Enantioselective synthesis of dihydrocouniarins via N-heterocyclic carbene-catalyzed cycloaddition of ketenes and o-quinone methides

Article abstract of DOI:10.1002/adsc.200900544

Chiral N-heterocyclic carbenes were found to be efficient catalysts for the formal [4. + 2] cycloaddition reaction of alky(aryl)ketenes and o-quinone methides to give the corresponding 3,3,4-trisubstituted 3,4-dihydrocoumarins in good yields with good dia

Full text of DOI:10.1002/adsc.200900544

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DOI: 10.1002/adsc.200900544
Enantioselective Synthesis of Dihydrocoumarins via
N-Heterocyclic Carbene-Catalyzed Cycloaddition of
Ketenes and o-Quinone Methides
Hui Lv,a Lin You,a and Song Yea,*
a
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, Peopleꢀs Republic of China
Fax : (+86)-10-6255-4449; e-mail: songye@iccas.ac.cn
Received: August 3, 2009; Revised: October 10, 2009; Published online: November 10, 2009
This paper is dedicated to Professor Li-Xin Dai on the occasion of his 85th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900544.
Abstract: Chiral N-heterocyclic carbenes were
found to be efficient catalysts for the formal [4+
2]cycloaddition reaction of alkyACTHNUTRGNEUNG(aryl)ketenes and o-
reactions,[8] intramolecular redox lactonization of o-
hydroxycinnamaldehydes,[9] and domino Michael ad-
dition/acyaltion of aryloxyacetaldydes.[10]
quinone methides to give the corresponding 3,3,4-
trisubstituted 3,4-dihydrocoumarins in good yields
with good diastereoselectivities and excellent enan-
tioselectivities.
However, the catalytic asymmetric synthesis of 3,4-
dihydrocoumarins is still rare,[7,8,11] and the enantiose-
lective synthesis of highly substituted 3,4-dihydrocou-
marins remains a challenge.
Recently, Lectka et al. reported the pioneering
enantioselective cycloadditions of the o-quinone me-
thide (QM) 1a and silylketene acetals to give 3,4-dis-
ubstituted 3,4-dihydrocoumarins in good yields with
highly enantioselectivities (Scheme 1).[11,12] It is inter-
esting that this reaction works for enolates generated
from silylketene acetals with chiral ammonium fluo-
Keywords: asymmetric catalysis; cycloadditions; di-
hydrocoumarins; ketenes; N-heterocyclic carbenes
3,4-Dihydrocoumarin derivatives are widely distribut- ride, but not for enolates generated from butyryl chlo-
ed in nature and are present as important active in- ride, thermodynamic Hꢁnigꢀs base and kinetic base of
gredients in many traditional Chinese herbal medi- the chiral catalyst benzoylquinidine.
cines.[1] Biological studies reveal that 3,4-dihydrocou-
N-Heterocyclic carbenes (NHCs) have been dem-
marins show versatile activities such as aldose reduc- onstrated as useful reagents for the synthesis of
tase inhibition, antiherpitic and HIV replication in- hetero
cyclic compounds,[13] excellent ligands for or-
hibition, thus making them attractive candidates as ganometallic compounds,[14] and versatile organocata-
lead compounds in drug discovery.[2] lysts for varied reactions.[15,16] In this context, Smith
AHCTUNGTRENNUNG
Great efforts have been devoted to the synthesis of et al. and our group independently found that eno-
dihydrocoumarins and many approaches have been lates generated from ketenes and catalytic chiral
developed. Beside the hydrogenation of coumarins, NHCs are versatile reagents for several formal [2+2]
hydroarylation of cinnamic acids and their derivatives and [4+2]cycloaddition reactions.[17] In this communi-
is an efficient method to construct dihydrocoumar-
ins.[3] Metal-mediated or metal-catalyzed reactions,
such as reaction of chromium Fishcer carbenes with
ketene acetals,[4] palladium-catalyzed cyclocarbonyla-
tion of o-isopropenylphenols,[5] rhodium-catalyzed re-
action of 3-(2-hydroxyphenyl)cyclobutanones,[6] were
also developed. In addition, several interesting ap-
proaches have been reported recently, including the
AlCl3-mediated reactions of a-hydroxyketene S,S-ace-
tals with arenes,[7] isocyanide-based four-component Scheme 1. Lectkaꢀs synthesis of dihydrocoumarins.
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Enantioselective Synthesis of Dihydrocoumarins
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cation, we report the preliminary results of the NHC- for cis-isomer and 91% ee for trans-isomer for the re-
catalyzed formal [4+2]cycloaddition of ketenes and action catalyzed by NHC 5a in THF at À208C
o-quinone methides 1 to give the highly substituted (entry 1). Solvent screening revealed that DME was
dihydrocoumarins.
the solvent of choice (entries 1–9).
