Diastereoselective [2+2] photocycloaddition of chiral cyclic enones with olefins in aqueous media using surfactants

Article abstract of DOI:10.3390/molecules18021626

We conducted diastereodifferentiating [2+2] photocycloadditions of cyclo-hexenones modified with a chiral 8-(p-methoxy phenyl)menthyl auxiliary with olefins in water. Although the photoreaction didn't proceed at all in pure water owing to very low solubil

Full text of DOI:10.3390/molecules18021626

Molecules 2013, 18, 1626-1637; doi:10.3390/molecules18021626
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Diastereoselective [2+2] Photocycloaddition of Chiral Cyclic
Enones with Olefins in Aqueous Media Using Surfactants
Yasuhiro Nishiyama 1, Mikiko Shibata 1, Takuya Ishii 1, Tsumoru Morimoto 1, Hiroki Tanimoto 1,
Ken Tsutsumi 2,* and Kiyomi Kakiuchi 1,*
1
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST),
8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan; E-Mails: y-west@ms.naist.jp (Y.N.);
s-mikiko@ms.naist.jp (M.S.); i-takuya@ms.naist.jp (T.I.); morimoto@ms.naist.jp (T.M.);
tanimoto@ms.naist.jp (H.T.)
2
Department of Applied Chemistry, Faculty of Engineering, Miyazaki University,
1-1 Gakuen Kibanadai-Nishi, Miyazaki 889-2155, Japan
* Authors to whom correspondence should be addressed; E-Mails: kakiuchi@ms.naist.jp (K.K.);
tsutsumi@cc.miyazaki-u.ac.jp (K.T.); Tel.: +81-743-72-6080 (K.K.); Fax: +81-743-72-6089 (K.K.).
Received: 7 January 2013; in revised form: 15 January 2013 / Accepted: 21 January 2013 /
Published: 28 January 2013
Abstract: We conducted diastereodifferentiating [2+2] photocycloadditions of
cyclo-hexenones modified with a chiral 8-(p-methoxy phenyl)menthyl auxiliary with
olefins in water. Although the photoreaction didn’t proceed at all in pure water owing to
very low solubility, the use of surfactants [sodium dodecyl sulfate (SDS) or dodecylamine
hydrochloride (DAH)] and additive (organic solvent) enabled the reactions to progress with
moderate to high conversions and yields. Furthermore, we synthesized a new menthol
derivative substrate containing a (p-octyloxy)phenyl group for enhancing hydrophobicity,
and elucidated that this new substrate was found to be a suitable chiral auxiliary in this
asymmetric photoreaction in aqueous system. The additive effect of organic molecules on
the yield and diastereoselectivity of the photo-adducts is also discussed.
Keywords: diastereoselectivity; [2+2] photocycloaddition; aqueous media; surfactant

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1. Introduction
Recently within organic synthetic chemistry, environmentally friendly reaction systems have
attracted a great deal of attention as “green chemistry” [1–4]. In these reactions, water is the most
versatile reaction medium owing to its unique nature, nontoxicity, abundance, low cost and ease of
waste treatment. Therefore, applications for organic reactions in water have been widely investigated
aiming to eliminate both the use of volatile (and toxic, in some cases) organic solvents and the
necessity of vigorous drying of solvents and substrates [5,6]. On the other hand, because many organic
molecules are hydrophobic, we must modify the reaction systems to enhance solubility when trying
reactions with organic molecules in water.
Photochemical reactions have also been described as “green” chemical processes, because the
driving force in reaction progress is simply light irradiation, which is considered clean energy [7,8].
Moreover, photoreactions have a complementary features compared to conventional thermal reactions.
For example, in contrast with conventional thermal reactions, it is well known that photochemical
[2+2] cycloaddition readily gives the distorted cyclobutane skeleton. Because this skeleton is synthetically
versatile, not only for natural-product precursors such as terpenoids with polyquinane skeletons
but also various unique compounds, much effort has been dedicated to this reaction, especially
asymmetric [2+2] photoreaction [9,10]. However there are few reports concerned with the asymmetric
photoreaction in aqueous media without use of a chiral host (such as a cyclodextrin). Previously, we
examined the enantioselective [2+2] photocycloaddition of cyclohexenonecarboxylic acid with
ethylene in water using cyclodextrin, and found the corresponding photocycloadducts were obtained in
very low yield (~27%) and stereoselectivity (~5.5% enantiomeric excess) [11]. On the other hand, we
have investigated a range of asymmetric [2+2] photocycloadditions in organic solvents and revealed
that the diastereodifferentiating photoreaction using menthol derivatives as chiral auxiliaries is one of
the most promising methods for achieving high diastereomeric excess (de) [12–16]. Thus, in this work,
we focused on the diastereoselective [2+2] photocycloaddition of cyclohexenones having chiral
menthol auxiliaries with olefins in water in order to develop a “greener” and more efficient
asymmetric photoreaction process. In addition, in terms of solubility, a water-surfactant reaction
system is better suited with organic reactions in aqueous media [17,18]. Thus we investigated the
diastereoselective [2+2] photocycloaddition of cyclohexenones having chiral p-substituted
8-phenylmenthyl auxiliaries with olefins, ethylene or cyclopentene, in water with/without surfactants.
