An efficient organocatalytic enantioselective Michael addition of aryl methyl ketones with 2-furanones: Highly functionalized chiral 3,4-substituted lactones

Article abstract of DOI:10.1039/c2cc35488h

The efficient asymmetric Michael addition reactions of aryl methyl ketones with 2-furanones were catalyzed by a simple and commercially available chiral 1,2-diphenyl-1,2-ethanediamine and p-TSA·H₂O as cocatalyst with good yields (up to 95%) and excellent enantioselectivities (up to >99% ee). A bi-functional catalytic mechanism for the reaction was proposed.

Full text of DOI:10.1039/c2cc35488h

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An Efficient Organocatalytic Enantioselective Michael Addition of Aryl
Methyl Ketones with 2-Furanone: Highly Functionalized Chiral 3,4-
Substituted Lactones
Wei Wang, Junfeng Wang, Shuo Zhou, Qi Sun, Zemei Ge, Xin Wang,* and Runtao Li*
5
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
ketones via enamine/iminium mechanism.6a,6b However, direct
The efficient asymmetric Michael addition reactions of aryl
construction of a chiral center at the αꢀposition of an aryl ketone
still has been rarely reported in enamine catalysis. Primary
45 amineꢀthioureas seem more effective in the activation of aryl
methyl ketones, but the Michael acceptors were mainly limited to
methyl ketones to 2-furanone were catalyzed by a simple and
commercially available chiral 1,2-diphenyl-1,2-ethanediamine
10 and p-TSA·H2O as cocatalyst with good yields (up to 95%)
and excellent enantioselectivities (up to >99% ee). A bi-
functional catalytic mechanism for the reaction was proposed.
highly active substrates, such as β
ꢀnitroolefins,7aꢀ7c nitrodiene.7d,7e
Our previous discovery showed 1,2ꢀprimary diamine was not
only very effective in the activation of aryl/alkyl ketones,8 α,βꢀ
50 unsaturated ketones and 2ꢀ(5H)ꢀfuranones by enamine/iminium
but also 1,3ꢀbifunctional substrates by hydrogen bonds.8c In this
context, it is promising that Michael addition reactions of aryl
methyl ketones to 2ꢀfuranone could be catalyzed by a suitable
amine catalyst.
55 After extensive screening, fortunately, we found the reaction of
acetonephenone 2a to 2ꢀfuranone 1a was very successful with
97% yield at room temperature catalyzed by ethylenediamine and
acetic acid (Table 1, entry 1). 2ꢀFuranone 1a represented a large
number of natural products with 5,5ꢀdisubstituted butyrolactones
60 in the structure.9 To demonstrate the asymmetric transformation,
chiral primary 1,2ꢀdiamines and acid additives were screened as
catalysts. Acyclic (1S,2S)ꢀ(ꢀ)ꢀ1,2ꢀdiphenylꢀ1,2ꢀethanediamine
showed much better enantiocontrol (Table 1, entry 3) than 1,2ꢀ
diaminocyclohexanes, which showed greater catalytic activity
65 with a 85% yield (Table 1, entry 2). However, secondary amine
catalysts LꢀProline (D) and dipeptide (E) did not show any
catalytic activity (Table 1 entries 4 and 5).
The γꢀbutyrolactone skeleton is present in more than 13 000
natural products, some of which show significant biological
15 activities such as antibiotic and antiꢀtumor properties.1 During the
past decades, different asymmetric approaches for these
compounds have been intensively studied2 and several natural
product and synthetic compound representatives are shown in
Figure 1.3 Clearly, direct Michael addition reactions of ketones to
20 2ꢀfuranone derivatives satisfy the principles of atom economy to
prepare these compounds. However, as far as we know, no direct
Michael addition reactions of aromatic ketones to 2ꢀfuranones
have been reported. This might be due to the low reactivity of
aromatic ketones and the stability of furanones, which undergo
25 decomposition under basic conditions.4 Usually highly active
reagents and metal catalysts are used for the addition to 2ꢀ
furanones, such as vinylboranes5a, lithium enolates5b, malonic
esters5c and alkyl free radicals5d. In the very few reports on the
adducts of aromatic ketones and 2ꢀfuranones, highly active zinc
30 enolates5e,5f tranformed from ketones, were employed as
nuclephiles to 2ꢀfuranones. Thus it is challenging and highly
desirable to develop the direct Michael addition reactions of
simple ketones to 2ꢀfuranones under mild reaction conditions.