The reaction of o-quinone methide 1a and phenyl-
Several other NHCs derived from pyrogutamic acid
ACHTUNGTRENNUNG(ethyl)ketene (2a) was investigated under the cataly- were then tested. NHC 5b, with a less sterically
sis of NHC 5,[17b,18] which was generated freshly from crowded TMS group, NHCs 5c and 5d, with N-(4-me-
NHC precursor 4 and Cs2CO3 as base (Table 1). We thoxy)phenyl and N-(2-isopropyl)phenyl substituents,
were happy to find that the corresponding 3,3,4-tri- showed similar results of diastereo- and enantioselec-
substituted-3,4-dihydrocoumarin 3a could be obtained tivties compared to NHC 5a (entries 10–12). The
in 73% with 5:1 ratio of cis/trans-isomers and 99% ee NHCs 5e and 5f, which feature a free hydroxy
group,[19] gave the dihydrocoumarin in moderate
yields but with low and opposite enantioselectivities
(entries 13 and 14).
Table 1. Optimization of reaction conditions.
Reactions at various temperatures (0, À20 and
À408C) showed comparable results (entries 3, 15 and
16). Decreasing the loading of the NHC 5a to
10 mol% made no notable change of the reaction,
while reaction with 5 mol% catalyst led to somewhat
decreased yield and diastereo- and enantioselectitvi-
ties (entries 17 and 18).
When we continued with the reactions in DME, it
was surprising to find that the results were varied for
independent runs and very low enantioselectivity was
sometimes observed. After careful investigation, we
found that use of strictly purified solvent DME led to
reactions with extremely low enantioselectivities
(entry 1, Table 2), and that the possible impurities
such as water and methanol influenced the reaction a
lot (entries 2 and 3). We were satisfied to find that
Entry Varied Condi-
tions[c]
Yield
[%][d]
cis:trans[e] ee
[%][f,g]
1
5a, THF
73
57
77
29
59
65
trace
32
trace
52
50
76
42
64
68
64
75
5:1
6:1
7:1
1:1
8:1
9:1
–
99, 91
98, 54
98, 79
69, 6
95, 54
97, 49
–
2
5a, ether
3
5a, DME
4
5
6
7
8
9
5a, dioxane
5a, toluene
5a, xylene
5a, n-hexane
5a, CH3CN
5a, DMF
Table 2. Investigation of additives.
3:1
–
6, 6
–
10
11
12
13
14
15
16
17
5b, DME
5c, DME
5d, DME
5e, DME
6:1
7:1
6:1
7:1
6:1
7:1
8:1
7:1
98, 87
99, 64
95, 85
À4, 26
À30, 64
97, 62
98, 81
99, 78
Entry Additive
Yield
[%][b]
cis:trans[c] ee
[%][d]
5f, DME
1
2
3
4
None
H2O (0.5 equiv.)
MeOH (0.6 equiv.) 96
PhCH2OH
(0.5 equiv.)
Ph2CHOH
(0.5 equiv.)
39
trace
5:1
–
7:1
4:1
0, 0
–
99, 96
84, 99
5a, DME, 08C
5a, DME, À408C
5a (10 mol%),
DME,
53
18
5a (5 mol%), DME 61
4:1
94, 67
5
38
3;1
10, 28
[a]
NHC 5 was generated from its precursor 4 with the base
Cs2CO3 (20 mol%) in the noted solvent at room temper-
ature for 30 min and used immediately.
DME in this table has not been fully purified and may
contain impurities such as traces of water and methanol.
The standard conditions are showed in the reaction
arrow.
6
7
Sc
Cu
N
2:1
–
1, 2
–
(0.1 equiv.)
pyrrole
MeOH (0.25 equiv.) 81
MeOH (0.12 equiv.) 77
[b]
[c]
8
9
10
35
3:1
5:1
5:1
29, 17
98, 86
97, 88
[d]
[e]
[f]
[a]
Total isolated yield of the cis- and trans-isomers.
The DME employed in this table was purified by double
distillation from sodium/benzophenone.
1
Determined by H NMR of the reaction mixture.
[b]
[c]
[d]
The ee of the cis-isomer followed by that of the trans-
isomer.
The minus ee value indicates the opposite enantiomer
was obtained as the major product.
Total isolated yield of the cis- and trans-isomers.
1
Determined by H NMR of the reaction mixture.
[g]
The ee of the cis-isomer followed by that of the trans-
isomer.
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Hui Lv et al.
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the reactions with methanol (0.6 equiv.) as an additive
led to a stable result of 96% yield as well as good dia-
stereo- and excellent enantioselectivity (entry 3).