In this study, we discuss the suitable menthol auxiliary and additive effect of organic molecules on
yield and selectivity in both aqueous and organic reaction systems.
2. Results and Discussion
2.1. Synthesis of Substrates 3a, 3b
Surfactants orient themselves in aqueous media to generate micelles, which due to the hydrophobic
interaction include organic molecules inside. Thus we prepared (−)-8-[(p-octyloxy)phenyl]menthol
(1b), which has a long alkyl chain to enhance hydrophobicity compared to that of
(−)-8-[(p-methoxy)phenyl]menthol (1a) already reported (Scheme 1). For the assembly of a new-type
chiral auxiliary, 1b was prepared from (R)-(+)-pulegone according to our previous procedure

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modifying Corey’s method [12–14,19–21]. After the protection of 1a, demethylation was carried out
with borane tribromide to give the corresponding menthyl acetate 2 as reported previously [22]. The
alkyl group was introduced into 2 and acetyl protection was removed to prepare the new menthol
auxiliary 1b almost quantitatively. The hydrophobic nature was increased by attaching an octyl unit.
Therefore, we think that 1b may be a more suitable chiral auxiliary than 1 for the reaction in an
aqueous system using a surfactant. The condensation of cyclohexen-3-one-1-carboxylic acid with the
menthols 1a, 1b with 1,3-diisopropylcarbodiimide (DIPC) and 4,4-dimethylaminopyridine (DMAP)
gave chiral cyclohexenonecarboxylates 3a, 3b in high yields.
Scheme 1. Synthetic route to substrates 3a, 3b.
2.2. Photoreaction
2.2.1. Photoreaction of 3a, 3b with Ethylene Gas as Coupling Partner
First of all, we tried the photoreaction of substrate 3a with ethylene in pure water, however the
reaction didn’t progress at all (Scheme 2, Table 1, entry 1). To drive this photoreaction in aqueous
media, we added a surfactant [sodium dodecyl sulfate (SDS) or dodecylamine hydrochloride (DAH)]
to this reaction. After bubbling the ethylene gas in water, SDS or DAH was added as a surfactant to the
water solution followed by mixing with substrate 3a. Then the photoreactions were carried out under
similar conditions. Nevertheless, we could not observe the reaction proceeding (Table 1, entries 2 and 3).
This could be explained by considering that substrate 3a showed poor solubility in water, but its
hydrophobicity was not large enough to be included in the micelle cavity. Then, we adopted compound
3b, whose hydrophobicity was larger than that of 3a, as a substrate and tried this photoreaction in
aqueous media with/without surfactants. As anticipated, the reaction of 3b in pure water did not
progress owing to its large hydrophobicity (Table 1, entry 13). However contrary to our expectations,
the reaction in aqueous media containing surfactants also didn’t progress at all (Table 1 entries 14–15).

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These results suggest that the photoreactions occurring in micelles produced with both surfactants and
menthol derivatives 1a or 1b with ethylene gas were not suitable for proceeding in aqueous media.
Scheme 2. Diastereoselective [2+2] photocycloaddition of 3a, 3b with ethylene in aqueous media.
Table 1. Diastereoselective [2+2] photocycloaddition of 3a,b with ethylene a.
