Chiral bicyclic guanidine as a versatile bronsted base catalyst for the enantioselective michael reactions of dithiomalonates and β-keto thioesters

Article abstract of DOI:10.1002/adsc.200700326

A chiral bicyclic guanidine was developed as a versatile Bronsted base catalyst for the enantioselective Michael reactions of dithiomalonates and β-keto thioesters using a range of acceptors including maleimides, cyclic enones, furanone and acyclic 1,4-di

Full text of DOI:10.1002/adsc.200700326

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DOI: 10.1002/adsc.200700326
Chiral Bicyclic Guanidine as a Versatile Brønsted Base Catalyst
for the Enantioselective Michael Reactions of Dithiomalonates
and b-KetoThioesters
Weiping Ye,a,b Zhiyong Jiang,a,b Yujun Zhao,a Serena Li Min Goh,a
Dasheng Leow,a Ying-Teck Soh,a and Choon-Hong Tana,*
a
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Republic of Singapore
Fax : (+65)-6779-1691; e-mail: chmtanch@nus.edu.sg
W. Y. and Z. J. made equal contributions to this work
b
Received: July 5, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A chiral bicyclic guanidine was developed
as a versatile Brønsted base catalyst for the enan-
tioselective Michael reactions of dithiomalonates
and b-keto thioesters using a range of acceptors in-
cluding maleimides, cyclic enones, furanone and
acyclic 1,4-dicarbonylbutenes.
acceptors, including maleimides, cyclic enones, fura-
none and acyclic 1,4-dioxobutenes.
Our initial investigation revealed that with 20
mol% of guanidine 1, dimethyl malonate 3 under-
went a Michael addition to N-ethyl maleimide 2a [Eq.
(1)]. The reaction was relatively slow, giving the Mi-
chael adduct 4 in only 20% yield after 96 h and with
47% ee. The a-proton acidity of thioesters is usually
higher than that of their corresponding esters due to
the poor overlap of the C(2p) and S(3p) orbitals. This
enhanced acidity makes thioesters useful enol equiva-
lents in the laboratory as well as in nature (e.g., as
acyl coenzyme A demonstrates). Seeking a more
Keywords: asymmetric catalysis; dithiomalonates;
guanidines; Michael addition; organic catalysis
Catalytic enantioselective Michael reactions are active donor, we prepared a series of S,S’-dialkyl di-
[1]
À
widely used for the construction of C C bonds. Tre- thiomalonates and they were tested in place of the di-
mendous advances have been achieved using Lewis alkyl malonates. Significant improvements in both re-
acidic, metal-based catalysts for the Michael reaction action rates and ee values were achieved [Eq. (2)].
of 1,3-dicarbonyl compounds.[2] Organocatalytic ap-
proaches have also gained wide popularity in recent
years.[3] Successful organocatalysts include imidazoli-
dines,[4] bifunctional thioureas,[5] Cinchona alkaloids
and derivatives,[6] quaternary ammonium salts[7] and a
proline-tetrazole.[8] These catalysts are typically re-
ported as highly effective for a particular type of Mi-
chael acceptor. Catalysts that are applicable for a
range of substrates are still of high interest.
Guanidines have been shown to catalyze the
Strecker reaction with high enantioselectivity.[9] Chiral
guanidines and guanidinium salts were also found to
be useful for several other base-catalyzed reactions.[10]
Recently, highly efficient axially chiral guanidine cata-
lysts were reported.[1] We have also reported a chiral
bicyclic guanidine-catalyzed anthrone Diels–Alder re-
action.[12] Herein, we report the development of chiral
bicyclic guanidine 1 as a versatile Brønsted base cata-
With 10 mol% of catalyst 1, the reaction between
lyst for the enantioselective Michael reactions of di- S,S’-di-tert-butyl dithiomalonate 5a and maleimide 2a
thiomalonates and b-keto thioesters using a range of was completed within 1 h at room temperature, giving
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Enantioselective Michael Reactions of Dithiomalonates and b-Keto Thioesters
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Table 2. Chiral bicyclic guanidine 1-catalyzed Michael reactions of ethyl maleimide and b-
keto esters [Eq. (3)].
