Enantiodifferentiating photoisomerization of cyclooctene included and sensitized by aroyl-β-cyclodextrins: A critical enantioselectivity control by substituents

Article abstract of DOI:10.1021/jo801439n

(Chemical Equation Presented) A series of 6-O-benzoyl-β-cyclodextrins (CDs) with methyl, methoxy, methoxycarbonyl, and bromo substituent(s) at the ortho-, meta-, and/or para-position(s) were synthesized as chiral sensitizing hosts for the use in supramole

Full text of DOI:10.1021/jo801439n

Enantiodifferentiating Photoisomerization of Cyclooctene Included
and Sensitized by Aroyl-ꢀ-cyclodextrins: A Critical
Enantioselectivity Control by Substituents
Runhua Lu,*,†,‡ Cheng Yang,§ Yujuan Cao,| Linhui Tong, Wei Jiao,‡ Takehiko Wada,§
Zhizhong Wang,‡ Tadashi Mori,§ and Yoshihisa Inoue*,§
Department of Applied Chemistry, College of Sciences, China Agricultural UniVersity,
Beijing 100094, China, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041,
China, Department of Applied Chemistry, Osaka UniVersity, Yamada-oka, Suita 565-0871, Japan,
Department of Chemistry and EnVironment, South China Normal UniVersity, Guangzhou 510006, China,
and Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
lurh@cib.ac.cn; inoue@chem.eng.osaka-u.ac.jp
ReceiVed July 4, 2008
A series of 6-O-benzoyl-ꢀ-cyclodextrins (CDs) with methyl, methoxy, methoxycarbonyl, and bromo
substituent(s) at the ortho-, meta-, and/or para-position(s) were synthesized as chiral sensitizing hosts for
the use in supramolecular enantiodifferentiating photoisomerization of (Z)-cyclooctene (1Z) to its chiral
(E)-isomer (1E). The complex stability constants (KS) of the modified ꢀ-CDs with 1Z in aqueous methanol
solutions were highly sensitive to the substituent(s) introduced to the benzoate moiety, and the log KS
values decreased linearly with slightly different slopes with increasing methanol content. The enantiomeric
excess (ee) of 1E obtained upon photosensitization with these hosts was a critical function of the size
and position of the substituent, varying from almost zero to 46% ee. This indicates that even an apparently
small structural difference between methyl and methoxy can critically affect the enantiodifferentiating
photoisomerization of a guest included in the chiral cavity, probably through manipulation of both the
orientation of ground-state 1Z and the subsequent rotational relaxation of excited 1Z inside the chiral
cavity.
Introduction
intermolecular chiral interactions of a photosubstrate with an
optically active moiety or compound,1a,2 in which chirality
transfer from the chiral source to the substrate is controlled by
Asymmetric photochemistry, or photochirogenesis, has at-
tracted considerable attention in recent years.1 Apart from the
absolute asymmetric synthesis with circularly polarized light,
photochirogenesis is achieved in general through intra- and/or
(1) (a) Inoue, Y. Chem. ReV. 1992, 92, 741. (b) Inoue, Y.; Ramamurthy, V.
Chiral Photochemistry; Marcel Dekker: New York, 2004. (c) Yang, C.; Fukuhara,
G.; Nakamura, A.; Origane, Y.; Fujita, K.; Yuan, D.-Q.; Mori, T.; Wada, T.;
Inoue, Y. J. Photochem. Photobiol. A: Chem. 2005, 173, 375. (d) Fukuhara, G.;
Mori, T.; Wada, T.; Inoue, Y. Chem. Commun. 2005, 4199. (e) Fukuhara, G.;
Mori, T.; Wada, T.; Inoue, Y. J. Org. Chem. 2006, 71, 8233. (f) Nakamura, A.;
Inoue, Y. J. Am. Chem. Soc. 2003, 125, 966.
† Department of Applied Chemistry, College of Sciences.
‡ Chengdu Institute of Biology, Chinese Academy of Sciences.
§ Department of Applied Chemistry, Osaka University.
| Department of Chemistry and Environment, South China Normal University.
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences.
(2) Everitt S. R. L.; Inoue, Y. In Organic Molecular Photochemistry,
Ramamurthy, V., Schanze, K. S., Eds.; Marcel Dekker: New York, 1999; p 71.
10.1021/jo801439n CCC: $40.75
Published on Web 08/30/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7695–7701 7695

Lu et al.
SCHEME 1. Enantiodifferentiating Geometrical
Photoisomerization of 1Z Sensitized by Chiral
Photosensitizers
SCHEME 2. 6-O-Mono(benzoyl)-ꢀ-cyclodextrins As Chiral
Sensitizing Hosts
relatively weak and short-lived interactions in the excited state.
