Enantioselective synthesis of polycyclic coumarin derivatives catalyzed by an in situ formed primary amine-imine catalyst

Article abstract of DOI:10.1021/ol201715h

A facile in situ formed primary amine-imine organocatalyst was developed in the asymmetric Michael addition of substituted 4-hydroxycoumarins to cyclic enones. A series of optically active polycyclic coumarin derivatives were obtained in high yields with excellent enantioselectivities up to 97% ee.

Full text of DOI:10.1021/ol201715h

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4382–4385
Enantioselective Synthesis of Polycyclic
Coumarin Derivatives Catalyzed by an in Situ
Formed Primary Amine-Imine Catalyst
Xi Zhu, Aijun Lin, Yan Shi, Jingyu Guo, Chengjian Zhu,* and Yixiang Cheng*
School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination
Chemistry, Nanjing University, Nanjing 210093, P. R. China
cjzhu@nju.edu.cn; yxcheng@nju.edu.cn
Received June 27, 2011
ABSTRACT
A facile in situ formed primary amine-imine organocatalyst was developed in the asymmetric Michael addition of substituted 4-hydroxycoumarins to cyclic
enones. A series of optically active polycyclic coumarin derivatives were obtained in high yields with excellent enantioselectivities up to 97% ee.
Coumarin derivatives are distributed in a large number
of natural products and are commonly used as versatile
intermediates in natural product synthesis.1 Modification
of this class of compound has been of great interest to
chemists due to their various biological activities to anti-
malarial, anticoagulant, and anti-HIV activities, etc.2
Although most of coumarin derivatives are currently pre-
scribed as the racemate, activity and metabolism are
markedly dissimilar for the two enantiomers.3 Therefore,
efficient asymmetric syntheses of coumarins are of long-
standing interest.4 Organocatalysis has proven itself a
valuable strategy in the preparation of the synthesis of
opticallyactivecoumarins5 sinceJørgensen reporteda one-
step synthesis of enantiomerically pure warfarin in 2003.6
They presented the first example of an imidazolidine
organocatalyst promoted asymmetric Michael reaction
ofcoumarin andR,β-unsaturatedketones.7 Chin and Chen
(4) (a) Demir, A. S.; Tanyeli, C.; Gklbeyaz, V.; Akgkn, H. Turk. J.
Chem. 1996, 20, 139. (b) Cravotto, G.; Nano, G. M.; Palmisano, G.;
Tagliapietra, S. Tetrahedron: Asymmetry 2001, 12, 707.
(5) (a) Tsuchiya, Y.; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006, 8,
4851. (b) Halland, N.; Velgarard, T.; Jøgensen, K. A. J. Org. Chem.
2003, 68, 5067.
(1) (a) Murray, R. D. H.; Mendez, J.; Brown, R. A. The Natural
Coumarins; Wiley: 1982. (b) Kennedy, R. O.; Thornes, R. D. Coumarins:
Biology, Applications and Mode of Action; Wiley: 1997. (c) Fylaktakidou,
K. C.; Hadjipavlou, D. J.; Litinas, K. E.; Nicolaides, D. N. Curr. Pharm. Des.
2004, 10, 3813.
(2) (a) Melliou, E.; Magiatis, P.; Mitaku, S.; Skaltsounis, A. L.;
Chinou, E.; Chinou, I. J. Nat. Prod. 2005, 68, 78. (b) Xie, L.; Takeuchi,
Y.; Cosentino, L. M.; McPhail, A. T.; Lee, K. H. J. Med. Chem. 2001, 44,
664. (c) Cravotto, G.; Nano, G. M.; Palmisano, G.; Tagliapietra, S.
Tetrahedron: Asymmetry 2001, 12, 707. (d) Ishikawa, T. Heterocycles
2000, 53, 453. (e) Ufer, M. Clin. Pharmacokinet. 2005, 44, 1227. (f)
Visser, L. E.; van Schaik, R. H. N.; van Vliet, M.; Trienekens, P. H.;
Smet, P. A. G. M. D.; Vulto, A. G.; Hofman, A.; van Duijn, C. M.;
Stricker, B. H. C. Clin. Pharmacol. Ther. 2005, 77, 479.
(6) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2003, 42, 4955.
(7) For selected organocatalytic conjugate additions to R,β-unsatu-
rated ketones, see: (a) Melchiorre, P.; Jørgensen, K. A. J. Org. Chem.
2003, 68, 4541. (b) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2004, 43, 1272. (c) Fonseca, M. T. H.; List, B. Angew.
Chem., Int. Ed. 2004, 43, 3958. (d) Peelen, T. J.; Chi, Y.; Gellman, S. H.
J. Am. Chem. Soc. 2005, 127, 11598. (e) Yang, J. Y.; Fonseca, M. T. H.;
List, B. J. Am. Chem. Soc. 2005, 127, 15036. (f) Hayashi, Y.; Gotoh, H.;
Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc.
2005, 127, 16028. (g) Prieto, A.; Halland, N.; Jørgensen, K. A. Org. Lett.
2005, 7, 3897. (h) Deiana, L.; Zhao, G. L.; Lin, S. Z.; Dziedzic, P.; Zhang,
Q.; Leijonmarck, H.; Cordova, A. Adv. Synth. Catal. 2010, 18, 3201. (i)
Yanai, H.; Takahashi, A.; Taguchi, T. Chem. Commun. 2010, 46, 8728.
(3) (a) O’Reilly, R. A. N. Engl. J. Med. 1976, 295, 354. (b) Wingard,
L. B.; O’Reilly, R. A.; Levy, G. Clin. Pharmacol. Ther. 1978, 23, 212. (c)
Rang, H. P.; Dale, M. M.; Ritter, J. M.; Gardner, P. Pharmacology, 4th
ed.; Churchill Livingstone: Philadelphia, 2001.
r
10.1021/ol201715h
Published on Web 07/19/2011
2011 American Chemical Society