the Michael adduct 6a in
97% yield and 78% ee
(Table 1, entry 1). This dra-
matic rate improvement al-
lowed us to conduct the re-
action at lower tempera-
tures. At À208C, the enan-
tioselectivity improved to
90% ee (entry 2). By low-
ering the temperature fur-
ther to À508C, the ee was
improved to 95% and the
Michael adduct was ob-
Entry
7 [R1, R2]
8
1 [mol%]
t [h]
Yield [%][a]
ee [%][b]
1
7a [Ph, Ph]
7b [Ph, Me]
7c [Ph, OEt]
7d [Ph, S-t-Bu]
7e [Me, S-t-Bu]
7f [4-MeOPh, S-t-Bu]
7g [Ph, SC(Me)2CH2C(Me)3]
8a
8b
8c
8d
8e
8f
8g
20
20
20
2
2
2
60
120
60
8
20
17
24
99
99
99
99
99
99
90
92
95, 96
88
94, 95
90, 90
94, 95
96, 96
2[c]
3[c,d]
tained with a yield of 98% 4[c]
5[c]
(entry 3). Subsequently, we
6[c,e]
developed a more hindered
dithiomalonate 5b. Inter-
estingly, the rate of reac-
tion with this donor was
not slower than with 5a.
The reactions of various
alkyl maleimides 2a–d and
5b were conducted with 2
7[c,f]
1
[a]
Isolated yield.
Chiral HPLC.
dr 1:1.
[b]
[c]
[d]
[e]
[f]
ee determined after decarboxylation.
À608C.
Methylmaleimide as acceptor.
Table 1. Michael addition of S,S’-dialkyl dithiomaloates to mol% of guanidine 1, adducts 8d–f were obtained in
alkyl maleimides catalyzed by bicyclic guanidine 1 [Eq. (2)].
high yields and high ees with diastereomeric ratios of
approximately 1:1 (entries 4–6). Once again, it was
observed that the reaction rate of the more hindered
donor 7g was comparable to that of 7f and it can op-
erate under a low catalyst loading of 1 mol%
(entry 7). At À508C, the reaction with 2a gave adduct
8g without compromising the yield and ee. We are
currently exploring b-keto thioesters containing elec-
tron-withdrawing aryl groups and we expect these to
be highly active donors.
Entry 2 [R] Yield ee
5
6
1
T
t
[mol%] [oC] [h] [%][a] [%][b]
1
2
3
4
5
6
2a [Et]
5a 6a 10
5a 6a 10
5a 6a 10
5b 6b 2
25
1
97
78
90
95
96
97
97
2a [Et]
2a [Et]
2a [Et]
2b [Me]
2c [n-
À20 4 99
À50 6 98
À50 20 99
À50 20 99
À50 24 87
5b 6c
2
5b 6d 2
C6H13]
Other cyclic substrates, such as cyclic enones and
furanone were also explored as substrates for this re-
action [Eq. (4)]. In general, these reactions were also
slow. Using 5–10 mol% of guanidine 1 as catalyst, 2-
cyclopenten-1-one 9a underwent Michael addition
with various thioesters (Table 3, entries 1–3), giving
adducts 10a–c in good enantioselectivities. With di-
7
2d [CH2- 5b 6e 2
c-hexyl]
À50 24 95
À70 14 94
97
97
8
2e [Bn]
5b 6f 5
[a]
[b]
Isolated yield.
Chiral HPLC.
mol% of guanidine 1. The corresponding adducts 6b– thiomalonate 5b, the catalyst loading can be de-
e (entries 4–7) were obtained in excellent yields (87– creased to 5 mol%. The reaction was completed in
99%) and high ees (96–97%). The reaction of benzyl 30 h, giving 10b in 91% yield and 97% ee (entry 2).
maleimide 2e and 5b required 5 mol% of guanidine The reactions with 2-cyclohexen-1-one 9b and 2
1; a lower temperature of À708C was needed to ach- furanone 9c with dithiomalonate 5b also worked well
ieve high ee for adduct 6f (entry 8). and gave adducts with good ees (entries 4 and 5). To
ACHTREUNG(5H)-
Further studies revealed that 1,3-diketones 7a, b the best of our knowledge, there were no previous re-
and b-keto ester 7c also add to maleimides with high ports of the catalytic enantioselective Michael addi-
enantioselectivity [Eq. (3)]. In these cases, the Mi- tion of 1,3-dicarbonyl donors to lactones.[13] The scar-
chael adducts 8a–c were all obtained in high yields city of such direct Michael reactions maybe due to
and good ees (Table 2, entries 1–3). However, these the labile nature of lactones under strongly basic and
reactions were slower and required 20 mol% of cata- Lewis acidic conditions.
lyst. Upon using aryl and alkyl b-keto thioesters 7d–f,
To extend the scope of this reaction, we searched
the reaction rate was considerably enhanced. Using 2 and found that methyl trans-4-oxo-4-phenylbut-2-
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Weiping Ye et al.
