Diastereoselective [2+2] photocycloaddition of polymer-supported cyclic chiral enone with ethylene

Article abstract of DOI:10.1016/j.tetlet.2004.01.010

The phenylmenthyl derivative, previously shown to be very effective chiral auxiliaries in the diastereoselective [2+2] photocycloaddition of cyclic enones with the simplest olefin, ethylene, was attached to poly(ethylene glycol)-grafted Wang resin. We the

Full text of DOI:10.1016/j.tetlet.2004.01.010

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1849–1851
Diastereoselective [2+2] photocycloaddition of polymer-supported
cyclic chiral enone with ethylene
Takuya Shintani, Kazunori Kusabiraki, Atsuko Hattori, Akinori Furutani, Ken Tsutsumi,
Tsumoru Morimoto and Kiyomi Kakiuchi*
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), Takayama, Ikoma, Nara 630-0192, Japan
Received 6 December 2003; revised 30 December 2003; accepted 6 January 2004
Abstract—The phenylmenthyl derivative, previously shown to be very effective chiral auxiliaries in the diastereoselective [2+2]
photocycloaddition of cyclic enones with the simplest olefin, ethylene, was attached to poly(ethylene glycol)-grafted Wang resin. We
then investigated the diastereoselective [2+2] photocycloaddition on solid support in several solvents. As the result, we accomplished
good selectivity in toluene as well as the recycle of the polymer-supported chiral auxiliary. This is the first example that bicy-
clo[4.2.0]octane derivative has been obtained photochemically on the solid support.
Ó 2004 Elsevier Ltd. All rights reserved.
Efficient constructions of stereogenic centers are of
increasing interest in synthetic organic chemistry. The
utilization of a chiral auxiliary is one of the most
promising methods for this purpose, and the wide
variety of chiral auxiliaries has been reported for
asymmetric synthesis.1 From the pioneering work of
CoreyÕs group,2 8-phenylmenthyl derivatives as chiral
auxiliaries have received great attention, and many
applications are found in the literature.3 Recently we
reported that the diastereoselective [2+2] photocyclo-
addition of cyclohexenonecarboxylates having 8-phe-
nylmenthol derivatives as a chiral auxiliary to the
simplest olefin, ethylene, proceeded in good yields and
diastereoselectivities.4
reported8 in spite of its powerful potential for the con-
struction of strained rings. Especially, to our best
knowledge, none of the diastereoselective photochemical
reactions on beads has yet been disclosed. We here
report on the first diastereoselective [2+2] photocyclo-
addition by the use of polymer-supported 8-phenyl-
menthyl derivative as a chiral auxiliary.
For the assembly of the polymer-supported chiral aux-
iliary, ())-8-[(p-methoxy)phenyl]menthol 1 was prepared
from (R)-(+)-pulegone according to the modified
CoreyÕs procedure.9 After the protection of the second-
ary alcohol, demethylation was carried out with borane
tribromide to give ())-8-[(p-hydroxy)phenyl]menthyl
acetate 2. The alkyl linker part was introduced into 2,
then the terminal silyl protection was removed to pre-
pare the linker-attached chiral auxiliary 3. We chose
Wang resin because of its easiness of handling. In
addition, selectivity of the photochemical reaction can
be easily determined by 1H NMR as d.e. when the
cycloadduct having the chiral auxiliary is cleaved from
the resin. The 8-phenylmenthyl derivative 3 was first
loaded onto Wang polystyrene resin. However, acetyl
protection was hardly removed, probably due to the
lack of affinity of polystyrene resin to the hydrolysis
conditions. In order to circumvent the problem,
poly(ethylene glycol)-grafted polystyrene Wang (PS-
PEG-Wang) resin (purchased from Watanabe Chemical
Industries, LTD., 1% divinylbenzene cross-linked, 100–
200 mesh) was employed. The chiral auxiliary 3 was
coupled with trichloroacetimidate type PS-PEG-Wang
Immobilization of chiral auxiliaries to polymer support5
results in the easier isolation of the product. In addition,
solid-phase reaction sometimes provides a unique
product as well as selectivity that may be difficult to
achieve by conventional methods.6 This is most likely
due to the unique interaction at the interface between
solid and liquid, and the highly hydrophobic environ-
ment within the polymer support. Numerous reports of
solid-phase organic synthesis are often published,7 but
photochemical reaction on solid support is rarely
Keywords: Diastereoselectivity; [2+2] Photocycloaddition; ())-8-Phe-
nylmenthyl; Chiral auxiliary; Polymer support.
* Corresponding author. Tel.: +81-743-726080; fax: +81-743-726089;
e-mail: kakiuchi@ms.aist-nara.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.010

