Highly diastereodifferentiating and regioselective [2+2]-photoreactions using methoxyaromatic menthyl cyclohexenone carboxylates

Article abstract of DOI:10.1016/j.tet.2012.10.074

Chiral Cyclohexenone 1a is irradiated in the presence of various alkenes to yield highly diastereodifferentiating (1S,6S) configurated oxobicyclo[4.2.0] octanes. For increasing the de of the reaction, we designed a new chiral auxiliary owing a methoxynaphthylmenthyl moiety b: cyclohexenone carboxylate 1b. Irradiation of 1b in the presence of various alkenes shows high diastereo- and regioselectivity, yielding (1S,6S)-bicyclo[4.2.0]octan-2-ones with a de of up to 96%.

Full text of DOI:10.1016/j.tet.2012.10.074

Tetrahedron 69 (2013) 782e790
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly diastereodifferentiating and regioselective
[2þ2]-photoreactions using methoxyaromatic menthyl
cyclohexenone carboxylates
a
,
a
b
a
a,
*
*
€
Inga Inhulsen , Naoya Akiyama , Ken Tsutsumi , Yasuhiro Nishiyama , Kiyomi Kakiuchi
a Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
b Department of Applied Chemistry, Faculty of Engineering, Miyazaki University, 1-1 Gakuen Kibanadai-Nishi, Miyazaki 889-2155, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2012
Received in revised form 23 October 2012
Accepted 25 October 2012
Available online 2 November 2012
Chiral Cyclohexenone 1a is irradiated in the presence of various alkenes to yield highly diaster-
eodifferentiating (1S,6S) configurated oxobicyclo[4.2.0]octanes. For increasing the de of the reaction, we
designed a new chiral auxiliary owing a methoxynaphthylmenthyl moiety b: cyclohexenone carboxylate
1b. Irradiation of 1b in the presence of various alkenes shows high diastereo- and regioselectivity,
yielding (1S,6S)-bicyclo[4.2.0]octan-2-ones with a de of up to 96%.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
[2þ2]-Photocycloaddition
Diastereodifferentiating
Chiral auxiliary
Cyclohexenone carboxylate
Regioselectivity
1. Introduction
opened a promising way of inducing asymmetry in (inter- and
intramolecular) photoreactions. For such kind of diastereoselective
Photochemical initiated cycloadditions are often used as a key
step not only in natural product synthesis but also to build up key
bond constructions in the complex molecule environment.1 Espe-
cially the [2þ2]-photoreaction of alkenones with olefins has been
of great interest and well investigated, as the formed strained
cyclobutane adducts are difficult to build under thermal conditions
but often found as a challenging structural motive in complex
synthesis.1 Nevertheless photoreactions can yield in a mixture of
stereo- and regioisomeric products because the reactions include
excited states, short lifetimes, and weak interactions. This is why
the [2þ2]-photoreaction is up to now not often being found in
stereoselective reaction sequences. As the [2þ2]-photoreaction is
a powerful tool to compose strained rings with up to four stereo-
centers in just one step, the stereoselective photoreaction is still
challenging the researcher mind. Different approaches as solid-
state photochemistry and supramolecular photochemistry,2 as
well as photochemical reactions using chiral auxiliaries and sensi-
tizers3 have up to now lead to great achievements in the field of
asymmetric photochemical synthesis. To the chromophore or the
alkene attached chiral framework has been widely used and
reactions, a wide range of natural products, such as menthol,4,5
camphor,3a tartaric acid,6a,b and bornyl6c has been used as chiral
auxiliary so far. However, generality as well as high selectivity in
diastereoselective photoreactions have not yet been elucidated. We
concentrated on using a menthol based chiral auxiliary attached via
carboxylate bond to the irradiated enone ensuring an easy removal
of the chiral auxiliary after the reaction.4 So far we found that the
best diastereomeric excess value (de) in a diastereodifferentiating
[2þ2]-photoreaction with ethylene could be achieved by attaching
an 8-(p-substituted-phenyl)menthyl-modified chiral auxiliary (a)
to the used cyclohexenone carboxylates. Irradiation of 8-(4-
methoxyphenyl)-menthyl attached cyclohexenone-carboxylate 1a
conducts in the presence of the simplest alkene, ethylene, with a de
up to 81%.4c We now expanded our research on developing a new
chiral auxiliary (b) introducing even higher de in a [2þ2]-
photoreaction. Here we report our result on [2þ2]-photoreactions
of chiral cyclohexenones 1a,b using methoxyarylmenthol based
auxiliaries, not only in regard to its diastereoselectivity but also to
its regioselectivity in the presence of various alkenes (see Fig. 1).
2. Results and discussion
* Corresponding authors. Tel.: þ81 0743 72 6085; fax: þ81 0743 72 6089 (I.I.);
tel.: þ81 0743 72 6080; fax: þ81 0743 72 6089 (K.K.); e-mail addresses: i-inhulsen@
As we could prove,4a the 8-(p-methoxysubstitutedphenyl)
menthyl attached cyclohexen-onecarboxylate 1a can exist in
€
ms.naist.jp (I. Inhulsen), kakiuchi@ms.naist.jp (K. Kakiuchi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.074

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I. Inhulsen et al. / Tetrahedron 69 (2013) 782e790
783
reactions conduct under nearly complete conversion of the cyclo-
hexenone to yield [2þ2]-photoproducts. The main product of the
reaction is independently of the used alkene a cis-fused (1S,6S)-
oxobicyclo[4.2.0]octane. Irradiation in the presence of 2-
methylbut-2-ene (d) led to the formation of three products: the
main product 2ad, its regioisomer 3ad as well as the diastereomer
4ad (wherein the configuration of the bridged carbons is 1R and
6R), conducting with a de (concerning the diastereodifferentiating
attack of the alkene 2ad/4ad) of 85% (entry 3). Photoreaction of 1a
with 2-methylprop-2-ene (e) yields four products. Main product of
the reaction was the 7,7-dimethyl-3-oxobicyclo[4.2.0]octane 2ae,
together with the byproduct, its diastereomer 4ae, which is formed
in a ratio of 8% (entry 5). Besides the cycloadducts, two 3-(2-
methylallyl)cyclohexanones (6ae/7ae) were found in the reaction.
These products are formed by H-transfer of the primary generated
biradical intermediate (see Fig. 3) and are known to be formed
when 2-methylprop-2-ene as the alkene partner is employed in
a [2þ2]-photoreaction.7
Fig. 1. Diastereoselective [2þ2]-photocycloaddition of 1a,b using chiral menthyl based
auxiliaries a and b in the presence of alkenes ceg, and stacked conformation of sub-
strate in a bracket.
(a)
different conformers, among with the stacked trans form, wherein
the cyclohexenone and the aryl moiety are located face to face to
each other, is the most likely to be populated at low temperature
(see Fig. 1). In this conformation one diastereotopic reaction side
(Re-face) is shielded by the chiral auxiliary making the attack of the
alkene from the Si-face side of the molecule being highly favored.
For enhancing the shielding of the Re-side of the cyclohexenone, we
developed a new chiral auxiliary, 6-methoxynaphthyl-menthyl (b),
which owns a methoxynaphthyl-moiety instead of the aryl moiety.
The used methoxymoiety in para-position will additionally stabi-
lize the desired conformation by acceptoredonor interactions.
Furthermore we investigated the influence of the substitution
pattern of the alkene to the de-value of the photoreactions.
Therefore we irradiated compounds 1a,b in the presence of dif-
ferent alkenes as ethylene (c), 2-methylbut-2-ene, (d) 2-methyl-
prop-2-ene (e), methacrylonitrile (f), and 2-methoxypropene (g).
In general, higher substituted asymmetric alkenes are not often
used in photoreactions, as due to its asymmetry the possible for-
mation of regioisomeric products will increase, causing a decrease
of the reaction’s selectivity. Considering the [2þ2]-photoreaction of
the cyclohexenone carboxylates 1a,b to asymmetric alkenes ceg,
a wide range of [2þ2]-photocycloadducts is possible to be built. The
primary attack from the alkene can occur from both diastereotopic
sides of the cyclohexenone yielding in diastereomeric products
(different in configuration at C-1 and C-6 (Fig. 2a)). If using an
asymmetric alkene as the reaction partner, the amount of possible
built cyclobutanes increases, as the regioselectivity of the reaction
has to be concerned as well. In dependence of the orientation of the
alkene toward the reacting double bond, the regioisomeric Head to
Head as well as the Head to Tail product can be formed (see Fig. 2b).
Fig. 2b also shows the possible diastereomeric products, which can
be obtained in dependence of the substitution pattern of the alkene
at the C-7 or C-8 position of the new formed cyclobutanes. Possible
from this reaction resulting regio- and diastereomers are shown in
Fig. 1.