Recently, a supramolecular approach to photochirogenesis,
which utilizes both the ground- and excited-state interactions
between a chiral host and a prochiral guest, has emerged as an
attractive extension of the conventional asymmetric photochem-
istry.3 Various hosts, including chirally modified zeolites,4
synthetic templates,5 cyclodextrins,1d,e,3a,e,d,6 proteins,7 and
DNA,8 have been used as chirality sources to give the
corresponding optically active photoproducts in good-to-excel-
lent stereoselectivities.
ingly, we have recently found that the enantioselectivity of 1E
produced upon sensitization with O-permethylated 6-O-benzoyl-
ꢀ-CD exhibits a critical dependence on temperature, indicating
that the entropy-related factors become crucial again as a
consequence of the flexible skeleton of permethylated CD.1d,e
Despite these intriguing features, the enantioselectivity obtained
by using CD-based sensitizing hosts still remained modest.
More recently, we have briefly reported that the photoisomer-
ization of 1Z sensitized by 6-O-(m-methoxybenzoyl)-ꢀ-CD gives
chiral 1E in up to 46% ee, which is the highest value ever
reported for supramolecular photochirogeneses with analogous
CD hosts.11 This result clearly indicates that even an apparently
trivial modification of the attached chromophore can critically
manipulate the stereochemical outcomes of the supramolecular
photochirogenesis within a CD cavity, and prompted us to
synthesize a series of 6-O-benzoyl-ꢀ-CDs with methyl, methoxy,
methoxycarbonyl, and bromo substituent(s) at the ortho-, meta-,
and/or para-position(s) (Scheme 2) for use in the supramolecular
enantiodifferentiating photoisomerization of 1Z to elucidate the
origin and the detailed mechanisms of this highly substituent-
dependent enantioselectivity.
Among these hosts, cyclodextrin (CD) is particularly attractive
for application in supramolecular photochirogenesis because of
its inherently chiral cavity, ready availability, and feasible
modification.9 Combining advantages of the catalytic nature of
photosensitization and the intimate interactions in the supramo-
lecular system, sensitizer-appended CDs provide an intriguing
access to chiral photochemistry.1,3,10 Benzoate and isomeric
phthalate derivatives of ꢀ-CD have been used as chiral sensitiz-
ing hosts for the enantiodifferentiating photoisomerization of
(Z)-cyclooctene (1Z) to give planar-chiral (E)-isomer (1E)
(Scheme 1). Upon inclusion of 1Z into the CD cavity in aqueous
solution, the hydrophobic benzoate moiety is forced to move
out of the cavity to some degree but still stays on the cavity
rim covering the substrate, which upon irradiation facilitates
the efficient energy and chirality transfer in a conformationally
restricted chiral environment to give optically active 1E. The
photosensitization of 1Z with 6-O-benzoyl-ꢀ-CD in aqueous
methanol solutions gives 1E in enantiomeric excess (ee) varying
from 1% to 10%, depending on the methanol content. The use
of slightly modified host, 6-O-(methyl phthaloyl)-ꢀ-CD, leads
to much better ee values of 10-23%, which also varies with
the methanol content but is totally independent of the reaction
temperature, revealing that the entropy factor does not play a
significant role in supramolecular photoisomerization of 1Z
included and sensitized by native CD-based hosts.3a,e,d Interest-
Results and Discussion
A series of sensitizer-appended ꢀ-CDs 3a-c, 4b-c, 6a,b,
and 7 (Scheme 2) were synthesized by the reactions of native
ꢀ-CD with the corresponding benzoyl chlorides in pyridine and
purified by repeated recrystallization. NMR and HR-MS spectral
studies were performed to confirm the structure of these chiral
sensitizing hosts. The solubilities of these hosts were poor in
general in pure water, but were considerably improved by adding
5-50% methanol to the aqueous solutions.
(3) (a) Inoue, Y.; Dong, F.; Yamamoto, K.; Tong, L.-H.; Tsuneishi, H.;
Hakushi, T.; Tai, A. J. Am. Chem. Soc. 1995, 117, 11033. (b) Sugahara, N.;
Kawano, M.; Wada, T.; Inoue, Y. Nucleic Acids Symp. Ser. 2000, 44, 115. (c)
Inoue, Y.; Wada, T.; Sugahara, N.; Yamamoto, K.; Kimura, K.; Tong, L.-H.;
Gao, X.-M.; Hou, Z.-J.; Liu, Y. J. Org. Chem. 2000, 65, 8041. (d) Gao, Y.-Y.;
Inoue, M.; Wada, T.; Inoue, Y. J Incl. Phenom. Macrocycl. Chem. 2004, 50,
111. (e) Tong, L.-H.; Lu, R. H.; Inoue, Y. Prog. Chem. 2006, 18, 533.
(4) Chong, K.-C.-W.; Sivaguru, J.; Shichi, T.; Yoshimi, Y.; Ramamurthy,
V.; Scheffer, J.-R. J. Am. Chem. Soc. 2002, 124, 2858.
(5) (a) Bach, T.; Bergmann, H.; Grosch, B.; Harms, K. J. Am. Chem. Soc.