Fig. 2 Catalysts screened for the asymmetric Michael Addition between
70
furanone 1a and acetophenone 2a.
J. Wang8a disclosed that the additives also showed significant
impact on the catalytic manner, such as 1,2ꢀdiamine catalyzed
Michael addition reactions would be stopped by adding 2
equivalents of strong acid (Table 1, entry 8). We next turned to
75 study the additive effect and found that our previously used weak
acid additives AcOH and PhCOOH only gave moderate
enantioselectivities (Table 1, entries 3 and 6), while stronger acid
CF3COOH gave quite satisfactory enantiocontrol (up to 95% ee)
35
Fig. 1 Representative natural and synthetic compounds with highly
substituted chiral γꢀbutyrolactones.
In the past decade, organocatalysis has undergone a major
development in constructing various enantiomerically enriched
compounds.6 In particular, amine catalysts, especially secondary
40 amines (LꢀProline and its derivatives) have proven to be
extraordinarily successful in the activation of aldehydes or
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with a lower yield (Table 1 entry 7). Much to our surprise, by
reducing the amount of strong acid to 1 equivalent of the diamine
2, entries 6 and 7). Hence, 20 mol% of (1S,2S)ꢀ(ꢀ)ꢀ1,2ꢀdiphenylꢀ
1,2ꢀethanediamine (C) and pꢀTSAꢁH2O as cocatalyst at 50℃ in iꢀ
catalyst, the reaction proceeded quite well with 96% ee and 53% 35 PrOH were accepted as the optimal conditions.
yield at r.t. (Table 1, entry 9). What’s more, the product yield
could be greatly improved (85% yield) without much loss of
enantioselectivity when heated to 50℃ (Table 1 entry 10). And
the dr values could be easily improved to nearly 99:1 after being
recrystallized once (See Supporting Information).
With the optimal conditions in hand, structural diversity of aryl
5
methyl ketones was then examined. As demonstrated in table 3,
this catalytic system was amenable to a very broad range of
aromatic ketones. Notably, electronꢀneutral, electronꢀpoor and
40 electronꢀrich acetophenones were all easily transformed with
good yields and high levels of enantiocontrol (Table 3, entries 1ꢀ
9, up to 99% ee). More importantly, heteroꢀaromatic methyl
ketones did not show a deleterious impact on the reaction
performance (Table 3, entries 10, 11, 15, 19, 20). For some
45 substrates (Table 3, entries 3, 4, 7, 10, 14, 15), the solubility of
their intermediates (enamine salts) in iꢀPrOH are not so good,
which led to the decrease of the reaction rate. However, the
reactions could be smoothly carried out in EtOH at a higher
temperature (70 ℃ ) with quite satisfactory yields and
50 enantioselectivities. Then we examined the reactivity of
furanones with bulkier substituents in γꢀposition. Both furanone
1b and 1c showed great product yields and ee% values (Table 3,
entries 21 and 22).
Table 1 Screening of catalysts for direct Michael reactions of 2ꢀfuranone
10 1a with acetophenone 2a
entry
cat.
additivea
temp.
(℃)
r.t.
r.t.
r.t.
r.t
r.t
r.t.
r.t
yield
(%)b
dr
ee
anti/sync
(%)d
1
2
3
4
5
6
7
8
9
A
B
C
D
E
C
C
C
C
C
AcOH
AcOH
AcOH
None
None
PhCOOH
CF3COOH
PTSAꢁH2O
PTSAꢁH2O
PTSAꢁH2O
97
85
54
n.r.
n.r.
63
37
trace
53
12.3/1
13.0/1
11.1/1
ꢀ
ꢀ
ꢀ36
75
ꢀ
ꢀ
ꢀ
8.8/1
12.4/1
ꢀ
13.6/1
8.5/1
75
95
ꢀ
96
91
Table 3 Substrate scope of diamine catalyzed Michael Addition of 2ꢀ
55 furanone 1a-c with acetylꢀketone 2a-t
r.t.
r.t.
