Enantiodifferentiating [2+2] photocycloaddition of cyclohexenone carboxylic acid with ethylene using 8-phenylmenthyl amine as a chiral template

Article abstract of DOI:10.1016/j.tetlet.2014.02.033

Enantiodifferentiating [2+2] photocycloaddition of cyclohexenone carboxylic acid with the smallest olefin, ethylene, was accomplished using 8-phenylmenthyl amine as a chiral template. Particularly, we succeeded in enhancing the enantiomeric excess (ee) value by selective excitation of a chiral substrate-template supramolecular complex.

Full text of DOI:10.1016/j.tetlet.2014.02.033

Tetrahedron Letters 55 (2014) 2123–2126
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Tetrahedron Letters
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Enantiodifferentiating [2+2] photocycloaddition of cyclohexenone
carboxylic acid with ethylene using 8-phenylmenthyl amine
as a chiral template
⇑
Yuuki Yanagisawa, Yasuhiro Nishiyama, Hiroki Tanimoto, Tsumoru Morimoto, Kiyomi Kakiuchi
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0101, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiodifferentiating [2+2] photocycloaddition of cyclohexenone carboxylic acid with the smallest
olefin, ethylene, was accomplished using 8-phenylmenthyl amine as a chiral template. Particularly, we
Received 26 December 2013
Revised 5 February 2014
Accepted 13 February 2014
Available online 20 February 2014
succeeded in enhancing the enantiomeric excess (ee) value by selective excitation of
substrate–template supramolecular complex.
a chiral
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
[2+2] Photocycloaddition
Enantiodifferentiating
Chiral template
Ethylene
Cyclobutane
Photochemical reactions are powerful tools compared to tradi-
tional thermal chemical reactions, as they allow the construction of
complex skeletons, in only one step.1 Especially, [2+2] photocyc-
loadditions have attracted great attention since they enable the
chemist to synthesize a strained four-membered ring that can be
used as a precursor for many biologically active compounds via
further ring-expansion reactions.2 Despite these valuable applica-
tions, a significant problem persists in photochemistry; namely,
control over regio- and stereoselectivity is difficult because of the
high energy and short life time of excited chemical species. Up to
the present, various kinds of approaches, such as chiral auxiliaries,3
chiral tethers,4 chiral sensitizers,5 confined media,6 and chiral crys-
tal7 were investigated for asymmetric [2+2] photocycloadditions.
Chiral templates also showed good potentials for affording enan-
tioselective products,8 however, these examples of intermolecular
asymmetric [2+2] photocycloadditions typically use relatively
large size olefins as a coupling partner.8 Our previous attempts at
enantiodifferentiating [2+2] photocycloadditions of cycloalke-
none–cyclodextrin complexes with the smallest olefin, ethylene,
have yielded adducts with only 8% enantiomeric excess (ee) and
yields of 6% in suspension.9 On the other hand, we have previously
reported highly diastereodifferentiating [2+2] photocycloadditions
using menthol derivatives as chiral auxiliaries,10 accomplishing up
to 96% diastereomeric excess (de) even using ethylene as a cou-
pling partner.11 These chiral auxiliaries were connected to an en-
one through an ester linkage, allowing the complex to adopt a
stacked conformation by p–p interaction between the a,b-unsatu-
rated carbonyl moiety and the arylmenthyl auxiliary, which func-
tions as a shielding block for the attack of ethylene from the Re
face (Fig. 1a).12
In this study, we extended this approach to an enantiodifferen-
tiating reaction (Scheme 1), whereby non-covalent bonds, such as
hydrogen bonding or acid–base interactions, can be used instead of
an ester bond (Fig. 1b). Combining a chiral template (C. Tem.) and
cyclohexenone carboxylic acid would make a chiral supramolecu-
lar complex similar in structure to the ester bond model (Fig. 1a).
Therefore, enantioselectivity can be introduced by a similar mech-
anism as for the corresponding diastereodifferentiating reaction.
This supramolecular approach offers not only high versatility of
coupling partner, but also bypasses two synthetic steps, that is
introduction and removal of the chiral auxiliary.
