Asymmetric epoxidation of alkenes catalyzed by a porphyrin-inspired manganese complex

Article abstract of DOI:10.1021/ol401812h

A novel strategy for catalytic asymmetric epoxidation of a wide variety of olefins by a porphyrin-inspired chiral manganese complex using H ₂O₂ as a terminal oxidant in excellent yield with up to greater than 99% ee has been successfully developed.

Full text of DOI:10.1021/ol401812h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Epoxidation of Alkenes
Catalyzed by a Porphyrin-Inspired
Manganese Complex
Wen Dai,†,‡,§ Jun Li,†,‡ Guosong Li,†,‡ Hua Yang,†,‡,§ Lianyue Wang,†,‡ and
Shuang Gao*,†,‡
Dalian Institute of Chemical Physics, the Chinese Academy of Sciences, Dalian, 116023,
People’s Republic of China, Dalian National Laboratory for Clean Energy,
People’s Republic of China, and University of Chinese Academy of Sciences,
Beijing 100049, People’s Republic of China
sgao@dicp.ac.cn
Received June 27, 2013
ABSTRACT
A novel strategy for catalytic asymmetric epoxidation of a wide variety of olefins by a porphyrin-inspired chiral manganese complex using H2O2 as
a terminal oxidant in excellent yield with up to greater than 99% ee has been successfully developed.
Optically active epoxides are without question one of the
most valuable and versatile building blocks in organic
synthesis.1 Ever since the pioneering work of the Sharpless
epoxidation of allylic alcohols and the KatsukiÀJacobsen
epoxidation of unfunctionalized alkenes, there has been
great progress in asymmetric epoxidation (AE) over the
past decades.2 Despite these advances, the demand for less
expensive, environmentally more benign catalytic systems
for the AE of olefins is urgently needed and of great signifi-
cance. Therefore, considerable efforts have been directed
toward the development of bioinspired or biomimetic AE
catalysts mimicking the reactivity of natural metalloenzymes
owing to metalloenzyme-catalyzed oxidations often exhi-
biting exquisite substrate specificity and operating under
mild conditions through inherently green processes in
recent years.1,3 Metalloporphyrins as P450 enzyme mimics
have been shown to be a class of versatile catalysts.4 Groves
and Meyers reported the first AE catalyzed by a chiral
ironÀporphyrin complex in 1983; after that, numerous
efforts have been dedicated to synthesizing various chiral
porphyrins as potential asymmetric epoxidation catalysts.5
To date, however, the catalytic AE of olefins based on
(3) (a) Yeung, H.-L.; Sham, K.-C.; Tsang, C.-S.; Lau, T.-C.; Kwong,
H.-L. Chem. Commun. 2008, 3801–3803. (b) Wu, M.; Miao, C. X.;
€
Wang, S.; Hu, X.; Xia, C.; Kuhn, F. E.; Sun, W. Adv. Synth. Catal. 2011,
† Dalian Institute of Chemical Physics.
353, 3014–3022. (c) Murphy, A.; Dubois, G.; Stack, T. J. Am. Chem. Soc.
2003, 125, 5250–5251. (d) Nehru, K.; Kim, S. J.; Kim, I. Y.; Seo, M. S.;
Kim, Y.; Kim, S.-J.; Kim, J.; Nam, W. Chem. Commun. 2007, 4623–
4625. (e) Wu, M.; Wang, B.; Wang, S.; Xia, C.; Sun, W. Org. Lett. 2009,
11, 3622–3625. (f) Ottenbacher, R. V.; Bryliakov, K. P.; Talsi, E. P. Adv.
‡ Dalian National Laboratory for Clean Energy.
§ University of Chinese Academy of Sciences.
(1) Gelalcha, F. G.; Bitterlich, B.; Anilkumar, G.; Tse, M. K.; Beller,
M. Angew. Chem., Int. Ed. 2007, 46, 7293–7296.
ꢀ
Synth. Catal. 2011, 353, 885–889. (g) GarciaÀBosch, I.; Gomez, L.;
(2) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974–5976. (b) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N.
J. Am. Chem. Soc. 1990, 112, 2801–2803. (c) Irie, R.; Noda, K.; Ito, Y.;
Matsumoto, N.; Katsuki, T. Tetrahedron Lett. 1990, 31, 7345–7348. (d)
Shi, Y. Acc. Chem. Res. 2004, 37, 488–496. (e) Marigo, M.; Schulte, T.;
Franzen, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710–15711.
