Combining silver catalysis and organocatalysis: A sequential michael addition/hydroalkoxylation one-pot approach to annulated coumarins

Article abstract of DOI:10.1021/ol502551u

A highly stereoselective one-pot procedure for the synthesis of five-membered annulated hydroxycoumarins has been developed. By merging primary amine catalysis with silver catalysis, a series of functionalized coumarin derivatives were obtained in good yields (up to 91%) and good to excellent enantioselectivities (up to 99% ee) via a Michael addition/hydroalkoxylation reaction. Depending on the substituents on the enynone, the synthesis of annulated six-membered rings is also feasible.

Full text of DOI:10.1021/ol502551u

Letter
pubs.acs.org/OrgLett
Combining Silver Catalysis and Organocatalysis: A Sequential
Michael Addition/Hydroalkoxylation One-Pot Approach to
Annulated Coumarins
Daniel Hack, Pankaj Chauhan, Kristina Deckers, Gary N. Hermann, Lucas Mertens, Gerhard Raabe,
and Dieter Enders*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: A highly stereoselective one-pot procedure for
the synthesis of five-membered annulated hydroxycoumarins
has been developed. By merging primary amine catalysis with
silver catalysis, a series of functionalized coumarin derivatives
were obtained in good yields (up to 91%) and good to
excellent enantioselectivities (up to 99% ee) via a Michael
addition/hydroalkoxylation reaction. Depending on the
substituents on the enynone, the synthesis of annulated six-
membered rings is also feasible.
econdary metabolites from phytobiochemical pathways
fulfill various life-sustaining roles in plants. For example,
synthesis of valuable chiral entities, especially in the context of
sequential catalysis.5 However, most reported procedures mainly
rely on expensive metal complexes, such as gold, palladium, and
iridium. Silver is a comparably cheaper metal and can be
employed as an alternative to facilitate these sequential
transformations. Silver salts of chiral organic molecules have
been used as binary catalytic systems in many asymmetric
transformations, but the sequential catalysis employing silver and
organocatalysts is less explored.6,7 Owing to the wide
applicability of coumarin derivatives and knowing the potential
of sequential catalysis,8 we envisaged the combination of silver
salts with chiral primary amines for the one-pot sequential
Michael addition/hydroalkoxylation of 4-hydroxycoumarins 1
with enynones 2 (Scheme 1).
S
coumarins, which originate from the shikimic acid pathway, are
vital for the regulation of oxidative stress, hormonal regulation,
and plant protection (Figure 1).1 Interestingly, biological activity
is not limited to plants only, as shown by warfarin and
phenprocoumon, which belong to the class of vitamin K
antagonists. Both inhibit the enzyme vitamin K epoxide
reductase, thus preventing blood clotting in humans and
animals.2 As a result, these anticoagulants have found wide
application as pharmaceuticals or rodenticides over the years.
Most of the organocatalytic asymmetric transformations
involving 4-hydroxycoumarins focus on Michael additions to
common electrophiles, such as simple enones, which undergo
electrophilic activation in the presence of primary amines.9,10 In
contrast, enynones 2 have not been used in this context so far.
Scheme 1. Intended Strategy
Figure 1. Bioactive coumarin derivatives.
Although the unprotected 4-hydroxyl group is necessary for
anticoagulant activity, other biologically active natural products
have been discovered in which the oxygen is embedded in an
annulated ring structure, as found in coumestrol and frutinone
A.3,4 The former interacts with estrogen receptors ERα and -β in
humans, while the latter is a potent inhibitor of CYP1A2.
Recently, the combination of transition metals with organo-
catalysts has emerged as a versatile one-pot strategy for the
Received: August 29, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502551u | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
These enynones are challenging Michael acceptors because both
the β- and δ-position are prone to nucleophilic addition after
electrophilic activation.
