Photochemical studies on exo-bicyclo[2.1.1]hexyl and bicyclo[3.1.0]hexyl aryl ketones: two approaches for synthesis of enantiomerically enriched cyclopentene derivatives

Article abstract of DOI:10.1016/j.tet.2009.10.011

Two approaches for the photochemical synthesis of cyclopentene derivatives through the Norrish type II cleavage reaction were described. Asymmetric studies using ionic chiral auxiliaries afforded enantiomeric excesses of up to 98% at the conversion of 85%

Full text of DOI:10.1016/j.tet.2009.10.011

Tetrahedron 65 (2009) 9952–9955
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Photochemical studies on exo-bicyclo[2.1.1]hexyl and bicyclo[3.1.0]hexyl
aryl ketones: two approaches for synthesis of enantiomerically enriched
cyclopentene derivatives
,
Guolei Zhao a, Chao Yang a, Qian Chen a, Jing Jin b, Xiao Zhang a, Liyan Zhao a, Wujiong Xia a
*
a The State Key Lab of Urban Water Resource and Environment, National Engineering Research Center of Urban Water Resource & The Academy of Fundamental
and Interdisciplinary Science, Harbin Institute of Technology, P.O. Box 3026, 2 # Yikuang Street, Harbin, Heilongjiang 150080, China
b School of Life Sciences, Wenzhou Medical College, Zhejiang, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two approaches for the photochemical synthesis of cyclopentene derivatives through the Norrish type II
cleavage reaction were described. Asymmetric studies using ionic chiral auxiliaries afforded enantio-
meric excesses of up to 98% at the conversion of 85%. The results were rationalized by single X-ray crystal
structures.
Received 2 September 2009
Received in revised form
30 September 2009
Accepted 4 October 2009
Available online 8 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Photochemical synthesis
Cyclopentene
Norrish type II
Chiral auxiliary
1. Introduction
type II cleavage process using the ionic chiral auxiliary method. The
ionic chiral auxiliary concept, developed by Scheffer and co-
Enantiomerically enriched cyclopentene derivatives have been
found to be crucial building blocks in the synthesis of naturally
occurring products, which are widely distributed throughout the
animal, bacterial, and plant kingdoms. Consequently, the syntheses
of such compounds have attracted the interest from organic
chemists.1 The general efficient methods involve intramolecular
carbon–hydrogen insertions of alkylidenecarbenes2, organo-
catalytic [3þ2] cyclizations,3 RCM reaction of the acyclic pre-
cursors4 and carbonyl allylation with cyclic allyl halide.5 Among
them stoichiometric amounts of metal catalysts should be first
prepared in multiple synthetic steps and/or halides were employed
in the reaction. For example, in the [3þ2] annulation reaction, the
planar chiral 2-phospha[3]ferrocenophanes were synthesized in
five steps and expensive reagents were involved. Therefore, room
exists for developing environmentally friendly approaches for
synthesis of enantiomerically enriched cyclopentenes, a feature
that has been embodied in the synthesis of natural products.6 As
part of research interest in solid-state organic photochemistry,7 we
found that such a goal can be achieved through a typical Norrish
workers, has proven to be a reliable method of asymmetric studies
on 1,4-hydroxybiradical behavior.8 We extended this method to the
asymmetric synthesis of cyclopentene derivatives owing to its
features that make this particular method attractive in terms of
general applicability: 1) it makes use of a large pool of commercially
available, inexpensive, optically pure amines; 2) the auxiliary is
easily attached and removed through acid–base chemistry; 3) ionic
solids are generally high melting, giving robust crystals (essential
for studying reactions in the solid state). In this paper, we present
what we have achieved in asymmetric photochemical studies on
exo-bicyclo[2.1.1]hexyl and bicyclo[3.1.0]hexyl aryl ketones.