2002, 124, 7982. (b) Grosch, B.; Orlebar, C.-N.; Herdtweck, E.; Kaneda, M.;
Wada, T.; Inoue, Y.; Bach, T. Chem. Eur. J. 2004, 10, 2179.
(6) (a) Rao, V.-P.; Turro, N.-J. Tetrahedron Lett. 1989, 30, 4641. (b)
Koodanjeri, S.; Joy, A.; Ramamurthy, V. Tetrahedron 2000, 56, 7003. (c)
Shailaja, J.; Karthikeyan, S.; Ramamurthy, V. Tetrahedron Lett. 2002, 43, 9335.
(d) Koodanjeri, S.; Joy, A.; Ramamurthy, V. Tetrahedron Lett. 2002, 43, 9229.
(e) Vizvardi, K.; Desmt, K.; Luyten, I.; Sandra, P.; Hoornaert, G.; Eycken, V. E.
Org. Lett. 2001, 3, 1173.
Structure of Modified CDs. To elucidate the structural
features of sensitizer-appended CDs 3-7, in particular the
orientation of the aromatic group introduced to the primary
rim, we performed the circular dichroism spectral study in
aqueous methanol solutions. As exemplified in Figure 1, these
modified ꢀ-CDs mostly displayed negative induced circular
dichroism (ICD) signals in the chromophore’s 1La (at shorter
1
λ) and Lb (at longer λ) regions, indicating that the benzoate
(7) (a) Zandomeneghi, M. J. Am. Chem. Soc. 1991, 113, 7774. (b) Lhiaubet-
Vallet, V.; Sarabia, Z.; Bosca, F.; Miranda, M. A. J. Am. Chem. Soc. 2004, 126,
9538. (c) Wada, T.; Nishijima, M.; Fujisawa, T.; Sugahara, N.; Mori, T.;
Nakamura, A.; Inoue, Y. J. Am. Chem. Soc. 2003, 125, 7492.
moieties are only partly included or just perching on the
primary rim, according to the sector rule.12,13 This is
(8) Wada, T.; Sugahara, N.; Kawano, M.; Inoue, Y. Chem. Lett. 2000, 1174.
(9) (a) Takahashi, K. Chem. ReV. 1998, 98, 2013. (b) Breslow, R.; Dong, S.
Chem. ReV. 1998, 98, 1997.
(11) Lu, R.; Yang, C.; Cao, Y.; Wang, Z.; Wada, T.; Jiao, W.; Mori, T.;
Inoue, Y. Chem. Commun. 2008, 3, 374–376.
(12) Kajtar, M.; Horvath-Toro, C.; Kuthi, E.; Szejtli, J. Acta Chim. Acad.
Sci. Hung 1982, 110, 327.
(10) Yang, C.; Mori, T.; Wada, T.; Inoue, Y. New J. Chem. 2007, 31, 697.
7696 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of a series of 6-O-Benzoyl-ꢀ-cyclodextrins
intensity of the negative ICD at 240 nm, while the same
procedure with 4c led to a switching of the positive ICD to a
1
negative one at the Lb band and a gradual decrease of ICD
intensity at the 1La band. These results clearly indicate that the
chromophore orientation is critically manipulated to accom-
modate the incoming 1Z.11 The smooth CD spectral changes
accompanied by isodichroic points suggest formation of sto-
ichiometric 1:1 complex shown below:
Ks
CD + 1Z a [CD·1Z]
Assuming the 1:1 stoichiometry, the differential circular
dichroism spectral data were quantitatively analyzed by the
nonlinear least-squares curve fitting method to give the complex
stability constant (KS) in aqueous solutions of varying methanol
contents.14 The KS values obtained in 10-50% methanol, as
well as those extrapolated to 0% methanol, are listed in Table
1. The KS values reported previously for 2 and 5a-c3c are also
included in the table; note that the present measurements with
3, 4, and 6 were carried out at 18 °C due to the instrumental
requirements, while the previous experiments with 2 and 5 were
at 25 °C. Nevertheless, we dare to include the previous data to
more broadly compare the stability constants for these structur-
ally related CD hosts, since we know that the KS for 5a is
roughly doubled from 650 to 1420 M-1 by reducing the
temperature from 25 to 15 °C,3c and would expect not the same
but similar, slightly smaller changes at 18 °C for other relevant
CD hosts used in this study. Certainly, a direct comparison
should be made for the data obtained for 3, 4, and 6.
FIGURE 1. CD spectra of 0.1 mM 3a (black), 3b (red), and 4b (blue)
in aqueous solutions containing 10% (solid line) and 50% (dashed line)
methanol.
