Tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid: A chiral derivatizing agent for the determination of the absolute configuration of secondary alcohols

Article abstract of DOI:10.1016/j.tetlet.2010.07.062

A new chiral derivatizing agent, tetrahydro-1,4-epoxynaphthalene-1- carboxylic acid (THENA), with a represented syn-periplanar disposition of O-Ca-CαO as a part of the bicyclic system to lock the aromatic residue conformation and the availability of an in

Full text of DOI:10.1016/j.tetlet.2010.07.062

Tetrahedron Letters 51 (2010) 4965–4967
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Tetrahedron Letters
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Tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid: a chiral derivatizing
agent for the determination of the absolute configuration of secondary alcohols
Suttipun Sungsuwan a, Nopporn Ruangsupapichart a, Samran Prabpai a, Palangpon Kongsaeree a,
Tienthong Thongpanchang a,b,
*
a Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
b National Center for Genetic Engineering and Biotechnology, Thailand Science Park, Klong Luang, Patumthani 12130, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
A new chiral derivatizing agent, tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid (THENA), with a
Received 3 June 2010
Revised 25 June 2010
Accepted 9 July 2010
Available online 15 July 2010
represented syn-periplanar disposition of O–C –C@O as a part of the bicyclic system to lock the aromatic
a
residue conformation and the availability of an internal reference proton for 1H NMR spectral alignment,
is introduced. In the determination of the absolute configuration of chiral secondary alcohols, THENA
offered good uniformity of
configuration.
Dd with high reliability, resulting in unambiguous assignment of the absolute
Ó 2010 Elsevier Ltd. All rights reserved.
The introduction of chiral derivatizing agents (CDAs),1 such as
analogous
MPA array
MPA array
Mosher’s acid 1,2 MPA 2,3
Ma
NP 3,4 2-NMA 4,5 2-ATMA 56 and
O
O
O
9-ATMA 6,7 has provided chemists with a set of tools for the deter-
mination of absolute configuration by analysis of diastereotopic
O
H
r ef
α
L
k
OH
α
O
α
OH
Free rotation
Href
NMR shifts (Dd). In general, these CDAs apply the favored confor-
Ar
R
No rotation
OH
mational equilibrium of the syn-periplanar array of Lk–C –C@O,1a
a
Lk = Locking group
THENA 7
for example, Lk = OMe in 2–6 (known as MPA array) (Fig. 1), and
the aromatic anisotropic effect from the Ar group to differentiate
the substitution patterns of the chiral substrate. Rotation around
Mosher's acid 1
MPA 2
(Lk = CF3, R = OMe, Ar = Ph)
(Lk = OMe, R = H, Ar = Ph)
(Lk = OMe, R = Me, Ar = 1-naphthyl)
M NP 3
α
the C –Ar bond, however, may generate additional conformational
a
options8 and, in some cases, result in ambiguous absolute stereo-
chemistry assignment.9 Here we report the design and synthesis
of tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid (THENA) 7
as a new CDA for the determination of the absolute configuration
of chiral secondary alcohols. The key features of THENA include
(i) the analogous MPA array as a part of the bicyclic system, to limit
the rotational degree of freedom of the aromatic moiety, (ii) the
observed anisotropic deshielding effect on the substituents, due
to the bicyclic tether, (iii) the presence of an internal reference pro-
ton (Href) to facilitate spectral alignment, and (iv) the low cost
straightforward synthesis.
2-NMA 4
2-ATMA 5
9-ATMA 6
(Lk = OMe, R = H,
(Lk = OMe, R = H,
(Lk = OMe, R = H,
Ar = 2-naphthyl)
Ar = 2-anthryl)
Ar = 9-anthryl)
Figure 1. Common chiral derivatizing agents (CDAs) 1–6 and tetrahydro-1,4-
epoxynaphthalene-1-carboxylic acid (THENA) (7). The MPA and the analogous MPA
arrays are highlighted in shade.
to give the acid 7 in 95% yield. The resulting acid was then resolved
by formation of an ester with (+)-(S)-menthol to yield a pair of dia-
stereomers (S,S)-12 (47%) and (R,S)-12 (46%). Finally, hydrolysis of
each diastereomer furnished the desired (S)- and (R)-THENA 7 in
95% and 97% yields, respectively.