(b)
Fig. 2. (a) Possible diastereomeric cyclobutanes in dependence of the attacking side of
the alkene; (1) attack from the Re-side yielding in (1R,6R)-oxobicyclo[4.2.0]octanes and
(2) attack from the Si-side yielding in (1S,6S)-oxobicyclo[4.2.0]octanes. (b) Possible
regioisomeric cyclobutanes built via photoreaction with asymmetric alkenes and
therefrom resulting diastereomers differing in the newly built asymmetric C-atom (C-
7/C-8) (only showed for the (1S,6S)-configurated diastereomer).
On irradiation of 1a in the presence of methacrylonitrile (f)
a highly diastereoselective and regioselective reaction was ob-
served. As the main product of the reaction the 7-methyl-5-
oxobicyclo[4.2.0]octane-7-carbonitrile 2af1 could be assigned. The
respective diastereomer 2af2 (owing a different configuration at the
C-7 atom (R-configurated)) as well as the (1R,6R)-fused di-
astereomer 4af were found in a ratio of 14:6, respectively. Note-
worthy to say is, that the reaction proceeds completely
regioselective, as no Head to Tail product can be found. Using
methoxypropene (g) as the alkene partner, a contrarious photo-
chemical behavior was found. The main product of the reaction is
the Head to Tail product 3ag. In this case, a number of byproducts
were produced but could not be assigned due to their small
amount. Remarkable is that all shown photoreactions, besides be-
ing highly diastereoselective in their attack toward the enone,
proceed with a high regioselectivity. Irradiation of 1a in the pres-
ence of alkenes def yielded the Head to Head adducts irrespective
of the substitution pattern of the used alkenes. These products are
formed via addition of the alkene from the Si-side face of the
cyclohexenone in high diastereoselectivity (regarding the config-
uration of the bicyclic framework). The formation of the Head to Tail
2.1. Photoreaction of 1a with alkenes ceg
Investigation of the influence of the alkene to the regio- and
diastereoselectivity of the [2þ2]-photoreaction was conducted by
irradiation of 1a in the presence of the alkenes ceg. The results are
shown in Table 1. Entry 1 shows the already published data4a of 1a
with the simplest alkene ethylene (c) for referring. All of the shown

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784
Table 1
the less substituted C-atom of the alkene. The two diastereomers
Photocycloadditions of 1aþb in the presence of alkenes cega
2af1 and 2af2 differ thereby in their configuration at the C-7 posi-
tion; 2af1: S-configurated, 2af2: R-configurated. Concerning the
diastereoselectivity of the reaction in adding to the enones, two
products (as shown in Fig. 2a) are possible to be formed. The as-
signment of the main products to be (1S,6S) configurated is based
on comparison to the photoproducts of irradiating 1b in the pres-
ence of ethylene (2bc). The cyclobutane obtained as the main
product can be proven to be (1S,6S) configurated by respective X-
ray analysis. The minor product, the (1R,6R) configurated oxobicy-
clo[4.2.0]octane, shows analogues signals in the 1H NMR spectra.
The characteristic signal of the proton at C-6 is shifted in the minor
product to higher applied field. As all of the here shown crude re-
actions mixtures of the irradiation of 1a in the presence of different
alkenes show analogues pairs of signals, the configuration of the
products 2adeag and 4adeag are highly presumable to be alike.
The configuration of the moiety at C-7 could be assigned by NOE
ꢀ
ꢁ
2ax ꢀ 4ax
2ax þ 4ax
d
Entry
1e
Alkene
Enone Product ratiob
Yieldc [%] de ¼
%
1a
1b
1a
90:9 (2ac/4ac)
96
97
82
81
92
85
2
3
100:4 (2bc/4bc)
100:8:11
(2ad/4ad/3ad)
4
1b
100:7:25
90
87
(2bd/4bd/3bd)
5
6
7
1a
1b
1a
100:8f (2ae/4ae) 85
100:<2f (2be/4be) 92
85
studies of the a-acidic proton of the carbonylgroup as well as for the
>95
90
methyl moiety at C-7. The measurements were conducted for
both of the two different diastereomers and are also supported
for compound 2af1 and 2af2 by NMR-Data of cyclobutane-
carbonitriles.7b,d,8 Based on this measurement the C-atom at C-7
has S-configuration allowing the most voluminous moiety to be
located on the less hindered side of the cyclohexenone (see Fig. 4).
However the described regioselectivity could not be found on ir-
radiation of 1a in the presence of 2-methoxyprop-1-ene (g). As the
isolated main product of the reaction, the Head to Tail adduct 3ag,
(C-8: R-configurated) could be characterized.
100:14:6
86
87
(2af1/g2af2/g4af)
8
9
1b
100:25:<2
>95
(2bf1/g2bf2/g4bf)
1a
1b
3ag
3bg
72
75
ndh
ndh
10
a
c¼0.05 mM of 1a, c¼0.005 mM of 1b in MCH, ꢀ78 ꢁC, c(alkene)¼20 M excess, for
using gaseous alkenes c and e: bubbling of the solution for 5 min at 25 ꢁC, irradiation
time in dependence of complete conversion monitored by NMR 1.5e6 h.
(a)
b
Assigned from the crude NMR-mixture.
c
Isolated yield after evaporation of the solvent and CC.
d
Determined by 1H NMR spectroscopy. For assigning the de-value using 1H NMR,
characteristic clearly separated signals caused by the proton at the C-6 atom of the
cyclobutanes were used.
e
(b)
Ref. 4a.
f
The reaction gave the products 6ae and 7ae additionally formed via [H]-transfer
in a ratio of 2:1 (see Fig. 3).
g
2af1/2bf1 and 2af2/2bf2 owns
a different configuration at C-7, 2af1/2bf1:
S-configurated/2af2/2bf2: R-configurated. The de value is given for the di-
astereomeric ratio of the bridge atoms of the bicyclic framework (C-1 and C-6).
h
The reaction yields various byproducts, therefore the de could not be de-
termined (nd).
Fig. 4. Favored orientation of the attacking alkene toward the cyclohexenone for (a)
methacrylonitrile and (b) methoxypropene and resulting configuration of the
cyclobutanes.
The finding on the regioselectivity of the [2þ2]-photoreaction is
just opposite to the ones found for using simple cyclo-
hexenones.7a,c,d,9 For suchlike compounds mainly the electron dis-
tribution is thought to govern the reaction’s regioselectivity. Using
more complex molecules, the influence of the steric hindrance tothe
reaction will become, as well as the influence of the used solvent,
predominant. An explanation for this highly regioselective and
diastereoselective behavior, can be given regarding the stereo-
chemistry of the molecule. As the Re-side is shielded by the naph-
thylmenthyl moiety, the attack will occur from the Si-side resulting
in a highly diastereoselective reaction, which yields cis-fused
(1S,6S)-configurated oxo-bicyclo[4.2.0]octanes. Concerning the re-
Fig. 3. Photoproducts of enones 1a,b with 2-methylprop-2-ene (e) via [H]-transfer (for
1a: product ratio of 2ae/6ae/7ae is 100:40:20; for 1b:2be/6be/7be is 100:15:15).
products could not be observed for these alkenes. The respective
regioisomer (3ax) was only observed as a minor product using
methylbut-2-ene (d). Alkenes e and f, which own two germinal
C-atoms, which clearly differs in their steric demand, show even
regioselective addition, as no Head to Tail product can be found.
Using methacrylonitrile (f) as the alkene partner, a regioselective as
well as highly diastereoselective photoreaction occurred. The main
product 2af1 is built via primary binding of the cyclohexenone to
action’s regioselectivity, an orientated
p-complex between the al-
kene and the enone moiety is likely to be formed, to which the
alkene, such as 2-methylprop-2-ene (e) and methacrylonitrile (f)
will approach from the most unhindered reaction quarter (see Fig. 4)
avoiding a steric hindrance with the menthyl moiety. Following ring
closure reaction of the 1,4-biradical intermediate will yield the C-7
atom S-configurated product 2af1 in the case of methacrylonitrile

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785
Table 2
(f). The R-configurated minor product 2af2 can only be obtained in
Photocycloadditions of 1b with alkene c at different temperaturesa
a trace amount. It should also be mentioned that interestingly the
Head to Head products are obtained, in sharp contrast to the results
of similar photoreactions of simple cyclohexenones, where the Head
toTail products are mainly obtained. These results also show that the
primary binding occurs at the b-atom of the enone yielding the 1,4-
biradical as shown in Fig. 3. Production of the ene products 6ae and
7ae via the same biracial species also supports the primary attack of
ꢀ
ꢁ
2bx ꢀ 4bx
2bx þ 4bx
c
Entry
Temperature [ꢁC]
Product ratiob (2bc/4bc)
de ¼
%
1
2
3
4
5
6
ꢀ100
ꢀ78
ꢀ60
ꢀ40
ꢀ20
0
98:2
96
92
87
79
70
63
100:4
93.5:6.5
89.5:10.5
85:15
81.5:18.5
the alkene at the b-atom of the enone. Using methoxypropene (g) as
a
c¼0.005 mM of 1b in MCH, ꢀ78 ꢁC, c(alkene)¼bubbling with ethylene gas for
the alkene partner, a different orientation to the reacting double
bond is observed to give the Head toTail adduct 3ag. The C-8 atom of
the newly formed cyclobutane will be R-configurated, allowing the
methoxygroup to avoid steric hindrance with the menthyl moiety.