To achieve our goal, we started the investigation by optimizing
the organocatalytic Michael addition of 4-hydroxycoumarin 1a to
enynone 2a using cinchona-derived primary amines.11 The
reaction of 1a with 2a in CH2Cl2 at room temperature in the
presence of 20 mol % 9-amino(9-deoxy)epi-quinine A and 40
mol % TFA afforded the desired product 3a within 16 h in 63%
yield and 68% ee (Table 1, entry 1). To circumvent this low
enantiomeric excess for the majority of chiral additives with
comparable yields (entries 8−12). With (S)-N- Boc-alanine in
hand as the best additive, we focused on the influence of the
temperature on the reaction. Naturally, a higher temperature
resulted in a faster but less selective reaction (entry 13), while at 4
°C a negligible increase in reaction time and yield was observed,
albeit with better enantiomeric excess (entry 14). However, a
lower temperature had a deleterious effect, leading to longer
reaction times and lower enantioselectivities (entry 15). A similar
impact was observed when the catalyst loading was decreased to
10 mol %; thus, 20 mol % had to be used (entry 16).
a
With the optimized conditions for the Michael addition in
hand, we shifted our focus to the cycloisomerization reaction
(Table 2). We envisioned that phosphine Au(I) catalysts, which
Table 1. Optimization Studies on the Michael Addition
a
Table 2. Optimization of the Cycloisomerization of 4a
b
c
b
entry cat.
additive
solvent t (h) yield (%)
ee (%)
entry
catalyst
solvent
toluene
t (min) yield (%)
c
1
A
B
C
D
A
A
A
A
A
A
A
A
A
A
A
A
TFA
TFA
TFA
TFA
TFA
TFA
TFA
DCM
DCM
DCM
DCM
CHCl3
THF
MTBE
THF
THF
THF
THF
THF
THF
THF
THF
THF
16
20
19
21
24
16
16
16
24
24
24
24
4
63
74
61
81
84
85
82
85
95
65
94
48
94
95
88
88
68
59
1
PPh3AuCl/AgNTf2
AgNTf2
AgNTf2
AgNO3
Ag2CO3
AgOAc
60
−
2
2
toluene
THF
30
79
c
3
−68
−60
72
3
>240
40
−
91
4
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene/THF 4:1
toluene
5
5
40
97
6
78
6
40
94
7
66
7
AgOTf
50
91
8
(S)-mandelic acid
(S)-N-Boc-ala
(S)-N-Boc-phe
(S)-N-Boc-leu
(S)-N-Boc-val
(S)-N-Boc-ala
(S)-N-Boc-ala
(S)-N-Boc-ala
(S)-N-Boc-ala
78
8
AgSbF6
CuI
30
91
9
82
9
>1 d
>1 d
4 h
40
traces
traces
94
10
11
12
13
14
15
16
81
10
11
PtCl2
80
Ag2CO3
Ag2CO3
d
80
12
97
d
e
f
a
76
Reaction conditions: 0.13 mmol of 3a, 10 mol % of catalyst, 1.3 mL
solvent, rt. Yield of isolated 4a after flash column chromatography.
Complicated mixture of products which could not be separated. In
b
26
96
72
86
c
d
57
eg
,
75
the presence of 20 mol % A and 40 mol % (S)-N-Boc alanine.
a
Reaction conditions: 0.5 mmol of 1a, 0.6 mmol of 2a, 20 mol % of
b
catalyst, 40 mol % additive, 1.0 mL solvent, rt. Yield of isolated 3a
after flash column chromatography. Enantiomeric excess was
c
are known to activate internal alkynes, would be an optimal
choice for this reaction. However, the initial reaction conditions
gave rise to a complex mixture of different products, most likely
6-endo-, 5-exo-, and other unidentified products (entry 1). In
contrast, a number of Ag(I) salts gave the 5-exo product in
excellent yields within 1 h in the absence of gold catalysts (entries
2−9). Ag2CO3 turned out to be the best catalyst, giving the
desired product 4a in 97% yield within 40 min. In addition, we
also tested other metal sources which act as carbophilic Lewis
acids, but the reaction seemed to be limited to silver salts only
(entries 9−10).
