Enantioselective organocatalytic conjugate addition of aldehydes to α,β-Unsaturated thiol esters

Article abstract of DOI:10.1002/adsc.200900449

The first example of an organocatalytic asymmetric Michael addition of aldehydes to α,βunsaturated thiol esters promoted by chiral diphenylprolinol silyl ether is presented. The reaction occurs with good yields, diastereoselectivity and excellent enantios

Full text of DOI:10.1002/adsc.200900449

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DOI: 10.1002/adsc.200900449
Enantioselective Organocatalytic Conjugate Addition of
Aldehydes to a,b-Unsaturated Thiol Esters
Shaolin Zhu,a You Wang,b and Dawei Maa,*
a
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: madw@mail.sioc.ac.cn
Department of Chemistry, Fudan University, Shanghai 200433, Peopleꢀs Republic of China
b
Received: June 30, 2009; Revised: August 3, 2009; Published online: October 21, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900449.
Abstract: The first example of an organocatalytic
asymmetric Michael addition of aldehydes to a,b-
unsaturated thiol esters promoted by chiral diphe-
nylprolinol silyl ether is presented. The reaction
occurs with good yields, diastereoselectivity and ex-
cellent enantioselectivity.
thiol esters as reactants, and found that they failed to
give any adducts under various reaction conditions
(Scheme 1). Inspired by the success in employing a-
keto-a,b-unsaturated esters as the Michael accept-
ors,[2c] we moved our attention to olefins 3, a,b-unsa-
turated thiol esters with a g-ester or amide moiety.
We were pleased to discover that the chiral amine-
catalyzed reaction of these special a,b-unsaturated
thiol esters with aldehydes proceeded smoothly to
give Michael adducts 4 in good yield and diastereose-
lectivity with excellent regioselectivity and enantiose-
lectivity. Herein we wish to detail our results.
Keywords: asymmetric catalysis; enamine activa-
tion; Michael addition; organocatalysis; a,b-unsatu-
rated thiol esters
The required (E)-a,b-unsaturated thiol esters were
prepared by a Wittig reaction of glyoxylate esters (or
In recent years, the Michael addition of aldehydes to amides) with thiol ester-derived ylides. We chose the
electron-deficient olefins using chiral amines as the reaction of n-pentanal 2a with thio ester 3a as the
organocatalysts has received much attention.[1] This model to explore the optimized reaction conditions.
transformation normally provides highly functional- As indicated in Table 1, this reaction worked in water
ized adducts with excellent enantioselectivity, thereby to afford 4a in 58% yield under the catalysis of
offering a powerful method for the assembly of bioac- 10 mol% of diphenylprolinol silyl ether
1 and
tive molecules. Although some highly reactive elec- 50 mol% of HOAc (entry 1). Changing the reaction
tron-deficient olefins, which include nitroalkenes,[2a,3] media to organic solvents such as chloroform, toluene
vinyl ketones,[4] maleimides,[5] benzoquinones,[6a] vinyl and dichloromethane failed to give improved results.
sulfones,[6b–e] vinyl phosphonates,[6f,g] alkylidenemalo- In these cases moderate yields were observed mainly
nates,[6h] a-keto-a,b-unsaturated esters,[2c] and g-keto- because of poor conversion (entries 2–4). However,
a,b-unsaturated esters,[2d] have been revealed as suita-
ble Michael acceptors for this reaction, more efforts
for the discovery of new Michael acceptors are still
required. This campaign would fully demonstrate the
synthetic usage of this reaction.
Thiol esters are useful synthetic intermediates that
can be converted into aldehydes, ketones and lactones
conveniently.[7] Compared with a,b-unsaturated esters,
a,b-unsaturated thiol esters are more electron-defi-
cient olefins. Thus, we decided to explore the possibil-
ity of whether the a,b-unsaturated thiol esters could
reacted with the aldehydes under the catalysis of
chiral amines. Initially, we tried to use some acrylic
thio esters and b-phenyl-substituted a,b-unsaturated a,b-unsaturated thiol esters.
Scheme 1. Organocatalytic Michael addition of aldehydes to
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Shaolin Zhu et al.