(f) Lifchits, O.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2010, 132,
10227–10229. (g) Nishikawa, Y.; Yamamoto, H. J. Am. Chem. Soc.
2011, 133, 8432–8435. (h) Tanaka, H.; Nishikawa, H.; Uchida, T.;
Katsuki, T. J. Am. Chem. Soc. 2010, 132, 12034–12041.
Polo, A.; Ribas, X.; Costas, M. Adv. Synth. Catal. 2012, 354, 65–70.
(h) Que, L.; Tolman, W. B. Nature 2008, 455, 333–340. (i) Wang, B.;
Miao, C. X.; Wang, S. F.; Xia, C. G.; Sun, W. Chem.;Eur. J. 2012, 18,
6750–6753.
(4) (a) Cui, X.; Xu, X.; Lu, H.; Zhu, S.; Wojtas, L.; Zhang, X. P.
J. Am. Chem. Soc. 2011, 133, 3304–3307. (b) Xu, X.; Lu, H.; Ruppel,
J. V.; Cui, X.; Lopez de Mesa, S.; Wojtas, L.; Zhang, X. P. J. Am. Chem.
Soc. 2011, 133, 15292–15295. (c) Lu, H.; Zhang, X. P. Chem. Soc. Rev.
2011, 40, 1899–1909.
r
10.1021/ol401812h
XXXX American Chemical Society

metalloporphyrins has not been developed into a practical
methodology for preparation of fine chemicals and
pharmaceutically important small molecules. First, this
unfortunate situation is largely attributed to the formidable
challenges associated with the synthesis of chiral porphyr-
ins and the highly planar structure of porphyrin ligands
that prohibits the introduction of chirality around the
metal center. In addition, the oxidant is more often iodo-
sylbenzene and 2,6-dichloropyridine N-oxide, which are
not considered environmentally friendly.
synergetic effect in the epoxidation of olefins with hydrogen
peroxide as the terminal oxidant in terms of activity and
enantioselectivity.7 In addition, the enantioselective intro-
duction and steric hindrance could be regulated by the chiral
oxazolines, which can be synthesized from commercially
available R or βamino acids. Herein, we report a general AE
method of olefins by a porphyrin-inspired chiral manganese
complex using H2O2 as the terminal oxidant in high yields
with excellent enantioselectivities (up to greater than
99% ee), as well as application of the method to the gram-
scale synthesis of optically pure epoxide and chiral drug
S-Levcromakalim.
For our investigations, we chose chromene 1a as the
model substrate because its product is of potential value
as a pharmaceutical intermediate.8 Initially, when 1a was
reacted with 0.2 mol % iron metals and ligand L2 in the
presence of H2O2/AcOH in acetonitrile, no epoxidation
was observed (Table 1, entries 1 and 2). By replacing
iron metals with MnCl2, the epoxidation resulted in only
low conversion of the starting material (Table 1, entry 3).
Gratifyingly, using Mn(OTf)2 led to a significant improve-
ment in terms of reactivity and enantioselectivity
(95% yield, 95% ee; Table 1, entry 5). Besides Mn(OTf)2,
Mn(OAc)2 could also be used, although the yield was
slightly lower than that obtained by using Mn(OTf)2
(Table 1, entry 4). After testing the loading of acetic acid,
we identified that the best results were achieved upon
addition of acetic acid (5.0 equiv) with respect to the
substrate (Table 1, entries 5À7). Preliminary results indi-
cated that the reaction temperature had certain effects on
the yield and enantioselectivity (Table 1, entries 5, 8, and 9).
The ee values could be promoted when the temperature
was decreased to 0 °C. The ee values remained the same by
further lowering the temperature to À20 °C. Subsequently,
examination of various ligands showed that L2 was the
best choice regarding yield and enantioselectivity under
the optimized conditions (Table 1, entries 5 and 10À13).
Finally, the catalyst loading was successfully lowered to
0.1 mol % with only a slight decrease in the yield (Table 1,
entry 14).
Figure 1. Design strategy for chiral ligand.