The reason for the different regioselectivity of this reaction might lie
in the fact that the additional repulsion caused by the methoxy-
propene’s oxygen atom suppresses the formation of the Head to
Head product, but will need further investigation to be carried out.
As all of the reactions of enone 1a show a diastereoselectivity
(<95%), which is not satisfying for synthetic organic reactions, we
now tried to increase the reaction’s selectivity by irradiating the
newly synthesized 6-methoxynaphthylmenthyl carboxylate 1b in
the presence of the alkenes ceg.
5 min at 25 ꢁC.
b
c
Assigned from the crude NMR-mixture.
Determined by 1H NMR spectroscopy for assigning of the de-value using 1H
NMR, characteristic clearly separated signals caused by the proton at the C-6 atom of
the cyclobutanes were used.
with ethylene showed a highly diastereoselective manner (entry 2).
The (1S,6S)-configurated oxobicyclo[4.2.0]octane 2bc was obtained
in a diastereoselectivity of 92%. The main product of the reaction is
the [2þ2]-photoproduct formed via attack of the alkene from the
less shielded Si-side of the cyclohexenone carboxylate. The absolute
configuration of 2bc could be assigned after chromatographic sep-
aration of the diastereomers by X-ray analysis (Fig. 5). Diaster-
eodifferentiating [2þ2]-photoreactions of 1b in the presence of
higher substituted alkenes deg proceeded with the complete con-
version of the starting material. The found products could be sepa-
rated and assigned completely by 2D-NMR, and were characterized
to be analogously formed cyclobutanes adducts to the ones
2.2. Photoreaction of 1b in the presence of alkenes ceg
The results on irradiation of 1b in the presence of the alkenes ceg
are listed in Table 1. As expected, photoreaction of compound 1b
Fig. 5. ORTEP-diagram of compound 2bc.10

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786
described above (for using 1a). They show the same photochemical
behavior concerning their regio- and diastereoselectivity (entries
3e10). Irradiation of 1b in the presence of 2-methylprop-2-ene (e)
and methacrylonitrile (f) yielded the main products 2be and 2bf1,
respectively, with high regioselectivity. The formation of other
regioisomers in the photoreaction of 1b with the alkenes def, is
suppressed due to the enhanced shielding of the Re-side of the
molecule. This may be the reason for the high regioselectivity. Ad-
ditionally an enhancement in the reaction’s de (toward the dia-
stereoselective addition to the enone) can be found. Irradiating the
cyclohexenecarboxylate 1a and 1b, we could find, that asymmetric
alkenes add regioselective as well as highly diastereoselective
yielding in (1S,6S)-configurated oxo-bicyclo[4.2.0]octanes. Using
the alkenes def, the reaction gave the Head to Head photoproducts
as the main product. The formation of the Head to Tail products is
depressed. Moreover we could not only succeed on an improvement
of the regioselectivity of the reaction but also on its diaster-
eoselectivity when using the methoxynaphthylmenthyl auxiliary
(b). The [2þ2]-photoreaction of 1b in the presence of alkene def
yielded highly diastereoselective the products 2bce2bf,
respectively.
Furthermore the effect of the temperature to the reaction was
investigated by irradiating 1b in the presence of ethylene (c) at
different temperatures. The results are given in Table 2. Entries 1e6
clearly show that decreasing the temperature of the reacting sys-
tem yields in higher de of the reaction. Irradiation at ꢀ100 ꢁC even
increases the de of the reaction to 96%. These results can be
explained regarding the structure of the enone 1b. The lower the
temperature, the more likely the enone 1b will be fixed in the
closed stacked trans conformation (see Fig.1), which induces a high
shielding of one diastereotopic reaction side of the enone yielding
in a high de. This stacked trans conformer can not only be stabilized
by decreasing the temperature but also by the substituent at the
aromatic ring. Irradiation of 1b, which owns a methoxymoiety at
the naphthylring shows higher de than its unsubstituted analogue
1a in the [2þ2]-photocycloadditions. This fact clearly supports the
results, which were found for the [2þ2]-photoreaction of analogues
methoxyphenyl- and the phenyl substituted cyclohexenone car-
boxylates compounds we investigated before.4a,d Herein, too, irra-
diation of the methoxyphenyl substituted analogue with ethylene
yield in higher de than its corresponding phenyl analogue. As re-
ported before4d the methoxymoiety at the aromatic ring seems to
stabilize the stacked trans conformer by additional donoreacceptor
to photochemically compose 7-substituted oxobicyclo[4.2.0]octanes
being highly diastereo- and regioselective in their product formation
by using 6-methoxynaphthylmenthyl chiral auxiliary (b).
4. Experimental section
4.1. General
All reagents were used without further purification. Air- and
moisture sensitive compounds were handled under nitrogen at-
mosphere using Schlenk technique; Column chromatography (CC):
Silica gel 60 N (SiO2; Kantokagaku mesh 63e210
mm); GC/EI-MS:
Shimadzu GC2010 High-resolution Mass-spectra (HRMS): JEOL
JMS-700; 1H- and 13C spectra: JOEL JNM-ECP 500 at 500 MHz and
125 MHz, resp.; d in parts per million rel to tetramethylsilane (TMS)
as internal standard, J in Hertz, spin multiplicity: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, and b¼broad; X-ray
analyses: Rigaku RAXIS-RAPID Imaging Plate diffractometer with
Mo ka radiation at 296 K. Melting points: Yanaco MP-500D micro
melting point apparatus. Optical rotations: JASCO DIP-1000 digital
polarimeter by using the sodium D line (solvent and concentration
as given); Infrared spectra (IR): JASCO FT/IR-420 spectrometer in
reciprocal centimeters; HPLC (Column Oven) Hitachi L-7300
(Pump), Hitachi L-7100 (UVevis Detector), Hitachi L-7420 and
HPLC (Pump), Hitachi C 150 (UVevis Detector), Hitachi L-7420.
4.2. Starting material
4.2.1. Syntheses of 1a,b. (ꢀ)-(1R,2S,5R)-5-Methyl-2-[1-methyl-1-(4-
methoxyphenyl)ethyl] cyclohexyl-3-oxo-1-cyclohexenecarboxylate
(1a) was prepared according to literature procedures.4c,d
(ꢀ)-(1R,2S,5R)-5-Methyl-2-[1-methyl-2-(6-methoxynaphthyl)ethyl]
cyclohexyl-3-oxo-1-cyclo-hexenecarboxylate (1b) was prepared as
followed. Starting from the commercial available 2-bromo-6-
methoxynaphthalene, (2S,5R)-2-(2-(6-methoxynaphthalen-2-yl)pr-
opan-2-yl)-5-methyl-cyclohexanone was prepared by Grignard re-
action with (R)-pulgeone following Yangs procedure.11 Colorless
solid, yield: 66%; mp 108e111 ꢁC; Rf (10% EtOAc/Hexane) 0.52; dH
(500 MHz, CDCl3): 7.74e7.65 (3H, m, CH), 7.48e7.42 (1H, m, CH),
7.15e7.10 (2H, m, CH), 3.91 (3H, s, COMe), 2.75 (1H, dd, J 12.9, 4.4 Hz,
CH), 2.27e2.24 (1H, m, CHaHb), 2.04 (1H, dd, J 12.5, 12.5 Hz, CH),
1.85e1.71 (2H, m, CHaHb), 1.54 (3H, s, CMe), 1.51 (3H, s, CMe),
1.54e1.40 (2H, m, CHaHb),1.23 (1H, dt, J 15.7, 5.3 Hz, CHaHb), 0.97 (3H,
d, J 6.7 Hz, CHMe); dC (125 MHz, CDCl3) 212.1, 157.3, 145.0, 132.6,
129.5, 128.7, 126.4, 125.0, 124.0, 118.6, 105.3, 59.3, 55.3, 52.4, 39.0,
36.3, 34.6, 29.1, 26.9, 23.3, 22.3; IR (KBr) 2938.0, 1710.6, 1600.6,
1454.1, 1282.7, 1269.9,1209.2,1159.1, 1033.7, 852.4, 809.0, 684.6; mp:
83e85 ꢁC; HRMS (ESI): (MþNa)þ found 333.1937. C21H26O2Na re-
quires 333.1933. Reduction of the above ketone leads to the re-
spective alcohol. For preparation of (1R,2S,5R)-2-(2-(6-methoxy
naphthalen-2-yl)propan-2-yl)-5-methylcyclohexanol the substi-
tuted cyclohexanone was solved in toluene and cooled to ꢀ40 ꢁC.
