(+)-Camphor derivative induced asymmetric [2 + 2] photoaddition reaction

Article abstract of DOI:10.1021/ol203314y

An efficient approach to construct an enantiomerically pure cyclobutane skeleton by means of the chiral auxiliary induced [2 + 2] photoaddition reactions has been described. This asymmetric photoreaction exhibited high diastereoselectivity and provided the photoadducts in excellent yields.

Full text of DOI:10.1021/ol203314y

ORGANIC
LETTERS
2012
Vol. 14, No. 3
776–779
(þ)-Camphor Derivative Induced
Asymmetric [2 þ 2] Photoaddition
Reaction
Guolei Zhao,† Chao Yang,†,‡ Hongnan Sun,† Run Lin,† and Wujiong Xia*,†,‡
State Key Lab of Urban Water Resource and Environment, the Academy of Fundamental
and Interdisciplinary Sciences, Harbin Institute of Technology, Harbin 150080,
China, State Key Lab of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China
xiawj@hit.edu.cn
Received December 12, 2011
ABSTRACT
An efficient approach to construct an enantiomerically pure cyclobutane skeleton by means of the chiral auxiliary induced [2 þ 2] photoaddition
reactions has been described. This asymmetric photoreaction exhibited high diastereoselectivity and provided the photoadducts in excellent
yields.
Cyclobutanes have been found to be core structural
features in a range of naturally occurring and biologically
active unnatural products.1 In addition, the inherent
strained cyclobutanes readily undergo transportation to
other ring systems by means of certain approaches,2 which
is a particularly efficient strategy for the construction of
complex natural product carbon skeletons, such as
(þ)-elemol,3 (þ)-valeranone,4 pentalenene,5 ingenol,6 gink-
golide B1,7 and merrilactone A.8 Therefore, there are
myriad methods developed to accomplish the synthesis of
these privileged building blocks. Among them, the [2 þ 2]
photoaddition reaction of olefins has been adopted as
the most popular method in this context.9 In particular,
† Harbin Institute of Technology.
‡ Lanzhou University.
(4) Takeshita, H.; Cui, Y. S.; Kato, N.; Mori, A. Bull. Chem. Soc. Jpn.
1993, 66, 2694–2699.
(5) (a) Lange, G. L.; Decicco, C. P.; Willson, J.; Strickland, L. A.
J. Org. Chem. 1989, 54, 1805–1810. (b) Lange, G. L.; Gottardo, C.
J. Org. Chem. 1995, 60, 2183–2187.
(6) (a) Kuwajima, I.; Tanino, K. Chem. Rev. 2005, 105, 4661–4670.
(b) Cha, J. K.; Epstein, O. L. Tetrahedron 2006, 62, 1329–1343.
(7) Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade,
A. S.; Thomas, J. B.; Watterson, S. H.; Wagman, A. S. J. Am. Chem. Soc.
2000, 122, 8453–8463.
(8) (a) Inoue, M.; Sato, T.; Hirama, M. J. Am. Chem. Soc. 2003, 125,
10772–10773. (b) Mehta, G.; Singh, S. R. Tetrahedron Lett. 2005, 46,
2079–2082.
(1) (a) Hansen, T. V.; Stenstrom, Y. Naturally Occurring Cyclo-
butanes. In Organic Synthesis:Theory and Applications; Hudlicky, T., Ed.;
Elsevier: Oxford, U.K., 2001; Vol. 5, pp 1ꢀ38. (b) Walker, R. P.; Faulkner,
D. J.; Van Engen, D.; Clardy, J. J. Am. Chem. Soc. 1981, 103, 6772–6773.
(c) Chi, Y.; Yan, W.; Li, J. Phytochemistry 1990, 29, 2376–2378. (d)
Fujiwara, Y.; Naithou, K.; Miyazaki, T.; Hashimoto, K.; Tsukamoto;
Mori, K.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 2497–2499. (e)
Tsukamoto, S.; Cha, B. C.; Ohta, T. Tetrahedron 2002, 58, 1667–1671.
(f) Wei, K.; Li, W.; Koike, K.; Chen, Y.; Nikaido, T. J. Org. Chem. 2005,
70, 1164–1176. (g) Dembitsky, V. M. J. Nat. Med. 2008, 62, 1–33.
(2) (a) Weedon, A. C. In Synthetic Organic Photochemistry; Horspool,
W. M., Ed.; Plenum Press: New York, 1984; pp 61ꢀ143. (b) Wong,
H. N. C.; Lau, K. L.; Tam, K. F. Top. Curr. Chem. 1986, 133, 83–157. (c)
Leemans, E.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2011, 111, 3268–
3333.