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Table 1. Optimization of reaction conditions.[a]
Table 2. Enantioselective Michael addition of aldehydes to
3-ethylsulfanylcarbonyl-acrylic acid ethyl ester 3a.[a]
Entry
Product
t
Yield
[%][b]
dr[c]
ee
[h]
[%][d]
1
2
22
48
100
94
7:1
7:1
>99
>99
Entry Solvent
Additive
t
Yield
dr[c]
ee
[h] [%][b]
[%][d]
1
2
3
4
5
6
7
8
H2O
HOAc
HOAc
HOAc
HOAc
24
24
24
24
24
22
58
42
47
58
85
100
96
85
6:1
12:1
3:1
6:1
6:1
7:1
>99
>99
95
>99
>99
>99
>99
>99
CHCl3
PhCH3
CH2Cl2
CH3CN HOAc
69[e]
90
9:1
6:1
8:1
8:1
>99
>99
>99
>99
MeOH
MeOH
MeOH
HOAc
3
4
5
38
27
36
26
PhCO2H 24
2:1
11:1
HOAc[e]
24
[a]
Reaction conditions: 2a (0.4 mmol), 3a (0.2 mmol),
10 mol% 1, 50 mol% HOAc, 0.4 mL of solvent, 08C for
1 h, then room temperature for the indicated time.
Isolated yield.
Determined by H NMR analysis.
Determined by chiral phase HPLC analysis for the syn-
[b]
[c]
[d]
1
100
95
product.
10 mol% HOAc was used.
[e]
6
the reaction in acetonitrile produced 4a in 85% yield
with 6:1 diastereoselectivity and greater than 99% ee
(entry 5), while a better yield was obtained when
methanol was chosen as a solvent (entry 6). To in-
crease the diastereoselectivity by slowing down the
reaction, we tried to switch the additive to benzoic
acid, but disappointingly found that the diastereose-
lectivity dropped dramatically (entry 7). However, re-
ducing the ratio of the catalyst 1 and HOAc gave im-
proved diastereoselectivity, but the reaction yield de-
creased slightly (entry 8). Based on these studies, we
decided to use methanol as a solvent, and a ratio of
1:5 for catalyst and additive in later investigations.
[a]
Reaction conditions: thio ester (0.2 mmol), aldehyde
(0.4 mmol), 10 mol% 1, 50 mol% HOAc, 0.4 mL of
methanol, 08C for 1 h, then room temperature for the in-
dicated time.
[b]
[c]
[d]
Isolated yield.
Determined by H NMR analysis.
1
Determined by chiral phase HPLC analysis for the syn-
product.
20 mol% 1 and 100 mol% HOAc were used.
[e]
Under these conditions, fumaric diesters did not give successfully as the Michael donors. However, the re-
the desired adducts, indicating that a thioester group action became slower when branched aldehydes such
is important in this case. Noteworthy is that in all as isovaleraldehyde were used (entry 3, Table 2). In
cases 4a was isolated as a single regioisomer, indicat- this case only a moderate yield (69%) was obtained
ing that this addition occurred exclusively at the b-po- even when the catalyst loading was increased. Besides
sition of the thio ester. This is understandable because these simple alkyl substituents, benzoxy-, olefin- and
the thio ester group and the ester group have an over alkyne-embodied substrates were compatible with
1000-fold difference in electron-withdrawing ability these conditions, giving the corresponding adducts in
(pKa is 21.0 for CH3COSEt, and 25.6 for excellent yields (entries 4–6). The additional function-
CH3COOEt).[8]
With the optimized reaction conditions in hand, we afford molecules with higher complexity.