Then 2 mol equiv of a 1.0 M DIBAL solution in hexane was added. The
reaction mixture was allowed to warm to room temperature and
stirred for additionally 12 h. After quenching with 1 N HCl and ex-
traction with dichloromethane, followed workup (organic layers
were washed with water and brine and dried over MgSO4, evapo-
ration of the solvent) yield the crude product, which was purified by
CC. Yield: 65%; Rf (17% EtOAc/Hexane) 0.24; dH (500 MHz, CDCl3):
7.72e7.68 (3H, m, CH), 7.51e7.49 (1H, m, CH), 7.14e7.11 (2H, m, CH),
3.91 (3H, s, OMe), 3.58 (1H, (dd(dd)), J 10.4, 10.4, 4.0, 4.0 Hz, CHOH),
1.85e0.86 (9H, m, CHaHb, CH), 1.52 (3H, s, CMe), 1.36 (3H, s, CMe),
0.88 (3H, d, J 6.7 Hz, CHMe); dC (125 MHz, CDCl3) 157.5, 146.5, 132.7,
129.4,128.8,127.0,125.6,123.1,118.7,105.4, 73.0, 55.3, 53.7, 45.2, 39.7,
34.9, 31.5, 28.6, 26.5, 24.3, 22.0; IR (KBr) 2944.8, 1599.7, 1379.8,
1207.0, 850.5; mp:108e111 ꢁC; HRMS (ESI): (MþNa)þ found
interactions. The resulting stronger
p-stacking between the aro-
matic ring and the enone causes an effective shielding of the Re-
side yielding in a highly diastereoselective reaction.
3. Conclusion
Irradiation of 1a in the presence of ethylene (c) gave the product
2ac with a de value of 81%. For enhancing the de in [2þ2]-
photoreactions we designed a new menthyl-based chiral auxiliary
owing a methoxynaphthyl moiety (b) ensuring even higher shielding
of one diastereotopic side of the stacked conformer. On irradiation of
1b in the presence of ethylene, we could succeed in finding a quanti-
tative and highly diastereoselective reaction, which converted 1b into
the [2þ2]-photocycloadduct 2bc with a de of up to 96%.
Moreover we investigated the photochemical behavior of asym-
metric alkenes in diastereodifferentiating [2þ2]-photoreactions. We
irradiated compound 1a in the presence of the alkenes def and could
prove that those reactions not only proceed with a high de but also
additionally are highly regioselective. Applying the newly synthe-
sized methoxynaphthylmenthyl attached cylohexenoncarboylate 1b
to these photoreactions, besides showing higher diastereoselectivity
in addition to the enone, an increase in the reaction’s regioselectivity
canbeobserved. Inconclusionwecouldsucceedonfinding a new way

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I. Inhulsen et al. / Tetrahedron 69 (2013) 782e790
787
29
335.2082. C21H28O2Na requires 335.2082; [
CH2Cl2).
a
]
ꢀ0.0368 (c 0.010,
91 (2), 67 (2), 55 (4%); HRMS (ESI): (MþNa)þ found 477.2981.
C29H42ONa requires 477.2980. Compound 2ad was followed by
(1R,6S,7R)-(1R,2S,5R)-2-(2-(4-methoxyphenyl)propan-2-yl)-5-
methyl-cyclohexyl 7,8,8-trimethyl-5-oxobicyclo[4.2.0]-octane-1-
carboxylate(3ad) (Fraction still contains 37% of 2ad, characterizes
as a mixture, 8.3 mg (0.017 mmol,11%); Rf (17% EtOAc/Hexane) 0.28;
yellow oil; dH (500 MHz, CDCl3) 7.15 (2H, d, J 8.9 Hz, CH), 6.82 (2H, d,
J 8.9 Hz, CH), 4.86 (1H, ddd, J 10.5, 10.5, 4.2 Hz, OCH), 3.79 (3H, s,
COMe), 3.11 (1H, d, J 10.5 Hz, COCHaCHMe), 2.37e2.21 (3H, m,
COCHMe, CHaHbCO, CHaHb), 2.11e1.33 (9H, m, CHaHb, CH), 1.30 (3H,
s, CMe), 1.20 (3H, s, CMe), 1.09 (3H, s, CMe), 1.02 (3H, s, CMe), 1.01
(3H, d, J 6.8 Hz, CHMe), 0.89e0.79 (2 H, m, CHaHb), 0.84 (3H, d, J
6.2 Hz, CHMe), 0.75e0.66 (1H, m, CHaHb); dC (125.0 MHz, CDCl3)
211.0, 173.3, 157.2, 142.3, 126.6, 113.3, 75.3, 55.1, 52.8, 50.5, 49.9,
43.6, 41.9, 41.5, 39.7, 38.6, 34.4, 32.1, 31.4, 31.3, 27.6, 27.1, 22.7, 21.7,
21.4,19.9,13.5; m/z (EIeGC/MS) 454 (Mþ, >1),149 (100),135 (4),121
(6), 109 (3), 91 (2), 67 (2), 55 (5%).
D
The chiral auxiliary was then attached to the 3-oxo-1-
cyclohexenecarboxylic acid following the literature procedure for
the preparation of 1a4a to give 1b. Colorless solid, yield: 86%; Rf (15%
EtOAc/Hexane) 0.22; dH (500 MHz, CDCl3): 7.63 (1H, d, J 8.7 Hz, CH),
7.59 (1H, d, J 8.9 Hz, CH), 7.46 (1H, dd, J 8.7, 1.8 Hz, CH), 7.43 (1H, s,
CH), 7.05 (1H, dd, J 9.0, 2.5 Hz, CH), 6.99 (1H, d, J 2.5 Hz, CH), 5.89
(1H, br s, C]CH), 5.04 (1H, ddd, J 10.7, 10.7, 4.7 Hz, OCH), 3.87 (3H, s,
COMe), 2.22 (1H, m, CH), 2.03 (1H, dd, J 13.6, 3.3 Hz, CHaHb), 1.89
(1H, d(dd), J 16.7, 7.8, 4.9 Hz, CHaHbCO) 1.81e1.23 (12H, m, CH,
CHaHb), 1.41 (3H, s, CMe), 1.02 (2H, m, CHaHb), 0.90 (3H, d, J 6.5 Hz,
CHMe); dC (125 MHz, CDCl3) 200.1, 165.1, 157.2, 147.6, 147.2, 132.4,
131.7, 129.0, 128.8, 126.7, 125.7, 121.9, 118.5, 105.6, 74.4, 55.4, 49.9,
41.8, 39.3, 36.9, 34.4, 31.3, 30.6, 30.3, 26.1, 23.8, 21.8, 21.4; IR (KBr)
2952.5, 1709.6, 1678.7, 1603.5, 1459.9, 1391.4, 1257.4, 1200.5, 1078.0,
1030.7, 960.4, 849.5, 810.9, 721.3; m/z (GC/EI-MS) 434 (5, Mþ), 199
(100), 167 (2), 158 (4), 144 (2), 95 (4), 67 (3), 55 (3%);
mp:118e121 ꢁC; HRMS (ESI): (MþNa)þ found 457.2452.
4.3.2.2. Photocycloaddition of 1a to 2-methylprop-2-ene (e). The
general procedure was followed. As 2-methylprop-2-ene (e) is
gaseous, the solution of 1a was saturated with it by bubbling
for 15 min. The compound 2ae elutes first to give 33.5 mg
(0.076 mmol, 51%) of (1S,6S)-(1R,2S,5R)-2-(2-(4-methoxyphenyl)
propan-2-yl)-5-methylcyclohexyl 7,7-dimethyl-5-oxobicyclo[4.2.0]
octane-1-carboxylate (2ae) as a yellowish oil; Rf (17% EtOAc/Hex-
ane) 0.33; dH (500 MHz, CDCl3) 7.18 (2H, d, J 8.7 Hz, CH), 6.80 (2H, d,
J 8.7 Hz, CH), 4.91 (1H, ddd, J 10.7, 10.7, 4.3 Hz, OCH), 3.79 (3H, s,
COMe), 2.91 (1H, s, COCHaCMe2), 2.27 (1H, ddd, J 18.9, 5.8, 5.8,
COCHaHb), 2.18 (1H, ddd, J 18.9, 5.8, 5.8, COCHaHb), 2.13 (1H, d, J
12.5 Hz, CHaHb), 1.99 (1H, ddd, J 14.8,14.8,10.6 Hz, CHCH), 1.89e1.82
(2H, m, CHaHb), 1.85 (1H, d, J 12.5 Hz, CHaHb), 1.82e0.97 (8H, m,
CHaHb, CH), 1.30 (3H, s, CMe), 1.22 (3H, s, CMe), 1.19 (3H, s, CMe),
0.96 (3H, s, CMe), 0.88 (3H, d, J 6.5 Hz, CHMe), 0.88e0.78 (1H, m,
CHaHb); dC (125.0 MHz, CDCl3) 211.3, 175.9, 157.1, 143.1, 126.4, 113.3,
75.6, 55.1, 54.7, 50.1, 42.6, 41.7, 41.3, 40.1, 39.5, 35.5, 34.5, 31.8, 31.3,
30.5, 27.8, 27.0, 26.7, 26.1, 21.8, 19.7; m/z (EIeGC/MS) 440 (Mþ, 1),
C28H34O4Na requires 457.2457; [
a
]
29 ꢀ0.301 (c 2.1, CH2Cl2).