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Table 3. Chiral bicyclic guanidine 1-catalyzed Michael reac-
tions of cyclic enones and furanone 9c [Eq. (4)].
and 3) showed no significant change in ee and yield.
A series of ethyl 4-oxo-4-arylbut-2-enoates 11d–k (en-
tries 4–11) with various aryl substitutents were pre-
pared. These were found to be excellent acceptors
and the substitution on the aromatic ring did not
affect the reaction in terms of yield and ee. As expect-
ed, reaction rates were slightly faster for substrates
with electron-poor aryl groups. This is a highly regio-
selective reaction; only the a-alkyl esters 12a–k were
detected. The other regioisomer in which the addition
occurs at the b-position to the ester group was not ob-
served at all. Absolute configurations and regiochem-
istry were determined through X-ray crystallography
(see Supporting Information).
In order to demonstrate the synthetic utility of this
methodology and to determine the absolute configu-
ration of the substituted succinimides 6a–f, the first
enantioselective synthesis of (S)-(+)-homo-b-proline
16 was carried out. (S)-(+)-homo-b-Proline is a
potent g-aminobutyric acid (GABA) agonist and
uptake inhibitor.[14] GABA is a neurotransmitter pres-
ent in 60–70% of all synapses and has been implicat-
ed in several neurological disorders such as anxiety,
Entry 9 Donor 10
1
T
t
Yield
ee
[mol%] [oC] [h] [%][a]
[%][b]
1
9a 5a
9a 5b
9a 7g
9b 5b
9c 5b
10a 10
10b 5
10c 10
10d 20
10e 20
À50 48 96
À50 30 91
À50 41 99
À20 60 86
À50 56 85
95
97
96, 98
90
96
2
3[c]
4
5
[a]
[b]
[c]
Isolated yield.
Chiral HPLC.
dr 1:1.
enoate 11a (Table 4, entry 1) was a useful acyclic Mi- pain, Parkinsonꢁs disease and epilepsy.[15] Current
chael acceptor [Eq. (5)]. With 5 mol% of guanidine methods to prepare enantiopure 16 include the reso-
1, dialkyl dithiomalonate 5b reacted smoothly to give lution of its racemate using pig liver esterase,[16] the
adduct 12a in 96% yield and 92% ee. The reactions use of (S)-(À)-1-phenylethylamine as a chiral auxilia-
of the ethyl and benzyl analogues 11b, c (entries 2 ry,[14d,17] and the chiral pool approach using aspartic
acid.[18] We embarked on the synthesis from 300 mg of
13, available in 92% ee from the chiral guanidine 1-
catalyzed Michael reaction (see Supporting Informa-
tion). Substituted succinimide 14 was obtained in
Table 4. Chiral bicyclic guanidine 1-catalyzed Michael reac-
tions of alkyl trans-4-oxo-4-arylbutenoates [Eq. (5)].
99% yield through the decarboxylation of one of the
thioesters (Scheme 1). No racemization was observed
Entry 11 [R3, R4]
Product Yield
[%][a]
ee
[%][b]
1
2
3
4
11a [Ph, Me]
11b [Ph, Et]
11c [Ph, Bn]
11d [3-MeOC6H4,
Et]
12a
12b
12c
12d
96
99
85
99
92
92
92
94
Scheme 1. Synthesis of (S)-(+)-homo-b-proline. Reagents
and conditions: a) NaCl (3 equivs.), DMSO/H2O (10:1),
1108C, 9 h (99%); b) LiAlH4, THF, reflux, 22 h (92%); c)
(i) HOOCNH4, Pd/C, MeOH, reflux, 0.5 h. (ii) CbzCl,
K2CO3, THF/H2O, À108C, 0.5 h. (iii) Jonesꢁ reagent, ace-
tone, À108C, 0.5 h. (iv) H2, Pd/C, MeOH, r.t., 2 h (80%
from 15).