reported the same strategy for the synthesis of pure warfarin
catalyzed by a primary amine and diamine, respectively.8
Recently, Xu and Wang independently developed the proce-
dure by chiral squaramides and an amine-thiourea catalyst.9
Good yields and excellent enantioselectivities were obtained
with the synthesis strategy above. However, most of the
previous research efforts have been limited to a Michael
addition reaction with unsubstituted coumarins to modified
acyclic enones. Cyclic enones, a special R, β-unsaturated sys-
tem, still remain as difficult substrates and have been rarely
employed as electrophiles in this process. Even for the only
example with a 2-cyclohexen-1-one as a cyclic enone donor,
the reaction activity was obviously low and a long reaction
time (6 days, 78% yield) was required.8a Since the conjugate
addition to cyclic enones is an important strategy for the
synthesis of active cyclic building blocks, it is therefore of
great demand to develop a more effective method to improve
the tolerance of cyclic enones and explore more coumarin
substrates.
promoted the aldol reaction via an enamine process.
Inspired by the finding, we considered that the procedure
could be extended to activate the cyclic R,β-unsaturated
ketones via an iminium process in the Michael reaction.12
Herein, we describe an asymmetric Michael reaction of
4-hydroxycoumarins and 2-cyclohexen-1-one catalyzed by
the in situ formed primary amine-imine catalyst with an
(R,R)-diphenylethane backbone to give polycyclic coumar-
in derivative adducts in high yields and excellent enantios-
electivities under mild conditions.
Scheme 1. Application of the in Situ Prepared Primary Amine-
Imine
Figure 1. Structure of diimine precatalysts.
In the preliminary investigation, a series of diimine
precatalysts with an (R,R)-diphenylethane backbone were
prepared (Figure 1, 1aÀ1g). When acidified with AcOH in
THF, the diimines largely converted to the primary amine-
imine, which could be obviously detected by the ESI-MS
analysis of the mixture.13 The addition of 4-hydroxycou-
marin 2a to 2-cyclohexen-1-one was selected as a model
reaction to explore the feasibility of the proposed strategy
catalyzed by a chiral primary amine-imine catalyst. The
results are summarized in Table 1.
Initially, diimine 1a was investigated as the precatalyst,
and the reaction failed to proceed without any additive.
When added with 10 equiv of AcOH, 1a afforded the desired
product in 96% yield with 86% ee in THF at room tem-
perature (entry 1). The product was found to exist in rapid
equilibrium with a pseudodiastereomeric hemiketal form
in solution. The equilibrium is very rapid, and therefore
no pseudodiastereomers are observed during HPLC ana-
lysis.7À9 (R,R)-dpen as catalyst was also investigated but
gave the desired adduct with a lower ee value (entry 2). Sub-
sequently, different diimines 1bÀ1g were probed as precata-
lysts, and 1f exhibited the best result (entry 7). We then inves-
tigated the effects of solvents with catalyst 1f. The results
(entries 7 and 9À12) showed that the best solvent was THF.
To further improve the enantioselectivity, the effect of
Recently, the primary amine-imine catalyst with an
(R,R)-cyclohexane backbone was first described by our
group asan efficient aminocatalyst for the aldol reaction of
R-keto esters with excellent enantioselectivity.10 The pri-
mary amine-imine catalyst (Scheme 1), which is unable to
be isolated due to instability,11 can be in situ generated by
taking advantage of the hydrolization of a chiral diimine
under acidic conditions. This could be identified obviously
using ESI-MS. A catalytic amount of chiral diimine with
AcOH afforded the active catalyst, which efficiently
(8) (a) Xie, J. W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J. G.;
Chen, Y. C. Org. Lett. 2007, 9, 413. (b) Kim, H.; Yen, C.; Preston, P.;
Chin, J. Org. Lett. 2006, 8, 5239.
(9) (a) Xu, D. Q.; Wang, Y. F.; Zhang, W.; Luo, S. P.; Zhong, A. G.;
Xia, A. B.; Xu, Z. Y. Chem.;Eur. J. 2010, 16, 4177. (b) Gao, Y. J.; Ren,
Q.; Wang, L.; Wang, J. Chem.;Eur. J. 2010, 16, 13068.
(10) Zhu, X.; Lin, A. J.; Fang, L.; Li, W.; Zhu, C. J.; Cheng, Y. X.
Chem.; Eur. J. 2011, 17, 8281.
(11) For the instability of the primary amine-imine, see: (a) Xia, Q.;
Ge, H.; Ye, C.; Liu, Z.; Su, K. Chem. Rev. 2005, 105, 1603. (b) Lopez, J.;
Liang, S.; Bu, X. Tetrahedron Lett. 1998, 39, 4199. (c) Campbell, E. J.;
Nguyen, S. T. Tetrahedron Lett. 2001, 42, 1221. (d) Sun, Y.; Tang, N.
J. Mol. Catal. A: Chem. 2006, 255, 171. (e) Daly, A. M.; Dalton, C. T.;
Renehan, M. F.; Gilheany, D. G. Tetrahedron Lett. 1999, 40, 3617. (f)
Renehan, M. F.; Schanz, H. J.; McGarrigle, E. M.; Dalton, C. T.; Daly,
A. M.; Gilheany, D. G. J. Mol. Catal. A: Chem. 2006, 231, 205.
(12) For examples of asymmetric reactions of R,β-unsaturated ke-
tones catalyzed by primary amines, see: (a) Bartoli, G.; Bosco, M.;
Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9,
1403. (b) Xie, J. W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen,
Y. C.; Wu, Y.; Zhu, J.; Deng, J. G. Angew. Chem., Int. Ed. 2007, 46, 389.
(c) Ricci, P.; Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre,
P. Adv. Synth. Catal. 2008, 350, 49. (d) Yang, Y. Q.; Zhao, G. Chem.;
Eur. J. 2008, 14, 10888. (e) Liu, C.; Lu, Y. X. Org. Lett. 2010, 10, 2278. (f)
Xue, F.; Liu, Lu.; Zhang, S. L.; Duan, W. H.; Wang, W. Chem.;Eur. J.
2010, 27, 7979. (g) Zhu, Q.; Lu, Y. X. Chem. Commun. 2010, 13, 2235.
(13) For ESI-MS spectra, see Supporting Information: 1f was acid-
ified with AcOH in THF.
Org. Lett., Vol. 13, No. 16, 2011
4383

