2-Naphthol as a powerful chromophore for the configurational assignment of carboxylic acid groups via the CD exciton chirality method

Article abstract of DOI:10.1016/S0957-4166(00)00116-6

A novel approach for the stereochemical assignment of carboxylic acid groups via the circular dichroism (CD) exciton chirality method using the 2- naphthyl chromophore is described. Direct esterification of carboxyl groups with 2-naphthol was effectively achieved with the employment of N,N-bis[2- oxo-3-oxazolidinyl]phosphorodiamidic chloride as the activating reagent. The method was tested with several model compounds, including both cyclic and acyclic dicarboxylic acids, and also applied to the natural product abietic acid. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00116-6

Tetrahedron: Asymmetry 11 (2000) 1741±1747
2
-Naphthol as a powerful chromophore for the
con®gurational assignment of carboxylic acid groups via the
CD exciton chirality method
Michaela Hartl and Hans-Ulrich Humpf*
Lehrstuhl fuÈr Lebensmittelchemie, UniversitaÈt WuÈrzburg, Am Hubland, 97074 WuÈrzburg, Germany
Received 26 January 2000; accepted 24 March 2000
Abstract
A novel approach for the stereochemical assignment of carboxylic acid groups via the circular dichroism
CD) exciton chirality method using the 2-naphthyl chromophore is described. Direct esteri®cation of
(
carboxyl groups with 2-naphthol was e€ectively achieved with the employment of N,N-bis[2-oxo-3-oxazo-
lidinyl]phosphorodiamidic chloride as the activating reagent. The method was tested with several model
compounds, including both cyclic and acyclic dicarboxylic acids, and also applied to the natural product
abietic acid. # 2000 Elsevier Science Ltd. All rights reserved.
1
. Introduction
The stereochemical assignment of chiral compounds has always been an important yet challenging
task. With the CD exciton chirality method a non-empirical procedure is available that allows
the quick, convenient and reliable determination of absolute con®gurations on a microscale. It
utilizes the interaction of the electric transition moments of two or more chromophores, which
may be identical (degenerate systems) or may not be identical (non-degenerate systems).
The chromophores can either be introduced by derivatization of functional groups or already be
present in the molecule, e.g., monoene and diene moieties. The interaction gives rise to char-
acteristic bisignate split CD curves and the signs of the two Cotton e€ects re¯ect the spatial
arrangement of the chromophores, leading to the assignment of the absolute con®guration. If the
orientation of the electric transition moments of the chromophores is clockwise (looking from the
chromophore in front to the chromophore in back), de®ned as a positive twist, the CD shows a
positive ®rst Cotton e€ect (CE) at longer wavelength and a negative second CE at shorter wave-
length and vice versa. Being extremely versatile, the exciton chirality method has an ever increasing
scope of application and has become a valuable tool for structure elucidation, particularly with
*
Corresponding author. Tel: +49-931-8885483; fax: +49-931-8885484; e-mail: humpf@pzlc.uni-wuerzburg.de
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00116-6