Yield/% c
(4+5)
d
de/% b
Entry Substrate
Solvent
Surfactant Additive
Conv./% b
(4-5)/(4+5)
1
2
3a
H2O
H2O
−
−
−
0
d
SDS
DAH
SDS
SDS
SDS
DAH
DAH
DAH
−
0
d
d
3
H2O
−
0
d
d
4
H2O
CH2Cl2
toluene
MCH e
CH2Cl2
toluene
MCH e
−
100
100
100
100
100
100
100
100
100
0
83
23
32
40
30
35
40
19
31
49
d
5
H2O
73
6
H2O
49
7
H2O
50
8
H2O
61
9
H2O
41
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CH2Cl2
toluene
MCHe
H2O
83
−
−
104
69
−
−
3b
−
−
d
H2O
SDS
DAH
SDS
SDS
SDS
DAH
DAH
DAH
−
−
0
d
d
H2O
−
0
d
d
H2O
CH2Cl2
toluene
MCH e
CH2Cl2
toluene
MCH e
−
62
52 f
16 f
64 f
52 f
16 f
64 f
98
52
42
37
52
42
37
12
23
41
H2O
73
H2O
92
H2O
62
H2O
73
H2O
92
CH2Cl2
toluene
MCH e
100
100
100
−
−
99
24
a
−
−
81
c
b
1
Irradiated for 3 h at 0 °C. (See the Experimental Section.) Determined by H-NMR. Determined by the
weight. d Not observed. e methylcyclohexane. f Isolated Yield.
Accordingly, we employed a new method of adding an organic solvent (3 volume %) into the
aqueous media as an additive. The photoreaction of substrate 3a or 3b gave the corresponding
photoadducts 4a and 5a or 4b and 5b, respectively, with moderate to high conversion (Table 1, entries 4–9,

Molecules 2013, 18
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16–21). It is clear that the additives affect the (4+5) reaction yield and diastereoselectivity
(de: (4−5)/(4+5)). In the case of 3a, the de values of photoproducts in aqueous media were mostly
similar with those in organic solvent (Table 1 entries 4–9 vs. entries 10–12). It seems as if the reaction
progressed in pure organic solvent, which was contained in the micelle. On the contrary, the de for the
photoreaction of 3b was highly enhanced by using additives compared to that in pure organic solvent,
though we could not observe the full conversion (Table 1 entries 16–21 vs. entries 22–24). We
previously reported that the de was affected by the relative population of the cyclohexenone-phenyl
ring-stacking conformers of 3a in the ground state. The 3a’s conformation was stabilized by the
electrostatic and/or dipole-dipole interactions between the C=O moiety of cyclohexenone and the OMe
group attached to the aromatic ring [13,19]. In the confined hydrophobic reaction media in micelles,
the hydrophobic bigger organic molecules may form the favorable conformer preferentially to afford
the high selectivity.
2.2.2. Photoreaction of 3a,b with Cyclopentene (liquid) as Coupling Partner
In the former reaction, we could not achieve the full conversion photoreaction of 3b with ethylene,
even by using surfactants and additives, though we were able to enhance the diastereoselectivity
compared the outcomes in pure organic solvent. In order to accomplish compatibility enhancing both
reaction efficiency and stereoselectivity, we conducted the photoreaction with liquid olefin
(cyclopentene) instead of gas olefin (ethylene) at 0 °C (Scheme 3). Though this photoreaction of 3a
should produce four diastereomeric isomers of photoadducts, cis-syn-cis products 6a, 7a and
cis-anti-cis products 8a, 9a in organic solvents, only three products (6, 8, and 9) were observed as
previous reported (Table 2, entries 10–12) [23]. The photoreaction of 3b also gave only three products
(compounds 6b, 8b, and 9b) in organic solvent (Table 2, entries 22–24). The photoreactions of both 3a
and 3b with cyclopentene in pure water did not progress at all. However, we could observe the
reaction proceeding when adding the surfactant (SDS or DAH) without additive, which was different
from the outcome in the case of using ethylene as coupling partner (Table 2, entries 1–3, 13–15). This
can be explained by considering that cyclopentene was able to play the role not only as a coupling
partner but also as an additive to solubilize the substrate in the micelle.
Scheme 3. Diastereoselective [2+2] photocycloaddition of 3a,b with cyclopentene in
aqueous media.

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The photoreaction of 3a in H2O with surfactant gave the very low de compared to those in organic
solvent (Table 2, entries 2, 3). As mentioned before, the de of this reaction of 3a is sensitive to the
solvent polarity. In aqueous media without additive, the high-polar water molecules may inhibit the
interactions between the C=O moiety and OMe moiety to decrease selectivity. On the contrary, the de
of this photoreaction of 3b is not sensitive to the solvent polarity in the low polar solvent (Table 2
entries 22–24) Furthermore, both surfactants inhibited the de lowering, and achieved almost the same
de as that in pure organic solvent (Table 2 entries 14, 15). Therefore, 3b may be included in the
micelle cavity mostly because of 3b’s large hydrophobicity, and the photoreaction progressed in the
low polarity circumstance inside the micelle cavity.
