ARKIVOC 2002 (vii) 167-196
Issue in Honor of Prof. S. V. Kessar
Catalytic, enatioselective Michael addition reactions
S. C. Jha and N. N. Joshi*
Division of Organic Synthesis, National Chemical Laboratory, Pune-411008, India.
E-mail: joshi@ems.ncl.res.in
Dedicated to Professor S.V.Kessar on the occasion of his 70th birthday
(received 28 May 02; accepted 12 Sep 02; published on the web 20 Sep 02)
Abstract
This review summarizes the tremendous achievements in the field of catalytic enantioselective
Michael addition reaction involving the attack of soft nucleophiles on α,β- unsaturated systems.
The reaction has evolved during past two decades, from stoichiometric to catalytic. A large
number of efficient catalytic systems have been used to generate chiral Michael adducts in high
optical purity. Several chiral alkaloids were used for the enantioselective addition of thiols and
dialkylmalonates to cyclic and linear enones to give product in moderate to high
enantioselectivity. Chiral crown ethers in conjugation with metal alkoxides were found to be the
catalyst of choice for the addition of substituted α-phenylesters to linear enones. Proline derived
catalysts gave product in moderate in moderate to high enantioselectivity where NO2 group was
present as an activator in either Michael donor or acceptor. BINAP based catalysts were found to
be superior in Michael addition of α-nitrile substituted esters to linear enones. A new class of
heterobimetallic catalysts based on BINOL ligand was found to be highly versatile for an array
of Michael donors and acceptors to provide products in very high optical purity. Metal
complexes based on chiral N,N-dioxides were found to be superior for the addition of arylthiols
to both linear and cyclic enones to have product in high enantiomeric excess.
Keywords: Michael addition, nucleophiles, catalysis, chiral ligands, enantioselectivity,
heterobimetallic
Contents
1.
2.
Introduction
Organocatalysts
2.1. Optically active alkaloids
2.2. Polymer supported catalysts
2.3. Crown ethers
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2.4. Chiral diamines
2.5. Amino acid and derivatives
2.6. Chiral oxazoline
3. Organometallic catalysts
3.1. Metal salts of amino acids
3.2. Metal-diamine complexes
3.3. Transition metal complexes
3.4. Heterobimetallic complexes
3.5. Chiral N,N-dioxides
3.6. Miscellaneous catalysts
4. Conclusions
1. Introduction
Michael addition reaction refers to the addition of carbanion to unsaturated systems in
conjugation with an activating group. As enormous amount of work has been documented in this
area, we will survey only the work involving catalytic enantioselective addition of stabilized soft
nucleophiles (eqn. 1).
C
C
+
O
C
EWG
base
EWG
EWG
C
C
EWG
C
O
(1)
H
EWG = CO2R, CO2NR2, CN, NO2 etc.
Essentially there are three ways to generate chiral adducts using Michael reaction namely,
(a) Addition of chiral Michael donor to achiral Michael acceptor – here the source of chirality is
present in the Michael donor which controls the new stereogenic center formed in the product.
(eqn. 2).
O
O
CH3
S
Ph
..
CO2Et
+
CO2Et
base
CO2t-Bu
CO2Et
Ph S
..
CO2Et
(2)
CO2Et
H3C
(b). Addition of achiral Michael donor to chiral Michael acceptor – here the source of chirality is
present in the Michael acceptor which controls the new stereogenic center formed in the product
(eqn. 3).
NR1R2
CH3NO2
+
R3
EtO
NR1R2
base
R3
O
O
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(c). Both the reactants i.e. Michael donor and Michael acceptor are achiral however the catalyst
used for the reaction is chiral (eqn. 4)
CO2R
CO2R
Chiral catalyst
+
(4)
O
O
O
O
It is the last type of reaction which has received much attention in recent times mainly
because of the easy availability of the starting reactants (as they are achiral or racemic) and also
because of the fact that reaction could be promoted by the use of chiral additive in catalytic
amount. The asymmetric Michael reaction could be categorized in two groups:
(i). Enantioselective addition of prochiral enolates i.e. Michael donor to acceptor.