50
10
85
aAdditive loading is 40 mol% (entries 1ꢀ3 and 6ꢀ8); for entries 9 and 10,
additive loading is 20mol%. b Isolated yield of the corresponding product;
c Determined by 1H NMR of the crude product. d Determined by chiralꢀ
15 phase HPLC.
entry
R, R
Ar
solvent
yield
dr
ee
Further screening of the solvent (Table 2, entries 1ꢀ4) indicated
that iꢀPrOH gave the highest enantioselectivity with a relatively
lower yield (Table 2, entry 2). In some cases, we observed that
precipitates appeared after we added the catalysts and the
20 substrates into iꢀPrOH, which was separated and identified as the
enamine salt formed by diamine monosalt and acetophenone (See
ESIꢀMS results of the intermediates in supporting information).
This further proved that primary amines and suitable acid could
be efficient catalysts to activate aromatic ketones.
(%)a (anti/syn)b (%)c
1
2
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Ph
4ꢀFPh
4ꢀClPh
4ꢀBrPh
iꢀPrOH 82(3a) 13.2/1
97
97
94
97
>99
82
82
92
92
94
79
93
95
94
92
96
94
87
98
iꢀPrOH 62(3b)
Ethanol 90(3c)
Ethanol 63(3d)
iꢀPrOH 56(3e)
iꢀPrOH
Ethanol 69(3g)
iꢀPrOH 74(3h)
9.1/1
9.7/1
9.0/1
8.1/1
9.5/1
8.1/1
8.8/1
11.8/1
9.0/1
3d
4d
5
4ꢀNO2Ph
4ꢀMePh
3ꢀClPh
3ꢀNO2Ph
3ꢀMeOPh
3ꢀpyridine
2ꢀfuran
3ꢀAcNHPh
3ꢀMePh
3ꢀFPh
2ꢀthiophene
4ꢀAcNHPh
6
85(3f)
7d
8
9
iꢀPrOH
Ethanol 71(3j)
87(3i)
10d Me, Me
11 Me, Me
12 Me, Me
13 Me, Me
14d Me, Me
15d Me, Me
16 Me, Me
iꢀPrOH 91(3k) 12.2/1
iꢀPrOH 64(3l) 11.4/1
iꢀPrOH 94(3m) 11.4/1
Ethanol 69(3n)
Ethanol 74(3o)
25 Table 2 Screening of solvents and catalyst loading for direct Michael
reactions of furanone 1a with acetonephenone 2a
9.0/1
9.5/1
iꢀPrOH 94(3p) 10.6/1
17 Me, Me 3,4,5ꢀ(MeO)3Ph iꢀPrOH 95(3q)
18 Me, Me 3,4ꢀ(OCH2O)Ph iꢀPrOH 78(3r)
19 Me, Me
7.2/1
8.0/1
12.7/1
iꢀPrOH 94(3s)
entry
Cat. C
(mol%)
20
20
20
20
20
10
5
solvent
yield
(%)a
82
66
65
74
82
75
61
Dr
ee
(%)c
95
97
91
90
97
92
91
anti/synb
14.5/1
13.0/1
12.1/1
13.2/1
13.2/1
12.8/1
10.7/1
20 Me, Me
21
22
3ꢀQuinoline
iꢀPrOH
EtOH
EtOH
54(3t)
73(3u) 10.8/1
92(3v) 14.8/1
8.1/1
93
93
93
1
2
3
EtOH
iꢀPrOH
DMF
DMSO
iꢀPrOH
iꢀPrOH
iꢀPrOH
Et, Et
Ph
Ph
4
5d
6d
7d
a Isolated yields of corresponding products. b Determined by 1H NMR of
crude products. c Determined by chiralꢀphase HPLC. d Reaction
temperature was 70℃ (it was 50℃ unless otherwise noted).