Table 2. Diastereoselective [2+2] photocycloaddition of 3a,b with cyclopentenea.
Ratio
(syn:anti) d
de (%) d
anti
Yield/% c
(6-9)
Entry Substrate Solvent Surfactant Additive Conv./% b
syn
6
(6:(8+9))
(8-9)
(8+9)
e
1
2
3a
H2O
H2O
−
−
−
0
e
e
e
SDS
DAH
SDS
SDS
SDS
DAH
DAH
DAH
−
100
100
100
100
100
100
100
100
100
100
100
0
87
39:61
51:49
56:44
55:45
59:41
52:48
49:51
47:53
53:47
51:49
52:48
e
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
e
11
11
65
60
49
53
55
54
59
86
53
e
3
H2O
−
76
4
H2O
CH2Cl2
toluene
MCH
CH2Cl2
toluene
MCH
−
66
5
H2O
80
6
H2O
63
7
H2O
32
8
H2O
40
9
H2O
32
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CH2Cl2
toluene
MCH
H2O
88
−
−
101
83
−
−
3b
−
−
e
H2O
SDS
DAH
SDS
SDS
SDS
DAH
DAH
DAH
−
−
100
100
100
100
100
100
100
100
100
100
100
47
43:57
45:55
43:57
41:59
43:57
40:60
40:60
42:58
40:60
40:60
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
52
54
52
53
52
43
47
37
55
53
53
H2O
−
45
H2O
CH2Cl2
toluene
MCH
CH2Cl2
toluene
MCH
−
28 f
48 f
66 f
44 f
49 f
31 f
77
H2O
H2O
H2O
H2O
H2O
CH2Cl2
toluene
MCH
−
−
99
−
−
81
40:60
a
b
1
c
Irradiated for 3 h at 0 °C. (See the Experimental Section.) Determined by H-NMR. Determined by the
weight. d Determined by HPLC (CHIRALPAK AD). e Not observed. f Isolated Yield.
On the other hand, when using the additives, the de values of each substrate were quite different
from the samples using ethylene gas. The de values of both substrates using SDS were almost the same
as those in the organic solvent (Table 2 entries 4–6, 16–18). Cyclopentene can be miscible with both

Molecules 2013, 18
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substrate and additive owing to cyclopentene’s nature, which is liquid and hydrophobic. This enables
the full conversion of the reaction, especially in the case of 3b. However, using DAH made the de
values lower in both substrates (Table 2 entries 7–9, 19–21). In the anionic surfactant (DAH), the
lower-polar additives than substrate might be included in the micelle cavity preferentially. Therefore,
the substrate might be expelled from the cavity slightly, and the de lowering might be induced by the
high-polar water.
3. Experimental
3.1. General
Most commercially available reagents were used without further purification. All reactions and
manipulations of air- and moisture-sensitive compounds were carried out under an atmosphere of dry
nitrogen using standard vacuum line techniques. Optical rotations ([α]) were determined on a JASCO
DIP-1000 digital polarimeter using the sodium D line. Infrared spectra (IR) were obtained on a JASCO
FT/IR-4200. High resolution mass spectra (HRMS) were obtained on a JEOL JMS-700 instrument.
Flash column chromatography was performed with Merck silica gel 60N. Proton nuclear magnetic
resonance spectra (1H-NMR) and carbon nuclear magnetic resonance spectra (13C-NMR) were
obtained on a JEOL JNM-ECP500NK. NMR spectra were reported as chemical shift in ppm (δ),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, td = triplet of doublet, ddd = double double
1
doublet, m = multiplet), coupling constant (Hz), and integration. H-NMR spectra were reported as
13
chemical shifts in ppm base on the peak of tetramethylsilane (TMS) (δ = 0.0 ppm). C-NMR spectra
were reported as chemical shifts in ppm based on the middle peak of CDCl3 (δ = 77.0 ppm).