(9) For recent reviews on photoaddition reactions, see: (a) Oppolzer,
W. Acc. Chem. Res. 1982, 15, 135–141. (b) Crimmins, M. T. Chem. Rev.
1988, 88, 1453–1473. (c) Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem.
Rev. 1995, 95, 2003–2020. (d) Hoffman, N. Chem. Rev. 2008, 108, 1052–
1103.
(3) Baldwin, S. W.; Martin, G. F.; Nunn, D. S. J. Org. Chem. 1985,
50, 5720–5723.
r
10.1021/ol203314y
Published on Web 01/20/2012
2012 American Chemical Society

the asymmetric [2 þ 2] photocycloaddition reactions,
which are known to efficiently prepare the enantiomer-
ically pure cyclobutane scaffold, have attracted consider-
able research interest from organic chemists.10,11 For
example, several valuable chiral auxiliaries derived from
(þ)-menthol,11a,b,d,f,j tartaric acid,11i and naphthalene11e
have been employed in the asymmetric [2 þ 2] photoaddi-
tion domain. Despite these advances, the research focused
on this issue is still in its early stages and the development of
an efficient and practical method is greatly desirable.
With our continuous efforts in the organic photo-
reactions,12 we endeavored in exploring an “ideal” chiral
auxiliary which features a series of applicability: (i) it can
be readily prepared from an available natural source, (ii)
easily removed after photoreaction, and (iii) lead to ex-
cellent stereoselectivity as well as satisfactory yield. A
literature survey showed that a variety of camphor-derived
auxiliaries had been widely implemented in the field of
asymmetric synthesis in the ground state, such as
DielsꢀAlder reaction,13 [3 þ 2] cycloaddition,14 aldol
addition,15 PausonꢀKhand reaction,16 BaylisꢀHillman
reaction,17 asymmetric cyclopentannelation,18 etc. We
therefore envisioned that natural (þ)-camphor derivative
1 might be an optimal candidate to achieve asymmetric
induction in organic photochemistry, owing to the steric
hindrance originated from the methyl groups on C-1 or/
and C-7. To the best of our knowledge, the examples of
camphor derivative induced asymmetric photoreactions
are still scarce.11a,h Herein, we report the asymmetric inter-
molecular [2 þ 2] photoaddition reactions by means of a
camphor-derived chiral auxiliary.
Initially, chiral auxiliary 1 was readily prepared in two
steps according to the literature procedure starting from
natural (þ)-camphor,19 which was then converted to the
amide 3 by condensation with carboxylic acid 2 in the
presence of carbonyl diimidazole (CDI). Sequential cycli-
zation reaction of 3 with phosphorus oxychloride led to the
oxazoline 420 in 86% isolated yield (Scheme 1).
(10) For recent reviews on asymmetric photoaddition reactions, see:
(a) Bach, T. Synthesis 1998, 683–708. (b) Namyslo, J. C.; Kaufmann,
D. E. Chem. Rev. 2003, 103, 1485–1537. (c) Lee-Ruff, E.; Mladenova, G.
Chem. Rev. 2003, 103, 1449–1483.
Scheme 1. Synthesis of Compound 4
(11) For selected examples, see: (a) Lange, G. L.; Decicco, C.; Tan,
S. L.; Chamberlain, G. Tetrahedron Lett. 1985, 26, 4707–4710. (b)
Hoffmann, N.; Scharf, H. D.; Runsink, J. Tetrahedron Lett. 1989, 30,
2637–2638. (c) Lange, G. L.; Humber, C. C.; Manthorpe, J. M. Tetra-
hedron: Asymmetry 2002, 13, 1355–1362. (d) Tsutsumi, K.; Endou, K.;
Furutani, A.; Ikki, T.; Nakano, H.; Shintani, T.; Morimoto, T.; Kakiuchi,
K. Chirality 2003, 15, 504–509. (e) Tsutsumi, K.; Nakano, H.; Furutani,
A.; Endou, K.; Merpuge, A.; Shintani, T.; Morimoto, T.; Kakiuchi, K. J.
Org. Chem. 2004, 69, 785–789. (f) Furutani, A.; Tsutsumi, K.; Nakano, H.;
Morimoto, T.; Kakiuchi, K. Tetrahedron Lett. 2004, 45, 7621–7624. (g) Le
Liepvre, M.; Ollivier, J.; Aitken, D. J. Eur. J. Org. Chem. 2009, 5953–5962.