1
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M. Hartl, H.-U. Humpf / Tetrahedron: Asymmetry 11 (2000) 1741±1747
newly isolated natural products.1,2 To date it has been used most commonly with compounds
bearing hydroxy or amino groups since they react readily with chromophores, disposing of a
carboxyl function activated as imidazole, triazole, ¯uoride or chloride.3
�6
Regarding its
application to carboxylic acid groups, a structural element often encountered in natural products,
very few strategies have been developed to date. For the con®gurational assignment of
a-hydroxy carboxylic acids the use of a 5-(p-carboxyphenyl)-10,15,20-triphenylporphyrin moiety
as a chromophore with a very large extinction coecient ("=350 000) is described. The method
comprises two steps since ethanolamine has to be introduced as a linker before derivatization
7
with the porphyrin moiety. Another possibility, well developed for hydroxy carboxylic acids, is
the employment of the chromophoric combination 2-naphthoate/9-methylanthryl group, which is
8,9
selectively introduced to the hydroxy and carboxy groups in a two-step procedure. These are,
to our knowledge, the only methods that report the use of the exciton chirality method with
carboxylic acids.
Therefore, the aim of our studies was the search for a suitable strategy for the chromophoric
derivatization of the carboxyl function. Though the 9-methylanthryl group can be introduced
9
easily by using the highly reactive diazomethane, its methyl moiety provides additional ¯exibility
and increases the number of possible conformations. Especially with acyclic compounds, whose
CD spectra are in¯uenced by the equilibrium mixture of preferred minimum energy conforma-
tions, this is an unwelcome e€ect, thus making the association of the observed CD spectrum with
the absolute stereochemistry more complex and dicult. Besides, due to their reactivity the diazo-
methanes are not very stable and begin to decompose when stored over longer time periods,
which is a problem encountered particularly with 2-naphthyldiazomethane. For this reason, the
direct esteri®cation with 2-naphthol seemed to be a more promising pathway and we present here
an e€ective and convenient method, which enables the exciton chirality circular dichroism to be
utilized for the stereochemical assignment of carboxylic acid groups.
2
. Results and discussion
For chromophoric derivatization of carboxylic acids a suitable one-pot/one-step reaction was
desired, leaving an extra activation of the carboxy group prior to esteri®cation with the naphthol
unnecessary. Also, the possibility of the direct employment of 2-naphthol seemed favorable as it
is a powerful chromophore with a large extinction coecient (lmax 222 nm, "=54 000, MeCN)
and easily available. Our search led us to a method that utilizes N,N-bis[2-oxo-3-oxazolidinyl]-
phosphorodiamidic chloride 1 for activation of the carboxyl group.10 This reagent is accessible in
a simple synthesis with 2-oxazolidinone and phosphorus pentachloride. The mechanism of acti-
vation is believed to consist of a nucleophilic substitution at the phosphorus atom by the
carboxylate anion followed by a nucleophilic attack of the hydroxy group at the carbonyl
moiety.10 We applied this method to several model compounds starting with trans-cyclohexane
dicarboxylic acid [Fig. 1(C)]. The reaction was quantitative and completed within several hours.
While the (1R,2R)-enantiomer was available in enantiomerically pure form, we had to employ a
racemic mixture of trans-cyclohexane dicarboxylic acid in order to obtain the data for the
(
¯
1S,2S)-enantiomer. The enantiomers were separated as their dinaphthyl derivatives since the
uorescence of the chromophoric products greatly facilitates puri®cation and allows a sensitive
detection. Fig. 1(A) shows the UV and CD spectra of both enantiomers. For the (1R,2R)-
1
11
dinaphthylester 5 (dashed line) the interaction between the B bands of the two chromophores
b

M. Hartl, H.-U. Humpf / Tetrahedron: Asymmetry 11 (2000) 1741±1747
1743
gives rise to a negative split CD curve with extrema at 225 nm (Á"=^73.9) and 216 nm
Á"=+55.5) and an amplitude A of ^129.4, thus establishing a negative chirality and re¯ecting a
(
counterclockwise orientation of the electric transition dipoles. The enantiomer (S,S)-5 [Fig. 1(A),
solid line] reveals a curve of similar shape but opposite Cotton e€ects (CE) at 225 nm (Á"=+75.8)
and 215 nm (Á"=^43.8), amplitude A=+119.6. These results are in agreement with predictions
based on a MontoCarlo conformational search using MacroModel 5.0.13 When compared to the
CD curve of the corresponding (1R,2R)-methylnaphthylester, obtained by derivatization with
naphthyldiazomethane (data not shown), the amplitude observed here is about 10-fold more
intense. These data demonstrate that the two enantiomers can be clearly distinguished via the CD
e€ects of their dinaphthylesters and the absolute con®guration of the trans-cyclohexane dicarboxylic
acid can be deduced from a single CD measurement.
Figure 1. UV and CD spectra of (A) (R,R)- and (S,S)-cyclohexane dicarboxylic acid dinaphthylester 5 and (B) (R)- and
(S)-malic acid dinaphthylester 6 in acetonitrile. (C) Chromophoric derivatization of trans-cyclohexane dicarboxylic
acid 3 and malic acid 4 to the corresponding naphthylesters (bar indicates the location of the electric transition dipole).