Regrettably, further studies revealed that THF, which is used
during the Michael addition, is inappropriate for the subsequent
cyclization because, similar to the initial reaction conditions, a
mixture of products was obtained (entry 3). Thus, the reaction
must be performed either in a mixture of toluene and THF (entry
11) or with the solvents changed prior to the addition of Ag2CO3.
To compensate for this inconvenience, there seemed to be no
notable deactivation of the silver catalyst in the presence of the
amine catalyst (entry 12), as there was no notable decrease in
yield or increase in reaction time when the reaction was
performed in the presence of amine catalyst A and (S)-N-Boc
determined by HPLC analysis on a chiral stationary phase of the O-
d
e
acetylated derivative 3a′. Reaction was carried out at 50 °C. Reaction
f
was carried out at 4 °C. Reaction was carried out at −16 °C.
g
Reaction was carried out with 0.1 mol % of A and 20 mol % (S)-N-
Boc alanine.
asymmetric induction, we replaced the catalyst A with primary
amines derived from cinchonidine B, quinidine C, and
cinchonine D, but no beneficial effect was observed (entries
2−4). In contrast, the choice of solvent had a noticeable effect on
the yield and enantiomeric excess, revealing THF as the most
suitable solvent (entry 6).
We questioned whether the enantiomeric excess could be
increased if chiral acidic additives, especially Boc-protected
amino acids, were employed instead of TFA, as shown in a
seminal publication by Melchiorre et al.12 This would change the
mechanism of activation and stereoinduction from pure iminium
activation to a mixed activation mode in which the chiral
protonated iminium ion is coordinated by a chiral anion, a
concept known as asymmetric counteranion directed catalysis
(ACDC).13 As anticipated, we observed a slight increase in
B
dx.doi.org/10.1021/ol502551u | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
alanine. This is a decisive advantage compared to gold-catalyzed
reactions, in which the presence of free amines or basic moieties
deactivate the gold catalyst, and strong acidic additives such as
TFA or harsher reaction conditions have to be employed to
retrieve the active gold species.14
With these optimized conditions in hand, we tested the
substrate scope of the one-pot Michael addition/cycloisomeri-
zation (Table 3). In the case of aryl-substituted enynones good
enynones with aliphatic substituents led to the formation of 6-
endo-products with comparable ee values but lower yields due to
a less selective ring formation (5b−c). In the case of a terminal
alkyne the 5-exo-product was obtained exclusively, albeit with
slightly lower enantioselectivity values (4t). Interestingly, we did
not observe isomerization of the 5-exo-products to furans under
the applied reaction conditions.
The proposed structure of the products, including the absolute
configuration, could be assigned by X-ray crystal structure
analysis of (S)-4g (Figure 2).15 To further demonstrate the
a
Table 3. Substrate Scope for the Sequential Catalysis
yield
bc
,
de
,
product
R1
R2
(%)
ee (%)
4a
4b
4c
4d
4e
4f
H
Ph
84 [52]
76 [55]
76 [56]
75
88 [94]
89 [94]
85 [89]
93
H
4-F-C6H4
4-Br-C6H4
4-F3C-C6H4
2,3-CH2OCH2-C6H3
3-Me-C6H4
3-MeO-C6H4
2-naphthyl
2-Cl-C6H4
1-naphthyl
2-furanyl
2-thienyl
4-Br-C6H4
4-F-C6H4
1-naphthyl
3-MeO-C6H4
Ph
H
Figure 2. X-ray crystal structure of (S)-4g.
H
H
67 [47]
80 [53]
82
81 [98]
89 [97]
93
H
practicability of our new protocol, we carried out a larger scale
synthesis of 4g on a 4 mmol scale. We obtained the same yield
(82%, 1.24 g) and a better stereoselectivity of 96% ee.