(h) Herzog, H.; Koch, H.; Scharf, H. D.; Runsink, J. Tetrahedron 1986, 42,
3547–3558. (i) Lange, G. L.; Decicco, C. Tetrahedron Lett. 1988, 29, 2613–
2614. (j) Lange, G. L.; Decicco, C.; Lee, M. Tetrahedron Lett. 1987, 28,
2833–2836.
(12) (a) Xia, W.; Yang, C.; Scheffer, J. R. J. Am. Chem. Soc. 2005,
127, 2725–2730. (b) Xia, W.; Shao, Y.; Gui, W.; Yang, C. Chem.
Commun. 2011, 47, 11098–11100. (c) Scheffer, J. R.; Xia, W. Top. Curr.
Chem. 2005, 254, 233–262. (d) Yang, C.; Xia, W.; Scheffer, J. R.;
Botoshansky, M.; Kaftory, M. Angew. Chem., Int. Ed. 2005, 44, 5087–
5089. (e) Yang, C; Xia, W; Scheffer, J. R. Tetrahedron 2007, 63, 6791–
6795. (f) Zhao, G.; Yang, C.; Chen, Q.; Jin, J.; Zhang, X.; Zhao, L.; Xia,
W. Tetrahedron 2009, 65, 9952–9955. (h) Yang, C.; Xia, W. Chem.;
Asian J. 2009, 4, 1774–1784.
(13) (a) Kouklovsky, C.; Pouilhes, A.; Langlois, Y. J. Am. Chem. Soc.
1990, 112, 6672–6679. (b) Denmark, S. E.; Schnute, M. E. J. Org. Chem.
1991, 56, 6738–6739. (c) Banks, M. R.; Blake, A. J.; Cadogan, J. I. G.;
Doyle, A. A.; Gosney, I.; Hodgson, P. K. G.; Thorburn, P. Tetrahedron
1996, 52, 4079–4094.
With the chiral reactant 4 in hand, the investigation on
the photoaddition reaction of 4 with enone 5a21 was then
carried out using a medium-pressure mercury lamp as a
light source through a Pyrex filter (λ > 300 nm), which was
widely used in [2 þ 2] photoaddition to minimize the
decomposition of adduct products11 (Scheme 2). To our
delight, the reaction occurred smoothly in CH2Cl2 to
provide the photoadduct 6a in 84% isolatd yield after
irradiation for 5 h. A mixture of diastereomers of 6a was
observed by NMR analysis, which could not be separated
by silica gel column chromatography. The 1H NMR
spectra of the diastereomers displayed a similar resonance
of the methyne protons at 3.15 ppm (d, J = 11.2 Hz)
for H-7 and 2.91 ppm (dd, J = 10.8, 3.6 Hz) for H-8,
(14) (a) Berranger, T.; Langlois, Y. J. Org. Chem. 1995, 60, 1720–
1726. (b) Kouklovsky, C.; Dirat, O.; Berranger, T.; Langlois, Y.;
Tran-Huu-Dau, M. E.; Riche, C. J. Org. Chem. 1998, 63, 5123–4128.
(15) (a) Bonner, M. P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113,
1299–1308. (b) Ahn, K. H.; Lee, S.; Lim, A. J. Org. Chem. 1992, 57,
5065–5066. (c) Palomo, C.; Oiarbide, M.; Garcıa, J. M. Chem. Soc. Rev.
´
2004, 33, 65–75. (d) Boeckman, R. K., Jr.; Conneu, B. T. J. Am. Chem.
Soc. 1995, 117, 12368–12369. (e) Boeckman, R. K., Jr.; Pero, J. E.;
Boehmler, D. J. J. Am. Chem. Soc. 2006, 128, 11032–11033. (f) Wang, Y.;
Hung, A.; Chang, C.; Yan, T. J. Org. Chem. 1996, 61, 2038–2043.
(17) Yang, K.; Chen, K. Org. Lett. 2000, 2, 729–731.
(18) Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem.
Soc. 2002, 124, 10091–10100.
ꢀ
(16) (a) Verdaguer, X.; Moyano, A.; Pericas, M. A.; Riera, A.;
(19) (a) Gawley, R. E.; Zhang, P. J. Org. Chem. 1996, 61, 8103–8112.
(b) Chen, Y. K.; Jeon, S. J.; Walsh, P. J.; Nugent, W. A. Org. Synth.
2005, 82, 87–92. (c) Shimizu, M.; Teramoto, Y.; FujisawaT.
Tetrahedron Lett. 1995, 36, 729–732. (d) Nugent, W. A. Chem. Commun.
1999, 1369–1370.
(20) The DFT calculations were performed with the use of B3LYP
6-31G*. The difference in strain energy between cis-4 and trans-4 is 1.8
kcal/mol in favor of trans-4.