First, we examined the non-covalent bond effect on the enanti-
oselectivity in the [2+2] photocycloaddition of carboxylic acid 1
with ethylene 2. Three types of C. Tem. 4–6 were examined. 8-Phe-
nylmenthol 4 was prepared by our previous reported procedure.10b
Oxime derivative 5 and 8-phenylmenthyl amine 6 were synthe-
sized by modified Kojima’s13 and Waldvogel’s14 methods. Stereo-
chemistry of these compounds was confirmed by X-ray
crystallography (4), comparing spectral data to the literature (5,
6) and NOE (6).15 The absolute configurations of photoadducts 3
⇑
Corresponding author. Tel.: +81 743 72 6080; fax: +81 743 72 6089.
E-mail address: kakiuchi@ms.naist.jp (K. Kakiuchi).
http://dx.doi.org/10.1016/j.tetlet.2014.02.033
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2124
Y. Yanagisawa et al. / Tetrahedron Letters 55 (2014) 2123–2126
Table 2
(b)
O
(a)
O
Effect of solvent on enantioselectivitya
Si face
HO
R
Si face
O
Entry
Solvent
ET(30)b
eec (%)
O
chiral auxiliary
Re face
1
2
Toluene
Et2O
CH2Cl2
MeCN
MeOH
33.9
34.5
40.7
45.6
55.4
18
10
8
4
3
O
substrate
Re f ace
substrate
chiral template
(C. Tem.)
3
R; OH, =NOH, NH2
4d
5
Figure 1. Models for chiral photoreaction. (a) Covalent bond model. (b) Non-
a
b
c
Reaction conditions: 6 (5 equiv), À78 °C, Irradiated for 2 h (>280 nm).
covalent bond model.
Ref. 17.
Error in ee upon GC analysis (InertCap CHIRAMIX) after methylation: <1%.
At À40 °C.
d
3
HOOC
R
S
S
8
especially high ee value (entry 1). It is noted that further stabiliza-
tion of the supramolecular complex may occur by interactions
4
(5)
(6)
( )
OH
NOH
NH2
R;
p–p
O
3
between the aromatic ring on C. Tem. and toluene. This type of
effect was previously reported, whereby naphthalene derivatives
as an additive could enhance de values.18 On the other hand, high
polar solvents showed worse selectivities, since these solvents
caused dissociation of 1Á6 supramolecular complex by a solvation
to 1 and 6 respectively.
Next, we investigated optimal amounts of 6 (Table 3). It is
assumed that a large amount of 6 could easily generate the supra-
molecular complex. As anticipated, the ee values were raised by
increasing the amount of 6. This tendency was also supported by
1H NMR titration experiments.15 On the contrary, the conversion
of starting material 1 did not change in the range of 1–5 equiv of
6 used, though the yield was decreased when decreasing the
amount of 6. That means free 1 also gave undesired products when
a small amount of 6 was used. Although the structures of the
byproducts were unknown, they were observed at every entry in
GC analysis.
Furthermore, we examined the temperature effect (Table 4).
The ee values showed temperature dependence, since lower tem-
perature promoted association ability of 1 and 6 (entries 1–3). Fur-
thermore, the conversions were also slightly increased with
decreasing temperature; this is attributed to the increased solubil-
ity of ethylene. The best conditions were established as shown in
entry 3.
Although we obtained an ee 18% in this reaction, this was
deemed insufficient for an enantiodifferentiating reaction. There-
fore, we implemented another strategy for improvement of enanti-
C. Tem.
HOOC
major
hν
+
+
solvent, Temp., 2 h
HOOC
R
R
O
1
5 mM
2
O
ent-3
minor
Scheme 1. Enantiodifferentiating [2+2] photocycloaddition.
were determined by comparison with the authentic sample de-
rived by the hydrolysis of the compounds obtained by correspond-
ing diastereoselective reaction and defined by X-ray
crystallography.11
As shown in Table 1, phenylmenthol 4, which would make the
simple pseudo–ester bond with carboxylic acid 1, did not give
any enantioselectivity; this is likely because the non-covalent link-
age (hydrogen bond) was not strong enough to make desired com-
plex compared to the dimer formation of 1 (entry 1).15 We next
used oxime derivative 5, a precursor of phenylmenthyl amine 6
having both proton donor (NOH) and proton acceptor (NOH).
