Diastereodifferentiating photodimerization of alkyl 2-naphthoates with chiral auxiliaries

Article abstract of DOI:10.1016/j.tetlet.2009.06.053

Photodimerization of alkyl 2-naphthoates with chiral auxiliaries resulted in cubane-like anti head-to-head photodimers in 93% yield and with up to 59% diastereomeric excess. After removal of the chiral auxiliaries enantiomers of cubane-like photodimer of 2-naphthalene carboxylic acid were obtained in 80% yield.

Full text of DOI:10.1016/j.tetlet.2009.06.053

Tetrahedron Letters 50 (2009) 4965–4968
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Tetrahedron Letters
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Diastereodifferentiating photodimerization of alkyl 2-naphthoates with
chiral auxiliaries
*
*
Hong-Xia Xu, Bin Chen, Li-Ping Zhang, Li-Zhu Wu , Chen-Ho Tung
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, The Chinese Academy of Sciences, Beijing 100190,
People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Photodimerization of alkyl 2-naphthoates with chiral auxiliaries resulted in cubane-like anti head-to-
head photodimers in 93% yield and with up to 59% diastereomeric excess. After removal of the chiral aux-
iliaries enantiomers of cubane-like photodimer of 2-naphthalene carboxylic acid were obtained in 80%
yield.
Received 15 May 2009
Revised 6 June 2009
Accepted 11 June 2009
Available online 13 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Chiral auxiliary strategy
Photodimerization
Cubane-like photodimer
Diastereoselectivity
Enantioselectivity in ground-state reactions is commonly
achieved by developing appropriate catalytic systems, and great
successes have been obtained during the past decades.1,2 In contrast,
there are considerably fewer examples of asymmetric induction in
photochemical transformations.3–9 A promising approach is to make
use of a removable chiral auxiliary and to connect the auxiliary to the
prochiral starting substrate by a covalent bond. The chiral auxiliary
in this case can bring about asymmetric induction during the photo-
chemical transformation and results in diastereomers. The yielding
diastereomerscanbeeasilyseparated, eveniftheasymmetricinduc-
tion is low. After the removal of the chiral auxiliary, the enantiome-
rically pure products can be obtained.4,10–13
Previously, we reported the photodimerization of methyl 2-naph-
thoate.14–17 Irradiation of this substrate results in a ‘cubane-like’ anti
head-to-head photodimer as the unique product (Scheme 1). This
photodimer is C2-symmetric, thus possesses chirality. Our interests
inthechirality ofthisphotodimeroriginate from the fact thatthe cub-
ane-like skeleton is strained and rigid, and the carboxylate can be de-
rived into a variety of function groups. Thus, the derivatives of this
photodimer might act as chiral ligands with C2 axis, and show appli-
cations in asymmetric catalysis. Since a chiral alcohol as chiral auxil-
iary can be readily introduced on the naphthoate, and such chiral
auxiliary is inert in the condition of irradiation and readily removed
from the photodimer, one can expect that chiral auxiliary strategy
might be a good choice for the synthesis of the enantiomerically pure
cubane-like photodimer. We found that this is indeed the case when
the chiral auxiliary is properly selected.
In the present Letter, we study the photodimerization of alkyl
2-naphthoates 1 with chiral auxiliaries as listed in Scheme 2
(1a–1g). We irradiated these substrates in degassed organic solu-
tions (ca. 1.9 ꢀ 10ꢁ2 M) with a light of wavelength longer than
280 nm.18 The photodimerization process was monitored by UV
absorption spectroscopy. After irradiation the products were iso-
lated by chromatographic column over silica and were analyzed
by HPLC. In contrast with methyl 2-naphthoate (Scheme 1), all
these substrates produce four isomers: head-to-head (HH, photo-
dimerization between two substituted rings) or head-to-tail (HT,
photodimerization between one substituted ring and one unsub-
stituted ring) isomers with syn or anti isomerism, denoted as
antiHH-2, synHH-2, antiHT-2, and synHT-2 (Scheme 2). For each sub-
strate the sum of the four photodimer yields is close to 100% on the
basis of the consumption of the starting material, suggesting that
another two possible cubane-like photodimers produced via the
photodimerization of the two unsubstituted rings (head-to-head
COOCH3
COOCH3
H3COOC
H3COOC
COOCH3
λ > 280 nm
hν
* Corresponding authors. Tel./fax: +86 10 82543578 (C.-H.T.).