1850
T. Shintani et al. / Tetrahedron Letters 45 (2004) 1849–1851
Table 1. Investigation of the effect of solvents
Entry Solvent Yield (%)
9c;d
1) TBSO(CH2)6OH
DIAD, PPh3,
D.e. (%)
1) Ac2O, DMAP,
Py, r.t.
8a;b
8
9
THF, r.t.
AcO
HO
AcO
(90%)
Methylcyclo- 20e
79
65
81
(>99%)
1
hexane
Toluene
CH2Cl2
MeOH
2) TBAF
2) BBr3, CH2Cl2,
-78 °C ~ -25 °C
2
3
4
68
30f
57
59
95
14
72
58
48
66
50
3
THF, r.t.
(96%)
(94% conv. based)
O
6
OMe
1
OH
2
OH
a The yields were determined by 1H NMR.
b The reaction were carried out for 5 h.
c Isolated yields.
3
d The reactions were carried out for 0.5–2 h.
e The starting material was remained in 30%.
f The starting material was remained in 14%.
NH
CCl3
O
1) NaOH aq.,
DMSO, 80 °C
O
AcO
O
O
2)
.
BF3 Et2O, CH2Cl2,
r.t.
omers in the 1H NMR spectrum as described previ-
ously.4 The results are summarized in Table 1. For
comparison, the results of photochemical reactions in
the solution-phase with ())-8-[(p-methoxy)phenyl]men-
thyl derivative 7 are also presented. In all cases, the
reaction proceeded and toluene was found to be the best
to provide the product in 68% yield with 72% d.e. (entry
2). This selectivity is slightly better than that in the
solution-phase synthesis in toluene. Methylcyclohexane
provided the product in 81% d.e. in the solution-phase,
while the corresponding solid-phase synthesis afforded
the product in 65% d.e. with the low chemical yield
(entry 1). This result was influenced by the low swelling
of the resin in methylcyclohexane. Interestingly, in
MeOH the cycloadduct was obtained in moderate yield
and selectivity whereas the corresponding reaction in the
solution-phase gave the product in low yield and selec-
tivity due to the low solubility of 7 against MeOH (entry
4). The partial degradation of the polymer backbone
was observed during the photochemical reaction. The
degrees of the chop were varied among the solvents and
affected to the yields. Our laboratory is now addressing
this event. Our attempt of this photochemical reaction in
water at room temperature resulted in the complex
mixture.
O
OH
5
O
6
O
O
6
DIPC, DMAP,
O
O
r.t.
4
6
Figure 1. Synthesis of polymer-supported chiral auxiliary.
resin10 to provide 4. Removal of the acetyl protection
was achieved under aqueous basic conditions followed
by condensation of cyclohexen-3-one-1-carboxylicacid 5
to give the polymer-supported chiral enone 6 (Fig. 1).
The loading level was estimated to be 0.19 mmol/g by
the cleavage of a small amount of the resin 6 (81%
against the original loading of PS-PEG-Wang).11
The effects of a solvent on the selectivity were investi-
gated. Photochemical reaction was carried out at )78 °C
in an appropriate solvent for 5 h by irradiating a sus-
pension of polymer-supported cyclohexenone carboxyl-
ate 6, saturated with ethylene with Pyrex-filtered light
(k > 280 nm) from
a high-pressure mercury lamp
(500 W) (Fig. 2). The resin was filtered and washed with
MeOH and CH2Cl2, then treated with 30% TFA in
CH2Cl2 at room temperature for 30 min. The resin was
filtered off, and evaporation of the filtrate gave a mixture
of two diastereomers 10. The d.e. was determined by
comparing the areas of distinct signals of the diastere-
Next, we attempted to recycle the polymer-supported
chiral auxiliary. The synthesis of the chiral auxiliary 1
was quite tough and the resin is still somewhat expen-
sive. Thus the reuse of this precious polymer-supported
chiral auxiliary is desirable. After the photochemical
reaction in toluene as described above, bicy-
clo[4.2.0]octan-2-one-6-carboxylic acid 11 was released
from the resin by hydrolysis (NaOH aq, DMSO, 80 °C).
The recovered polymer-supported chiral auxiliary 12
was then coupled with cyclohexen-3-one-1-carboxylic
acid 5 to reproduce 6. The photochemical reaction was
carried out again to provide 8. To determine the yield
and diastereoselectivity, a small amount of 8 was treated
with TFA to give 10. The results are summarized in
Table 2. Although the loading level was decreased by the
recycle due to the partial degradation, both yields and
selectivities were stable at each photochemical reaction
(Fig. 3).
O
O
CH2=CH2
ν (>280 nm)
O
O
h
in solvent, -78 °C
O
O
8, 9
6, 7
R
R
+ isomer
6, 8 :
R =
O
O
6
OMe
7, 9 : R =
In conclusion, the polymer-supported chiral auxiliary
was efficiently prepared and utilized for the diastereo-
Figure 2. Diastereoselective [2+2] photocycloaddition.