Bernardes, V.; Greene, A. E.; Alvarez-Larena, A.; Piniella, J. F. J.
Am. Chem. Soc. 1994, 116, 2153–2154. (b) Fonquerna, S.; Moyano, A.;
ꢀ
Pericas, M. A.; Riera, A. J. Am. Chem. Soc. 1997, 119, 10225–10226. (c)
ꢁ
Verdaguer, X.; Vazquez, J.; Fuster, G.; Bernardes, V.; Greene, A. E.;
ꢀ
Moyano, A.; Pericas, M. A.; Riera, A. J. Org. Chem. 1998, 63, 7037–
7052. (d) Marchueta, I.; Montenegro, E.; Panov, D.; Poch, M.;
ꢀ
Verdaguer, X.; Moyano, A.; Pericas, M. A.; Riera, A. J. Org. Chem.
ꢀ
2001, 66, 6400–6409. (e) Verdaguer, X.; Moyano, A.; Pericas, M. A.;
Riera, A.; Greene, A. E.; Piniella, J. F.; Alvarez-Larena, A. J. Organo-
met. Chem. 1992, 433, 305–310.
(21) Lange, G. L.; Otulakowski, J. A. J. Org. Chem. 1982, 47, 5093–
5096.
Org. Lett., Vol. 14, No. 3, 2012
777

whereas 13C NMR spectra showed two separate reso-
nances of the methyne carbons at 44.9, 44.7 ppm for C-7
and 38.4, 38.3 ppm for C-8. Specifically, the evidence from
correlations obtained from an HMQC spectrum allowed
signals of C-7 and C-8 to be assigned. In addition, the
doublets and coupling constant of 11.2 Hz for H-7 sug-
gested the stereochemistry of adducts 6a assigned to be
cis-anti-cis based on the typically anti coupling constant.22
Table 1. Survey Photoaddition Conditions of 4 with 5aa
molar
ratio
time
(h)
yieldc
(%)
ded
entry
5a/4
solventb
temp
rt
(%)
1
1/5
5/1
1/1
1/5
1/5
1/5
1/5
1/5
1/5
1/5
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
C6H6
5
91 (84)
7
83
95
94
81
82
85
90
95
87
84
2
rt
5
3
rt
5
16
4
rt
5
82
5
rt
5
89
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0 °C
ꢀ20 °C
ꢀ20 °C
rt
5
90
Scheme 2. Diastereoselective [2 þ 2] Photoaddition of 4 with 5a
7
8
5
1
97 (92)
45
9
1
38
10
rt
10
89
a Substrate 5a (0.2 mmol, 0.033 M in solvent). b Solvent was purged
with N2 prior to use. c Yield determined by GC analysis; isolated yield in
parentheses. d De % analyzed by HPLC on Atlantis dC18 column.
Table 2. Survey of Different Carboxylic Estera
On the basis of the above analysis, only the head-to-tail
adduct was observed as a single regioisomer in this process.
Indeed, the excellent regioselectivity of this reaction was
not surprising for us because the similar situation had been
well documented in previous work22 and also could be
explained in terms of the transition state analysis on the
[2 þ 2] photoaddition reaction by Somekawa and co-
workers,23 in which the calculations showed that the trans-
ition state energy barriers for the HT adducts were lower than
those for the HH adducts, leading to the selectivity preference.
However, to our delight, a good diastereoselectivity with an
83% diastereomeric excess (de) was achieved by HPLC
analysis. In comparison, only a 20% de was obtained when
the substrate 3 was reacted with 5a under similar conditions.
Upon initial results, further exploration of reaction
conditions was performed for this asymmetric photoreac-
tion procedure. As highlighted in Table 1, the molar ratio
of reactants had a significant effect on the reaction results.
For example, the poor yields were obtained when the
molar ratio of 5a and 4 was increased from 1:5 to 5:1 even
1:1 (Table 1, entries 2, 3), and the homodimerization
product derived from 5a was observed in this process based
upon GC-MS analysis. This might bring about significantly
diminished yields during the crossed intermolecular photo-
addition of 5a with 4. Notably the desired product 6a
formed in this case exhibited an excellent diastereomeric
excess (95% de) albeit a low yield (7%). Sequential inves-
tigations indicated that the reaction occurred smoothly in
various solvents without loss of diastereoselectivity coupled
with high conversions (Table 1, entries 4, 5).