The optically active acid 7 was prepared from commercially
available and low cost starting materials. As summarized in Scheme
1, methyl furan-2-carboxylate (8) was reacted with benzenediazo-
nium-2-carboxylate (9), generated from the reaction between
anthranilic acid and iso-pentyl nitrite, in boiling 1,2-dichloroethane
to yield the racemic bicyclic ester 10 in 87% yield.10 The ester was
then subjected to catalytic hydrogenation with H2 over Pd-C (97%
yield) followed by ester hydrolysis with KOH in MeOH/1,4-dioxane
X-ray analysis11 of the THENA ester (R,S)-12 (Fig. 2) established
the absolute configuration of the THENA acid. In addition, the X-ray
structure confirmed the conservation of the analogous MPA plane
*
(the syn-periplanar disposition of the O–C –CO–O–C –H) in the
a
THENA ester derivative.
Accordingly, a pair of diastereomers derived from both enanti-
omers of THENA 7 with an optically active secondary alcohol
should provide distinctive NMR characteristics. The presence of
Href which is not influenced by the diastereotopic environment
can serve as an internal reference for spectral alignment and thus
* Corresponding author. Tel.: +662 201 5319; fax: +662 201 5139.
E-mail address: tettp@mahidol.ac.th (T. Thongpanchang).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.062

4966
S. Sungsuwan et al. / Tetrahedron Letters 51 (2010) 4965–4967
O
O
+
O
N2
CO2Me
+
ClCH2CH2Cl
reflux, 10 h
H2 / Pd-C,
-
EtOAc, 12 h
CO2
CO2Me
CO2Me
8
9
rac -10 (87%)
rac-11 (97%)
KOH,
O
O
MeOH/
1,4-dioxane,
3 h
KOH
1. (COCl)2, DMF (cat.),
rt, 3 h
2. (+)-(S)-menthol,
DMAP (cat.), Et3N,
rt, 8 h
MeOH/1,4-dioxane,
3 h
CO2H
CO2(+)-(S)-menthyl
O
(
S
)-(+
)-7(95%)
(S,S)-12 (47%)
O
O
3. Chromatography
Separation
CO2H
KOH
rac-7 (95%)
MeOH/1,4-dioxane,
3 h
CO2H
CO2(+)-(S)-menthyl
12
(R
)-(
−
)-7(97%)
(R,S)- (46%)
Scheme 1. Synthesis and resolution of optically active THENA 7.
L1: ΔδSR < 0 L2: ΔδSR > 0
L1: ΔδSR < 0 L2: ΔδSR > 0
OR*
OR
+0.05
-0.05
-0.06
+0.04
-0.04
+0.06
(S)-13
OR*
(R)-14
OR*
Ph
Ph
+0.04
-0.04
Figure 2. ORTEP diagram of the X-ray crystal structure of (R,S)-12, indicating the R
configuration of the THENA moiety and the analogous MPA plane.
(S)-16
(R)-15
OR*
OR*
+0.05
-0.05
-0.04
Ph
Ph
-0.03
-0.03
+0.03
+0.03
+0.04
(R)-17
(S)-18
-0.06
-0.12
+0.06
+0.12
OR*
OR*
-0.09
-0.09
+0.09
+0.09
+0.03
-0.05
+0.05
-0.03
+0.01
+0.04
-0.02
-0.02
+0.01
-0.01
+0 . 01
-0.03
+0.01
-0.03
-0.02
+0.02
(R)-19
(S)-12
Figure 3. Influence of the anisotropic deshielding effect on subsituents L1 and L2 in
a pair of diastereomeric esters derived from (a) (S)-THENA and (b) (R)-THENA. (c)
The proposed model to correlate between the
? denotes an unknown absolute configuration of the chiral alcohol) and the absolute
configuration. Dashed line represents the plane.