3.2. Materials
3.2.1. Preparation of (1R,2S,5R)-5-methyl-2-(2-(4-(octyloxy)phenyl)propan-2-yl)cyclohexanol (1b)
A mixture of 2 [22] (200 mg, 0.689 mmol), Cs2CO3 (898 mg, 2.76 mmol) and CH3(CH2)7OMs
(287 mg, 1.38 mmol) in dimethylformamide (DMF) (7.0 ml) was stirred for 12 h at 65 °C under
nitrogen atmosphere. The reaction mixture was cooled to room temperature and water added. The
resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried
over MgSO4. The resulting material was purified by silica gel column chromatography (Hexane:
AcOEt = 8:1; Rf = 0.40). A mixture of the purified product (277 mg, 0.689 mmol) and 1.0 M NaOH
aq. (3.5 mL) in ethanol (30 mL, 0.02 M) was stirred for 8 h at 85 °C under nitrogen atmosphere. The
reaction mixture was cooled to room temperature and the solvent was removed under a reduced
pressure. The resulting mixture was extracted with CH2Cl2. The organic layer was washed with brine,
and dried over MgSO4. The resulting material was purified by silica gel column chromatography
(hexane:EtOAc = 8:1; Rf = 0.27), and the product 1b was obtained (248 mg, 99%). Colorless oil,
[α]D24 = −0.03, c = 0.06 in MeOH; 1H-NMR (CDCl3) δ: 7.29 (2H, d, J = 5.8 Hz), 6.84 (2H, d, J = 5.8 Hz),
3.91 (2H, t, J = 6.4 Hz), 3.51 (1H, td, J = 10.4, 4.1 Hz), 1.85–1.83 (2H, m), 1.78–1.72 (3H, m), 1.69–1.62
13
(2H, m), 1.47–1.26 (17H, m), 1.03 (1H, ddd, J = 25.2, 13.0, 3.2 Hz), 0.92–0.86 (8H, m); C-NMR
(CDCl3) δ:157.11, 142.78, 126.68(2C), 114.27(2C), 72.83, 67.81, 54.05, 45.19, 38.99, 34.87, 31.77,

Molecules 2013, 18
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31.54, 31.41, 29.28, 29.19, 29.13, 26.39, 26.03, 23.98, 22.59, 21.94, 14.04; IR (neat) 3551, 3437,
2921, 1609, 1511, 1470, 1386, 1293, 1249, 1184, 1122, 1026, 964, 829 cm−1; HRMS(ESI) Calcd for
C24H40O2Na (M+Na)+ 383.2926, Found 383.2925.
3.2.2. Preparation of (1R,2S,5R)-5-methyl-2-(2-(4-(octyloxy)phenyl)propan-2-yl)cyclohexyl
3-oxocyclohex-1-enecarboxylate (3b)
A mixture of 1b (248 mg, 0.689 mmol), DMAP (39.7 mg, 0.325 mmol), and cyclohexenone
carboxylic acid (135 mg, 0.964 mmol) in CH2Cl2 (3.45 mL) was stirred and dropped DIPC (320 μL,
2.07 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 12 h. The resulting
mixture was added into water and extracted with diethyl ether. The organic layer was washed with
brine, and dried over MgSO4. The resulting material was purified by silica gel column chromatography
(hexane:EtOAc = 8:1; Rf = 0.23), and the product 3b was obtained (330 mg, 99%). Colorless oil,
24
1
[α]D = −0.03, c = 0.06 in MeOH; H-NMR (CDCl3) δ: 7.13–7.11 (2H, m), 6.72–6.71 (2H, m), 6.23
(1H, s), 4.98 (1H, td, J = 10.7, 4.7 Hz), 3.93–3.81 (2H, m), 2.35–2.31 (2H, m), 2.30–2.09 (2H, m),
2.08–2.00 (1H, m), 1.97–1.78 (4H, m), 1.76–1.67 (3H, m), 1.50–1.29 (10H, m), 1.28 (3H, s),
13
1.27–1.19 (2H, m), 1.16 (3H, s), 1.05–0.91 (2H, m), 0.91–0.86 (6H, m); C-NMR (CDCl3) δ:200.29,
165.25, 156.70, 148.65, 143.52, 132.32, 126.17(2C), 113.67(2C), 74.97, 67.68, 50.45, 41.77, 38.83,
37.51, 34.43, 31.83, 31.30, 29.64, 29.43(2C), 29.26, 26.33, 26.15, 24.37, 23.41, 22.67, 21.81, 21.78,
14.10; IR (neat) 2955, 1730, 1609, 1579, 1512, 1470, 1368, 1245, 1184, 1124, 1027, 982, 905,
829 cm−1; HRMS(ESI) Calcd for C31H46O4Na (M+Na)+ 505.3294, Found 505.3296.