Recently, in view of the difficulty in the synthesis of chiral
porphyrin, Niwa and Nakada developed an easily prepared
1,8-(bisoxazolyl)-carbazole iron complex with porphyrin-
like properties for the AE of trans-stilbene derivatives
applying iodosobenzene in the presence of sodium tetrakis-
[3,5-bis(trifluoromethyl)phenyl]borate (NaBARF).6 Un-
fortunately, the types of substrates are limited, and the
oxidant is environmentally unfriendly. With this back-
ground in mind, it was envisioned that we could develop a
new alternative to porphyrins that fulfills structural require-
ments of the porphyrins in some way, which possesses a
long conjugation and strong donor moieties and can also
obtain good results for the AE of a relatively wide range of
substrates using an environmentally benign oxidant. To our
delight, we designed and synthesized a totally new type of
tetradentate nitrogen based ligands that can be simply
prepared, are structurally diverse, and are sterically tunable
as well as allows easy introduction of chirality (Figure 1).
The tetradentate ligands have relatively long conjugation
and two NÀH moieties that exhibit strong σ-donation.
Moreover, Katsuki and co-workers disclosed that NÀH
groups in the organometallic catalyst have a significant
With the optimized conditions in hand, we turned our
attention to examining the scope of substrates using the
Mn(OTf)2ÀL2 complex (Table 2). As expected, a wide
variety of olefins could be efficiently epoxidized efficiently
within short reaction times, providing the corresponding
chromene derivatives (entries 1À15), indene (entry 16),
1,2-dihydronaphthalene (entry 17), and trans-stilbene ep-
oxides (entry 18) in high yields and excellent enantioselec-
tivities. It is noteworthy that various electron-withdrawing
(5) (a) Collman, J. P.; Wang, Z.; Straumanis, A.; Quelquejeu, M.;
ꢀ
ꢀ
Rose, E. J. Am. Chem. Soc. 1999, 121, 460–461. (b) Perollier, C.; Pecaut,
J.; Ramasseul, R.; Marchon, J.-C. Inorg. Chem. 1999, 38, 3758–3759. (c)
Rose, E.; Ren, Q. Z.; Andrioletti, B. Chem.;Eur. J. 2004, 10, 224–230.
(d) Berkessel, A.; Frauenkron, M. J. Chem. Soc., Perkin Trans. 1 1997,
2265–2266. (e) Zhang, R.; Yu, W.-Y.; Lai, T.-S.; Che, C.-M. Chem.
Commun. 1999, 409–410. (f) Berkessel, A.; Kaiser, P.; Lex, J. Chem.;
Eur. J. 2003, 9, 4746–4756. (g) Collman, J. P.; Brauman, J. I.; Hampton,
P. D.; Tanaka, H.; Bohle, D. S.; Hembre, R. T. J. Am. Chem. Soc. 1990,
112, 7980–7984. (h) Konishi, K.; Oda, K.; Nishida, K.; Aida, T.; Inoue,
S. J. Am. Chem. Soc. 1992, 114, 1313–1317. (i) Sundermeyer, J. Angew.
Chem., Int. Ed. 1993, 32, 1144–1146. (j) Collman, J. P.; Lee, V. J.; Zhang,
X.; Ibers, J. A.; Brauman, J. I. J. Am. Chem. Soc. 1993, 115, 3834–3835.
(k) Groves, J. T.; Myers, R. S. J. Am. Chem. Soc. 1983, 105, 5791–5796.
(6) Niwa, T.; Nakada, M. J. Am. Chem. Soc. 2012, 134, 13538–13541.
(7) (a) Matsumoto, K.; Sawada, Y.; Saito, B.; Sakai, K.; Katsuki, T.
Angew. Chem., Int. Ed. 2005, 44, 4935–4939. (b) Sawada, Y.; Matsumoto,
K.; Kondo, S.; Watanabe, H.; Ozawa, T.; Suzuki, K.; Saito, B.; Katsuki,
T. Angew. Chem., Int. Ed. 2006, 45, 3478–3480. (c) Sawada, Y.;
Matsumoto, K.; Katsuki, T. Angew. Chem., Int. Ed. 2007, 46, 4559–
4561. (d) Kondo, S.; Saruhashi, K.; Seki, K.; Matsubara, K.; Miyaji, K.;
Kubo, T.; Matsumoto, K.; Katsuki, T. Angew. Chem., Int. Ed. 2008, 47,
10195–10198. (e) Matsumoto, K.; Oguma, T.; Katsuki, T. Angew. Chem.,
Int. Ed. 2009, 48, 7432–7435. (f) Egami, H.; Oguma, T.; Katsuki, T.