E-mail addresses: lzwu@mail.ipc.ac.cn (L.-Z. Wu), chtung@mail.ipc.ac.cn (C.-H.
Tung).
Scheme 1. Photodimerization of methyl 2-naphthoate.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.053

4966
H.-X. Xu et al. / Tetrahedron Letters 50 (2009) 4965–4968
O
O
O
O
O
OR
OR
OR
OR
O
OR
hν
2
+
+
+
λ > 280 nm
O
OR
1
OR
O
O
RO
OR
antiHH-2
synHH-2
antiHT-2
synHT-2
H
H
H
H
S
S
H
S
R
O
S
R
O
S
COOMe
COOMe
=
R
H
O
O
a
b
c
d
e
f
g
Scheme 2. The structure of the photodimers.
Table 1
Diastereoselectivity of photodimerization of alkyl 2-naphthoates
Substrate
Solvent
Temperature (°C)
Relative yield (%)
dea (%)
antiHH-2
antiHT-2
synHT-2
antiHH-2
antiHT-2
synHT-2
1a
1b
1c
1d
1e
1f
1g
1a
1a
1a
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Methanol
20
20
20
20
20
20
20
8
88
84
89
93
76
93
95
87
83
84
8
10
7
4
16
5
4
8
10
9
4
6
4
3
8
2
1
5
7
7
ꢁ54
55
ꢁ58
ꢁ59
ꢁ20
22
ꢁ30
34
ꢁ30
ꢁ27
<5
<5
<5
ꢁ32
ꢁ12
ꢁ11
32
ꢁ35
32
ꢁ27
ꢁ9
<5
<5
36
<5
ꢁ56
ꢁ44
ꢁ50
20
ꢁ5
13
11
Methanol
a
de (%) = (A ꢁ B)/(A + B).
isomer with syn and anti isomerism) were not formed. The regi-
oselectivity in the photodimerization in terms of the HH/HT ratio
is clearly dependent on the substrate (Table 1). As expected, the
substrate with a less bulky group (1f and 1g) favors the formation
of head-to-head photodimers. For any substrate the main product
is antiHH-2 and its yield accounts for 76–95% of the overall prod-
ucts. Although photodimer synHH-2 was isolated, the ratio of its
yield to the total products is less than 2%. Thus in Table 1 only
the relative yields of antiHH-2, antiHT-2, and synHT-2 are given.
The regioselectivity in terms of the antiHT/synHT ratio is less
dependent on the chiral auxiliary.
low diastereoselectivity (<5% de for any diastereomeric pair). Sec-
ond, for all the substrates the level of chiral induction in the forma-
tion of the head-to-head photodimer is significantly greater than
that for the head-to-tail photodimers. For example, when the
photodimerization is carried out in cyclohexane at 20 °C, the de
Photodimers antiHH-2, antiHT-2, and synHT-2 each consist of a
pair of diastereomers. We could resolve the diastereomeric mix-
tures of all the three photodimers by HPLC either with an achiral
or a chiral column. Figure 1 shows the typical HPLC traces of pho-
todimers of 1a and 1b. For each pair of diastereomers, the first peak
on HPLC trace is arbitrarily assigned as A and the second peak as B.