SCHEME 3. Proposed Conformations of 3b and 4b in 10%
Aqueous Methanol Solution
It is interesting to note that ꢀ-CDs 4b,c with a methoxy
substituent show stabilities obviously higher than methyl-
and dimethoxy-substituted ꢀ-CDs 3a,b and 6a,b by factors
of 2.1-4.6 in 10% methanol. This variation in KS due to the
very small structural difference in host structure suggests that
the substituent plays a decisive role in adjusting the chro-
mophore conformation upon synergic binding of 1Z. The
chromophores attached to CD reduce the surface area of
included 1Z exposed to the aqueous solution and enhance
the van der Waals interaction within the cavity. In such a
situation, it is likely that the substituent coincluded into the
cavity critically influences the guest’s position and orientation
in the cavity and therefore the KS value.
The significantly higher KS values observed for methoxy-
substituted 4b and 4c may suggest that the methyl group of 4b
and 4c, possessing more conformational freedoms than that of
3a and 3b, can manipulate their spatial orientation to match
the geometry of 1Z. For dimethoxy-substituted 6a, the bulkier
chromophore may disturb its coinclusion with 1Z in the cavity,
not exhibiting as high a KS value as those obtained with 4b and
4c. The substitution position on the benzene ring is also very
important in affecting the complex affinity as the ortho-
substituted 3a shows much larger KS than its meta-analogue
3b.
reasonable since the short ester linker may prevent deep
penetration of the benzoate into the cavity. On the other hand,
the aromatic moiety lying over the hydrophobic cavity can
reduce the net surface area exposed to the solvent and
enhance the hydrophobicity of the modified CD cavity. It
should be noted that the chromophore conformation is not
necessarily the same in different modified CDs, and the
1
positive ICD observed in the La region of m-methoxyben-
zoyl-modified 4b in 10% methanol solution suggests that the
benzoate moiety penetrates deeper into the cavity than the
ortho- and para-substituted 4a and 4c, while the positive ICD
1
observed at the Lb band of 3b indicates that the benzene
plane is positioned oblique rather than flatly (Scheme 3). Such
an exceptional behavior indicates that a small structural
difference in substituting group and position can critically
influence the orientation of chromophore in the cavity. The
chromophore orientation is sensitive also to the solvent
composition, as indicated by the fact that the circular
dichroism signals go more negative upon increasing the
content of methanol from 10% to 50%, probably due to
shallower penetration into the cavity.
Complexation of 1Z with Modified CDs. The complexation
behavior of 1Z with modified ꢀ-CDs 3, 4, and 6 was studied in
methanol-water mixtures by means of circular dichroism
spectral titration, and the results were compared with those
obtained previously with 2 and 5.3c As shown in Figure 2,
addition of 1Z to a solution of 3a caused a gradual increase in
Increasing methanol content significantly decreases the bind-
ing affinity of the hosts. To quantitatively analyze the effect of
methanol on the complexation behavior, we plotted the natural
logarithm of KS as a function of the fraction of methanol FM to
give good straight lines ln KS ) aFM + b for all of the ꢀ-CDs
employed, as shown in Figure 3. The slope a indicates the
(14) Inoue, Y.; Yamamoto, K.; Wada, T.; Everitt, S.; Gao, X.-M.; Hou, Z.-
J.; Tong, L.-H.; Jiang, S.-K.; Wu, H.-M. J. Chem. Soc., Perkin Trans. 2 1998,
1807.
(13) Tong, L.-H.; Hou, Z.-J.; Inoue, Y.; Tai, A. J. Chem. Soc., Perkin Trans.
2 1992, 1253.
J. Org. Chem. Vol. 73, No. 19, 2008 7697

Lu et al.
FIGURE 2. CD spectral changes of (a) 0.059 mM 3a upon increasing the concentration of 1Z from 0 to 2.8 mM and (b) 0.055 mM 4c upon
increasing the concentration of 1Z from 0 to 2.5 mM in 10% aqueous methanol.
TABLE 1. Complex Stability Constant (KS) and Free Energy
Change (-∆G°) for the 1:1 Inclusion Complexation of 1Z with
Modified CDs in Methanol-Water Mixtures
host
temp/°C
MeOH/%
KS/M-1
-∆G°/kJ mol-1
2b
25
0
50
0
10
25
50
0
10
25
50
0
10
25
50
0
10
25
50
0
25
50
50
0
50
0
50
0
20100
1440
24.5
18.0
22.8b
20.7
18.6
16.6
22.0b
19.3
18.0
14.8
25.3b
22.8
21.1
18.9
25.3b
22.5
20.8
17.7
24.1
20.0
16.0
17.6
29.8
21.3
29.1
19.6
23.8b
21.1
20.3
18.7
23.4b
21.0
19.9
16.9
3a
3b
4b
4c
18
18
18
18
25
12500b
8960
3580
1530
9000b
5000
2790
670
33900b
23110
11120
4200
FIGURE 3. Logarithm of the complex stability constant (KS) of 1Z
with 3a (s), 3b (0), 4b (2), 4c (b), and 6b (4) at 18 °C as a function
of the methanol content (FM) in methanol-water mixture.