D
4.3. Photocycloadditions of 1a and 1b to alkenes ceg
Photolysis was conducted using an ultrahigh pressure mercury
500 W lamp (Ushio) combined with a Unisoku CoolspeK cryostat
(for analytical measurements) at ꢀ78 ꢁC. Irradiation was carried out
in a quartz cell using a Pyrex filter (>280 nm). Preparative photo-
reactions were carried out in a Pyrex flask (>280 nm) equipped
HALOS 400 W high-pressure Hg lamp at ꢀ78 ꢁC.
4.3.1. General procedure for photoreactions. Photoreactions were
carried out by irradiation of 0.15 mmol of a 0.05 mM (0.005 mM for
1b) N2-degassed solution of 1a,b in methylcyclohexane (MCH) in
the presence of a 20 M excess of the alkene (in the case of ethylene
and 2-methylprop-2-ene a gas-saturated solution is used) at ꢀ78 ꢁC
until complete conversion of the cyclohexenone (monitored by 1H
NMR). After evaporation of the solvent and the excess alkene the
products were separated by CC (conditions as given below) and
fully characterized by 1H and 2D-NMR-spectroscopy.
As the diastereoisomeric cycloadducts 3ad, 5ad were obtained
in very small amounts only the main product of the reaction could
be isolated and characterized. The assignment of these compounds
as the respective diastereomers was conducted from the product
mixtures’ 2D-NMR data files, which shows characteristic signals for
these bicyclo[4.2.0]octanes. The diastereomeric excess value (de) of
the reactions was assigned (if not given differently) by 1H NMR.
149 (100), 121 (7), 109 (3%); HRMS (ESI): (MþNa)þ found 463.2823.
29
C28H40ONa requires 463.2824; [
a
]
þ0.4906 (c 1.17, CH2Cl2). This
D
fraction was followed by (S)-(1R,2S,5R)-2-(2-(4-methoxy-phenyl)
propan-2-yl)-5-methylcyclohexyl-(2-methylall-yl)-3-oxo-cyclo-
hexane-carboxylatey (6ae) 14.5 mg (0.033 mmol, 22%), yellow oil; Rf
(17% EtOAc/Hexane) 0.28; dH (500 MHz, CDCl3) 7.22 (2H, d, J 8.8 Hz,
CH), 6.83 (2H, d, J 8.8 Hz, CH), 4.87 (1H, s, C]CHaHb), 4.86 (1H, ddd, J
10.3, 10.3 4.3 Hz, OCH), 4.66 (1H, s, C]CHaHb), 3.77 (3H, s, OMe);
2.26 (1H, d, J 14.3 Hz, CHaHbC]CH2), 2.18 (1H, d, J 14.3 Hz, CHaHb),
2.13 (1H, d, J 6.7 Hz, CHaHbC]CH2), 2.31e2.09 (3H, m, CHaHb), 2.02
(1H, ddd, J 12.1,12.1, 3.5 Hz, CH),1.94e0.78 (11H, m, CH, CHaHb),1.68
(3H, s, MeC]CH2), 1.30 (3H, s, CMe), 1.17 (3H, s, CMe), 0.88 (3H, d, J
6.5 Hz, CHMe); dC (125.0 MHz, CDCl3) 209.9, 174.8, 157.1, 143.1, 140.7,
126btained in this work that the alkene attacks preferentially from
the Si-side of the enone to produce 1S stereochemistry.
4.3.2. Photocycloadditions of 1a
4.3.2.1. Photocycloaddition of 1a to 2-methyl-2-butene (d). A
solution of 1a (0.15 mmol) was irradiated in the presence of 2-
methylbut-2-ene (d) for 90 min. Work up: CC, SiO2. The major
product, (1S,6S,8S)-(1R,2S,5R)-2-(2-(4-methoxyphenyl) propan-2-
yl)-5-methylcyclohexyl7,7,8-trimethyl-5-oxobicyclo-[4.2.0]octane-
1-carboxylate (2ad), elutes first to give 47.3 mg (0.104 mmol, 70%,
sample includes 10% of 4ad). Rf (17% EtOAc/Hexane) 0.28; yellow
oil, dH (500 MHz, CDCl3) 7.18 (2H, d, J 8.6 Hz, CH), 6.80 (2H, d, J
8.6 Hz, CH), 4.92 (1H, ddd, J 10.7, 10.7, 4.3 Hz, OCH), 3.79 (3H, s,
COMe), 3.05 (1H, s, COCHCMe2), 2.42e2.38 (1H, m, CHaHbCO), 2.30
(1H, q, J 7.3 Hz, CHMe), 2.12e1.34 (10H, m, CHaHb, CH), 1.30 (3H, s,
CMe), 1.22 (3H, s, CMe), 1.18 (3H, s, CMe), 1.00e0.84 (2 H, m, CHaHb),
0.96 (3H, s, CMe), 0.94 (3H, d, J 7.3 Hz, CHMe), 0.86 (3H, d, J 6.5 Hz,
CHMe), 0.79e0.76 (1H, m, CHaHb); dC (125.0 MHz, CDCl3) 211.0,
175.6, 157.4, 143.0, 126.5, 113.3, 75.3, 55.1, 53.8, 50.2, 46.8, 44.4, 41.7,
40.3, 40.0, 39.6, 34.5, 32.6, 31.9, 31.3, 29.4, 25.0, 24.6, 21.8, 20.3, 20.0,
9.2; m/z (EIeGC/MS) 454 (Mþ, 1), 149 (100), 135 (3), 121 (6), 109 (3),
4.3.2.3. Photocycloaddition of 1a to methacrylonitrile (f). For ir-
radiation of 1ain the presence of f the generalprocedurewas followed
to yield after evaporation of the solvent and excess alkene the complex
product mixture (2af1/2af2/4af 100:14:6, respectively). Separation
by CC gives 5.2 mg (0.012 mmol, 8% as yellow oil) of first eluting
product (1S,6S,7R)-(1R,2S,5R)-2-(2-(4-methoxyphenyl)propan-2-
yl)-5-methylcyclo-hexyl7-cyano-7-methyl-5-oxobicyclo[4.2.0]octane-
1-carboxylate) (2af2), Rf (17% EtOAc/Hexane) 0.43; dH (500 MHz,
CDCl3) 7.22 (2H, d, J 8.8 Hz, CH), 6.77 (2H, d, J 8.6 Hz, CH), 5.00 (1H,
ddd, J 10.7, 10.7, 4.4 Hz, OCH), 3.76 (3H, s, COMe), 2.97 (1H, s,
y
Data determined by 2D-NMR-spectra analysis.

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I. Inhulsen et al. / Tetrahedron 69 (2013) 782e790
788
COCHCCNMe), 2.62 (1H, d, J 12.6 Hz, CNMeCCHaHb), 2.30 (1H, ddd,
J 18.5, 5.8, 5.8 Hz, CHHbCO), 2.23e2.14 (2H, m, CHaHb CH),1.98 (1H, d,
J 12.6 Hz, CNMeCCHaHb), 1.87e1.15 (10H, m, CHaHb, CH), 1.31 (3H, s,
CMe), 1.30 (3H, s, CCNMe), 1.15 (3H, s, CMe), 0.99e0.90 (1H, ddd,
J 12.7,13.0, 3.9 Hz, CHaHb), 0.90 (3H, d, J 6.5 Hz, CHMe); dC (125.0 MHz,
CDCl3) 206.7, 173.5, 156.9, 143.8, 126.2, 123.5, 113.3, 76.2, 55.1, 50.1,
49.3, 43.5, 41.5, 40.7, 39.9, 39.0, 34.3, 31.4, 31.0, 29.6, 29.6, 26.6, 24.3,
22.3, 21.8, 19.1; m/z (EIeGC/MS) 451 (Mþ, 1), 173 (1), 149 (100),
6.5 Hz, CHMe); dC (125.0 MHz, CDCl3) 212.6,175.1,157.3,146.7,132.5,
129.3, 128.8, 126.5, 125.4, 122.6, 118.6, 105.4, 75.2, 55.3, 49.5, 48.3,
45.7, 41.7, 39.8, 38.6, 34.5, 31.3, 29.5, 28.3, 27.6, 26.9, 25.8, 21.8, 21.3,
20.5; m/z (EIeGC/MS) 462 (Mþ, 5), 355 (2), 286 (1), 207 (29), 199
(100), 141 (3), 67 (6%); [
a
]
29 þ0.71 (c 0.80, CH2Cl2). Structure of 2bc
D
was determined by X-ray analysis, mp: 103e105 ꢁC. C60H76O8;
colorless block (0.30ꢂ0.25ꢂ0.15 mm); orthorhombic; space
group¼P212121 (#19); Z¼4; a¼6.29568(15), b¼24.4418(7),
3
121 (7), 109 (3), 67 (2), 55 (5%); HRMS (ESI): (MþNa)þ
c¼33.6194(8) A; V¼5173.3(2) A ; rcalcd 1.188 g cmꢀ3. wR¼0.0473
and R¼0.1251.