Table 1. Asymmetric Michael Addition of 4-Hydroxycoumarin
to 2-Cyclohexen-1-one
Table 2. Asymmetric Michael Addition of 4-Hydroxycoumarins
to Cyclic Enones
t
yield
(%)b
ee
entrya
catalyst
1a
solvent
THF
additive
--/AcOH
(h)
(%)c
1
24
--/92
--/86
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
(R, R)-dpen THF
--/AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
24 92/96 49/75
1b
1c
1d
1e
1f
1g
1f
1f
THF
THF
THF
THF
THF
THF
Toluene AcOH
MeOH AcOH
CH2Cl2 AcOH
36
36
36
36
36
36
48
72
48
72
36
36
93
91
90
92
94
92
68
57
90
9
93
94
94
94
94
78
76
78
88
87
86
89
91
88
79
63
88
68
92
93
95
90
95
95
91
92
1f
1f
1f
1f
1f
1fd
1fe
1ff
1fg
1fh
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
AcOH
C2H5COOH
C3H7COOH
hexanoic acid 36
hexanoic acid 36
hexanoic acid 36
hexanoic acid 72
hexanoic acid 36
hexanoic acid 36
a Unless otherwise noted, the reaction was carried out with 0.1 mmol
of 2-cyclohexen-1-one, 0.1 mmol of 4-hydroxycoumarin, 10 equiv of a
Brønsted acid, and a 10 mol % loading of diimine in 0.5 mL of THF at
room temperature. b Isolated yield. c Determined by chiral HPLC. The
absolute configurations were established as R. d With 5 mol % loading of
1f. e With 20 mol % loading of 1f. f Carried out at 0 °C. g With 5 equiv of
hexanoic acid loading. h With 20 equiv of hexanoic acid loading.
a Carried out with 0.1 mmol of enone, 0.1 mmol of substituted
4-hydroxycoumarin compounds, 10 equiv of hexanoic acid, and a
10 mol % loading of diimine 1f in 0.5 mL of THF at room temperature
for 36 h. b Isolated yield. c Determined by chiral HPLC. d The absolute
configuration was established as R.
additives was investigated. A series of Brønsted acids
screened showed that aliphatic acids had a slight effect on
enantioselectivity enhancement. Hexanoic acid was the best
additive which afforded the adduct with 95% ee (entries
13À15). Decreasing the catalyst loading of 1f to 5 mol %
led some loss of ee value while increasing the 1f loading to
20 mol % provided no improvement of enantioselectivity
(entries 16À17). The reaction temperature was also studied.
It seems that lowering the reaction temperature to 0 °C led to
little improvement of the enantioselectivity and caused low
reactivity (entry 18). In addition, the loading of hexanoic
acid is probed and 10 equiv of hexanoic acid to 4-hydro-
xycoumarin afforded the product with the highest enantios-
electivity (entries 19À20). Optimization of reaction condi-
tions revealed that the reaction carried out with a 10 mol %
loading of 1f and 10 equiv of hexanoic acid in 0.5 mL of THF
at room temperature afforded the adduct with the best
reactivity (94% yield) and enantioselectivity (95% ee) in 36 h
(entry 15).
substituents (entries 2À6) and electron-withdrawing sub-
stituents (entries 7À9) on aromatic rings were introduced
and showed good toleration in the reaction. It appears that
the position and electronic properties of substituents on
aromatic rings have a limited effect on the activity and
selectivity of this process. Benzo-4-hydroxycoumarins were
also investigated (entries 10À11). Although slightly lower
yields of the Michael adducts were obtained, high enan-
tioselectivities were maintained. 2-Cyclohepten-1-one and
2-cycloocten-1-one were employed as electrophiles in the
process and showed good enantioselectivities (entries
12À13). Benzalacetone and chalcone as acyclic enones were
also introduced and were well-tolerated (entries 14À15).
Moreover, we probed the asymmetric Michael addition
reaction of 4,4-dimethylcyclohex-2-enone, which gave the
adduct in a high yield with 95% ee (entry 16). In addition,
the reaction can be successfully extended utilizing 4-hydro-
xy-6-methyl-2-pyrone as the Michael donor, which afforded
an excellent result (entry 17). 1-Methyl-4-hydroxycarbos-
tyril, a 4-hydroxycoumarin analogue, was also employed,
With the optimized conditions, the substrate generality
was investigated. As summarized in Table 2, generally, the
Michael reactions proceeded smoothly with a variety of
substituted 4-hydroxycoumarins and 2-cyclohexen-1-one to
generate the corresponding adducts with high enantioselec-
tivities. The 4-hydroxycoumarins with electron-donating
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Org. Lett., Vol. 13, No. 16, 2011