2. Results and discussion
Our strategy for synthesis of the above ketones 2 and 9 was
started from norbornene 1 and bicyclo[2.2.1]heptadiene 6, re-
spectively. As shown in Schemes 1 and 2, according to the reported
procedures7c,9, norbornene 1 was converted to the ketone 2
through a straightforward pathway. Irradiation of 2a in acetonitrile
solution with a 450 W medium mercury pressure lamp under N2
for 24 h gave the cyclization product 5 in 30% yield and the cleavage
product 4 in 66% yield.10 In this reaction, compound 5 containing
a plane of symmetry is an achiral molecule, which is not suitable for
* Corresponding author. Tel.: þ86 451 86403193; fax: þ86 451 86402588.
E-mail address: xiawj@hit.edu.cn (W. Xia).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.011

G. Zhao et al. / Tetrahedron 65 (2009) 9952–9955
9953
H
4
O
OH
3'
1. hv, crystalline
steps
3
1
2. CH2N2 workup
2
ISC
X
X
2
3
1
-
+
a. X = COOMe b. X = COOH c. X = COO NH3-R*
OH
O
COOMe
ISC
+
COOMe
4
5
Scheme 1.
X
N
O
COOH
H
O
steps
O
i
Hx
Hy
ii
H
H
9
8
7
6
a. X = COOMe
b. X = COOH
iii
iv
X
c. X = COO- +NH3-R*
ISC
v
HO
4
Hy
ISC
H
10
Scheme 2. (i) PtO2, H2, ethyl acetate; CDI, MeO(Me)NH.HCl, CH2Cl2; (ii) IC6H4CO2CH3, iPrMgBr, THF; (iii) Na2CO3, THF/H2O (1:5); 10% HCl; (iv) R*NH2, Et2O; (v) hv, solid state; CH2N2
workup.
asymmetric studies, whereas the formation of cyclopentene 4 is the
conversion of achiral reactants to chiral products, which is ideal for
asymmetric photochemical studies. Therefore, the carboxylic ester
2a was hydrolyzed with LiOH in THF/H2O followed by conc. HCl
workup to give the carboxylic acid 2b in quantitative yield. The
compound 2b was then treated with a variety of optically pure
amines to form the corresponding ammonium carboxylate salts 2c.
Such salts are required to crystallize in chiral space groups, which
provide the asymmetric environment responsible for chiral in-
duction. Crystals of the salts 2c (3–5 mg) were crushed between
two microscope slides and sealed in a polyethylene bag under ni-
trogen, and irradiated with a 450 W medium mercury pressure
lamp. After irradiation, the photoproduct was treated with ethereal
diazomethane to give the methyl esters, which were then analyzed
by chiral HPLC to obtain enantiomeric excess values and by GC to
give the conversions. The results are summarized in Table 1.
As it can be seen inTable 1, the enantiomeric excess (ee) as high as
98% was obtained in the solid state. To rationalize the results ob-
served, the X-ray single crystal structure of the (S)-(-)-1-phenylethyl
amine salt of the keto acid 2b was determined and presented in
Table 1
Asymmetric studies on the irradiation of salts 2c and 9c in the solid statea
Amine
2c
9cf
d
d
T (ꢀC)
convb (%)
eec (%)
[a
]
5:4e
T (ꢀC)
convb (%)
eec (%)
[a]
(S)-(-)-1-phenylethylamine
ꢁ20
rt
rt
85
21
53
27
74
51
97
53
31
48
67
91
98
>98
98
92
77
81
91
93
92
ꢁ
ꢁ
ꢁ
þ
þ
þ
ꢁ
ꢁ
ꢁ
þ
þ
þ
23:74
20:79
21:77
20:79
22:75
21:77
23:75
22:77
21:77
21:77
20:79
22:76
ꢁ20
rt
rt
59
70
96
41
79
95
32
25
57
67
89
95
76
66
43
90
67
55
60
55
25
74
67
64
þ
þ
þ
ꢁ
ꢁ
ꢁ
þ
þ
þ
þ
þ
þ
(R)-(þ)-1-phenylethylamine
ꢁ20
ꢁ20
rt
rt
rt
rt
rt
(R)-(-)-1-Cyclohexylethylamine
(1S,2R)-(-)-cis-1-amino-2-indanol
ꢁ20
ꢁ20
rt
rt
rt
ꢁ20
rt
rt
72
60
53
ꢁ20
rt
rt
a
Samples were irradiated through Pyrex using a 300-W hanovia medium-pressure mercury lamp.