OR*
OR*
Dd Dd
SR value (
SR = d(S,?) À d(R,?) where
+0.05
-0.06
+0.02
+0.06
-0.02
-0.06
-0.05
-0.03
+0.03
+0.02
+0.04
-0.08
+0.02
-0.02
-0.03
+0.02
0.00
-0.01
0.00
0.00
the chemical shift difference (
Dd) can then be calculated explicitly.
A model to correlate d with the absolute configuration assign-
D
(R)-20
(S)-21
ment is proposed as follows (Fig. 3). Related to MPA and its analogs,
OR*
0.00
+0.10
the THENA ester should adopt a syn-periplanar arrangement of the
-0.09
12
*
+0.01
0.00
+0.03
O–C –CO–O–C –H (dashed line) and therefore position the sub-
a
-0.02
-0.02
stituents L1 and L2 on either the left or the right side of the plane.
It should be emphasized that, since the aromatic moiety of the
bicyclic ester is conformationally locked, a deshielding anisotropic
effect, as opposed to a shielding effect from the phenyl ring of the
MPA, is observed exclusively. Moreover, the structural rigidity in
the bicyclic system eliminates the conformational equilibrium
+0.03
+0.05
(R)-22
Figure 4. Chemical shift difference values (D ) and the assigned absolute
dSR
configuration of the tested chiral alcohols. Substituents with positive values are
on the right while those with negative values are on the left. Dashed line represents
the plane.
around the C –Ar bond, leading to an unambiguous calculation of
a
the
Dd values.

S. Sungsuwan et al. / Tetrahedron Letters 51 (2010) 4965–4967
4967
Thus substituents L2 of the diastereomer derived from (S)-THE-
NA should be influenced by the anisotropic deshielding effect and
their chemical shifts should appear at a lower field (Fig. 3a). In
analogy, the chemical shifts of substituents L1 of the diastereomer
derived from (R)-THENA should also be shifted to a lower field
the Center of Excellence for Innovation in Chemistry (PERCH-CIC)
for S.S. and N.R. are gratefully acknowledged.
Supplementary data
(Fig. 3b). Consequently, given
D
d
SR = d(S,?) À d(R,?) where ? repre-
Supplementary data (detailed experimental procedures and 1H
and 13C NMR spectra of compounds 7, and 10–22) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.07.062.
sents the unknown configuration of chiral alcohols (Fig. 3c), the
protons on L1 should have negative
the protons on L2 should have positive
the absolute configuration can then be deduced.
D
dSR values (
D
D
dSR <0) while
dSR >0) and
dSR values (
D
Application of THENA as a CDA for the determination of the
absolute configuration of chiral secondary alcohols was demon-
strated. Eleven chiral secondary alcohols with known absolute con-
figuration were esterified with the acid chloride of both (S)- and
(R)-THENA 7, following a modified Trost method,3a to give the cor-
responding esters in 69–92% yields. The spectra of both diastereo-
mers were aligned with respect to the chemical shift of Href, and
References and notes
1. (a) Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17–118; (b) Seco, J.
M.; Quiñoá, E.; Riguera, R. Tetrahedron: Asymmetry 2001, 12, 2915–2925.
2. (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543–2549; (b)
Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519; (c) Sullivan, G. R.;
Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143–2147.
3. (a) 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; (b) Latypov, S. K.; Seco, J. M.; Quiñoá, E.; Riguera, R.
J. Am. Chem. Soc. 1998, 120, 877–882; (c) Garcia, R.; Seco, J. M.; Vazquez, S. A.;
Quiñoá, E.; Riguera, R. J. Org. Chem. 2002, 67, 4579–4589.
the chemical shift difference (Dd
SR) of the corresponding protons
in the diastereomeric (S)- and (R)-esters, respectively, was com-
puted and the values shown in Figure 4. It is worth mentioning
that, although the
Dd
SR values of the THENA esters were relatively
4. (a) Kuwahara, S.; Naito, J.; Yamamoto, Y.; Kasai, Y.; Fujita, T.; Noro, K.;
Shimanuki, K.; Akagi, M.; Watanabe, M.; Matsumoto, T.; Watanabe, M.;
Ichikawa, A.; Harada, N. Eur. J. Org. Chem. 2007, 2007, 1827–1840; (b) Kasai,
Y.; Sugio, A.; Sekiguchi, S.; Kuwahara, S.; Matsumoto, T.; Watanabe, M.;
Ichikawa, A.; Harada, N. Eur. J. Org. Chem. 2007, 2007, 1811–1826; (c) Kasai, Y.;
Taji, H.; Fujita, T.; Yamamoto, Y.; Akagi, M.; Sugio, A.; Kuwahara, S.; Watanabe,
M.; Harada, N.; Ichikawa, A.; Schurig, V. Chirality 2004, 16, 569–585.