ꢀ
ꢀ
29
found 474.2621. C28H37NO4Na requires 474.2620; [
a
]
þ0.3647
D
(c 0.18, CH2Cl2). This fraction was followed by 29.9 mg (0.066 mmol,
44%) of a yellow oil consisting of (1S,6S,7S)-(1R,2S,5R)-2-(2-(4-
methoxyphenyl)-propan-2-yl)-5-methylcyclohexyl7-cyano-7-
methyl-5-oxobicyclo [4.2.0]octane-1-carboxylate (2af1). Rf (17%
EtOAc/Hexane) 0.37; dH (500 MHz, CDCl3) 7.17 (2H, d, J 8.8 Hz, CH),
6.80 (2H, d, J 8.6 Hz, CH), 4.91 (1H, ddd, J 10.7,10.7, 4.4 Hz, OCH), 3.79
(3H, s, COMe), 3.01 (1H, s, COCHaCCNMe), 2.38 (1H, d, J 12.6 Hz,
CNMeCCHaHb), 2.52 (1H, ddd, J 18.5, 5.8, 8.6 Hz, CHaHbCO), 2.34 (1H,
ddd, J 18.5, 8.6, 5.8 Hz, CHaHbCO), 2.15 (1H, d, J 12.6 Hz, CNMeC-
CHaHb), 2.05 (1H, ddd, J 12.3, 12.3, 3.4 Hz, CH), 2.00e1.52 (8H, m,
CHaHb, CH), 1.58 (3H, s, CCNMe), 1.27 (3H, s, CMe) 1.16 (3H, s, CMe),
1.09 (1H, ddd, J 13.6, 12.6, 3.4 Hz, CHaHb), 0.97 (1H, dd, J 12.0, 12.0,
3.4 Hz, CHaHb), 0.91e0.82 (1H, m, CHaHb), 0.88 (3H, d, J 6.5 Hz,
CHMe); dC (125.0 MHz, CDCl3) 207.1, 173.6, 157.1, 143.3, 126.1, 122.6,
113.4, 76.2, 55.1, 54.0, 49.7, 43.3, 41.6, 40.7, 39.2, 39.1, 34.4, 31.4, 31.3,
29.3, 28.0, 26.7, 26.5, 26.0, 21.7,19.6; m/z (EIeGC/MS) 451 (Mþ,1),173
The second fraction consists of 33.3 mg (0.072 mmol, 48%) of
(1R,6R)-(1R,2S,5R)-2-(2-(6-methoxynaphthalen-2-yl)propan-2-yl)
-5-methylcyclohexyl5-oxobicyclo[4.2.0]octane-1-carboxylate (4bc)
as a yellow oil; Rf (17% EtOAc/Hexane) 0.28; dH (500 MHz, CDCl3)
7.69 (1H, d, J 8.6 Hz, CH), 7.66 (1H, d, J 9.7 Hz, CH), 7.55 (1H, s, CH),
7.46 (1H, dd, J 8.6, 1.9 Hz, CH), 7.11e7.06 (2H, m, 2H, CH), 4.98 (1H,
ddd, J 10.6, 10.6, 4.5 Hz, OCH), 3.90 (3H, s, COMe), 2.67 (1H, dd, J 9.2,
8.8 Hz, COCH), 2.31 (1H, d(dd), J 16.9, 7.5, 5.4 Hz, CHaHb), 2.19e2.08
(2H, m, CHaHbCHaHb), 1.90e0.83 (15H, m, CH, CHaHb), 1.41 (3H, s,
CMe), 1.27 (3H, s, CMe), 0.86 (3H, d, J 6.5 Hz, CHMe); dC (125.0 MHz,
CDCl3) 212.3, 175.3, 157.2, 146.6, 132.6, 129.3, 128.8, 126.6, 125.4,
122.6, 118.6, 105.4, 75.2, 55.3, 49.5, 48.2, 45.8, 41.9, 39.8, 38.7, 34.4,
31.3, 30.2, 28.0, 27.4, 26.9, 26.1, 21.8, 20.8, 20.7; m/z (EIeGC/MS) 462
(Mþ, 5), 286 (1), 207 (15), 199 (100), 141 (2), 67 (3%). HRMS (ESI):
(MþNa)þ found 485.2666. C30H38O4Na requires 485.2667; [
ꢀ1.5486 (c 0.26, CH2Cl2).
a]
29
D
(1), 149 (100), 121 (7), 109 (3), 67 (2), 55 (5%), HRMS (ESI): (MþNa)þ
29
4.3.3.2. Photocycloaddition of 1b to 2-methyl-2-butene (d).
Irradiation of 1b in the presence of 2-methyl-2-butene (d) yields
compounds 2bd, 3bd, and 4bd as a mixture. The major product,
(1S,6S,8R)-(1R,2S,5R)-2-(2-(6-methoxynaphthalen-2-yl)propan-2-yl)
-5-methylcyclohexyl7,7,8-trimethyl-5-oxobicyclo[4.2.0]oct-ane-1-ca
rboxylate (2bd)was obtained as lightyellowoil;25.3mg(0.050 mmol,
33%). Rf (17% EtOAc/Hexane) 0.49; dH (500 MHz, CDCl3) 7.66 (2H, d, J
8.6 Hz, CH), 7.55 (1H, d, J 1.0 Hz, CH), 7.44 (1H, dd, J 8.6, 1.0 Hz, CH),
7.13e7.09(2H, m, CH), 4.99(1H, ddd, J 10.4,10.4, 4.6 Hz, OCH), 3.92 (3H,
s, COMe), 3.05 (1H, s, COCHCMe2), 2.22 (1H, m, CHMe), 2.25e2.16 (2H,
m, CHaHbCO, CHaHb), 2.09 (1H, ddd, J 12.2,12.2, 3.6 Hz, CH), 2.10e0.96
(10H, m, CHaHb, CH), 1.76 (1H, ddd, J 13.3, 13.9, 2.6 Hz, CH), 1.40 (3H, s,
CMe),1.33 (3H, s, CMe),1.14 (3H, s, CMe), 0.91 (3H, s, CHMe), 0.86(3H, d,
J 6.5 Hz, CHMe), 0.84 (3H, d, J 7.4 Hz, CHMe); dC (125.0 MHz, CDCl3)
211.1, 175.8, 157.4, 146.1, 132.6, 129.5, 128.8, 126.7, 125.3, 123.1, 118.7,
105.5, 75.4, 55.4, 53.9, 49.8, 46.8, 44.4, 41.9, 40.4, 40.3, 40.0, 34.4,
32.6, 31.7, 31.1, 29.1, 27.3, 25.0, 24.6, 21.9, 20.1, 14.2; m/z (EIeGC/
MS) 504 (Mþ, 5), 199 (100), 185 (2), 171 (5), 158 (3), 141 (2), 81 (2),
found 474.26120. C28H37NO4Na requires 474.2620; [
(c 1.38, CH2Cl2).