Conversion % based on GC.
b
c
d
e
f
Ee % analyzed on chiral OD-H column with hexane:isopropanol¼99.5:0.5 as the eluting solvent.
Sign of rotation at the sodium
Based on GC analysis.
D-line.
9c was the sole photoproduct if no prolonged time was employed.

9954
G. Zhao et al. / Tetrahedron 65 (2009) 9952–9955
Figure 1. X-ray crystal structures of (S)-(-)-1-phenylethylamine salts of keto acids (a) 2b and (b) 9b. (The chiral auxiliary was omitted for clarity).
Figure 1. It is of interesttopointout that, for the arylketone 2, there is
only one -hydrogen could be abstracted in the first step of Norrish
type II reaction. As a result, the factor of distance between oxygen
geometrically disfavored in the crystalline state. Finally, a control
experiment was conducted by irradiation of the salts 9c in metha-
nol, which led to racemic product 4. This is typical and highlights
the critical importance of carrying out the reactions in the solid
state and avoiding conditions that could lead to crystal softening or
melting. Therefore, the enantioselectivity is the result of pre-
organization of the reactant in a homochiral conformation favorable
for the formation of a single enantiomer of the product.
g
and H4 for the determination of ee could be excluded. Therefore, the
enantioselectivity is controlled by the geometric parameters 41 and
11
44.
Under the influence of the chiral auxiliary, (S)-(-)-1-phenyl-
ethyl amine, the keto acid 2b recrystallized in a homochiral
conformation, in w0hich C2–C3 bond was preferentially cleaved than
0
C2–C30 (41¼16ꢀ, 41 ¼78ꢀ, 44
¼
44 ¼35ꢀ), affording one enantiomer of
photoproduct 4.12 In contrast, formation of the optical antipode of
the photoproduct 4 obtained by rupture of C2–C30 requires a large
amplitude rotation of the aryl group, which is topochemically for-
bidden in the solid state. Therefore, high ee (>98%) of the (S)-(-)-1-
phenylethyl amine salt of the keto acid 2b was obtained.
3. Conclusion
In summary, the present study reports two convenient ap-
proaches for synthesis of the enantiomerically enriched cyclo-
pentene derivative via a Norrish type II photoreaction. Remarkably,
it should be pointed out either optical isomer of the cyclopentene
derivative could be produced through the photochemical synthesis
pathway by simply switching the chirality of the auxiliary. The
work on the asymmetric syntheses of other key intermediates for
bioactive natural products is ongoing in our group.
Crystallographic data for the structures in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 265555, 735645.Copies of
the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: þ44 (0)1223 336033 or
e-mail:deposit@ccdc.cam.ac.uk).
Next we turn to the asymmetric studies on bicyclo[3.1.0]hexyl
aryl ketones 9. The synthesis of compound 9a was started from
bicyclo[2.2.1]heptadiene 6, which was first converted to the car-
boxylic acid 7 according to the literatures.13 Hydrogenation of 7 with
PtO2 followed by the treatment with 1,10-carbonyldiimidazole and
N,O-dimethyl hydroxyl amine hydrochloride afforded the amide 8 in
63% yield (two steps), which was then reacted with Grinard reagent
at ꢁ40 ꢀC to give the target compound 9 in 37% yield. Irradiation of
compound 9a in acetonitrile with a 300 W medium-pressure mer-
cury lamp for 2 h at room temperature afforded cyclopentene 4 in
53% yield. For the asymmetric studies, compound 9awas hydrolyzed
with Na2CO3 in THF/H2O (1:5) and acidified with 10% HCl to give the
carboxylic acid 9b in 75% yield, whichwasthen treated with avariety
of optically pure amines to form the corresponding ammonium
carboxylate salts 9c. Irradiation of 9c in the solid state according to
the procedures as mentioned above afforded the enantiomerically
enriched cyclopentene 4, the results are listed in Table 1.