5
6
7
8
11e [2-naphthyl, Et] 12e
11f [4-t-BuC6H4, Et] 12f
99
87
90
99
92
94
91
94
11g [4-PhC6H4, Et]
11h [3,5-Me2C6H4,
Et]
12g
12h
9
11i [2-furyl, Et]
11j [4-ClC6H4, Et]
12i
12j
99
99
94
90
92
90
10
11[c]
11k [4-CNC6H4, Et] 12k
[a]
when 14 was analyzed using chiral HPLC. Reduction
of 14 with LiAlH4 went smoothly to generate the N-
benzyl-homo-b-prolinol 15. Jonesꢁ oxidation of 15 was
Isolated yield.
[b]
[c]
Chiral HPLC.
À708C.
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Enantioselective Michael Reactions of Dithiomalonates and b-Keto Thioesters
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capricious and gave side products on some occasions. Experimental Section
Exchanging the amino protecting group from a Bn to
a Cbz group circumvented this problem. This is fol- Typical Procedure for the Michael Reaction
lowed by Jonesꢁ oxidation and hydrogenolysis. These
few steps were carried out efficiently, without the
need of chromatographic purification and were ach-
ieved with a yield of 80% yield from 15. This efficient
enantioselective synthesis of (S)-(+)-homo-b-proline
16 (overall yield of 73% from 13) allowed the unam-
biguous assignment of the absolute configuration of
succinimides 6a–f. The optical rotation of the synthet-
ic (S)-(+)-homo-b-proline 16 matched well with
values reported in the literature.
N-Ethylmaleimide 2a (0.1 mmol, 1.0 equiv., 12.5 mg) and di-
thiomalonate 5b (0.3 mmol, 3.0 equivs., 108 mg) were dis-
solved in toluene (0.395 mL) and stirred at À508C for
30 min. A pre-cooled solution of catalyst 1 (0.002 mmol,
0.02 equivs., 0.447 mg in 5 mL toluene) was added and the
reaction mixture was stirred at À508C. Upon completion of
the reaction (20 h), the reaction mixture was loaded onto a
short silica gel column and purified by gradient elution with
hexane/ethyl acetate mixtures (0–10/1 ratio). After removing
the solvent, product 6b was obtained as colorless oil; yield:
43.6 mg (99%).
In summary, we have shown that chiral bicyclic gua-
nidine 1 is a versatile Brønsted base catalyst for enan-
tioselective Michael reactions. This is the first exam-
ple of highly enantioselective Michael reactions of di-
thiomalonates and b-keto thioesters. These donors
were previously avoided as they might poison organo-
metallic catalysts. We have shown that they are excel-
lent alternatives to conventional 1,3-dicarbonyl com-
pounds. Both reaction rates and enantioselectivities
can be dramatically improved. We postulate that
many other organocatalytic reactions could benefit
from this active donor, allowing a significant reduc-
tion in the catalyst loading. Thioesters are amenable
to modification and mild conditions for decarboxyla-
tion were demonstrated in the synthesis of (S)-(+)-
homo-b-proline 16. Thioesters can be easily trans-
formed into ketones, aldehydes or b-keto esters.[19]
The dithiomalonate group can also be directly re-
duced to a saturated alcohol using Raney nickel.[20]
We have also shown that chiral bicyclic guanidine 1
is versatile and compatible for a range of Michael ac-
ceptors. Maleimides are extremely useful substrates in
asymmetric catalytic Michael reactions.[21] A large
number of biologically interesting a-substituted succi-
nimides,[22] functionalized pyrrolidines[23] and other
heterocycles can potentially be obtained via this ap-
proach. We demonstrated this through the first enan-
tioselective synthesis of (S)-(+)-homo-b-proline 16.
Simple ring opening procedures would also mean
rapid entry to functionalized open chain deriva-
tives.[24] Michael addition of cyclic enones with 1,3-di-
carbonyl compounds are well studied using organo-
metallic catalysts. However, there are fewer organoca-
talytic examples.[8,25] Both 2(5H)-furanone 9c and the
alkyl 4-oxo-4-arylbut-2-enoates 11a–k are substrates
that are much less studied and there are only a few
isolated examples of asymmetric Michael reactions
using these substrates.[4b,13,25a,26] This methodology can
thus provide a variety of new enantiopure compounds
such as 10e and 12a–k which are inaccessible using
other approaches.
Supporting Information
Experimental procedures, characterization and spectroscopic
data (PDF) are available as Supporting Information.
Acknowledgements
This workis supported by a grant (R-143–000–222–112) and
scholarship (to WY) from the National University of Singa-
pore. We thankthe Medicinal Chemistry Program for finan-
cial support and Dr Martin J. Lear for useful suggestions.
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