)-D
-serine Methyl Ester: Yield 91%. [α]2D3 = –28 (c
1
= 0.5 in MeOH). H NMR (400 MHz, CDCl3): δ = 8.36 (s, 1 H),
3
7.86–7.93 (m, 4 H), 7.52–7.60 (m, 2 H), 7.29 [d, J(H,H) = 6.8 Hz,
1 H], 4.93–4.96 (m, 1 H, α-CH), 4.11–4.14 (m, 2 H, β-CH2), 3.85
(s, 3 H, OCH3), 2.71 [t, 3J(H,H) = 6.0 Hz, 1 H] ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.2, 167.9, 134.9, 132.4, 130.5, 129.0,
128.5, 127.9, 127.8, 127.7, 126.8, 123.5, 63.3, 55.3, 52.8 ppm.
MS(ESI): m/z = 274.4 [M + H]+.
[2]
[3]
[4]
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(R)-3b Methyl Ester: Yield 85%. [α]2D3 = +159 (c = 0.5 in MeOH).
1H NMR (400 MHz, CDCl3): δ = 7.84–7.87 (m, 4 H), 7.52–7.55
(m, 2 H), 7.45–7.47 (m, 1 H), 4.48 (br. s, 1 H, α-CH), 4.25 [dd,
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3
2J(H,H) = 9.2, J(H,H) = 6.7 Hz, 1 H, β-CH], 4.12 [dd, 2J(H,H) =
3
9.2, J(H,H) = 3.0 Hz, 1 H, β-CH], 3.53 (s, 3 H, OCH3), 1.87 (s, 3
H, gem-CH3), 1.78 (s, 3 H, gem-CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.8, 168.6, 134.8, 133.5, 132.5, 128.5, 128.3, 127.8,
127.1, 126.8, 125.6, 123.4, 96.9, 67.0, 61.2, 52.6, 24.7, 24.1 ppm.
MS(ESI): m/z = 314.5 [M + H]+.
(R)-3b: Yield 95%; m.p. 180–184 °C. [α]2D2 = +180 (c = 0.5 in
1
MeOH). H NMR (400 MHz, [D6]DMSO): δ = 13.0 (br. s, 1 H),
7.93–8.00 (m, 4 H), 7.55–7.60 (m, 2 H), 7.49 [dd, 3J(H,H) = 8.4,
4J(H,H) = 1.5 Hz, 1 H], 4.62–4.63 (m, 1 H, α-CH), 4.28 [dd,
3
2J(H,H) = 9.0, J(H,H) = 7.0 Hz, 1 H, β-CH], 4.01 [dd, 2J(H,H) =
9.0, 3J(H,H) = 2.9 Hz, 1 H, β-CH], 1.72 (s, 3 H, gem-CH3), 1.66
(s, 3 H, gem-CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
171.9, 167.7, 135.0, 132.9, 132.1, 128.4, 127.9, 127.7, 127.1, 126.7,
125.6, 124.1, 95.6, 66.8, 60.6, 24.7, 24.0 ppm. HRMS(FAB): calcd.
for C17H18NO4 [M + H]+: 300.1236; found 300.1238.
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[8] SpartanЈ06 (Wavefunction, Inc.) was used for the calculation.
A Monte Carlo conformation search was performed by using
the semi-empirical AM1 model to find the lowest energy con-
formation, which was then used as an initial structure for the
ab initio geometry optimization (RHF/6-31G**).
(S)-3-(2-Naphthoyl)-2,2-dimethyloxazolidine-4-carboxylic Acid [(S)-
3b]: The procedure described for (R)-3a was followed except that
l-serine methyl ester hydrochloride and 2-naphthoyl chloride were
used instead of d-serine methyl ester hydrochloride and benzoyl
chloride, respectively. The spectroscopic data were virtually iden-
tical to those of (R)-3b except [α]2D2 = –178 (c = 0.5 in MeOH).
General Procedure for the Preparation of ΨPro Esters: (S)- or
(R)-3, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl,
1.5 equiv.), and 4-(dimethylamino)pyridine (0.1 equiv.) were dis-
solved in DMF. To the solution was added DIEA (2.5 equiv.) fol-
lowed by a secondary alcohol (1.0 equiv.). After stirring overnight,
the mixture was diluted with EtOAc and washed with brine. The
organic layer was dried with anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was purified by SiO2
chromatography.
[9] T. Takahashi, H. Kameda, T. Kamei, M. Ishizaki, J. Fluorine
Chem. 2006, 127, 760–768.
[10] NMR Solvent Data Chart, Cambridge Isotope Laboratories,
Inc., Andover, MA.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the NMR spectra and characterization data for
pseudoprolines and their esters.
Received: February 16, 2011
Published Online: April 19, 2011
Eur. J. Org. Chem. 2011, 2920–2923
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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