Moreover, a stronger interaction was expected between 1 and 5
compared to homologous binding (carboxyl–carboxyl and
oxime–oxime).16 However, 5, having an sp2 carbon at C-3 position
also did not show any enantioselectivity (entry 2). Presumably, the
stereochemistry of the C-3 position must be important for intro-
ducing enantioselectivity. In contrast, phenylmenthyl amine 6 gave
a moderate enantioselectivity (entry 3). That means both acid–
base interactions between amine and carboxylic acid, and menthyl
skeleton are surely necessary for making the desired chiral supra-
molecular complex that introduces enantioselectivity.
To obtain further information on conditions for optimal enanti-
oselectivity, we next investigated the solvent effect (Table 2). As
shown in Table 2, less polar solvents showed better selectivities
and had a good correlation to ET(30) values.17 This tendency can
be explained by the fact that a lower solvent polarity enhances
acid–base interactions, which become strong enough to form a sta-
ble supramolecular complex in solution. Notably, toluene gave an
oselectivity; namely,
a selective excitation approach. It was
reported that such a strategy was very effective for controlling
the stereoselectivity in supramolecular reaction.19 Therefore, we
anticipated this strategy may also be effective for improving ee
of this reaction. In the above reaction, we used over 280 nm exci-
tation wavelength; however, this wavelength excites all chemical
species. Especially, free carboxylic acid 1, whose reaction faces
were not controlled by C. Tem., or self-association complex of 1,
afforded racemic products 3 and some byproducts as already men-
tioned. On the other hand, if we can preferentially irradiate the
Table 3
Effect of C. Tem. equivalents on enantioselectivitya
Table 1
Entry
6 (equiv)
Conv.b (%)
Yieldb (%)
eec (%)
Effect of C-3 substituent of an 8-phenylmenthyl derivative on enantioselectivitya
1
2
3
1
3
5
84
83
74
16 (19)d
25 (30)d
40 (54)d
8
10
18
Entry
C. Tem.
eeb (%)
1
2
3
OH (4)
@NOH (5)
NH2 (6)
0
0
18
a
Reaction conditions: toluene, À78 °C, Irradiated for 2 h (>280 nm).
b
Determined by GC analysis (ZB-WAXpuls) using naphthalene as an internal
a
Reaction conditions: toluene, C. Tem. (5 equiv), at À78 °C, irradiated for 2 h
(>280 nm).
standard.
c
Error in ee upon GC analysis (InertCap CHIRAMIX) after methylation: <1%.
b
d
Error in ee upon GC analysis (InetrCap CHIRAMIX) after methylation: <1%.
Yield based on conversion.

Y. Yanagisawa et al. / Tetrahedron Letters 55 (2014) 2123–2126
2125
Table 4
(a)
Effect of temperature on enantioselectivitya
Entry
Temp (°C)
Conv.b (%)
Yieldb (%)
eec (%)
1
2
3
0
67
73
74
22 (33)d
32 (44)d
40 (54)d
13
17
18
À40
À78
a
Reaction conditions: toluene, irradiated for 2 h (>280 nm).
Determined by GC analysis (ZB-WAXpuls) using naphthalene as an internal
b
standard.
c
Error in ee upon GC analysis (InertCap CHIRAMIX) after methylation: <1%.
Yield based on conversion.
d
supramolecular complex where one face for the attack of ethylene
is blocked, this would enhance the ee value (Fig. 2).
(b)
Thus, we measured CD and UV spectra of 1, 6, and a mixture of 1
and 6, to estimate the absorption band of the supramolecular com-
plex to determine an appropriate excitation wavelength. As shown
in Figure 3, free 1 did not show any CD signal (a, gray dotted line)
and free 6 barely showed a minus signal (a, black dashed line). In
contrast, the mixture of 1 and 6 gave a minus molar ellipticity va-
lue more than 10 times larger than that of 6 alone (red line). From
these spectra, the new CD signal derived from supramolecular
complex 1Á6 was estimated (a, blue line). Furthermore, UV spectra
showed similar results. Interestingly, free 1 (b, gray dotted line)
showed a trough of UV absorption at approximately 330 nm, while
supramolecular complex 1Á6 (blue line) showed large UV absorp-
tion in same region. Therefore, a 330 nm excitation wavelength
was thought to be best for enhancing the ee value.