3.2.3. Photoproduct; (1S,6S)-(1R,2S,5R)-5-methyl-2-(2-(4-(octyloxy)phenyl)propan-2-yl)cyclohexyl 5-
oxobicyclo[4.2.0]octane-1-carboxylate (4b, Major Compound)
Colorless oil, [α]D24 = 1.2, c = 0.4 in MCH; 1H-NMR (CDCl3) δ: 7.17 (2H, d, J = 9.2 Hz), 6.79 (2H,
d, J = 9.2 Hz), 4.90 (1H, td, J = 10.7, 4.3 Hz), 3.90 (2H, t, J = 6.7 Hz), 3.04 (1H, dd, J = 9.8,
7.6 Hz), 2.42–2.35 (1H, m), 2.30–2.18 (2H, m), 2.17 (1H, s), 2.14–2.06 (1H, m), 2.04–1.94 (2H, m),
1.94–1.88 (1H, m), 1.88–1.77 (4H, m), 1.77 (2H, d, J = 7.0 Hz), 1.70–1.62 (1H, m), 1.62–1.53 (2H, m),
13
1.50–1.40 (3H, m), 1.38–1.23 (11H, m), 1.19 (3H, s), 1.08–0.92 (2H, m), 0.88 (6H, m); C-NMR
(CDCl3) δ:216.61, 175.08, 156.72, 143.08, 126.36(2C), 113.83(2C), 75.32, 67.85, 50.10, 48.47, 45.83,
41.75, 39.36, 38.91, 34.50, 31.83, 31.31, 30.92, 29.82(2C), 29.39, 28.26, 27.18, 26.94, 26.92, 26.10,
22.66, 21.79, 21.37, 20.75 14.11; IR (neat) 2927, 2869, 1709, 1250 cm−1; HRMS(ESI) Calcd for
C33H50O4Na (M+Na)+ 533.3607, Found 505.3605.
3.2.4. Photoproduct; (1R,6R)-(1R,2S,5R)-5-methyl-2-(2-(4-(octyloxy)phenyl)propan-2-yl)cyclohexyl
5-oxobicyclo[4.2.0]octane-1-carboxylate (5b, Minor Compound)
24
1
Colorless oil, [α]D = −0.7, c = 1.1 in MCH; H-NMR (CDCl3) δ: 7.18 (2H, d, J = 8.5 Hz), 6.80
(2H, d, J = 8.5 Hz), 4.92 (1H, td, J = 10.7, 4.3 Hz), 3.92 (2H, t, J = 6.4 Hz), 2.93 (1H, t, J = 7.9Hz),
2.42–2.25 (2H, m), 2.21–2.12 (3H, m), 2.02–1.68 (10H, m), 1.63–1.57 (2H, m), 1.57–1.52 (2H, m),
1.48–1.39 (3H, m), 1.31 (6H, m), 1.29 (5H, m), 1.20 (3H, s), 0.89 (3H, d, J = 5.5 Hz), 0.87 (3H, t,
13
J = 7.3 Hz); C-NMR (CDCl3) δ: 212.37, 175.28, 156.83, 142.97, 126.39(2C), 113.90(2C), 75.42,

Molecules 2013, 18
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67.89, 50.02, 48.46, 45.94, 41.87, 39.43, 38.89, 34.47, 31.84, 31.34, 30.37, 29.39(2C), 29.26, 28.23,
27.59, 27.01, 26.67, 26.12, 22.67, 21.79, 21.15, 20.89 14.12; IR (neat) 2952, 2856, 1714, 1250 cm−1;
HRMS(ESI) Calcd for C33H50O4Na (M+Na)+ 533.3607, Found 533.3605.
3.2.5. Photoproduct; (3aR,3bS,7aS,7bS)-(1R,2S,5R)-5-methyl-2-(2-(4-(octyloxy)phenyl)propan-2-yl)
cyclohexyl 7-oxodecahydro-1H-cyclopenta[3,4]cyclobuta[1,2]benzene-3b-carboxylate
(6b, cis-syn-cis, Major Compound)
Colorless oil, [α]D24 = 2.0, c = 4.1 in MCH; 1H-NMR (CDCl3) δ: 7.16 (2H, d, J = 8.3 Hz), 6.77 (2H,
d, J = 8.3 Hz), 4.95 (1H, td, J = 10.5, 4.4 Hz), 3.89 (2H, t, J = 6.4 Hz), 3.04 (1H, d, J = 6.1 Hz), 2.57
(1H, q, J = 7.9 Hz), 2.52–2.47 (1H, m), 2.29 (1H, td, J = 18.5, 5.3 Hz), 2.16–1.99 (3H, m), 1.95–1.83
(4H, m), 1.81–1.65 (4H, m), 1.55–1.39 (8H, m), 1.39–1.23 (9H, m), 1.18 (3H, s), 1.12–0.94 (4H, m),
13
0.93–0.80 (8H, m); C-NMR (CDCl3) δ:213.62, 175.56, 156.45, 142.46, 126.50(2C), 113.50(2C),
75.13, 67.99, 50.03, 48.13, 45.60, 45.46, 41.90, 39.16, 38.64, 34.50, 31.60, 31.52, 31.13, 30.99, 30.67,
29.39(2C), 29.26, 28.26, 27.61, 27.03, 26.45, 26.13, 22.57, 21.15, 21.12, 20.09, 14.13; IR (neat) 2927,
2869, 1708, 1137 cm−1; HRMS(ESI) Calcd for C36H54O4Na (M+Na)+ 573.3920, Found 573.3914.