34900b
20200
9640
is canceled out, so that only the solvation to G has to be
seriously considered. The ∆G°desol and ∆G°rel are directly
affected by the solvent composition. The ∆G°ass should also
be sensitive to the solvent composition in an indirect manner,
since the chromophore conformation, being susceptive to the
solvent, significantly influences the guest orientation in the
cavity. We therefore divide the ∆G°ass into two parts, i.e.,
one originating from the CD moiety (∆G°CD) and the other
from the chromophore (∆G°chrom), to obtain eq 2, which is
2430
16700
3250
650
1420
5aa
15
25
5ba
5ca
6a
170000
5390
25
18
124000
2680
18400b
10730
6640
10
25
50
0
10
25
50
different from that for native ꢀ-CD only by ∆G°chrom
:
∆G°total ) ∆G°desol + ∆G°CD + ∆G°chrom + ∆G°rel
1760
6b
18
15600b
10300
6300
(2)
In a methanol-water mixture, ∆G°total is considered to be a
weighted average of the contributions from methanol (M) and
water (W), and we can rewrite eq 2 as:
1710
a Reference 3c; measured at 25 °C. b Value extrapolated from the data
at higher methanol contents.
∆G°total ) FM∆G°desol(M) + (1 - FM)∆G°desol(W) + ∆G°CD
R F ∆G°chrom(M) + (1 - FM)∆G°chrom(W) + F ∆G°
+
+
[
]
M
M
rel(M)
sensitivity of KS to the methanol content, while the intercept b
equals the KS value extrapolated to pure water.
(1 - FM)∆G°rel(W) (3)
The Gibbs free energy change upon host-guest complexation
is a function of the surface area change upon merger of two
solvent voids containing a host and a guest (G) into a single
solvent void of the complex. As formulated in eq 1, the total
free energy change (∆G°total) originates primarily from the
desolvation of a guest G (∆G°desol), the association of G with
host CD (∆G°ass), and the release of solvent molecules from
the cavity (∆G°rel).
where R is a correction factor for the solvation energy, reflecting
the sensitivity of complexation affinity to the chromophore
solvation. Equation 3 can then be rewritten as:
ln K ) - F (∆G°desol(M) - ∆G°desol(W) + R∆G°chrom(M)
-
[
S
M
R∆G°chrom(W) + ∆G°rel(M) - G°rel(W)) + ∆G°desol(W)
+
∆G°CD + R∆G°chrom(W) + ∆G°rel(W) /RT ) aF + b (4)
]
M
where
∆G°total ) ∆G°desol + ∆G°ass + ∆G°rel
(1)
a ) - ∆G°desol(M) - ∆G°desol(W) + R∆G°chrom(M)
-
(
As a first approximation, we assume that the solvation
effect is comparable for free CD and complex [CD · G] and
R∆G°chrom(W) + ∆G°rel(M) - ∆G°rel(W) /RT (5)
)
7698 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of a series of 6-O-Benzoyl-ꢀ-cyclodextrins
The intercept b is the complex stability constant extrapolated
to 0% methanol, or pure water. As can be seen from Table 2,
the b value varies from 9.10 to 10.46, or KS from 9000 to 34900
M-1, indicating that all of these modified ꢀ-CDs can form very
stable 1:1 complexes with 1Z in pure water. The methoxy-
substituted hosts 4b and 4c give the b values larger than any of
the other modified CDs, revealing that they have the most
positive (or least negative) R∆G°chrom(W) values.
We can estimate the complex stability constants in pure
methanol from the sum of a and b. The KS values thus obtained
(60-480 M-1) for complexation in pure methanol (Table 2)
indicate that even in pure methanol, ꢀ-CDs can bind 1Z
moderately. The good linear relationship of ln KS against FM
indicates that the chromophore conformation varies smoothly
rather than abruptly upon increasing the methanol content.
b ) - ∆G°desol(W) + ∆G°CD + R∆G°chrom(W)
+
(
∆G°rel(W) /RT (6)
)
Since ∆G°desol(M), ∆G°desol(W), ∆G°rel(M), and ∆G°rel(W) are
considered to be approximately equal for all host molecules,
the difference in a observed for various ꢀ-CD hosts is deduced
to arise from the R(∆G°chrom(M) - ∆G°chrom(W)) value, the
differential solvation energy of chromophore in water and
methanol. On the other hand, the difference in a observed for
various ꢀ-CD hosts is ascribed to the difference in solvation
energy of the chromophore. Therefore, the R∆G°chrom(M)
-
R∆G°chrom(W) for 3b and 4c are inferred to be more significant
than the other modified ꢀ-CDs as suggested by their larger a
values (Table 2).
TABLE 2. The Slope (a) and Intercept (b) Obtained from the
Linear Fitting of the Data Shown in Figure 3 to ln KS ) aFM + b
and the Estimated KS(W) Obtained by Extrapolating the Data to
Pure Water and KS(M) Obtained by Extrapolating to Pure Methanol
Enantiodifferentiating Photoisomerization of 1Z with
Modified CDs. Photoisomerization of 1Z included and sensi-
tized by modified ꢀ-CDs was performed in aqueous methanol
solutions of varying methanol contents at different temperatures.