yield
(%)b
de
(%)c
entry
R
temp
rt
1
2
3
4
5
6
7
8
9
Me
Me
84, 6a
92, 6a
83, 6b
89, 6b
76, 6c
88, 6c
50, 6d
64, 6d
trace, 6e
83
90
84
93
74
89
79
89
ꢀ
ꢀ20 °C
rt
Et
Et
ꢀ20 °C
rt
iPr
iPr
ꢀ20 °C
rt
Bn
Bn
ꢀ20 °C
rt
(ꢀ)-
Menthyl
a Substrate 5 (0.2 mmol, 0.033 M in solvent); solvent was purged with
N2 prior to use. b Isolated yield. c De % analyzed by HPLC on Atlantis
dC18 column.
entries 6ꢀ8). When the reaction was conducted at ꢀ20 °C,
the best result was achieved in 90% de with a 92% isolated
yield (Table 1, entry 7). In general, low conversion led
to high de values in this process (Table 1, entries 8, 9). No
significant decrease in de value was observed after com-
plete conversion of the substrate 5a with a prolonged
reaction time (Table 1, entry 10).
It should be pointed out that a higher diastereoselec-
tivity was obtained as the reaction was conducted at a
lower temperature without any decrease in yields (Table 1,
With the optimized conditions, we investigated the
influence of different carboxylic esters 2 on reaction effi-
ciency in this process. As can be seen in Table 2, irradiation
of a variety of esters uniformly led to the corresponding
products in good yield with 74%ꢀ93% de values (entries
1ꢀ8) except for entry 9 in which only a trace amount of
product was obtained due to the steric hindrance.
(22) Lange, G. L.; Organ, M. G.; Lee, M. Tetrahedron Lett. 1990, 31,
4689–4692.
(23) Omar, H. I.; Odo, Y.; Shigemitsu, Y.; Shimo, T.; Somekawa, K.
Tetrahedron 2003, 59, 8099–8105.
778
Org. Lett., Vol. 14, No. 3, 2012

kinetically controlled to generate 6a as the major adduct
leading to a diastereomeric excess. During the course of
photoaddition, the isomerization reaction of trans-4 to
cis-4 was observed, in which the photoaddition of 5a with
trans-4 and cis-4 from the endo face lead to 6a and
diastereomer-6a respectively based upon the diastereos-
electivity model (Scheme 4). Obviously, the photoisomer-
ization of 4 could not be excluded from the factors
responsible for diminished diastereoselectivity. To add
credence to the existence of cis-4 during the reaction, a
control experiment was conducted by direct irradiation
of trans-4 in the absence of 5a at room temperature
and ꢀ20 °C, which led to cis-4 in 35% and 20% conversion
respectively (Scheme 4). Such a result is responsible for the
fact that lower conversion and temperature led to higher
diastereoselectivity. In addition, the computational meth-
od was utilized in calculations of the strain energy of the
photoproducts 6a. Based on DFT calculations (B3LYP
6-31 G*), the difference in strain energy between major
adduct 6a and its diastereomer is 2.8 kcal/mol, which
means that major adduct 6a is more thermodynamically
stable than its diastereomer and preferred to be formed in
the reaction.
Scheme 3. Removal of the Chiral Auxiliary
To demonstrate the potential applications of this proce-
dure for synthetic transformations, the removal of the
chiral auxiliary from a photoproduct was conducted by
treatment of photoadduct 6a with benzyl chloroformate to
afford compound 7a in 84% yield, which was then hydro-
lyzed with LiOH and esterified with CH2N2 to give a
carboxylic ester 8 in 90% yield (Scheme 3).
In summary, we have developed an efficient approach
for asymmetric [2 þ 2] photoaddition reactions. This easily
enables access to the enantiomerically pure cyclobutanes
through the utilization of a chiral auxiliary. Importantly,
the natural camphor-derived auxiliarycould be introduced
and removed through simple synthetic steps. Remarkably,
an excellent diastereoselectivity and a synthetically useful
isolated yield were afforded in this process. The further
application of the chiral auxiliary in other photochemical
reactions, as well as in natural product synthesis, is on-
going in our group and will be reported in due course.
Scheme 4. Proposed Mechanism
Acknowledgment. We are grateful for financial support
from China NSFC (Nos. 20802013, 21002018, and 2107-
2038), the Fundamental Research Funds for the Central
Universities (No. HIT.BRET2.2010001), WZSTP (No.
G20100056), and ZJSTP (No. 2011C23116).
Finally, to rationalize the diastereoselectivity observed
in the reactions, a plausible mechanism is proposed as
depicted in Scheme 4. The excited state 5a obtained upon
UV light irradiation would be preferred to attack from the
less sterically congested endo face of substrate 4, which is
Supporting Information Available. Experimental de-
tails. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 3, 2012
779