5. (a) Kusumi, T.; Takahashi, H.; Xu, P.; Fukushima, T.; Asakawa, Y.; Hashimoto, T.;
Kan, Y.; Inouye, Y. Tetrahedron Lett. 1994, 35, 4397–4400; (b) Seco, J. M.;
Latypov, S.; Quiñoá, E.; Riguera, R. Tetrahedron Lett. 1994, 35, 2921–2924.
6. Kouda, K.; Kusumi, T.; Xu, P.; Kan, Y.; Hashimoto, T.; Asakawa, Y. Tetrahedron
Lett. 1996, 37, 4541–4544.
7. (a) Seco, J. M.; Tseng, L.-H.; Godejohann, M.; Quiñoá, E.; Riguera, R. Tetrahedron:
Asymmetry 2002, 13, 2149–2153; (b) Seco, J.; Quiñoá, E.; Riguera, R. Tetrahedron
1999, 55, 569–584; (c) Seco, J.; Latypov, S. K.; Quiñoá, E.; Riguera, R. Tetrahedron
1997, 53, 8541–8564.
8. Latypov, S. K.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Org. Chem. 1996, 61, 8569–
8577.
9. (a) Joshi, B. S.; Newton, M. G.; Lee, D. W.; Barber, A. D.; Pelletier, S. W.
Tetrahedron: Asymmetry 1996, 7, 25–28; (b) Kusumi, T.; Fujita, Y.; Ohtani, I.;
Kakisawa, H. Tetrahedron Lett. 1991, 32, 2923–2926; (c) Ohtani, I.; Kusumi, T.;
Kashman, Y.; Kakisawa, H. J. Org. Chem. 1991, 56, 1296–1298; (d) Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096.
10. (a) Chuang, S.-C.; Sander, M.; Jarrosson, T.; James, S.; Rozumov, E.; Khan, S. I.;
Rubin, Y. J. Org. Chem. 2007, 72, 2716–2723; (b) Stiles, M.; Miller, R. G. J. Am.
Chem. Soc. 1960, 82, 3802; (c) Best, W.; Collins, P.; McCulloch, R.; Wege, D. Aust.
J. Chem. 1982, 35, 843–848.
smaller than those of the MPA analogs due to the weaker deshiel-
ding effect, the use of Href as an internal reference facilitated reli-
able calculation of the
D D
dSR value. In addition, the signs of dSR
of the protons situated on the same side of the plane were ob-
served with uniformity. Thus, according to the proposed model,
substituents with positive
side of the plane (dashed line) while substituents with negative
dSR values (L1) were on the left, and the absolute configurations
Dd
SR values (L2) were placed on the right
D
of the chiral alcohols were then assigned. It was found that, in all
cases, the absolute configurations derived from the experimental
data and the proposed model were all satisfactorily in good agree-
ment with the known configuration.
In conclusion, a new chiral derivatizing agent, THENA (7), has
been prepared. The application of THENA (7) as a CDA in the
NMR shift difference method is realized, and its potential as a can-
didate for single derivative methods3b,c to determine the absolute
configuration is very promising. Further investigations on the
application of THENA 7 in determining the absolute configuration
of chiral secondary alcohols and of other systems, as well as its
application in natural products chemistry are currently in progress.
11. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 772662. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.
12. Latypov, S. K.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Org. Chem. 1995, 60, 504–
515.
Acknowledgments
Financial support from the Thailand Research Fund
(RMU4980021) and fellowships from the Development and Promo-
tion of Science and Technology Talents program (DPST) and from