The 1H NMR spectra of each optically pure diastereomer are given
in Supplementary data. The circular dichroism (CD) spectra for
each pair of diastereomers are mirror image, while their UV–vis
absorption spectra are not distinguishable from each other. Figure
2 gives the examples of the CD spectra for pair of antiHH-2a-A and
antiHH-2a-B and that of antiHH-2b-A and antiHH-2b-B. The de values
for all the diastereomer pairs were calculated and are listed out in
Table 1. Evidently, the degree of the asymmetric induction is con-
trolled by the nature of the chiral auxiliary. First, the position of the
chiral center in the auxiliary shows a remarkable influence on the
chirality of the products. For the substrates with the chiral center
immediately connected to the carboxyl group (1a–1f), appreciable
level of diastereoselectivity (up to 59% de, Table 1, antiHH-2d) was
achieved. In contrast, the substrate with the chiral center separated
from the carboxyl group by one carbon atom (1g) afforded very
Figure 1. The typical HPLC traces of the antiHH, antiHT, and synHT photodimers of 1a
and 1b; column: Daicel IA (chiral); eluting solvent: (a) hexane/ethanol = 7:3; (b)
hexane/ethanol = 8:2; (c) hexane/isopropanol = 6:4; (d) hexane/ethanol = 5:5; and
(e) hexane/isopropanol = 6:4. For each diastereomeric pair the first peak on the
HPLC trace is termed as A, and the second peak as B.

H.-X. Xu et al. / Tetrahedron Letters 50 (2009) 4965–4968
4967
values of the antiHH photodimers for 1a–1d are in the range of 54–
160
120
80
59%, while those for their antiHT and synHT photodimers are below
35%. This observation is consistent with the expectation that the
steric interactions between the two chiral auxiliaries of the reac-
tant molecules in the course of the formation of the head-to-head
photodimers are greater, thereby the chiral induction is greater
compared with those in the head-to-tail photodimer formation.
Third, a comparison of the results for substrates 1a–1d with 1e
shows that the bulky of chiral auxiliary is not the only factor of
the chiral induction. Although the chiral auxiliary in 1e is at least
as bulky as those in 1a–1d, the de values of all the photodimers
for 1e are evidently smaller than those for 1a–1d. Fourth, 1a and
1b are configurational isomers. 1a with (S)-chiral auxiliary
enhanced formation of diastereomers B for antiHH and antiHT pho-
todimers, and diastereomer A for synHT photodimer, while 1b with
(R)-chiral auxiliary enhanced formation of the opposite diastereo-
mers for all the three photodimers, and their respective de values
are almost identical. This result indicates that the system is well
behaved in the sense that the optical antipode of the chiral auxil-
iary gave the opposite diastereomers of the products. We noted
that 1d and 1f each also possesses an (S)-chiral auxiliary. However,
in contrast with 1a these substrates produce synHT-2d-B and
antiHH-2f-A as their major diastereomer, respectively. Presently,
the absolute configuration of the photodimers has not been estab-
lished, and diastereomers A and B are defined in terms of their
eluted sequence in the HPLC trace. The switch in the eluted se-
quence of the major and minor diastereomers of synHT-2d and
antiHH-2f likely results from the difference in their chromatograph
behavior. Indeed, by changing the eluting solvent, the eluted se-
quence can be switched. This conclusion is also supported by their
respective CD spectra. For example, antiHH-2f-A shows negative ef-
fect in 190–205 nm and positive effect in 205–245 nm. This CD
spectrum is the same as that of antiHH-2a-B and opposite to that
of antiHH-2a-A (Fig. 2). This observation suggests that antiHH-2f-A
and antiHH-2a-B have the same absolute configuration.
HH
anti
-2a-B
40
0
-40
-80
HH
anti
-2a-A
180
200
220
240
260
280
300
Wavelength/nm
150
100
50
HH
anti
-2b-B
0
-50
-100
-150
HH
anti
-2b-A
200
220
240
260
280
300
Wavelength/nm
Figure 2. The CD spectra for the pair of antiHH-2a-A and antiHH-2a-B (a) and that of
antiHH-2b-A and antiHH-2b-B (b).
cyclohexane is observed upon the decrease in temperature from
20 °C to 8 °C, in methanol at ꢁ5 °C the de for antiHH-2a (50%) is sig-
nificantly increased compared with that at 20 °C (44%).