However, some esterification of the ketene with
methanol was observed when methanol was added as
additive.[20] Thus, sterically hindered alcohols, which
react very slowly with ketenes,[21] were employed (en-
tries 4 and 5). Lewis acids and the base pyrrole were
also tested as the additives, but no desired result was
obtained (entries 6–8). The loadings of the additive
methanol were also investigated (entries 3, 9 and 10).
With the optimized reaction conditions in hand, a
Scheme 2. Reactions of o-quinone methide 1b.
series of other aryl
ACHTUNGTRENNUNG
(Table 3). While phenylAHCTUNTGRENNUNG
corresponding dihydrocoumarin in high yield but with responding dihydrocumarin in 33% yield without
low diastereo- and moderate enantioselectivity enantioselectivity (entry 11).
(entry 2), phenyl
G
G
The reaction of o-quinone methide 1b with a cin-
tyl)ketene gave the desired products in good yields namyl substituent also gave dihydrocoumarins in
with good diastereo- and high enantioselectivities (en- very good yields with moderate diastereo- and ex-
tries 3 and 4). Both ketenes with electron-donating
ACHTUNGTRENcNGNU ellent enantioselectivities for both diastereomers
and electron-withdrawing substituents worked very (Scheme 2).
well (entries 5–8). However, the reaction of sterically
The proposed catalytic cycle is depicted in Figure 1.
crowed ketenes, such as (2-naphthyl)ethyl ketene and The addition of NHC to ketenes gives enolates 6,
(2-chlorophenyl)ethylketene, were sluggish (entries 9 which react with o-quinone methides 1 via an inverse
and 10). The reaction of diphenylketene gave the cor- electron demand [4+2]cycloaddition to give adduct
7, followed by fragmentation to furnish the final prod-
uct 3 and regenerate the NHC.
The absolute stereochemistry of compound 3ag was
Table 3. Catalytic enantioselective synthesis of 3,3,4-trisub-
stituted 3,4-dihydrocoumarins.
determined by X-ray analysis to be (3R,4S),[22] and
other dihydrocoumarins prepared from QM 1a[23]
were assigned the same configuration based on the di-
rection of their specific optical rotations. This stereo-
chemical outcome is consistent with our previously re-
ported planar transition mode (Figure 2).[17d] Both less
sterically crowded conformations are adapted for the
Entry 3aa–ak (Ar, R)
Yield
[%][b]
cis:trans[c] ee
[%][d,e]
À
CACTHNUTRGNENG(U NHC) CACHTUGNTREN(NGUN enolate) single bond and the C=C double
bond of the enolate in the proposed model.
1
2
3
4
5
6
aa: Ph, Et
96
92
90
67
7:1
2:1
9:1
4:1
6:1
4:1
99, 96
51, FS
98, 85
97, 96
98, 86
96, FS
ab: Ph, Me
ac: Ph, n-Pr
ad: Ph, n-Bu
ae: 4-MeC6H4, Et 94
af: 4-MeOC6H4,
Et
80
7
8
9
10
11
ag: 4-ClC6H4, Et
ah: 4-BrC6H4, Et 96
ai: 2-naphthyl, Et 30
aj: 2-ClC6H4, Et
ak: Ph, Ph
90
7:1
7:1
3:1
–
99, FS
99, FS
58, FS
–
trace
33
–
0
[a]
The esterification of ketenes with methanol is the ob-
served side reaction with a ratio of 3 to ester of about
3:1.
[b]
[c]
[d]
[e]
Total yields of the cis- and trans-isomers.
1
Determined by H NMR of the reaction mixture.
Determined by chiral HPLC.
The ee of the cis-isomer followed by that of the trans-
isomer. FS=failed to separate the two enantiomers in
Daicel Chiralpak columns.
Figure 1. Proposed catalytic cycle.
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Enantioselective Synthesis of Dihydrocoumarins
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retention times: 29.6 min (cis-minor), 34.8 min (trans-
major), 39.2 min (cis-major), 42.0 min (cis-minor)].
Acknowledgements
Financial support from National Natural Science Foundation
of China (No. 20602036, 20872143), the Ministry of Science
and Technology of China (2009ZX09501-018) and the Chi-
Figure 2. Possible stereochemical model.
In conclusion, a highly enantioselectitive synthesis nese Academy of Sciences are greatly acknowledged.
of 3,3,4-trisubstituted 3,4-dihydrocoumarins was real-
ized by the chiral NHC-catalyzed formal [4+2]cyclo-
addition of arylACHTUNGTRENNUNG(alkyl)ketenes and o-quinone me-
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1
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Adv. Synth. Catal. 2009, 351, 2822 – 2826