a
]
þ0.4975
D
4.3.2.4. Photocycloaddition of 1a to methoxypropene (g). Following
the general procedure, irradiation of 1a in the presence of g gave
a complex reaction mixture. The main product (1R,6S,8R)-(1R,2S,5R)-
2-(2-(4-methoxyphenyl)propan-2-yl)-5-methylcyclohexyl8-methoxy
-8-methyl-5-oxobicyclo[4.2.0]-octane-1-carboxylate (3ag) could be
obtained by HPLC separation, 20.3 mg (0.045 mmol, 30%). Rf (17%
EtOAc/Hexane) 0.22; yellow oil, dH (500 MHz, CDCl3) 7.15 (2H, d, J
8.8 Hz, CH), 6.82 (2H, d, J 8.8 Hz, CH), 4.92 (1H, ddd, J 10.6, 10.6, 4.3 Hz,
OCH), 3.79 (3H, s, COMe), 3.30 (3H, s, OMe), 3.17 (1H, dd, J 10.2, 10.2 Hz,
COCHCH2), 2.43 (1H, ddd, J 15.0, 7.5, 7.5 Hz, CHaHbCO), 2.32e2.29 (3H,
m, CHaHb), 2.20e1.18 (7H, m, CHaHb, CH), 1.85 (1H, ddd, J 12.2, 12.2,
3.3 Hz, CH), 1.36 (3H, s, CMe), 1.23 (3H, s, CMe), 1.20 (3H, s, CMe);
1.22e0.81 (2H, m, CHaHb), 0.85 (3H, d, J 6.5 Hz, CHMe), 0.76e0.68 (1H,
m, CHaHb); dC (125.0 MHz, CDCl3) 210.5,173.4,157.2,142.1,126.6,113.4,
77.3, 76.8, 58.4, 55.2, 51.4, 50.5, 41.9, 39.9, 38.4, 38.1, 36.8, 34.4, 31.8,
30.9, 27.5, 25.0, 22.9, 21.8, 21.5, 19.2; m/z (EIeGC/MS) 456 (Mþ, <1),
55 (4%); HRMS (ESI): (MþNa)þ, found 527.3136. C33H44O4Na requires
29
527.3137; [
a
]
þ0.9661 (c 0.64, CH2Cl2). This fraction was followed
212 (2), 149 (100), 135 (17), 121 (10), 72 (25), 55 (4%); HRMS (ESI):
D
29
(MþNa)þ found 479.2773. C28H40O5Na requires 474.2773; [
6749 (c 0.91, CH2Cl2).
a]
þ0.
by 5.9 mg (0.012mmol, 8%)of (1R,6S,7R)-(1R,2S,5R)-2-(2-(6-methoxy-
aphtalen-2-yl) propan-2-yl)-5-methylcylohexyl7,8,8trimethyl-5-
oxobicyclo[4.2.0]octane-1-carboxylate (3bd) as a light yellow oil,
Rf (17% EtOAc/Hexane) 0.42; dH (500 MHz, CDCl3) 7.67 (2H, d, J,
8.6 Hz, CH), 7.52 (1H, s, CH), 7.40 (1H, dd, J 8.6, 1.8 Hz, CH), 7.12e7.06
(2H, m, CH), 4.92 (1H, ddd, J 10.5,10.5, 4.2 Hz, OCH), 3.90 (3H, s, OMe),
3.14 (1H, d, J 10.6 Hz, COCHaCHMe), 2.37e2.24 (3H, m, COCHMe,
CHaHb, CHaHb), 2.07e1.00 (12H, m, CH, CHaHb),1.34 (3H, s, CMe),1.32
(3H, s, CMe), 1.08 (3H, s, CMe), 1.04 (3H, s, CMe), 1.02 (3H, d, J 6.8 Hz,
CHMe), 0.83 (3H, d, J 6.3 Hz, CHMe); dC (125.0 MHz, CDCl3) 213.5,
173.3,157.4,145.5,132.6,129.4,128.6,126.6,125.3,123.8,118.6,105.4,
75.4, 55.3, 52.9, 50.1, 50.0, 43.6, 41.9, 41.5, 40.5, 36.8, 34.4, 32.1, 31.4,
31.0, 27.7, 27.1, 22.6, 21.7, 21.4,19.9,13.5; m/z (EIeGC/MS) 504 (Mþ, 5),
D
4.3.3. Photocycloaddition of 1b
4.3.3.1. Photocycloaddition of 1b to ethylene (c). As the minor
product 4bc was obtained in only 2% yield using MCH as the solvent
in the photoreaction. The isolation of the product 4bc was con-
ducted from a sample using dichloromethane as solvent where the
product ratio of 2bc/4bc was 1:0.3. For the separation of 2bc, the
general procedure for photochemical reactions as given was fol-
lowed. CC yielded first eluting 61.6 mg (0.13 mmol, 89%) of (1S,6S)-
(1R,2S,5R)-2-(2-(6-methoxy-naphthalen-2-yl)propan-2-yl)-5-met-
hylcyclohexyl 5-oxobicyclo-[4.2.0]octane-1-carboxylate (2bc); Rf
(17% EtOAc/Hexane) 0.31; colorless crystals; dH (500 MHz, CDCl13)
7.67e7.65 (2H, m, CH), 7.55 (1H, s, CH), 7.46e7.45 (1H, m, CH),
7.12e7.07 (2H, m, CH), 4.98 (1H, ddd, J 10.6, 10.6, 4.4 Hz, CH), 3.90
(3H, s, OMe), 2.82 (1H, ddd, J 9.2, 9.2, 6.2 Hz, COCH), 2.22 (1H, dddd,
J 23.0, 6.7, 6.7 Hz, CHaHbCO), 2.02e1.98 (1H, m, CHaHb), 1.90e0.83
(16H, m, CH, CH2), 1.42 (3H, s, CMe), 1.26 (3H, s, CMe), 0.97 (3H, d, J
199 (100),185 (3),171 (5),141 (3), 81 (2), 71 (6), 55 (7%). HRMS (ESI):
29
(MþNa)þ found 527.3137. C33H44O4Na requires 527.3137; [
þ0.1862 (c 0.21, CH2Cl2).
a]
D
4.3.3.3. Photocycloaddition of 1b to 2-methylprop-2-ene
(e). Following the general procedure in the presence of e, 1b

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I. Inhulsen et al. / Tetrahedron 69 (2013) 782e790
789
yielded a mixture of 2be/6be/7be (1:0.15:0.15) with a de of >95%.
Separation by CC gave the major compound (1S,6S)-(1R,2S,5R)-2-
(2-(6-methoxynaphtalen-2-yl)propanyl)-5methylcyclohexyl7,7-di-
methyl-5-oxobicyclo[4.2.0]octane-1-carboxylate (2be) as light
yellow oil; 28.6 mg (0.058 mmol, 39%); Rf (17% EtOAc/Hexane)
0.38; dH (500 MHz, CDCl3) 7.65 (2H, m, d, J 8.7 Hz, CH), 7.55 (1H, s,
CH); 7.45 (1H, m, CH); 7.12e7.09 (2H, m, CH), 4.97 (1H, ddd, J 10.7,
10.7, 4.3 Hz, OCH), 3.91 (3H, s, COMe), 2.83 (1H, s, COCHCMe2), 2.17
(1H, ddd, J 12.4, 12.4, 3.2 Hz, CH), 2.15 (1H, ddd, J 17.3, 5.6, 5.6 Hz,
CHaHbCO), 2.05 (1H, d, J 12.4 Hz, CHaHb), 1.90e1.86 (1H, m, CHaHb),
1.82e1.67 (2H, m, CH, CHaHb), 1.68 (1H, d, J 12.5 Hz, CHaHb),
1.62e0.99 (8H, m, CHaHb, CH); 1.41 (3H, s, CMe), 1.28 (3H, s, CMe),
1.18 (3H, s, CMe), 0.90 (3H, s, CMe), 0.88 (3H, d, J 6.4 Hz, CHMe),
0.88e0.78 (1H, m, CHaHb); dC (125.0 MHz, CDCl3) 211.3, 176.0,
157.3, 146.5, 132.5, 129.3, 128.8, 126.5, 125.3, 122.7, 118.5, 105.5,
75.5, 55.3, 54.7, 49.5, 42.3, 41.7, 41.1, 39.9, 39.7, 35.0, 34.5, 31.8,
31.3, 30.0, 27.0, 26.9, 26.8, 26.0, 21.8, 19.4; m/z (EIeGC/MS) 490
(Mþ, 4), 279 (1), 199 (100), 169 (1), 158 (4), 141 (2), 56 (3%); HRMS
CH2Cl2). This fraction is followed by (1S,6S,7S)-(1R,2S,5R)-2-(2-(6-
methoxy-naphthalen-2-yl)propan-2-yl)-5-methylcyclohexyl-7-
cyano-7-methyl-5-oxobicyclo[4.2.0]octane-1-carboxylate (2bf1);
38.5 mg (0.077 mmol, 51%); Rf (17% EtOAc/Hexane) 0.48; dH
(500 MHz, CDCl3) 7.65 (1H, d, J 9.5 Hz, CH), 7.64 (1H, d, J 9.5 Hz, CH),
7.52 (1H, s, CH), 7.44 (1H, dd, J 8.6,1.9 Hz, CH), 7.13e7.08 (2H, m, CH),
4.95 (1H, ddd, J 10.7, 10.7, 4.5 Hz, CH), 3.91 (3H, s, OMe), 2.89 (1H, s,
CHCCNMe), 2.37e2.31 (1H, m, CHaHb), 2.22 (1H, ddd, J 12.2, 12.2,
3.6 Hz, CH), 2.01 (1H, d, J 12.8 Hz, CMeCNCHaHb), 1.88 (1H, d, J
12.8 Hz, CMeCNCHaHb), 2.01e0.96 (12H, m, CH, CHaHb), 1.42 (3H, s,
CCNMe), 1.38 (3H, s, CMe); 1.23 (3H, s, CMe), 0.88 (3H, d, J 6.6 Hz,
CHMe); dC (125.0 MHz, CDCl3) 207.0, 173.9, 157.5, 146.7, 132.6, 129.3,
128.8, 126.7, 125.3, 122.6, 122.5, 118.9, 105.6, 76.2, 55.5, 54.1, 49.3,
43.2, 41.8, 40.4, 39.8, 38.9, 34.5, 31.4, 31.3, 29.0, 28.6, 26.8, 26.5, 22.7,
21.9, 19.5; m/z (EIeGC/MS) 501 (Mþ, 4), 199 (100), 171 (5), 158 (3),
141 (2), 81 (2), 79 (2), 67 (2), 55 (5%); HRMS (ESI): (MþNa)þ found
29
524.2776. C32H39NO4Na requires 524.2777; [
CH2Cl2).