(ii). Enantioselective addition of enolates to prochiral Michael acceptor (Figure 1).
CH2=CH-Z
Nu
O
O
H
H
X
X
Y
Y
H
Prochiral
donor
Prochiral
acceptor
O
O
ZCH2CH2
H
X
X
Y
Y
Reaction of Prochiral Donor
H Nu
Reaction of Prochiral Acceptor
Figure 1
In the former reaction, there is discrimination of the enantioface of the prochiral Michael
donor, and the asymmetric centers are formed on the donor. In the latter reaction, there is
discrimination of the enantioface of the prochiral Michael acceptor and the resulting asymmetric
centers are formed on the Micahel acceptor. Since the first reported1 example of catalytic
enantioselective Michael addition reaction by Wynberg in 1975, there has been plethora of
publications in this area and the reaction has become one of the important methods for the
enantioselective C-C bond formation. Several chiral additives have been used for promoting the
reaction including chiral alkaloids, chiral diamines, chiral alkoxides, chiral amino acids, chiral
lanthanoide complexes etc. Due to the wide variations in the nature of catalyst used for the
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reaction, it becomes important to classify Michael reaction according to the kind of catalyst used.
Broadly they can be categorized in two groups viz. organo catalysts and organometallic catalysts.
2. Organo Catalysts
2.1. Optically active alkaloids
Various alkaloids based on cinchona and ephedra have been used for the enantioselective
Michael addition. Indeed the catalytic enantioselective Michael reaction first reported1 by
Wynberg utilized optically active quinine as catalyst for the addition of 1-oxo-2-indanecarboxylate (1) to methyl vinyl ketone giving Michael adduct (2) in 68 % ee (eqn- 5).
CO2CH3
O
CO2CH3
quinine
+
(5)
toluene, rt
O
O
O
1
(68% ee)
2
Various chiral cinchona alkaloids which have been used for Michael addition reaction are
shown in Figure 2.
H
N
H
HO
N
HO
H
HO
MeO
N
3
+
CF3
N
5
4
N
Br
+
R4
N
HO
H
N
R'
OR
Cl
N
Br
+
MeO
MeO
X
N
N
6
7
H
N
Br
H
+
O
HO
OMe
N
8
N
H3C
+
OH
N
9
Figure 2
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Addition of aromatic thiols to conjugated cycloalkenones was also reported. Quinine or N(p-nitrobenzyl) quininium chloride (6) showed comparable catalytic activity (eqn. 6).2, 3
SH
O
SR
O
6 (0.5 mol%)
toluene, rt
+
R
X
(6)
R'
R
R'
40% ee
Catalysts containing the β-hydroxy amine moiety (cinchona and ephedra) gave higher
reaction rates and higher ee than the catalyst without a hydroxyl functionality. Polar solvents and
concentrated reaction solutions were counterproductive for the enantioselectivity. It was
proposed4 that erythro cinchona and ephedra alkaloids catalyze the reaction via tight transition
state complex comprising all the three species viz. thiol, enone and the catalyst (Figure 3).
R
k1
N
R
k1
H
N
+
H
H
S
OH
OH
MeO
R=
N
k2
k2
R
O
N
+
H
H
S
O
H
R
O
R
N
+
H
H
+
H
S
H
S
O
O
H
N
H
O
O
Tranistion state
Product + Catalyst
Figure 3
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An electrostatic interaction between the thiol anion and the ammonium cation and a hydrogen
bond between the catalyst hydroxyl group and the enone carbonyl group stabilizes the geometry
of these complexes whereas steric factors imposes a free energy difference between the two
possible orientations of the enone which results in the formation of unequal amounts of R and S
products. Threo cinchona alkaloids and the catalyst without a hydroxyl group lack at least one of
the stabilizing interactions leading to less stabilized transition states and consequently lower
enantioselectivity.