A plausible mechanism for the reported sequential catalysis is
depicted in Scheme 2. Upon condensation with the primary
amine A and interactions of two molecules of (S)-N-Boc alanine,
the enynone 2 forms a LUMO-activated chiral iminium ion.
Similar to recent DFT calculations by Melchiorre et al., the two
4g
4h
4i
H
H
79
92
H
81
94
4j
H
75
80
4k
4l
H
78
99
H
76 [59]
54
77 [96]
92
4m
4n
4o
4p
4q
4r
4s
4t
6-Me
6,7-CH2OCH2-
56
94
7-MeO
74
94
Scheme 2. Proposed Catalytic Mechanism
6-Cl
60
98
6-Cl
91
73
7-MeO
Ph
58
93
6,7-CH2OCH2-
Ph
72
83
H
H
H
H
84
70
5b
5c
butyl
52
90
cyclopentyl
32
89
a
Reaction conditions: 0.8 mmol of enynone, 0.5 mmol of
hydroxycoumarin, 20 mol % of catalyst, 40 mol % (S)-N-Boc alanine,
1.0 mL of THF, 4 °C, 24−48 h; after completion, removal of THF,
b
addition of 5.0 mL of toluene, 10 mol % Ag2CO3, rt, 1−24 h. Yield of
c
isolated 4 or 5 after flash column chromatography. In brackets, yield
d
after one recrystallization from n-pentane/ethyl acetate. Enantiomeric
excess was determined by HPLC analysis on a chiral stationary phase.
e
In brackets, enantiomeric excess after one recrystallization from n-
pentane/ethyl acetate.
yields (54−91%) and excellent enantioselectivities were
obtained (73−99% ee) irrespective of electronic and steric
effects (4a−s), though bulky substituents normally resulted with
an increased reaction time in the cyclization step. Hydrox-
ycoumarins bearing different substituents were also tolerated
(4m−s). In all cases with aryl substituents on the enynone the 5-
exo-products were obtained, which can be verified by 4J-coupling
3
of the olefinic proton (around −2 Hz) compared to the J-
coupling of the endo-product (around 4 Hz). In contrast,
C
dx.doi.org/10.1021/ol502551u | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Park, E.; Kim, B.; Sohn, E. J.; Oh, B.; Lee, E.-O.; Lee, H.-J.; Kim, S.-H.
Bioorg. Med. Chem. Lett. 2014, 24, 2560.
(4) Di Paolo, E. R.; Hamburger, M. O.; Stoeckli-Evans, H.; Rogers, C.;
Hostettmann, K. Helv. Chim. Acta 1989, 72, 1455. (b) Thelingwani, R.
S.; Dhansay, K.; Smith, P.; Chiballe, K.; Masimirembwa, C. M.
Xenobiotica 2012, 42, 989.
(5) For selected reviews on combinations of transition metals with
organocatalysts, see: (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38,
2745. (b) Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2999. (c) Loh, C. C.
J.; Enders, D. Chem.Eur. J. 2012, 18, 10212. (d) Du, Z.; Shao, Z. Chem.
Soc. Rev. 2013, 42, 1337.
(6) For an overview on silver organic chemistry, see: (a) Naodovic, M.;
Yamamoto, H. Chem. Rev. 2008, 108, 3132. (b) Belmont, P.; Parker, E.
Eur. J. Org. Chem. 2009, 6075. (c) Harmata, M. Silver in Organic
Chemistry; Wiley: Hoboken, NJ, 2010. (d) Abbiati, G.; Rossi, E. Beilstein
J. Org. Chem. 2014, 10, 481.
(7) For recent examples on organocatalysis and silver catalysis: Ding,
́ ́
Q.; Wu, J. Org. Lett. 2007, 9, 4959. (b) Arroniz, C.; Gil-Gonzalez, A.;
Semak, V.; Escolano, C.; Bosch, J.; Amat, M. Eur. J. Org. Chem. 2011,
3755. (c) Zhang, Q.-W.; Xiang, K.; Tu, Y.-Q.; Zhang, S.-Y.; Zhang, X.-
M.; Zhao, Y.-M.; Zhang, T.-C. Chem.Asian J. 2012, 7, 894. (d) Ortín,
I.; Dixon, D. J. Angew. Chem., Int. Ed. 2014, 53, 3462.
(8) For recent examples of organocatalytic sequential one-pot
reactions, see: (a) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C.
Chem.Eur. J. 2010, 16, 2852. (b) Enders, D.; Urbanietz, G.; Cassens-
Sasse, E.; Keeß, S.; Raabe, G. Adv. Synth. Catal. 2012, 354, 1481.
(c) Hong, B.-C.; Dange, N. S.; Ding, C.-F.; Liao, J.-H. Org. Lett. 2012,
14, 448. (d) Dange, N. S.; Hong, B.-C.; Lee, C.-C.; Lee, G.-H. Org. Lett.
2013, 15, 3914. (e) Li, X.; Yang, L.; Peng, C.; Xie, X.; Leng, H.-J.; Wang,
B.; Tang, Z.-W.; He, G.; Ouyang, L.; Huang, W.; Han, B. Chem.
Commun. 2013, 8692. (f) Chauhan, P.; Mahajan, S.; Loh, C. C. J.; Raabe,
G.; Enders, D. Org. Lett. 2014, 16, 2954.
molecules of (S)-N-Boc alanine should play a pivotal role in the
reactivity and selectivity of this supramolecular catalytic
assembly.16 One of the counteranions will interact with the
protonated quinuclidine moiety of the primary amine catalyst by
hydrogen bonding, thus shielding the Si-face of the iminium ion.
This represents the stereochemical defining element responsible
for π-facial discrimination. The second counteranion acts as a
mediator in a network of hydrogen bonds between the iminium
proton and 4-hydroxy-coumarin. Thereby the nucleophile
becomes activated while being set up to the Re-face for the
subsequent attack on the iminium ion. The nucleophilic attack
will yield intermediate 3 after hydrolysis, which will then enter
the second catalytic cycle. This cycle is initiated by coordination
of Ag(I) to the alkyne moiety and electrophilic activation that
allows for the hydroalkoxylation of the triple bond by attack of
the nucleophilic hydroxy group. Similar to Au(I)-catalyzed
cycloisomerizations, the trans-specific addition should follow
Markovnikov’s rule and electronic factors. Thus, depending on
the substituent on the alkyne, 5-exo-dig and 6-endo-dig ring
formations are observed (see Supporting Information for a more
detailed explanation). The products are obtained after
regeneration of the silver catalyst and proton transfer.
In conclusion, we have developed a convenient one-pot
sequential Michael addition/hydroalkoxylation by merging silver
catalysis with primary amine catalysts. The combination gives
rise to pharmaceutically interesting annulated coumarins in good
yields and excellent enantioselectivities. Further investigations
on the application of sequential catalysis by silver catalysis and
organocatalysis are in progress in our laboratories.
(9) (a) Rueping, M.; Merino, E.; Sugiono, E. Adv. Synth. Catal. 2008,
350, 2127. (b) 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. (c) Wang, J.; Lao,
J.; Hu, Z.; Lu, R.-J.; Nie, S.; Du, Q.; Yan, M. ARKIVOC 2010, 9, 229.
(d) Mei, R.-Q.; Xu, X.-Y.; Peng, L.; Wang, F.; Tian, F.; Wang, L.-X. Org.
Biomol. Chem. 2013, 11, 1286. (e) Chang, X.; Wang, Q.; Wang, Y.; Song,
H.; Zhou, Z.; Tang, C. Eur. J. Org. Chem. 2013, 2164. (f) Suh, C. W.;
Han, T. H.; Kim, D. Y. Bull. Korean Chem. Soc. 2013, 34, 1623.
(10) For selected examples of asymmetric conjugate additions to
enones, see: (a) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2003, 42, 4955. (b) Kim, H.; Yen, C.; Preston, P.; Chin, J. Org.
Lett. 2006, 8, 5239. (c) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.;
Deng, J.-G.; Chen, Y.-C. Org. Lett. 2007, 9, 413. (d) Dong, Z.; Wang, L.;
Chen, X.; Liu, X.; Lin, L.; Feng, X. Eur. J. Org. Chem. 2009, 5192.
(e) Kristensen, T. E.; Vestli, K.; Hansen, F. K.; Hansen, T. Eur. J. Org.
Chem. 2009, 5185. (f) Zhu, X.; Lin, A.; Shi, Y.; Guo, J.; Zhu, C.; Cheng,
Y. Org. Lett. 2011, 13, 4382.
ASSOCIATED CONTENT
* Supporting Information
Chemical synthesis, analytical data, and NMR spectra. This
material is available free of charge via the Internet at http://pubs.
acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: enders@rwth-aachen.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11) (a) Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 9748.
(b) Moran, A.; Hamilton, A.; Bo, C.; Melchiorre, P. J. Am. Chem. Soc.
D.H. thanks the DFG (International Research Training Group
“Selectivity in Chemo- and Biocatalysis”-Seleca) and D.E. thanks
the European Research Council (ERC Advanced Grant 320493
“DOMINOCAT”) for financial support. Dedicated to Professor
Johann Mulzer on occasion of his 70th birthday.
2013, 135, 9091. (c) Cassani, C.; Martín-Rapun, R.; Arceo, E.; Bravo, F.;
́
Melchiorre, P. Nat. Protoc. 2013, 8, 325.
(12) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.;
Melchiorre, P. Org. Lett. 2007, 9, 1403.
(13) Mahlau, M.; List, B. Angew. Chem., Int. Ed. 2013, 52, 518.
(14) Young, P. C.; Green, S. L. J.; Rosair, G. M.; Lee, A.-L. Dalton
Trans. 2013, 42, 9645.
(15) CCDC 1021374 (for 4g) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(16) Moran, A.; Hamilton, A.; Bo, C.; Melchiorre, P. J. Am. Chem. Soc.
2013, 135, 9091.
REFERENCES
■
(1) Murray, R. D. H.; Medez, J.; Brown, S. A. The Natural Coumarins:
Occurrence, Chemistry and Biochemistry; Wiley: New York, 1982.
(b) Musa, M. A.; Cooperwood, J. S.; Khan, M. O. F. Curr. Med. Chem.
2008, 15, 2664.
(2) (a) Whitlon, D. S.; Sadowski, J. A.; Suttie, J. W. Biochemistry 1978,
17, 1371. (b) Fasco, M. J.; Principe, L. M. J. Biol. Chem. 1982, 257, 4894.
(c) Gebauer, M. Bioorg. Med. Chem. 2007, 15, 2414.
(3) (a) Miksicek, R. J. J. Steroid. Biochem. Mol. Biol. 1994, 49, 153.
(b) Morito, K.; Aomori, T.; Hirose, T.; Kinjo, J.; Hasegawa, J.; Ogawa,
S.; Inoue, S.; Muramatsu, M.; Masamune, Y. Biol. Pharm. Bull. 2002, 25,
48. (c) Kshirsagar, U. A.; Parnes, R.; Goldshtein, H.; Ofir, R.; Zarivach,
R.; Pappo, D. Chem.Eur. J. 2013, 19, 13575. (d) Cho, S.-Y.; Cho, S.;
D
dx.doi.org/10.1021/ol502551u | Org. Lett. XXXX, XXX, XXX−XXX