The E/Z ratio and the enantiomeric excess (ee) of 1E produced
in the initial stage (2-5 min of irradiation) and the near
photostationary state (pss) (30-60 min of irradiation) at each
temperature are shown in Table 3, along with some of the
relevant data previously reported for 2 and 5a-c.3c
host
a
b
KS(W) ) exp(b) a + b KS(M) ) exp(a + b)
3a
3b
4b
4c
6a
6b
-4.32
-5.09
9.43
9.10
-4.23 10.43
12500
9000
33900
34900
18400
15600
5.11
4.81
6.20
6.14
5.22
5.21
170
60
480
170
180
180
-5.32 10.46
-4.60
-4.56
9.82
9.77
TABLE 3. 1E/1Z (E/Z) Ratio and Enantiomeric Excess (ee) of 1E Obtained in the Photoisomerization of 1Z Mediated by Modified CDs 2,
3a-c, 4a-c, 5a-c, 6a,b, and 7 in Aqueous Methanola
host
2b
MeOH/%
0
T/°C
hν/min
E/Z
ee/%
host
MeOH/%
50
T/°C
hν/min
E/Z
ee/%
25
5
60
2
60
2
60
5
60
5
60
10
30
60
5
60
2
10
60
5
60
10
30
5
60
5
10
30
60
5
60
5
10
30
60
5
10
30
60
0.05
0.29
0.06
0.58
0.15
0.76
0.01
0.14
0.13
0.27
0.14
0.29
0.39
0.02
0.27
0.07
0.17
0.35
0.11
0.16
0.13
0.24
0.11
0.46
0.09
0.15
0.30
0.20
0.01
0.49
0.11
0.25
0.29
0.38
0.68
0.65
0.43
0.38
-9.7
-5.7
-10.7
-4.0
-9.4
-5.0
-6.4
-1.5
-4.6
-3.7
-5.4
-5.1
-3.0
-3.6
-3.5
-4.3
-2.9
-3.3
-13.6
-1.2
-17.4
-18.1
-15.4
-7.1
-15.7
-11.7
-8.0
-5.4
-12.2
-5.3
-11.8
-9.9
-6.7
-5.0
-13.1
-11.9
-3.8
-1.0
3c
25
5
10
20
5
30
5
5
5
30
5
30
5
30
5
5
5
30
5
30
5
30
2
40
2
60
40
5
0.32
0.58
0.64
0.19
0.44
0.24
0.19
0.07
0.23
0.08
0.13
0.18
0.19
0.12
0.14
0.12
0.20
0.24
0.13
0.21
0.36
0.09
0.42
0.21
0.60
-13.4
-12.5
-10.8
4.3
25
50
10
25
25
25
0
4ac
4b
50
10
25
3.5
-5
0
25
-45.8
-39.6
-40.8
-32.8
-33.3
-31.1
-30.2
-26.3
-6.0
-9.4
-10.6
-10.3
-10.8
-7.3
-12.7
-9.1
18.7
3a
0
25
50
10
25
25
25
50
0
4c
-5
0
25
25
25
50
50
50
25
25
25
25
3b
10
25
0
25
0
5ab
5bb
17.5
-1.7
0.3
25
5cb
6a
50
10
25
0
25
-5
0
0.61
1.9
c
c
5
5
30
5
5
30
5
30
20
5
50
10
0
6b
10
0.11
0.14
0.11
0.19
0.20
0.09
0.11
0.08
0.05
0.23
-34.2
-38.9
-38.1
-31.9
-30.0
-7.0
25
25
0
25
50
0
3c
25
-6.6
7
10
50
25
25
-6.9
-9.0
20
-7.3
a Irradiated at 254 nm under argon in aqueous methanol solution; [1Z] ) 1.5 mM, [host] ) 0.05-0.15 mM, depending on the host solubility.
b Reference 3c. c Reference 3d. d 1E not detected (E/Z < 0.01).
J. Org. Chem. Vol. 73, No. 19, 2008 7699

Lu et al.
The E/Z ratio obtained at near pss appreciably increases in
general with increasing methanol content from 10% to 50%.