3.2.6. Photoproduct; (3aS,3bS,7aS,7bR)-(1R,2S,5R)-5-methyl-2-(2-(4-(octyloxy)phenyl)propan-2-yl)
cyclohexyl 7-oxodecahydro-1H-cyclopenta[3,4]cyclobuta[1,2]benzene-3b-carboxylate
(8b, cis-anti-cis, Major Compound)
Colorless oil, [α]D24 = 0.8, c = 1.1 in MCH; 1H-NMR (CDCl3) δ: 7.14 (2H, d, J = 8.6 Hz), 6.80 (2H,
d, J = 8.6 Hz), 4.82 (1H, td, J = 10.7, 4.3 Hz), 3.92 (2H, td, J = 6.6, 2.2 Hz), 3.01 (1H, d, J = 6.1 Hz), 2.70
(1H, q, J = 6.6 Hz), 2.56 (1H, t, J = 7.6 Hz), 2.45 (1H, td, J = 18.5, 5.3 Hz), 2.21–2.15 (1H, m),
2.11–2.01 (2H, m), 1.94–1.86 (2H, m), 1.79–1.72 (8H, m), 1.58–1.42 (7H, m), 1.39–1.25 (9H, m),
1.24 (3H, s), 1.17 (3H, s), 0.99–0.92 (2H, m), 0.89–0.84 (6H, m); 13C-NMR (CDCl3) δ:213.46, 175.46,
156.83, 142.97, 126.39(2C), 113.90(2C), 75.42, 67.89, 50.02, 48.46, 45.94, 45.46, 41.87, 39.43, 38.89,
34.47, 31.84, 31.80, 31.34, 30.81, 30.37, 29.39(2C), 29.26, 28.23, 27.59, 27.01, 26.67, 26.12, 22.67,
21.79, 21.15, 20.89, 14.12; IR (neat) 2928, 2871, 1708, 1187 cm−1; HRMS(ESI) Calcd for C36H54O4Na
(M+Na)+ 573.3920, Found 573.3920.
3.2.7. Photoproduct; (3aR,3bR,7aR,7bS)-(1R,2S,5R)-5-methyl-2-(2-(4-(octyloxy)phenyl)propan-2-yl)
cyclohexyl 7-oxodecahydro-1H-cyclopenta[3,4]cyclobuta[1,2]benzene-3b-carboxylate
(9b, cis-anti-cis, Minor Compound)
24
1
Colorless oil [α]D = −1.1, c = 1.1 in MCH; H-NMR (CDCl3) δ: 7.15 (2H, d, J = 7.9 Hz), 6.77
(2H, d, J = 7.9 Hz), 4.89 (1H, td, J = 10.4, 4.4 Hz), 3.90 (2H, t, J = 6.4 Hz), 3.10 (1H, d, J = 6.1 Hz),
2.56 (1H, q, J = 7.9 Hz), 2.52–2.40 (1H, m), 2.29 (1H, m), 2.16–1.99 (3H, m), 1.95–1.83 (4H, m),
1.81–1.65 (4H, m), 1.55–1.43 (8H, m), 1.40–1.23 (9H, m), 1.19 (3H, s), 1.12–0.91 (4H, m), 0.83–0.73
13
(8H, m); C-NMR (CDCl3) δ:213.13, 175.76, 156.55, 142.43, 126.43(2C), 112.31(2C), 75.12, 67.73,
50.04, 48.30, 45.44, 45.42, 41.93, 39.06, 38.06, 34.54, 31.28, 31.50, 31.03, 30.79, 30.70, 29.43(2C),
29.36, 28.20, 27.46, 27.03, 27.00, 26.13, 22.51, 21.14, 21.02, 20.01, 14.03; IR (neat) 2928, 2829,
1702, 1127 cm−1; HRMS(ESI) Calcd for C36H54O4Na (M+Na)+ 573.3920, Found 573.3921.