a Isolated yields of the corresponding products. b Determined by 1H NMR
of crude products. c Determined by chiralꢀphase HPLC. d 1a:2a=1:1.2
(0.5mmol:0.6mmol), unless otherwise noted 1a:2a=1:5
30 (0.5mmol:2.5mmol)
The absolute configuration was confirmed to be (3S,4R) by the
60 Xꢀray structure of 3d (Figure 3). The great outcome achieved by
1:1 of diamine and strong acid prompted us to propose a distinct
catalytic mechanism from those formerly raised by our group.8a,8b
Based on ESIꢀMS results of the intermediates (see supporting
information [M1+1]+ = 315; [M2ꢀ1]ꢀ = 171), we deduced that an
We also attempted to reduce the catalyst loading to 10 mol% and
5 mol%, but the product yield and ee value were sacrificed (Table
2
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35 aCrystal data for 3d: C17H19BrO5, M = 383.24, orthorhombic, a = 6.941(3)
Å b = 11.055(4) Å c = 22.261(8) Å α = 90.00°, β = 90.00°, γ = 90.00°, V
= 1708.1(11) Å3, T = 295(2) K, space group P212121, Z = 4, ꢁ(CuKα) =
3.480 mmꢀ1, 15439 reflections measured, 3330 independent reflections
(Rint = 0.0619). The final R1 values were 0.0347 (I > 2σ(I)). The final
40 wR(F2) values were 0.0863 (I > 2σ(I)). The final R1 values were 0.0378
(all data). The final wR(F2) values were 0.0894 (all data). Flack parameter
= ꢀ0.008(19).
inꢀsitu formed monosalt actually acted as a bifunctional catalyst.
One of the primary amine groups activated acetophenone by the
enamine intermediate, and the other primary amine salt of pꢀTSA
formed hydrogen bonds with the 1,3ꢀdiester groups, which could
form both transition states TS1 and TS2 (Figure. 4). It is clearly
that TS2 is sterically unfavorable and TS1 is more feasible
leading to the product with (3S,4R) configuration.
5
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3
4
5
Fig. 3 Xꢀray structure of 3d.
10
H
H
H
H
O
O
Ph
NH
Ph
Ph
Ph
O
O
S
S
N
NH3 NH
O
O
H3
O
O
O
O
hindered
O
Re-face
O
O
O
Si-face
6
7
TS1
TS2
Fig.4 Proposed transitional states.
Conclusions
In summary, we have developed the efficient direct asymmetric
15 Michael addition reactions of aryl methyl ketones with 2ꢀ
furanones catalyzed by a simple and commercially available
(1S,2S)ꢀ(ꢀ)ꢀ1,2ꢀdiphenylꢀ1,2ꢀethanediamine and PTSAꢁH2O as
cocatalyst. A broad range of aromatic ketones were transformed
with good yields (up to 95% yield) and excellent
20 enantioselectivities (up to 99% ee). This reaction provides
alternative access to synthetically and biologically interesting
highly substituted chiral γꢀLactones. We fully expect this new
method could be further applied to a broader substrate scope,
leading to a variety of biologically interesting molecules useful in
25 medicinal chemistry. The bioactivity studies of chiral γꢀLactones
are currently underway in our group.
8
9
(a) J. Wang, X. Wang, Z. Ge, T. Cheng, R. Li, Chem. Commun., 2010,
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We are grateful for financial support from the National Natural
Science Foundation of China (No. 20972005).
Notes and references
30 a State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University, Beijing 100191, China
† Electronic Supplementary Information (ESI) available: [Detailed
experimental procedures and spectral data for compounds 3a to 3v; single
crystal for 3d was recrystallized from EtOH and Water. Crytal data for 3d:
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NH2
.
PTSA H2O
NH2
R
O
O
O
O
O
R
R
R
(20mol%)
O
i-PrOH or EtOH
Ph
EtOOC
50 oC or 70 o
C
EtOOC
Ph
The first direct organocatalytic Michael addition between 2-furanone and aryl-ketones was
catalyzed by vicinal primary diamine salts with good product yields (up to 95%), entioselectivities
(up to 99%), and diastereoselectivities (anti:syn 7.2:1 to 13.2:1).