As shown in Table 1, the enantiomeric excess of up to 90% was
obtained. For the salts studied, there was a decline in photoproduct
ee with increasing conversion, which is presumably due to the
breakdown in order of the crystal lattice as product replaces starting
material. To rationalize the enantioselectivity observed in the solid
state, the X-ray crystal structure of the (S)-(-)-1-phenylethylamine
salt was determined and is presented in Figure 1b. As shown in
Figure 1b, the enantioselectivity of the asymmetric studies on
compound 9c in the crystalline state was attributed to conforma-
tional factors. Under the influence of the ionic chiral auxiliary, the
carboxylate reactant crystallizes in a homochiral conformation in
which the carbonyl oxygen is significantly closer to Hb (2.78 Å) than
to Ha (3.98 Å). As a result, the Hb is abstracted preferentially,
affording a 1,4-biradical that leads to one enantiomer of the final
cleavage photoproduct. The optical antipode of the photoproduct
results from Ha abstraction, which requires a large amplitude ro-
tation of the pendant aryl group that is topochemically and
4. Experimental
4.1. General methods
Commercial spectral grade solvents were used for photochem-
ical experiments unless otherwise stated. Infrared spectra were
recorded on a Perkin–Elmer 1710 Fourier transform spectrometer.
Melting points were determined on a Fisher-Johns apparatus. Low-
resolution mass spectra were obtained from a Kratos MS 50 in-
strument using electron impact (EI) ionization at 70 eV. 1H NMR
spectra were obtained at 400 MHz on Bruker AV-400 instrument.
13C NMR spectra were recorded at 100 MHz.
4.2. Bicyclo[3.1.0]hex-6-endo-carboxylic acid-N-methoxy-N-
methyl amide (8)
The known compound 7 was synthesized from a procedure
modified from that of Meinwald et al. was used.13
Platinum oxide catalyst (264 mg, 1.16 mmol) was suspended in
88 mL of ethyl acetate and reduced with hydrogen gas at 2 atm.
Pressure in a hydrogen bomb for about 12 h. The acid 7 (1.5 g,
12 mmol) was dissolved in 20 mL of ethyl acetate and was then

G. Zhao et al. / Tetrahedron 65 (2009) 9952–9955
9955
added to the prereduced catalyst. The hydrogenation was contin-
ued overnight. The solution was filter through a pad of Celite and
washed with ethyl acetate. The solvent was removed in vacuo,
crystallized from petroleum ether to yield 1.1 g of hydrogen re-
duced acid.
formed upon acidification was removed by extraction with ether.
The combined organic fractions were washed with water and dried
over magnesium sulfate. Removal of the solvent in vacuo gave
a white solid, which was recrystallized from methanol to afford 9b
(230 mg, 75.4%) as a white solid.
A solution of the above acid (600 mg, 4.76 mmol) in 20 mL of
anhydrous dichloromethane was cooled to 0 ꢀC, treated with 1,10-
carbonyldiimidazole (932 mg, 5.76 mmol) and stirred for 30 min.
N,O-Dimethyl hydroxyl amine hydrochloride (1172 mg, 12 mmol)
was then added, and the resultant suspension was warmed to room
temperature, stirred for 24 h, and filtered. The precipitate was
washed with diethyl ether and the filtrate was washed with water,
brine, and dried over anhydrous sodium sulfate. The solvent was
concentrated in vacuo to yield 720 mg (90%) of Weinreb amide. 1H
4.6. General procedure for synthesis of salts (9c)
To a solution of acid 9b (70 mg, 0.3 mmol) in diethyl ether
(10 mL) was added an equivalent of optically pure amide. Upon the
addition, the precipitate formed immediately. The resulting sus-
pension was filtered by suction to give the salt, which was then
recrystallized from methanol.