between enone and amine gives the active iminium. The
4-hydroxycoumarin introduced by hydrogen bonding is
much more accessible to attack the active iminium from
the Re face, affording the major stereoisomer.
In conclusion, we have successfully demonstrated that
the in situ formed primary amine-imine catalyst is an
excellent aminocatalyst for an enantioselective Michael
addition reaction of substituted 4-hydroxycoumarin com-
pounds and cyclic enones. High yields and excellent en-
antioselectivities were achieved for a series of substituted
4-hydroxycoumarin compounds. Cyclic enones showed
excellent toleration in the process, which explored a new
strategy for the synthesis of optically active polycyclic
coumarin derivatives.
Figure 2. Proposed transition state for the reaction and X-ray
crystal structure of compound 4a.
Acknowledgment. We gratefully acknowledge the Na-
tional Natural Science Foundation of China (20832001,
20972065, 21074054) and the National Basic Research
Program of China (2007CB925103, 2010CB923303) for
their financial support. Fundamental Research Funds for
the Central Universities (1082020502) is also acknowledged.
and high enantioselectivity (88% ee) was achieved with a
little reduction of yield (entry 18).
The absolute configuration of product 4a was deter-
mined to be R by using single-crystal X-ray diffraction
(Figure 2).14 Based on the result, we proposed a transition
state for the catalytic asymmetric Michael reaction. The
chiral diimine is hydrolyzed under acidic conditions and
converted to a primary amine-imine catalyst. The interaction
Supporting Information Available. Experimental pro-
cedures, structural proofs, NMR spectra and HPLC
chromatograms of the products, and CIF file of enantio-
pure 4a. The material is available free of charge via the
Internet at http://pubs.acs.org.
(14) CCDC 823543 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc. cam.ac.uk/
data_request/cif.
Org. Lett., Vol. 13, No. 16, 2011
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