1
744
M. Hartl, H.-U. Humpf / Tetrahedron: Asymmetry 11 (2000) 1741±1747
We also applied this method to malic acid 4, serving as a representative example for acyclic
compounds [Fig. 1(C)]. Enantiomerically pure (S)-4 and (R)-4 were converted to their naphthyl-
esters, the CD spectra of which are depicted in Fig. 1(B). (S)-Malic acid dinaphthylester 6 (solid
line) shows a negative couplet with a negative ®rst CE (225 nm, Á"=^5.5) and a positive second
CE (215 nm, Á"=+6.8) and an overall amplitude A of ^12.3. Its enantiomer (R)-6 reveals a
mirror image CD curve with extrema at 224 nm (Á"=+5.9) and 215 nm (Á"=^7.0), amplitude
A=+12.9 [Fig. 1(B), dashed line]. With non-cyclic compounds lacking a ®xed conformation, the
CD spectrum is in¯uenced by the equilibrium mixture of the possible staggered conformational
isomers and represents the sum of all contributions, which in the case of opposite e€ects may
lead to diminished amplitudes.12 This factor can probably be held responsible for the relatively
small A values observed for (R)-6 and (S)-6. However, the crucial point is the agreement of the
13
CD e€ects with the predictions based on theoretical calculations using MacroModel 5.0 and the
modi®ed Allinger MM2 force ®eld. The preferred minimum energy conformations for both
enantiomers were obtained after energy minimization and a MonteCarlo conformational
search and showed a clockwise orientation of the chromophoric transition moments for the
(R)-enantiomer, predicting a positive chirality, and a counterclockwise arrangement for
the S-enantiomer [see (S)-6, Fig. 1(B)], suggesting a negative chirality, exactly as was experimentally
observed.
Since the derivatization procedure emerged to work quickly and e€ectively, we were interested
to apply it to natural products with more demanding steric structures. The diterpene abietic acid
7 is a well known major constituent of gum or wood rosin and is used in the manufacturing of
lacquers, soaps, and plastics. The molecule consists of the typical hydrophenanthrene system and
contains an (R)-con®gured carboxylic group in position 1 (Fig. 2B). This group was successfully
Figure 2. (A) UV and CD spectra of abietic acid mononaphthylester 8 in acetonitrile. (B) Conversion of abietic acid 7
to the chromophoric derivative 8 (bars indicate the locations of the electric transition dipoles).

M. Hartl, H.-U. Humpf / Tetrahedron: Asymmetry 11 (2000) 1741±1747
1745
derivatized with 2-naphthol to yield the mononaphthylester 8. For exciton coupling at least two
1
chromophores are required and in the case of abietic acid the B band of the napthyl group
b
interacts with the diene moiety at ca. 235 nm ("=21 500, MeCN) already pre-existing in the
molecule. The resulting CD spectrum is shown in Fig. 2(A). It is characterized by extrema at 233
nm (Á"=+32.7) and 218 nm (Á"=^44.3), constituting a positive chirality, just as expected from
the orientation of the two transition moments as the structure in Fig. 2(B) demonstrates. The
amplitude A of +77.0 is about 2.5-fold higher than the one revealed by the previously synthesized
methylnaphthylester obtained by derivatization with 2-naphthyldiazomethane (A value of
+
29.7).14 This ®nding is similar to the results for the cyclohexane dicarboxylic acid and supports
the assumption that with compounds having a ®xed conformation the naphthyl derivatives
generally yield stronger CD e€ects than the corresponding methylnaphthylesters, which have
greater conformational ¯exibility due to the additional methyl moiety.
3
. Conclusions
The presented one-step method has been shown to be a potent and e€ective way for the esteri-
cation of carboxylic acids with 2-naphthol, achieving conversion to the naphthylester under
®
mild conditions and in high yields. It enables the circular dichroism exciton chirality method to be
utilized for the stereochemical assignment of carboxyl groups, a moiety that is often encountered
in natural products, but for which only very few CD approaches had been developed so far. The
chromophoric derivatization with 2-naphthol yields highly ¯uorescent products, thus facilitating
puri®cation and allowing one to work on a microscale. This can be especially valuable with the
con®gurational assignment of natural products as the amounts of enantiomerically pure or
enriched material may be rather limited. The examples with the model compounds and abietic acid
demonstrate the versatility of this approach, working both for cyclic and acyclic compounds.
Although the amplitudes for the latter are smaller than for cyclic substances, nonetheless unambiguous
stereochemical assignment is possible.
4
. Experimental
4
.1. General experimental procedures
1
H NMR spectra were recorded in CDCl on a Bruker WM 400 or a DMX 600 spectrometer
3
(Bruker, Ettlingen, Germany) operating at 400 and 600 MHz, respectively. Chemical shifts are
relative to CHCl (ꢀ=7.26ppm); coupling constants (J) are given in Hertz (Hz). Electrospray
3
ionization mass spectra (ESI-MS) were measured via loop injection on a Finnigan TSQ 7000
Triple Stage Quadrupol mass spectrometer equipped with an ESI interface (Finnigan MAT,
Bremen, Germany). Electron impact-high resolution mass spectra (EI-HRMS) were measured on
a Finnigan MAT 90 mass spectrometer (Finnigan MAT, Bremen, Germany). UV±vis and CD
spectra were recorded as acetonitrile solutions in a 1 cm cell on a Shimadzu UV-2101 PC
spectrometer and a Jasco J-600 spectropolarimeter, respectively (Jasco, Gross-Umstadt,
Germany). The UV±vis and CD spectra were obtained in spectral grade solvents (Merck,
Darmstadt, Germany). All derivatization reactions were carried out in gradient grade solvents
dried over molecular sieves. For HPLC analyses a Knauer Maxi Star pump and a Knauer

1
746
M. Hartl, H.-U. Humpf / Tetrahedron: Asymmetry 11 (2000) 1741±1747
variable wavelength monitor UV detector were used (Knauer, Berlin, Germany). Chromato-
graphic separations were performed on a Eurospher 100 C18 column (250Â4 mm, Knauer,
Berlin, Germany) and enantiomeric separation was achieved on a Ceramospher Chiral RU-1 column
(
(
250Â4.6 mm, Shiseido, Tokyo, Japan). 1R,2R-Cyclohexane dicarboxylic acid was from Merck
Darmstadt, Germany); all other chemicals were purchased from Fluka (Neu-Ulm, Germany).
4
.2. Preparation of N,N-bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride 1
To a solution of oxazolidinone (6.96 g, 80 mmol) in nitromethane (76 mL), phosphorus pen-
tachloride (8.32 g, 40 mmol) was added in one portion. The solution was stirred for 4 h at room
ꢀ
ꢀ
temperature, for 1 h at 40±45 C and then cooled to 0 C. A mixture of water (3 mL) and 1,2-
dimethoxyethane (10 mL) was added within 5 min and the solvent was removed under reduced
pressure. The resulting white crystals were ®ltered, washed with 1,2-dimethoxyethane and dried at
ꢀ
^1
^1
1
5
0 C, yield 60%. IR (KBr): ꢁ=1765 cm (CˆO), 760 cm (P±Cl). H NMR (CDCl ): ꢀ 4.20
3
(
4H, t, J=8.1 Hz), 4.55 (4H, t, J=8.1 Hz) ppm.
4
.3. General procedure for the preparation of the naphylesters
In a dry glass vial 10 mg of the carboxylic acid was dissolved in dry dichloromethane or aceto-
nitrile (0.5 mL), then triethylamine (2 equiv. per COOH group) and 2-naphthol 2 (1.04 equiv. per
COOH group) were added. For activation N,N-bis[2-oxo-3-oxazolidinyl]phosphorodiamidic
chloride 1 (1 equiv. per COOH group) was added and the resulting suspension was stirred at
room temperature. After about 10 min the reagent had completely dissolved. The mixture was
monitored via thin layer chromatography and allowed to react until no starting material could be
detected (<24 h).
After treatment with slightly basic water (0.5 mL) the organic layer was separated and dried
over Na SO . The esters were further puri®ed by preparative thin layer chromatography (TLC)
and/or high performance liquid chromatography (HPLC).
2
4
4
.3.1. trans-(1R,2R)-Cyclohexane dicarboxylic acid dinaphthylester (R,R)-5
Prepared from enantiomerically pure 1R,2R-cyclohexane dicarboxylic acid (R,R)-3 in dichloro-
methane as solvent. Puri®ed by HPLC on a Eurospher 100 C18 column using an acetonitrile/
+
water gradient and UV detection at 222 nm. ESI-MS m/z: 442 [M+NH ] . EI-HRMS m/z for
4
1
C H O calcd 424.1675, found 424.1675. H NMR (CDCl ): ꢀ 1.70 (4H, m), 2.0 (2H, brd,
2
8
24
4
3
J=8.8 Hz), 2.44 (2H, brd, J=12.9 Hz), 3.08 (2H, m), 7.22 (2H, d, J=8.8 Hz), 7.47 (4H, t, J=3.5
Hz), 7.55 (2H, s), 7.77 (2H, d, J=8.8 Hz), 7.85 (4H, d, J=8.8 Hz) ppm.
4
.3.2. trans-(1S,2S)-Cyclohexane dicarboxylic acid dinaphthylester (S,S)-5
Prepared from racemic trans-cyclohexane-1,2-dicarboxylic acid. Puri®cation by HPLC on a
Eurospher 100 C18 column using an acetonitrile/water gradient and UV detection at 222 nm. The
enantiomeric separation of the chromophoric derivatives was achieved on a Ceramospher Chiral
ꢀ
RU-1 column at 50 C with 100% methanol. Assignment of the enantiomers was done according
+
to their elution order by comparison with (R,R)-5. ESI-MS m/z: 442 [M+NH ] . EI-HRMS m/z
4
1
for C H O calcd 424.1675, found 424.1671. H NMR (CDCl ): ꢀ 1.70 (4H, m), 2.0 (2H, brd,
28
24
4
3
J=8.8 Hz), 2.42 (2H, brd, J=12.9 Hz), 3.08 (2H, m), 7.22 (2H, d, J=8.8 Hz), 7.47 (4H, t, J=3.5
Hz), 7.55 (2H, s), 7.79 (2H, d, J=8.8 Hz), 7.87 (4H, d, J=8.8 Hz) ppm.

M. Hartl, H.-U. Humpf / Tetrahedron: Asymmetry 11 (2000) 1741±1747
1747
4
.3.3. (S)-(^)-Malic acid dinaphthylester (S)-6
Reaction was performed in acetonitrile as solvent. Excess of 2-naphthol was removed by prep-
arative TLC [silica gel, chloroform:methanol (14:2)] and the product was further puri®ed by
+
1
HPLC (Eurospher 100 C18, acetonitrile/water, UV 222 nm). ESI-MS m/z: 404 [M+NH ] . H
4
NMR (CDCl ): ꢀ 3.38 (2H, dd, J=5.2/4.8 Hz), 4.94 (1H, dd, J=4.8 Hz), 7.30 (2H, d, J=8.8 Hz),
3
7
.50 (4H, t, J=5.2 Hz), 7.63 (2H, s), 7.81 (2H, d, J=7.4 Hz), 7.88 (4H, d, J=8.8 Hz) ppm.
4
.3.4. (R)-(+)-Malic acid dinaphthylester (R)-6
Residual 2-naphthol was separated from the product by preparative TLC [silica gel, chloroform:
methanol (14:2)] and further puri®cation was achieved by HPLC (Eurospher 100 C18, acetonitrile/
+
1
water, UV 222 nm). ESI-MS m/z: 404 [M+NH ] . H NMR (CDCl ): ꢀ 3.38 (2H, dd, J=5.5/5.0
4
3
Hz), 4.94 (1H, dd, J=4.8 Hz), 7.30 (2H, d, J=8.8 Hz), 7.50 (4H, t, J=5.2 Hz), 7.63 (2H, s), 7.81
(2H, d, J=8.1 Hz), 7.88 (4H, d, J=8.8 Hz) ppm.
4
.3.5. Abietic acid naphthylester 8
The product was separated from residual 2-naphthol by preparative TLC on silica gel plates
[
using an acetonitrile/water gradient and UV detection at 222 nm. EI-HRMS m/z for C H O
diethyl ether:pentane (1:1)]. Further puri®cation was by HPLC on a Eurospher 100 C18 column
30
36
2
1
calcd 428.2715, found 428.2717. H NMR (CDCl ): ꢀ 0.90 (3H, s), 1.02 (3H, d, J=7.0 Hz), 1.04
3
(3H, d, J=6.6 Hz), 1.42 (3H, s), 5.48 (1H, m), 5.82 (1H, s), 7.16 (1H, d, J=8.8 Hz), 7.45 (1H, t,
J=7.0 Hz), 7.47 (1H, s), 7.49 (1H, t, J=6.8 Hz), 7.80 (1H, d, J=8.6 Hz), 7.84 (2H, d, J=8.8 Hz)
ppm.
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2
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1
0. Diago-Meseguer, J.; Palomo-Coll, A. L.; Fernandez-Lizarbe, J. R.; Zugaza-Bilbao, A. Synthesis 1980, 547±551.
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simulation.
3
; at least 1000 conformers were searched for each
1
È
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2
29.