The ee at the initial stage (2-5 min of irradiation) decreases to
some extent at higher methanol contents due to the increasing
contribution of external sensitization in the bulk solution, which
is inherently less enantiodifferentiating. Interestingly, the tem-
perature does not appear to significantly influence the enanti-
oselectivity at least at -5 to 25 °C, as exemplified by a small
decrease (from 46% to 41% ee) for 4b or even a small increase
(from 34% to 38% ee) for 6b by raising the temperature. These
results are consistent with the previous observation with 2 and
5a, demonstrating again the low-entropy environment of the
rigid cavity of ꢀ-CD.3c
Substituent Effects on Enantioselectivity. As can be seen
from Table 3, the E/Z ratio and the ee of 1E are critically
affected by the substituent and its position introduced to the
benzene ring of the host. For example, the pss E/Z ratio in 50%
aqueous methanol at 25 °C varies widely from the lowest 0.11
(for 6b) or 0.19 (for 4b) to the highest 0.76 (for 2), and most
of the hosts, except for 6a, afford the ratio in a range of 0.4-0.6,
which is an advantage of supramolecular photosensitization
within a CD cavity for preparing highly strained 1E in view of
the much lower E/Z ratios (0.05-0.28) obtained by conventional
photoisomerization of 1Z with the same aromatic sensitizer (not
incorporating ꢀ-CD) due to the less-efficient energy transfer to
1Z than to 1E. These observations indicate that the energy
transfer from the sensitizer moiety to 1Z within the CD cavity
is highly dependent on both the type and position of the
substituent introduced to the benzene ring. It is somewhat
surprising that the brominated host 7 can give comparable E/Z
ratios of up to 0.23 despite that bromine may accelerate the
intersystem crossing to triplet, which is known to afford much
smaller E/Z ratios (<0.1) in general.13 The near pss E/Z ratio,
as a measure of the efficiency of energy transfer, does not appear
to be directly related to the complex stability constant KS (Table
1), as demonstrated by the fact that the strongest binders 4b
and 4c merely afford modest E/Z ratios around 0.2 in 10%
methanol solution at 25 °C.
FIGURE 4. Schematic potential energy diagram for the ground and
excited states of 1Z and 1E.
substituent on the benzoate moiety greatly affects its orientation
in the cavity.
It is also interesting to compare the results obtained with
methoxy-substituted hosts 4a-c and 6a,b. The higher ee values
for 4b and 6b indicate that the m-methoxy is conformationally
most favorable in enhancing the ee of 1E. The additional
methoxy introduced at the para position (6b) does not signifi-
cantly alter the chiral environment of the original cavity of 4b.
Thus, the methoxy at the meta position should dominate the
enantiodifferentiating processes in the cavity, since para-
substituted host 4c gives 1E in only modest ee. However, the
coexistence of meta- and ortho-substituents significantly reduces
the sensitizing ability of host 6a, indicating that 1Z is included
indeed (Table 1) but has little access to the sensitizer moiety in
the cavity of 6a.
The enantiodifferentiating photoisomerization of 1Z mediated
by a sensitizing host (Sens) is essentially reversible and may
be illustrated as shown in Figure 4. In the initial stage of the
reaction, the reverse isomerization from 1E is negligible and
the product’s ee is determined by the relative rate of the
rotational relaxation of 1Z’s double bond to a pair of enantio-
meric perpendicular singlets, i.e. (R)- and (S)-1p which are
precursors to (R)- and (S)-1E, within the excited-state complex
[1Z· · ·Sens]*. It is likely that both the rotational relaxation to
(R)- and (S)-1p on the excited-state potential surface and the
subsequent decay to (R)- and (S)-1E on the ground-state surface,
occurring within the chiral cavity, are enantiodifferentiating in
principle.
The product’s absolute configuration and ee are even more
critically affected by the type and position of substituent(s)
introduced. In 10-50% methanol solutions, o-methylated host
3a affords (R)-1E in low ee values (2-6%), while o-methoxy-
lated 4a and o-methoxycarboxylated 5a give the antipodal
product in better ee values (4-19%). In contrast, the use of
meta-substituted 3b, 4b, and 6b (excepting 5b, which carries a
sensitizer moiety located outside the cavity, and is less efficient
in enantiodifferentiation, with the same being true for 5c)3c leads
to the formation of (S)-1E in much higher ee values of 18%,
46%, and 39%, respectively, in 10% methanol, which, however,
deteriorated in 25% and 50% methanol due to the less efficient
binding in these more hydrophobic solvents. The 46% ee
obtained is the highest value ever reported for a supramolecular
photosensitization with analogous hosts.3c
The 46% ee obtained with 4b indicates that the CD cavity
configured jointly by the inherently chiral glucopyranose walls
and the m-methoxylbenzoate has an overall preference for the
R-absolute configuration to the S by a factor of 2.7. As stated
above, there are two distinct potentially enantiodifferentiating
processes that are pivotal to the supramolecular photochirogen-
esis: (1) the rotational relaxation of 1Z to (R)- and (S)-1p within
the chiral host cavity to a pair of diastereomeric CD complexes,
[(R)-1p· · ·4b] and [(S)-1p· · ·4b], and (2) the subsequent decay
of these diastereomeric complexes to (R)- and (S)-1E, which
can proceed at different rates. Thus, the geometrical matching
of the enantiomers is crucial in both of these steps involving 1p
It shouold be noted that the ortho-, meta-, and para-isomeric
sensitizing host series 3, 4, and probably 6 (again excepting 5
due to the conformational difference)13 share the same trend in
product’s eesthe meta isomer always affords the highest value,
the para the second best, and the ortho the lowest. This reveals
that the enantiodifferentiation within the cavity is primarily
controlled by the steric, rather than electronic, effects, which is
in line with the circular dichroism spectral elucidation that the
1
and 1E. The p enantiomer that is better induced fitted to the
CD cavity upon rotational relaxation will be favored in the first
step. If the rotation to the opposite direction is disfavored in
the first step, further rotation to give the final product is
anticipated to be highly discouraged, and hence the favored 1p
enantiomer will have a better (or at least the same) chance to
7700 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of a series of 6-O-Benzoyl-ꢀ-cyclodextrins
decay to 1E of the same absolute configuration. In this specific
case, the cavity of 4b is deduced to be matched to the
dimensions of (R)-1p and (R)-1E much better than their
antipodes. This rationalization may be supported by the fact
that the ee of 1E obtained gradually declines upon prolonged
irradiation in all examined cases, which indicates that the
preferentially produced 1E enantiomer is better accommodated
in the host cavity to revert to 1Z at a rate faster than that for
the less favored antipodal product. We may conclude therefore
that the chiral CD cavity is exploited twice in a synergetic
cavity modified with the aromatic chromophore, featuring the
supramolecular photochirogenesis.