The influence of experimental condition on the regio- and dia-
stereoselectivity in the photodimerization of these substrates
was studied. Neither the irradiation time nor the concentration
of the substrates has any significant influence on the product dis-
tribution. However, solvent can alter the degree of stereoselectivi-
ty. As shown in Table 1, in methanol at room temperature (20 °C)
the HH/HT selectivity is slightly reduced, and the decrease in the
diastereoselectivity of the photodimers is even more evident com-
pared with the results in cyclohexane. The de value of antiHH-2a
decreases from 54% in cyclohexane to 44% in methanol, and those
of antiHT-2a and synHT-2a decrease from ca. 30% in cyclohexane to
ca. 12% in methanol. The influence of temperature on the selectiv-
ity is somewhat complicated. While virtually no change in both the
HH/HT selectivity and the diastereoselectivity of the products in
The mechanism of the stereoselectivity in the above-mentioned
photodimerization has not been fully understood. We observed
excimer emission under the substrate concentration used for syn-
thesis. We have demonstrated that the yield of the photodimers is
dependent on the square of the light intensity, suggesting that
their formation is a two-photon process.19 Recently in the study
of photodimerization of methyl 3-methoxy-2-naphthoate we could
isolate the [4+4] cycloaddition intermediate, and provided the di-
rect evidence for the two-photon mechanism in the formation of
the cubane-like photodimer.20 Thus, we proposed a tentative
scheme to illustrate the diastereoselectivity in the formation of
antiHH-2 (Scheme 3). Absorption of the first photon by 1 leads to
Scheme 3. A tentative scheme for illustration of the asymmetric induction in the photodimerization of alkyl 2-naphthoates.

4968
H.-X. Xu et al. / Tetrahedron Letters 50 (2009) 4965–4968
the formation of an excimer. The excimer either goes back to the
starting substrate, or undergoes [4+4] cycloaddition yielding the
intermediate. The intermediate now has two possible paths for fur-
ther reaction: either absorption of the second photon to give the
cubane-like photodimer, or cleavage to re-form the starting sub-
strate that can then be fed back into the reaction cycle. The excimer
and [4+4] intermediate all have two configuration isomers p and q.
In the two isomers, the degree of the steric interactions between
the two chiral auxiliaries is different. Thus, one of the isomers,
for example, ep and ip preferentially undergoes forward reaction
in the reaction sequence, and another isomer, eq and iq undergoes
backward reaction. Thus, if the rate constants for the formation of
(Nos. 2006CB806105, G2007CB808004 and 2007CB936001), and
the Bureau for Basic Research of Chinese Academy of Sciences.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.053.
References and notes
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2. Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley-Interscience: New
York, 1994.
excimers ep and eq (k1 and k0 ) are reasonably assumed to be the
1
3. Everitt, S. R. L.; Inoue, Y.. In Molecular and Supramolecular Photochemistry;
Ramamurthy, V., Schanze, K. S., Eds.; Marcell Dekker: New York, 1999; Vol. 3, p
71.
4. Hoffmann, N.; Peter, J.-P. In Molecular and Supramolecular Photochemistry;
Inoue, Y., Ramamurthy, V., Eds.; Chiral Photochemistry; Marcell Dekker: New
York, 2004; Vol. 11, p 179.
5. Inoue, Y. In Molecular and Supermolecular Photochemistry; Inoue, Y.,
Rammamurthy, V., Eds.; Chiral Photochemistry; Marcell Dekker: New York,
2004; Vol. 11, p P129.
6. Sivaguru, J.; Natarajan, A.; Kaanumalle, L. S.; Shailaja, J.; Uppili, S.; Joy, A.;
Ramamurthy, V. Acc. Chem. Res. 2003, 36, 509.
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Angew. Chem., Int. Ed. 2008, 47, 1.
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Soc. 2007, 129, 3478.
10. Buschmann, H.; Scharf, H. D.; Hoffmann, N.; Plath, M. W.; Runsink, J. J. Am.
Chem. Soc. 1989, 111, 5367.
11. Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P. Angew. Chem., Int. Ed.