a
]
þ0.05688 (c 0.8,
D
(ESI): (MþNa)þ found 513.2980. C32H42O4Na requires 513.2980;
29
[
a]
þ0.5639 (c 1.8, CH2Cl2). The followed fraction consists of
4.3.3.5. Photocycloaddition of 1b to 2-methoxypropene (g).
Irradiation of 1b in the presence of f led to a complex mixture out of
which the main product (1R,6S,8R)-(1R,2S,5R)-2-(2-(6-metho-
xynaphthalen-2-yl)propan-2-yl)-5-methylcyclohexyl 8-methoxy-
8-methyl-5-oxo-bicyclo[4.2.0]octane-1-carboxylate (3bg) could be
isolated in a yield of 35% (26.1 mg, 0.052 mmol) by CC. Rf (17%
EtOAc/Hexane) 0.18; yellow oil, dH (500 MHz, CDCl3) 7.67 (1H, d,
J 8.7 Hz, CH), 7.66 (1H, d, J 8.7 Hz, CH), 7.52 (1H, s, CH), 7.39 (1H, d,
J 8.7 Hz, CH), 7.13e7.12 (1H, m, CH), 7.10 (2H, m, CH), 4.98 (1H, ddd,
J 10.6, 10.6, 4.8 Hz, OCH), 3.90 (3H, s, OMe), 3.30 (3H, s, OMe), 3.18
(1H, dd, J 10.2, 10.2 Hz, CHCHaHb), 2.37 (1H, ddd, J 23.3, 5.8, 5.8 Hz,
CHaHbCO), 2.29e0.80 (14H, m, CH, CHaHb), 1.37 (3H, s, CMeOMe),
1.32 (6H, s, CMe), 0.85 (3H, d, J 6.3 Hz, CHMe), 0.75e0.68 (1H, m,
CHaHb); dC (125.0 MHz, CDCl3) 210.5,173.4,157.3,145.3, 132.5, 129.4,
128.6, 126.6, 125.3, 123.3, 118.6, 105.3, 77.7, 76.8, 58.4, 55.3, 51.6,
50.0, 42.0, 40.5, 38.4, 38.0, 36.9, 34.3, 31.7, 31.4, 27.6, 25.0, 22.5, 21.8,
21.5, 19.2; m/z (EIeGC/MS) 506 (Mþ, 1), 434 (4), 285 (5), 212 (4), 199
D
(1R,2S,5R)-2-(2-(6-methoxynaphthalen-2-yl)propan-2-yl)-5-met-
hylcyclohexyl-(1S)- and (1R)-(2-methylallyl)-3-oxocyclohexane
carboxylate (6be) and (7be) as light yellow oil;z 6.9 mg
(0.014 mmol, 9%) of the 1:0.9 mixture of Rf (17% EtOAc/Hexane)
0.27; dH (500 MHz, CDCl3) 7.71e7.66 (2H, m, CH); 7.57 (1H, s, CH),
7.51e7.46 (1H, m, CH), 7.12e7.07 (2H, m, CH), 4.99 (1H, ddd, J 10.6,
10.6, 4.4 Hz, OCH), 3.90 (3H, s, COMe), 2.37 (1H, d, J 14.8 Hz,
CHaHbC]CH2), 2.15 (1H, d, J 14.3 Hz, CHaHb), 2.02 (1H, d, J
14.8 Hz, CHaHbC]CH2), 2.16e0.86 (17H, m, CH, CHaHb), 1.62 (3H, s,
MeC]CH2), 1.42 (3H, s, CMe), 1.25 (3H, s, CMe), 0.84 (3H, d, J
6.5 Hz, CHMe); dC (125.0 MHz, CDCl3) 209.3, 174.8, 158.5, 146.7,
140.7, 132.6, 129.4, 128.8, 125.5, 122.9, 118.7, 115.6, 105.5, 76.9, 55.5,
49.6, 49.0, 47.6, 45.0, 39.5, 41.5, 40.1, 34.4, 32.9, 31.4, 27.6, 27.3,
26.1, 24.7, 24.6, 21.8, 21.5; m/z (EIeGC/MS) 490 (Mþ, 3), 199 (100),
185 (4), 158 (3), 144 (2), 107 (1), 69 (1), 55 (5%). While the ste-
reochemistry of the C-1 atom was not determined, we assumed
the major product was 1S and the minor product to be 1R con-
figurated, according to the results obtained in this work that the
alkene attacks preferentially from the Si-side of the enone to
produce 1S stereochemistry.
(100), 185 (14), 158 (2), 141 (3), 91 (2), 72 (44), 55 (7%); HRMS (ESI):
29
(MþNa)þ found 529.2773. C32H42O5Na requires 529.2930; [
þ0.3051 (c 1.5, CH2Cl2).
a]
D
Acknowledgements
4.3.3.4. Photocycloaddition of 1b to methacrylonitrile (f).
Photoreaction of 1b in the presence of f yielded the product mix-
ture (2bf1/2bf2 100:25) with a de of >95% after evaporation of the
solvent and the excess alkene. Separation by CC gave 8.5 mg
(0.017 mmol, 12%) of first eluting product, (1S,6S,7R)-(1R,2S,5R)-2-
(2-(6-methoxynaphthalen-2-yl)-propan-2-yl)-5-methylcyclohex-
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. I.I. gratefully
thank the Japanese Society for the Promotion of Science (JSPS)
for the JSPS Postdoctoral Fellowship Program (Short-term) for
North American and European Researchers. We gratefully ac-
knowledge the assistance of Mr. Katao and of Ms. Nishiyama in
performing the X-ray measurements and the HRMS measure-
ments (respectively).
yl7-cyano-7-methyl-5-oxobicyclo[4.2.0]
octane-1-carboxylate
(2bf2) as a light yellow oil; Rf (17% EtOAc/Hexane) 0.57; dH
(500 MHz, CDCl3) 7.65 (1H, d, J 8.7 Hz, CH), 7.62 (1H, d, J 9.0 Hz, CH),
7.53 (1H, s, CH), 7.12e7.08 (2H, m, CH), 7.03 (1H, d, J 2.5 Hz, CH), 5.07
(1H, ddd, J 10.7, 10.7, 4.5 Hz, OCH), 3.91 (3H, s, OMe), 2.87 (1H, s,
CHCCNMe), 2.50 (1H, d, J 13.3 Hz, CNMeCCHaHb), 2.36 (1H, ddd, J
12.1, 12.1, 3.7 Hz, CHaHb), 1.98e1.84 (3H, m, CHaHb), 1.76 (1H, d,
J 13.6 Hz, CNMeCCHaHb), 1.72e0.87 (11H, m, CHaHb), 1.44 (3H, s,
CCNMe), 1.23 (3H, s, CMe), 1.17 (3H, s, CMe), 0.92 (3H, d, J 6.5 Hz,
CHMe); dC (125.0 MHz, CDCl3) 206.3, 175.6, 157.3, 147.2, 131.3, 129.2,
128.7, 126.6, 125.6, 123.6, 122.1, 118.7, 105.9, 76.2, 55.4, 50.1, 48.8,
43.4, 41.2, 40.5, 29.6, 39.4, 34.3, 31.4, 29.7, 29.5, 29.2, 26.6, 23.1, 21.8,
21.4, 18.8; m/z (EIeGC/MS) 501 (Mþ, 5), 199 (100), 171 (5), 158 (3),
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524.2776. C32H39NO4Na requires 524.2776; [
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D
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