Figure 3. CD spectra (a) and UV spectra (b) of [1], [6], mixture of [1] and [6], and
[1Á6] complex under reaction conditions.
Based on the spectral results, we examined the wavelength ef-
fect (Table 5). Various glass filters were used to get the desired
wavelength. Using light of wavelengths longer than 240 or
280 nm (entries 1 and 2) gave the same ee values; this was because
not only 1Á6 complex but also free enone 1 were excited and re-
acted in this wavelength region. Meanwhile, when using a filter
to obtain more than 290 nm excitation wavelength, the ee value
was increased slightly, although it required a longer reaction time
due to the small absorption coefficient (entries 3–6). These results
were in good agreement with the UV spectra as mentioned before.
Namely, light irradiation of around 330 nm wavelength may sup-
press the reaction of free 1 providing racemic products. Moreover,
entry 4 showed the best result (24% ee) and the yield based on the
reacted 1 was 61%. Furthermore, using 1 equiv of 6 also showed
slight enhancement of the ee value (entry 5) comparing to that
using shorter excitation wavelength (Table 3, entry 1; 8% ee). How-
ever, the yield based on reacted 1 was only 15%, which was similar
value when irradiated through Pyrex filter (Table 3, entry 1; 19%).
It is because 1 to 6 association was not enough and side reactions
which derived from free 1 were not able to inhibit when only
1 equiv of 6 was used. Based on these results, this approach accom-
plished not only enhanced ee values but also inhibited side
Table 5
Effect of excitation wavelength on enantioselectivitya
Entry
Irr. time (h)
h
m
(nm)
eeb (%)
1
2
3
4
5g
6
7
2
2
6
6
6
6
6
>240c
18
18
20
24
11
22
21
>280d
>290e
>320f
>320f
300–400 (kmax = 360)h
340–480 (kmax = 390)i
a
b
c
d
e
f
Reaction conditions: 6 (5 equiv), toluene, À78 °C.
Error in ee from GC analysis (InertCap CHIRAMIX) after methylation: <1%.
UV-27.
Pyrex.
IHU 310.
IHU 340.
1 equiv of 6 was used.
UV-36B.
C-39A.
g
h
i
O
irr.
*
*
*
*
HOOC
O
> 280 nm
+
+
NH3
HOOC
NH2
O
O
O
O
Ph
6*
+
NH2
1*
[1•6]*
O
O
HOOC
1
6
O
+
+
absorbance is
drived from [1·6] complex
NH3
NH2
Ph
6
[1•6]*
1
Figure 2. Differences in excited species as a function of excitation wavelength.

2126
Y. Yanagisawa et al. / Tetrahedron Letters 55 (2014) 2123–2126
reactions when using appropriate equivalent of chiral template. In
addition, considering the corresponding diastereodifferentiating
reaction afforded 55% de using a strong covalent bond,12 this result
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Although there are a few reports on controlling stereochemistry
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enantioselectivity by a selective excitation wavelength effect in
the ground state.
In conclusion, we have utilized the chiral 8-phenylmenthyl
amine template 6 for the [2+2] photocycloaddition reaction of
the smallest olefin, ethylene, to give enantiocontrolled photoad-
ducts. Moreover we demonstrate a new approach for enhancing
the ee values by preferential irradiation of a supramolecular com-
plex in the ground state. This method not only enhanced ee values
but also suppressed undesired side reactions.
Acknowledgments
We thank Ms. Nishikawa Y. for obtaining HRMS. This work
was supported in part by a Grant-in-Aid for Scientific Research
B (No. 24310101) from the Ministry of Education, Culture, Sports,
Science and Technology of the Japanese Government (MEXT) and
the Foundation for Nara Institute of Science and Technology
(NAIST).
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Supplementary data
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Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
033.
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