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3.3. Photolysis with Additive and Surfactant
3.3.1. Photolysis of 3a,b with Ethylene
Irradiation was carried out in a quartz cell placed in a Unisoku CoolspeK cryostat maintained at a
given temperature, and then irradiated at wavelengths > 280 nm by a 500-W high-pressure mercury
lamp through a 5-cm water layer and Pyrex glass filter, except for the reaction of 3b with surfactant
and additive. Irradiation of those samples was carried out in a Pyrex flask (>280 nm) installed in a
water-cooled quartz immersion apparatus using HALOS 500 W high-pressure Hg lamp as the light
source. A mixture of substrate, surfactants (0.10 M), additive (3%) and water (0.01 M) which was
purged with ethylene for 10 min was irradiated at 0 °C. After 3 h irradiation, the resulting SDS mixture
was extracted with diethyl ether. The organic layer was washed with brine, and dried over MgSO4
(In the case of using DAH, the resulting mixture was washed by NaHCO3 aq at first. Next, the mixture
was extracted with diethyl ether after adding 2N-HCl aq. The organic layer was washed with brine,
and dried over MgSO4.). After evaporation, each product (4a,b, 5a,b) was observed as a mixture of
diastereomers. Only for 3b with surfactant and additive, we conducted column chromatography
separation (hexane:EtOAc = 5:1 ; Rf = 0.37) for calculating yield because the separation was very
difficult. The diastereomeric excess (de) value was determined by 1H NMR. The identification method
was followed by analogous compounds in our previous work.
3.3.2. Photolysis of 3a,b with Cyclopentene
Irradiation was carried out in a quartz cell placed in a Unisoku CoolspeK cryostat maintained at a
given temperature, and then irradiated at wavelengths >280 nm by a 500-W high-pressure mercury
lamp through a 5-cm water layer and Pyrex glass filter, except for the reaction of 3b with surfactant
and additive. Irradiation of those samples was carried out in a Pyrex flask (>280 nm) installed in a
water-cooled quartz immersion apparatus using HALOS 500 W high-pressure Hg lamp as the light
source. A mixture of substrate, surfactant (0.10 M), additive (3%), and cyclopentene (0.075 M) and
water (0.01 M) which was purged with nitrogen for 10 min were irradiated at 0 °C. After 3 h
irradiation, the resulting SDS mixture was extracted with diethyl ether. The organic layer was washed
with brine, and dried over MgSO4. (In the case of using DAH, the resulting mixture was washed by
NaHCO3 aq. at first. Next, the mixture was extracted with diethyl ether after adding 2 N-HCl aq. The
organic layer was washed with brine, and dried over MgSO4.) After evaporation, each photoadduct
(6a, b, 8a, b, 9a, b) was obtained as diastereomers mixture. Only for 3b with surfactant and additive,
we conducted column chromatography separation (hexane:EtOAc = 5:1; Rf = 0.44 (6b), 0.37 (8b, 9b))
for calculating yield because the separation was very difficult. The de value was determined by HPLC
(CHIRALPAK AD, 1.0 mL/min, n-hexane/2-propanol = 98/2).
4. Conclusions
In summary, we developed the diastereoselective [2+2] photocycloaddition of chiral
cyclohexenones with olefins in aqueous media. Contrary to our expectations, we could not make the
photocycloadditions with ethylene gas proceed in water-surfactant (SDS) media, even after using a

Molecules 2013, 18
1636
large hydrophobic substrate like 3b. On the contrary, we could achieve the photoreactions using
cyclopentene as a coupling partner in that media. By the addition of a small amount of CH2Cl2,
toluene, or MCH, we succeeded in performing the asymmetric photoreactions in aqueous media
similar to the reaction in organic solvents. Though we couldn’t observe a more efficient photoreaction
using cyclopentene as coupling partner, we elucidated that the new-type chiral menthol auxiliary 1b
containing a (p-octyloxy)phenyl group was superior, especially in the asymmetric photoreaction using
ethylene in aqueous solution. These results show a new and effective “green” reaction using light and
water, with high yield and stereoselectivity.
Acknowledgments
We thank Yoshiko Nishikawa and Yuriko Nishiyama for their help in HRMS measurements. This
work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) of the Japanese Government and by the Foundation
for Nara Institute of Science and Technology.
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Sample Availability: Samples of the compounds are available from the authors.
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