al groups in these products can be further modified to
explored the scope and limitations of the reaction by
We next checked the scope of the reaction by using
varying the aldehydes. The results are summarized in different thio esters. As shown in Table 3, the ethyl,
Table 2. In general, the Michael adducts were ob- benzyl and tert-butyl ester moieties have limited influ-
tained in good yield and diastereoselectivity with ex- ence on the yield of this reaction, while high diaste-
cellent enantioselectivity (entries 1–6). Not only n- reoselectivity and enantioselectivity were also ob-
pentanal, but also other linear aldehydes such as 3- tained (entries 1, 2 and entries 4–6). Meanwhile, the
phenylpropanal (entry 2, Table 2), could be employed substituents at the sulfur atom play an important role
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Enantioselective Organocatalytic Conjugate Addition of Aldehydes
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Table 3. Enantioselective Michael addition of n-pentanal to
3-sulfanylcarbonyl-acrylic acid ester.[a]
Entry
Product
t
Yield
[%][b]
dr[c]
ee
[h]
[%][d]
1
2
3
4
5
6
19
99
12:1
9:1
>99
>99
>99
>99
>99
>99
21
100
100
99
Scheme 2. Synthesis of d-lactones 5 and hydrazone 6.
23
12:1
12:1
9:1
tuted thio esters, using 2 mol% catalyst could give sat-
isfactory results (entries 8 and 9). These results indi-
cated that the ability for promoting the reaction is
Et~Bn<Ph<p-BrPh~CH2CF3, which is consistent
with the order of their electron-withdrawing ability.
Additionally, it was found that the ester group can be
changed to an amide without any significant effect on
the reaction rate, but provided the adduct 4o with
moderate enantioselectivity (entry 10).
Reduction of compounds 4a and 4g with NaBH4
followed by treatment with TsOH afforded d-lactones
5a and 5g in good yields [Eq. (1), Scheme 2], indicat-
ing that the present products could be converted into
some useful chiral building blocks.
4[e]
3.5[e]
5[e]
94
90
9:1
7
8
2[e]
7[f]
93
91
12:1
8:1
>99
92
Based on previous studies, the present Michael ad-
ducts should have syn selectivity.[9] This hypothesis
was further confirmed by an X-ray analysis of hydra-
zone 6 (Figure 1) that was generated from the reac-
tion of 4k with p-toluenesulfonylhydrazide [Eq. (2),
Scheme 2].[10]
In conclusion, we have revealed that g-ester substi-
tuted a,b-unsaturated thiol esters could react with al-
dehydes to deliver the corresponding Michael ad-
ducts, which provides another successful example for
chiral amine-catalyzed Michael additions. Considering
9
7[f]
92
92
8:1
8:1
>99
10
5[e]
82
[a]
Reaction conditions: thio ester (0.2 mmol), aldehyde
(0.4 mmol), 10 mol% 1, 50 mol% HOAc, 0.4 mL of sol-
vent, 08C for 1 h, then room temperature for the indicat-
ed time.
[b]
[c]
[d]
Isolated yield.
Determined by H NMR analysis.
1
Determined by chiral phase HPLC analysis for the syn-
product.
5 mol% 1 was used
2 mol% 1 was used.
[e]
[f]
for reaction rate. For examples, when phenyl thio
esters were employed, excellent results were obtained
by using 5 mol% catalyst in less than 5 h (entries 4–
6). The 4-bromophenyl thio ester reacted faster than
corresponding phenyl thio ester (compare entries 4
and 7). For 4-bromophenyl- and trifluoroethyl-substi- Figure 1. X-ray crystal structure of the hydrazone 6.
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Shaolin Zhu et al.
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that the diverse functional groups in these adducts are
ready for further conversions, the present method
may find wide applications in organic synthesis.
Experimental Section
General Procedure for Organocatalytic Michael
Addition of Aldehydes to a,b-Unsaturated Thiol
Esters
To a suspension of catalyst 1 (1–10 mol%), HOAc (5–50
mol%) and a,b-unsaturated thiol esters (0.20 mmol) in
methanol was added aldehyde (0.4 mmol) at 08C. After the
reaction mixture had been stirred for 1 h at the same tem-
perature, it was allowed to warm to room temperature. The
stirring was continued until the a,b-unsaturated thiol ester
was consumed (monitored by TLC). The reaction mixture
was directly loaded on a silica gel column, and eluted with
30:1 to 15:1 n-pentane and ethyl acetate to afford the Mi-
chael adduct.
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Acknowledgements
We are grateful to the Chinese Academy of Sciences and the
National Natural Science Foundation of China (grant
20621062) for their financial support.
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Adv. Synth. Catal. 2009, 351, 2563 – 2566