J. Am. Chem. Soc. 2010, 132, 5886–5895.
(8) Lee, N. H.; Muci, A. R.; Jacobsen, E. N. Tetrahedron Lett. 1991,
32, 5055–5058.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Screening of Reaction Conditions
Table 2. Substrate Scope of Epoxidation
AcOH
entry
metal
FeCl2
ligand
[equiv]
% yielda
% eeb
1
L2
L2
L2
L2
L2
L2
L2
L2
L2
L1
L3
L4
L5
L2
5
5
5
5
5
3
6
5
5
5
5
5
5
5
À
À
2
Fe(OTf)2
MnCl2
À
À
3
<5
78
95
32
88
89
92
15
72
30
66
89
À
4
Mn(OAc)2
Mn(OTf)2
Mn(OTf)2
Mn(OTf)2
Mn(OTf)2
Mn(OTf)2
Mn(OTf)2
Mn(OTf)2
Mn(OTf)2
Mn(OTf)2
Mn(OTf)2
94
95
84
94
94
90
84
92
88
92
92
5
6
7
8c
9d
10
11
12
13
14e
c
a Isolated yield. b Determined by chiral HPLC analysis. À20 °C.
d 30 °C. e Mn(OTf)2 (0.1 mol %), L2 (0.1 mol %), 3 h.
and -donating substituents such as halogen, nitro, nitrile,
ester, and hydroxymethyl were equally well tolerated. In
addition, a good yield and moderate enantioselectivity
were also obtained for the reaction of terminal olefin
(entry 19).
a Isolated yield. b Determined by chiral HPLC analysis.
Gratifyingly, a moderate yield and enantioselectivity
could alsobe obtainedfor the reaction of electron-deficient
4-methoxychalcone (Table 2, entry 20). With this result in
hand, we performed an intermolecular competition reac-
tionbetween 1aand3atodetermine the natureofthe active
oxidant (Scheme 1). It was found that an electron-rich
alkene showed an obvious advantage compared to an
electron-deficient compound in yield and enantioselectiv-
ity, suggesting that the nature of the active oxidant is
possibly electrophilic. However, more work is required to
determine the mechanistic aspect.
Scheme 1. Competitive Experiment between 1a and 3a
To further evaluate the practical utility, the epoxidation
of chromene 1a was carried out on gram scale, and the
desired product was furnished with 92% yield and 94% ee
(Scheme 2). Moreover, the ligand L2 could be recovered
via procedures of extraction and silica gel column chro-
matography, respectively. The absolute configuration of
epoxide 2a was determined to be S,S by comparison of the
HPLC retention times and optical rotation with data
reported in literature.9
Finally, to broaden the application of our methodology,
we focused on the gram-scale synthesis of an antihyper-
tensive drug S-Levcromakalim (Scheme 3). Treatment
of the (S,S)-epoxidate 2a with pyrrolidin-2-one under
(9) (a) Hashihayata, T.; Ito, Y.; Katsuki, T. Tetrahedron 1997, 53,
9541–9552. (b) Liao, S.; List, B. Angew. Chem., Int. Ed. 2010, 49, 628–
631.
Org. Lett., Vol. XX, No. XX, XXXX
C

In summary, we have successfully developed a highly
efficient and general catalytic AE method that employs a
low loading of an inexpensive and easily prepared por-
phyrin-inspired chiral manganese complex and H2O2,
allowing for general epoxidation of a wide variety of
olefins in excellent yield with ee values up to greater than
99%. To the best of our knowledge, this is the first example
of a porphyrin-inspired system for AE with H2O2 under
environmentally friendly and mild conditions. Moreover,
this work provides a new strategy for designing ligand-
based catalysts, which play one of the central roles in
homogeneous catalysis. Mechanistic study and extension
of the strategy to other reactions are in progress.
Scheme 2. Gram-Scale Synthesis of Epoxide 2a
Scheme 3. Gram-Scale Synthesis of the Chiral Drug
S-Levcromakalim
Acknowledgment. We are grateful to Prof. Yong-
Gui Zhou and Dr. Min Gong for their valuable discus-
sions. This work was gratefully financially supported
by the National Basic Research Program of China
(2009CB623505).
Supporting Information Available. Experimental pro-
cedures, compound characterization data, and HPLC
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
the conditions reported in the literature yielded the
S-Levcromakalim with up to 97% ee.10
(10) (a) Evans, J. M.; Fake, C. S.; Hamilton, T. C.; Poyser, R. H.;
Watts, E. A. J. Med. Chem. 1983, 26, 1582–1589. (b) Bergmann, R.;
Eiermann, V.; Gericke, R. J. Med. Chem. 1990, 33, 2759–2767.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX