Asymmetric organocatalysis: An efficient enantioselective access to benzopyranes and chromenes

Article abstract of DOI:10.1002/chem.200800836

A method was proposed for the development of diaryl prolinol by catalyzed and enatioselective reaction of diketones with α,β-unsaturated aldehydes to produce biologically active chromenones. The study found that the reaction of α-β-unsaturated aldehydes with a chiral secondary amine can produce an intermediary iminium ion. The study observed that catalysis of the transformation can be achieved and the chromenone can be isolated in good yields. The study also observed that the enantioselective addition-cyclization cascade reaction of diketone with aldehyde and 10 mol% of dyarylprolinol catalyst can produce the 2-hydroxychromenone in a yield of 78%. The organocatalytic addition-acetalization reaction can be used to produce 2-hydroxychromenones with different aliphatic and aromatic substituents.

Full text of DOI:10.1002/chem.200800836

COMMUNICATION
DOI: 10.1002/chem.200800836
Asymmetric Organocatalysis: An Efficient Enantioselective Access to
Benzopyranes and Chromenes
[a]
Magnus Rueping,* Erli Sugiono, and EstíbalizMerino
Functionalized chromenes and benzopyranes are impor-
tant compounds which, due to their biological activity, find
wide application in medicinal chemistry. They display not
only spasmolytic, diuretic, clotting, antiviral, anti-tumoral,
and anti-anaphylactic activity, but can also be used as pig-
ments, photo-active materials, and biodegradable agrochem-
icals. Furthermore, benzopyranes and chromenes are com-
ponents of numerous natural products.[1]
Based on their frequent occurrence, extensive application,
and the lack of existing enantioselective preparative meth-
ods, we decided to develop an asymmetric, organocatalytic,
synthetic route starting from 1,3-diketones 1 and a,b-unsatu-
rated aldehydes 2.
ing acetalization was anticipated to result in the desired en-
antiomeric enriched chromenones[3] and their derivatives.[4]
We began our experimental investigations with the trans-
formation of cyclohexane-1,3-dione (1a) with a,b-unsaturat-
ed aldehyde 2a employing catalytic amounts of diarylproli-
nol silyl ethers[5] 3a and 3b. Even the initial experiments re-
vealed that catalysis of the transformation could be achieved
and that the chromenone 4a can be isolated in good yields
and enantioselectivities if diphenylprolinol ether 3 was em-
ployed as the catalyst (Table 1). This is in contrast to the use
of tertiary or primary amines,[6] Lewis acids,[7] or Brønsted
acids,[8] which result exclusively in the formation of the con-
densation products.
The addition–cyclization cascade reaction can be carried
out in various polar and apolar solvents (Table 1, entries 3–
7); very high enantioselectivities are obtained in dichloro-
methane at À208C with catalyst 3b (Table 1, entry 3).
To further optimize the reaction conditions the catalyst
loading of 3a and 3b, as well as the temperature, were
varied (Table 2). Whereas the use of low catalyst loadings
Table 1. Diarylprolinol ether catalyzed enantioselective synthesis of
chromenone 4a in different solvents.
This would not only be a valuable example of such a
metal-free, enantioselective reaction but would allow fast
and efficient access to these desirable products. We assumed
that the reaction of a,b-unsaturated aldehydes 2 with a
chiral secondary amine would result in the formation of an
intermediary iminium ion.[2] This would subsequently react
with a diketone 1 in a 1,4-addition reaction and the follow-
Entry[a]
T [8C]
3
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
À20
0
3a
3a
3b
3a
3a
3a
3a
CH2Cl2
CH2Cl2
CH2Cl2
toluene
DMSO
Et2O
67
85
44
80
76
44
62
88
88
98
92
71
92
94
[a] Prof. Dr. M. Rueping, Dr. E. Sugiono, Dr. E. Merino
Degussa Endowed Professorship
À20
À20
RT
À20
À20
Institute for Organic Chemistry and Chemical Biology
Johann Wolfgang Goethe-University Frankfurt am Main
Max-von-Laue Strasse 7, 60438 Frankfurt am Main (Germany)
Fax : (+49)69-798-29248
Bu2O
E-mail: M.Rueping@chemie.uni-frankfurt.de
[a] Reaction conditions: Cyclohexadione 1a, aldehyde 2a (1.5 equiv) and
20 mol% 3. [b] Yield of isolated product after column chromatography.
[c] Enantiomeric excess was determined by HPLC.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800836.
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did not alter the observed enantioselectivities, the yield
could be considerably increased by using milder tempera-
tures. Interestingly, catalyst 3b demonstrated better reactivi-
ty than catalyst 3a, which may be due to the electron-with-
drawing trifluoromethyl substituents. Hence, the enantiose-
lective addition–cyclization cascade reaction[9] of diketone
1a with aldehyde 2a in the presence of 10 mol% of diaryl-
this transformation, and a variety of 2-hydroxychromenones
4a–h can be isolated in good yields and with excellent enan-
tioselectivities (up to 97%).
This efficient and highly enantioselective method was also
successfully applied to other diketones, such as dimedone
1b (Table 4). Yet again the organocatalytic addition–acetali-
zation sequence provided a series of 2-hydroxychromenones
5a–l with various aliphatic (Table 4, entries 1–5) and aro-
matic (Table 4, entries 6–12) substituents with excellent en-
antiomeric excesses (87–96% ee).
A
a yield of 78% and a remarkable enantiomeric excess of
96% ee (Table 2, entry 5).
Table 2. Influence of catalyst loading and temperature on the enantiose-
lective addition–acetalization cascade.
Table 4. Extended scope of the diarylprolinol catalyzed enantioselective
addition-cyclisation cascade.
Entry[a]
Product
3
R
Yield [%][e]
ee [%][f]
Entry[a]
3
Mol% 3
T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
3b
3b
3b
3b
3b
3a
3a
3a
3a
3a
3a
3b
C2H5
C3H7
C4H9
C7H15
C10H21
Ph
2-NO2Ph
2-ClPh
2-BrPh
2-CH3Ph
2,4-(CH3)2Ph
3-BrPh
62
73
68
67
67
89
49
64
63
69
76
48
94
95
96
96
96
94
92
92
92
88
87
92
1
2
3
4
5
6
3a
3a
3b
3b
3b
3b
10
20
10
10
10
20
0
89
67
69
67
78
44
88
88
92
96
96
98
À20
RT
10
0
À20
5e
5 f[b]
5g[b]
5h[c]
5i[c]
5j[b]
5k[b]
5l[d]
9
[a] Reaction conditions: Cyclohexadione 1a, 2a (1.5 equiv) in dichloro-
methane. [b] Yield of isolated product after column chromatography.
[c] Enantiomeric excess was determined by HPLC.
10
11
12
[a] Reaction conditions: Cyclohexadione 1b, aldehyde 2 (1.3 equiv) and
10 mol% 3b. [b] With 20 mol% 3a at 08C. [c] With 20 mol% 3a at room
temperature. [d] With 20 mol% 3b. [e] Yield of isolated product after
column chromatography. [f] Enantiomeric excess was determined by
HPLC.
Using these optimized conditions, we examined the scope
of the new diarylprolinol ether catalyzed enantioselective
reaction of diketone 1 with various a,b-unsaturated alde-
hydes 2 (Table 3).
In general, aliphatic as well as aromatic a,b-unsaturated
aldehydes can for the first time be successfully applied in
The chromenones 4 are not only important biologically
active compounds and components of natural products,[10]
but also valuable substrates for the synthesis of further phar-
macologically interesting compounds. For instance, the 2-hy-
droxychromenones 4a can readily be oxidized to the lac-
tones 6a in the presence of PCC and without loss of enan-
tiomeric excess (Scheme 1a). The chromenones can also be
directly transformed into the corresponding cyclic ethers,
the oxadecalinones 7. The reaction proceeds with good
yields as demonstrated for the first time with compounds 4a
and 4 f. Hence, the transformation of 4a and 4 f with sodium
borohydride results in the intermediary alcohol which, fol-
lowing an acid catalyzed substitution, gives the oxadecali-
nones[11] 7a and 7 f (Scheme 1b). Furthermore, the com-
pounds 7a and 7 f could be transformed under oxidative
conditions into the enantiomerically enriched benzopyranes
8a and 8 f, whereby no loss of enantiomeric excess occurs
(Scheme 1c).
Table 3. Scope of the diarylprolinol ether catalyzed enantioselective syn-
thesis of chromenones.
Entry[a]
Product
3
R
Yield [%][d]
ee [%][e]
8
2
3
4
5
6
7
8
4a
4b
4c
3b
3b
3b
3a
3a
3a
3a
3a
C3H7
C7H15
78
66
67
77
51
78
95
76
96
96
96
94
93
96
87
97
C10H21
2-NO2Ph
2-ClPh
2-BrPh
3-BrPh
4-BrPh
4d[b]
4e[c]
4 f[b]
4g[b]
4h[b]
[a] Reaction conditions: Cyclohexadione 1a, 2 (1.3 equiv) and 10 mol%
3b. [b] With 20 mol% 3a. [c] With 20 mol% 3a at room temperature.
[d] Yield of isolated product after column chromatography. [e] Enantio-
meric excess was determined by HPLC.
The constitution und configuration of the products was
determined by using X-ray crystallography. Suitable crystals
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Chem. Eur. J. 2008, 14, 6329 – 6332

Asymmetric Organocatalysis
COMMUNICATION
Scheme 1. Reaction conditions: a) PCC, CH2Cl2, RT; b) NaBH4, H2SO4;
c) I2, MeOH, reflux.
Scheme 2. Diarylprolinol ether catalyzed enantioselective synthesis of hy-
droxylchromenones.
of compound 5i were obtained which enabled the assign-
ment of the absolute configuration (Figure 1).
The catalytic, enantioselective, addition–acetalization re-
action presented here should also enable enamides to be ap-
plied in these efficient yet mild transformations. Further-
more, this organocatalytic reaction should allow facile
access to various natural products and biologically active de-
rivatives, which is the focus of our current research.
Acknowledgements
The authors acknowledge Evonik Degussa and the DFG (Priority Pro-
gramme Organocatalysis) for financial support as well as the Ministerio
de Educacion y Ciencia, Spain, for a stipend given to E.M.
Figure 1. Molecular structure of compound 5i.[12]
Keywords: asymmetric catalysis
·
Brønsted acids
·
chromenes · domino reactions · organocatalysis
With regards to the mechanism, we assume that organoca-
talytic, highly enantioselective addition–cyclization sequence
starts with the activation of the a,b-unsaturated aldehydes 2
by the prolinol ether 3 forming the iminum ion A. This then
reacts with the diketone 1 in a 1,4-addition to give inter-
mediate B. Subsequent hydrolysis and half acetalization pro-
vides the desired hydroxychromenone 4 or 5, and the cata-
lyst 3 is regenerated (Scheme 2).
In summary we report the development of a diaryl proli-
nol ether catalyzed, enantioselective reaction of diketones
with a,b-unsaturated aldehydes that provides valuable, bio-
logically active chromenones. In these efficient addition–
acetalization cascade reactions, diverse aliphatic and aro-
matic a,b-unsaturated aldehydes, as well as various dike-
tones, can be successfully applied and the 2-hydroxychrome-
nones can be isolated in good yields and with excellent
enantioselectivities (87–98% ee) (Tables 3 and 4). The 2-hy-
droxychromenones can subsequently be transformed not
only into the corresponding lactones but also into useful ox-
adecalinones and benzopyranes (Scheme 1). No change in
the enantiomeric excess is observed and generally good
yields are obtained.
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Received: December 28, 2007
Revised: May 8, 2008
Published online: June 24, 2008
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