Experimental Section
Complexation Study. The complexation behavior of 1Z with
3a-c, 4b-c, 6a,b, and 7 was investigated and the complex stability
constants (KS) were determined by circular dichroism spectrometric
titration, according to the procedures reported previously.3c–e,15
Photolysis. Aqueous methanol solutions (5 mL) containing 1Z
(1.5 mM) and modified ꢀ-cyclodextrin (0.054-0.108 mM, deter-
mined by the solubility) were irradiated at 254 nm in quartz tubes
under an argon atmosphere at temperatures ranging from -5 to 25
°C by using a 30-W low-pressure mercury lamp fitted with a Vycor
filter. Each photolyzed sample was poured into a 10% aqueous KOH
solution (5 mL), and the resulting mixture was extracted with
pentane (1 mL). The organic extract was analyzed by gas chro-
matography on a Shimadzu CBP-20 (PEG) column for the E/Z ratio
and then extracted with a 20% aqueous silver nitrate solution (2
mL) at 0 °C. The aqueous phase containing [Ag+ ·1E] complex
was washed twice with pentane (1 mL) and added to a 28% aqueous
ammonia solution at 0 °C, and the liberated 1E was extracted with
pentane (0.5 mL). The ee of 1E obtained was determined by chiral
GC on a Supelco ꢀ-DEX 225 column.
1
manner, first in the excited-state rotation to p and then in the
ground-state rotation to the final product 1E, which is a major
advantage of the supramolecular photochirogenesis.
Conclusions
In this study, a series of substituted benzoate-modified CDs
were synthesized and used as chiral sensitizing hosts for
mediating the enantiodifferentiating photoisomerization of
cyclooctene. The conformational variation of these modified
CDs and their complexation behavior with 1Z were examined
by circular dichroism spectroscopy in water-methanol mixed
solvents to reveal that the orientation of chromophore, and
therefore the complex stability constant (KS), are highly
sensitive to both the type and position of the introduced
substituents. The chromophore conformation is smoothly
varied by changing the methanol content to give a linear
relationship of ln KS with the methanol fraction.
The supramolecular photosensitization of 1Z mediated by the
modified CDs gave chiral 1E, enantiomeric excess of which
was critically affected by the substituent introduced to the
sensitizer moiety to give the highest ee values of 39-46% upon
sensitization with m-methoxylbenzoate-appended ꢀ-CDs, which
is attained by manipulating the excited-state rotational relaxation
from prochiral substrate 1Z to enantiomeric perpendicular singlet
(R/S)-1p and the subsequent decay to the corresponding final
product (R/S)-1E. Both of these successive processes are
stereochemically driven to the same direction by the chiral CD
Acknowledgment. Financial support from the Chinese
Natural Science Foundation (No.. 20772120), the CAS-JSPS
Exchange Program, and the Japan Science and Technology
Agency (ICORP and PRESTO) is greatly acknowledged. We
are also grateful for Dr. Gaku Fukuhara and Hiroyuki Kishida
for their useful suggestions and assistance in the GC and CD
experiments.
Supporting Information Available: Experimental details,
1
syntheses, and H and 13C NMR spectra of 3a-c, 4b,c, 6a,b,
and 7. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO801439N
(15) Tong, L. H. Inclusion Complextion and Photosensitization of Cy-
clooctene with ꢀ-Cyclodextrin 6-O-Benzeate. In Final Rep. Inoue Photochiro-
genesis Project (ERATO, JST) 2001, 8, 13.
J. Org. Chem. Vol. 73, No. 19, 2008 7701