NMR (CDCl3, 400 MHz):
d 3.72 (s, 3H), 3.24 (s, 3H), 2.01 (m, 2H),1.84
(m, 2H), 1.66 (m, 4H), 1.25 (m, 1H). 13C NMR (CDCl3, 100 MHz):
4.7. General procedure for the irradiation of salts
in the solid state
d
173.25, 60.84, 26.27, 24.7, 23.08, 22.08. IR (NaCl) vmax: 3044, 2979,
2937, 2869, 1655, 574 cmꢁ1. LRMS (EI): 169 (Mþ), 154, 138, 109, 81,
53. Anal. Calcd for C9H15NO2: C, 63.88; H, 8.93; N, 8.28. Found: C,
63.34; H, 8.97; N, 8.23.
The salt crystals (2–5 mg) were crushed between two Pyrex
microscope slides and sealed in a polyethylene bag under a positive
pressure of nitrogen. The sample was irradiated from both sides
with a 450 W medium-pressure mercury lamp. After irradiation,
the salt crystals were suspended in an excess of ethereal diazo-
methane solution and allowed to stand until dissolution was
complete. Ether and excess diazomethane were removed in vacuo
and the residue was taken up in methylene chloride and passed
through a short plug of silica gel to remove the chiral auxiliary. The
residue was then submitted to HPLC analysis to give the enantio-
meric excesses and GC analysis to give the conversions.
4.3. Bicyclo[3.1.0]hex-6-endo-1-(4-carbomethoxyphenyl)
methanone (9a)
A solution 393 mg (1.5 mmol) of methyl 4-iodobenzoate in
15 mL of anhydrous THF was cooled to ꢁ40 ꢀC and 0.75 mL (2 M,
1.5 mmol) of iPrMgBr was added. The reaction mixture was stirred
for 1 h at ꢁ40 ꢀC whereupon 127 mg (0.75 mmol) of compound 8 in
4 mL of anhydrous THF was added. The solution was warmed
slowly to room temperature and stirred overnight. The reaction was
quenched with excess of 10% HCl solution and extracted with
diethyl ether. The combined extracts were washed with water and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuo and the residue purified by chromatography on silica gel
with pet ether–ethyl acetate (30:1) to afford a methyl ester 9a as
Acknowledgements
Financial supports from the New Century Excellent Talent Pro-
gram of Chinese Ministry of Education (No.NCET-06-0341 and
NCET-07-0242), Science Foundation of Harbin City (No. 01310800),
program of excellent Team in HIT, China NSFC (No. 20802013) are
gratefully acknowledged.
a colorless solid (68 mg, 37%). 1H NMR (CDCl3, 400 MHz):
4H), 3.95 (s, 3H), 2.03–1.85 (m, 7H),1.61–1.57 (m,1H), 0.95–0.87 (m,
1H). 13C NMR (CDCl3, 100 MHz):
198.8, 166.4, 141.2, 133.7, 129.7,
d 8.13 (s,
d
128.4, 52.4, 27.3, 26.1, 26.0, 22.7. IR (KBr) vmax: 2952, 1723, 1670,
1574, 1503, 1440, 1411, 1278, 1211, 1108, 1015 cmꢁ1. LRMS (EI): 244
(Mþ), 213, 178, 163, 147, 135, 120, 103, 91, 76, 67, 50. Anal. Calcd for
C15H16O3: C, 73.75; H, 6.60. Found: C, 73.62; H, 6.81.
References and notes
1. Shinohara, Y.; Kurata, T.; Kitano, H.; Matsumoto, K.; Takahashi, I.; Hosoi, S.; Ota,
T.; Hatanaka, M. Synlett 2002, 1245.
2. Gilbert, J. C.; Giamalva, D. H.; Weerasooriya, U. J. Org. Chem. 1983, 48, 5251.
3. Voituriez, A.; Panossian, A.; Fleury-Bregeot, N.; Retailleau, P.; Marinetti, A. J. Am.
Chem. Soc. 2008, 130, 14030.
4.4. Irradiation of compound 9a in acetonitrile
4. Ghosh, A. K.; Kulkarni, S. S.; Xu, C. X.; Shurrush, K. Tetrahedron: Asymmetry
2008, 19, 1020.
5. Tan, X. H.; Tao, C. Z.; Hou, Y. Q.; Luo, L.; Liu, L.; Guo, Q. X. Chin. J. Chem. 2005, 23,
237.