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12. Clayden, J.; Knowles, F. E.; Menet, C. J. J. Am. Chem. Soc. 2003, 125, 9278.
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Morimoto, T.; Kakiuchi, K. J. Org. Chem. 2004, 69, 785.
14. Tung, C.-H.; Wang, Y.-M. J. Am. Chem. Soc. 1990, 112, 6322.
15. Tung, C.-H.; Wu, L.-Z.; Yuan, Z.-Y.; Su, N. J. Am. Chem. Soc. 1998, 120, 11594.
16. Tung, C.-H.; Wu, L.-Z.; Zhang, L.-P.; Chen, B. Acc. Chem. Res. 2003, 36, 39.
17. Wu, X.-L.; Luo, L.; Lei, L.; Wu, L.-Z.; Liao, G.-H.; Tung, C.-H. J. Org. Chem. 2008,
73, 491.
18. The irradiation was carried out in organic solution with a 500 W high-pressure
mercury lamp as a light source. For example, 1a was dissolved in a degassed
cyclohexane solution (250 mg, 1.9 ꢀ 10ꢁ2 M) in a Pyrex tube, which also served
as a light filter to cut off the light below 280 nm. The irradiation was monitored
by UV–vis absorption spectra. After irradiation the resulting mixture was
concentrated under reduced pressure and the products were purified by
column chromatography on silica with dichloromethane as the eluent to afford
the mixture of dimers. The mixture of dimers was further separated by HPLC,
using an achiral ODS-3 column and a chiral IA column.
same, the diastereoselectivity of the cubane-like photodimer
(antiHH-2) would be generated at two levels: in the first selectivity
level the rate constant ratio of k2/k is greater than k0 /kꢁ0 1, and in
ꢁ1
ꢁ2
the second level of selectivity k3/k is greater than k02/k0
.
3
ꢁ2
The chiral auxiliaries in photodimers 2 can be easily removed by
hydrolysis inClaisen base solution(6.25 M KOH in the mixed solvents
of methanol and water with v/v 3:1). For example, refluxing the solu-
tion of antiHH-2aat 90 °C for 3 h followedby quenching the hydrolysis
with 1 N HCl at 0 °C afforded the cubane-like antiHH photodimer of 2-
naphthalene carboxylic acid (antiHH-3) as a white precipitate in 80%
yield. The hydrolysis of both the diastereomeric mixture of antiHH
-
2a and its optically pure diastereomer (the major and the minor)
was performed. Thus, both racemic and enantiomerically pure
antiHH-3 were obtained. We were not able to prepare a single crystal
from the enantiomerically pure antiHH-3. However, the crystal of the
racemic antiHH-3 enantiomer mixture was obtained by recrystalliza-
tion from ethanol solution. X-ray analysis indicates that the cubane-
like skeleton is well retained during the hydrolysis.21
To summarize, we have successfully made use of chiral auxiliary
strategytobringabouttheasymmetricinductioninthephotodimer-
ization of alkyl 2-naphthoates for the first time. Moderate diastereo-
meric induction in the formation of the antiHH-2 photodimers was
achieved. Spectroscopy and X-ray structural analysis revealed that
the cubane-like skeleton of the antiHH photodimer is well retained
after the removal of the chiral auxiliary. We are currently applying
this photodimer as a chiral ligand in asymmetric catalysis.
Acknowledgments
19. Tung, C.-H.; Li, Y.; Yang, Z.-Q. J. Chem. Soc., Faraday Trans. 1994, 90, 947.
20. Luo, L.; Liao, G.-H.; Wu, X.-L.; Lei, L.; Tung, C.-H.; Wu, L.-Z. J.Org. Chem. 2009, 74,
3506.
21. Wu, X.-L.; Lei, L.; Wu, L.-Z.; Liao, G.-H.; Luo, L.; Shan, X.-F.; Zhang, L.-P.; Tung,
C.-H. Tetrahedron 2007, 63, 3133.
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 20732007, 20728506, and
20672122), the Ministry of Science and Technology of China