T. Shintani et al. / Tetrahedron Letters 45 (2004) 1849–1851
Table 2. Recycle of polymer-supported chiral auxiliary
1851
Acknowledgements
Cycle
Loading of 6
(%)a
Yield of 10
(%)b
D.e. of 10 (%)c
This work was supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas (417) from the Ministry
of Education, Culture, Sports, Science and Technology
(MEXT) of the Japanese Government, and Foundation
for Nara institute of Science and Technology.
1
2
3
75
67
50
82
78
86
71
65
69
a Based on the original loading of Wang resin (0.24 mmol/g).
b Based on the loading of 6 in each step.
c The d.e.s were determined by 1H NMR.
References and notes
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Cycloadditions; Wiley-VCH: Weinheim, 1999; (b) White-
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6908–6909.
O
O
O
3. (a) For recent articles of application of ())-phenylmenthyl
derivative as a chiral auxiliary, see: Wipf, P.; Stephenson,
C. R. J. Org. Lett. 2003, 5, 2449–2452; (b) Tsuji, R.;
Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry
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OH
OR*
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O
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O
O
10
O
6
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HO
O
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R* =
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O
6
6
O
O
O
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12
OH
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O
OH
11
Figure 3. Recycle of polymer-supported chiral auxiliary.
8. (a) Blankespoor, R.; DeVries, T.; Hansen, E.; Kallemeyn,
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11. The loading level was estimated by comparing the area of
distinct signal of the crude product with that of internal
standard(1,1,2,2-tetrachloroethane).
selective [2+2] photocycloaddition reaction. The cyclo-
adduct was obtained in good yields and diastereoselec-
tivities. Besides that, the polymer-supported chiral
auxiliary was reusable up to three cycles. The present
polymer-supported chiral auxiliary is applicable to a
series of diastereoselective reactions.3 Our further
investigation to address the degradation and to seek
more effective supports as well as to apply the polymer-
supported chiral auxiliary to stereoselective thermody-
namic reactions will be reported in due course.