6. Natarajan, A.; Ng, D.; Yang, Z.; Garcia-Garibay, M. A. Angew. Chem., Int. Ed. 2007,
46, 6485.
7. (a) Xia, W.; Yang, C.; Patrick, B. O.; Scheffer, J. R.; Scott, C. J. Am. Chem. Soc. 2005,
127, 2725; (b) Scheffer, J. R.; Xia, W. Top. Curr. Chem. 2005, 254, 233; (c) Yang, C.;
Xia, W.; Scheffer, J. R.; Botoshansky, M.; Kaftory, M. Angew. Chem., Int. Ed. 2005,
5087; (d) Xia, W.; Scheffer, J. R.; Botoshansky, M.; Kaftory, M. Org. Lett. 2005, 7,
1315; (e) Xia, W.; Scheffer, J. R.; Brian, O. P. CrystEngComm 2005, 7, 728; (f) Xia,
W.; Yang, C.; Scheffer, J. R.; Patrick, B. O. CrystEngComm 2006, 8, 388; (g) Yang,
C.; Xia, W.; Scheffer, J. R. Tetrahedron 2007, 63–6791.
The solution of 9a (40 mg, 0.164 mmol), in acetonitrile (20 mL)
was purged with N2 for 15 min and irradiated with 300 W medium-
pressure mercury lamp for 2 h. After irradiation, the solvent was
removed in vacuo and the residue was purified by chromatography
with pet ether–ethyl acetate (30:1) to afford photoproduct 4
(21 mg, 53%). Mp 97–97.5 ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.10 (d,
J¼8.8 Hz, 2H), 7.97 (d, J¼8.8 Hz, 2H), 5.77 (m, 1H), 5.69 (m, 1H), 3.93
(s, 3H), 3.25 (m, 1H), 3.10 (m, 1H), 2.98 (m, 1H), 2.35 (m, 2H), 2.19
(m, 1H), 1.46 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 200.0, 166.3,
140.4, 133.9, 133.7, 131.5, 129.8, 128.0, 52.4, 45.1, 41.2, 31.8, 30.0. IR
(KBr) nmax: 2953, 2927, 1727, 1279, 1108, 769, 711 cmꢁ1. LRMS (EI):
244 (Mþ), 229, 179, 163, 147, 104, 76, 50. Anal. Calcd for C15H16O3: C,
73.75; H, 6.60. Found: C, 73.81; H, 6.57.
8. (a) Scheffer, J. R. Can. J. Chem. 2001, 79, 349; (b) Gamlin, J. N.; Jones, R.; Lei-
bovitch, M.; Patrick, B.; Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203.
9. Padwa, A.; Eisenberg, W. J. Am. Chem. Soc. 1972, 94, 5852.
10. For a general review of the Norrish type II reaction, see: Wagner, P.; Park, B. S. In
Organic Photochemistry; Padwa, A., Ed.; Marcel Dekker: New York, NY, 1991;
Vol. 11, Chapter 4.
11. 41 presents the angle between the p orbital on atoms C1 and the C2–C3 or/and
C2–C30 bonds. 44 presents the angle between the p orbital on atoms C4 and the
C2–C3 or/and C2–C30 bonds. The ideal value for both parameters is 0ꢀ.
12. The (R)-1-phenylethylamine salt and the (S)-1-phenylethylamine salt are
conformational enantiomers and afford the enantiotropic products in the solid-
state photoreaction. All attempts to get the same conversions of these two salts
in the reaction to compare the enatioselectivity were failed.
13. Meinwald, J.; Labana, S. S.; Chadha, M. S. J. Am. Chem. Soc. 1963, 85, 582.
4.5. Synthesis of carboxylic acid (9b)
Methyl ester 9a (350 mg, 1.43 mmol) was suspended in a water
(100 mL) and THF (20 mL) solution containing 3.04 g (28.7 mmol)
of sodium carbonate. The solution was stirred for 30 h at room
temperature and acidified with 10% HCl. The white precipitate