Conn et. al. reported5 enantioselective addition of 2-alkylindanones to methyl vinyl ketone.
Using [p-(trifluoromethyl)benzyl] cinchoninium bromide (5) the Michael adduct (10) was
obtained in upto 80% ee and in 95% overall yield (eqn.7).
Cl
Cl
O
O
Cl
Cl
5, toluene
+
(7)
H
MeO
O
MeO
O
10 (80% ee)
Colonna et. al. reported6 the addition of thiols to α,β-unsaturated sulphoximides to obtain the
product, albeit in low enantiomeric excess. Several catalysts like quinine, N-benzyl quininium
chloride (6), N-dodecyl-N-methyl ephedrinium bromide were examined (eqn. 8).
O
O
O
O
N N S
CH2
+
6, CH2Cl2
RSH
N N S
R
* C SR
R
O
H2
(8)
O
13% ee
Mukaiyama et. al. reported7 asymmetric addition of thiophenol to dialkyl maleate using
catalysts like cinchonine, cinchonidine, quinine, quinidine. Although product with ee as high as
86% was obtained the overall yield was only 7% that to after several days of stirring at 0 0C.
However reaction at 20 0C gave product (11) in 92% yield and in 55% ee (eqn.9).
CO2R
CO2R
+
CO2R
PhSH
catalyst
toluene
(9)
Ph
CO2R
11
Matsumoto et. al. carried out addition of nitromethane to chalcone under high pressure.
Various cinchona based alkaloids were used for the reaction , quinidine giving the best result8
with up to 26% enantioselectivity (eqn. 10).
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+
PhCH CHCOPh
chiral base
high pressure
CH3NO2
CH2NO2
Ph
C CH2COPh
H
(10)
26% ee
A novel synthesis of optically active 2-phenylpropionic acid or esters which can be used for
the synthesis of [S]-naproxen, a non steroidal anti-inflammatory agent, was reported by Dike et.
al.9 The key step in the reaction was the enantioselective protonation of the prochiral carbanion
generated in the addition of benzene thiol to α-aryl acrylates catalyzed by cinchona alkaloids.
Amongst various alkaloids used, quinidine gave the best result. An interesting feature of this
addition was the formation of a new chiral center one atom away from the incoming sulphur
atom. The benzene thiol group can be removed easily by standard Raney-nickel desulphurization
to give the corresponding α-aryl propionates (Scheme-1).
O-iPr
Ar
+
4
toluene
PhSH
H
SPh
O-iPr
Ar
O
O
H
1. Raney-Nickel
2. AcOH - HCl
3. Crystallisation
Ar
CH3
O-iPr
O
[S] Naproxen (85% ee)
Scheme 1
Recently Skarzewski et. al. reported10 enantioselective addition of thiophenols to chalcones
in the presence of cinchonine to give Michael adduct (12) in up to 80% ee (eqn. 11).
1
R
R
R
1
R
2
+
R3SH
2
cinchonine (1.5 mol%)
toluene
O
R3S
(11)
O
12 (27-80% ee)
11
Kim et. al. reported the addition of malonates and nitromethane to chalcone using chiral
quaternary ammonium salts derived from cinchona. Cinchona derived alkaloids (e.g. 8) were
used giving product in up to 70% ee (eqn. 12 & 13).
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CO2R
O
1
Ar
Ar
+
2
CH2(CO2R)2
O
CO2R
8 (10 mol%)
Ar
K2CO3 , toluene
(12)
Ar
45-70% ee
O
1
Ar
Ar
+
2
O2 N
8 (7 mol%)
CH3NO2
O
1
t-BuOK, toluene
(13)
2
Ar
Ar
35-91% ee
O’Donell et. al. reported12 the preparation of optically active unsaturated α-amino derivatives
by the conjugate addition of schiff base ester derivatives (13) to Michael acceptor using
cinchona derivatized (7) along with non ionic phosphazene bases (Schwesinger bases)
BEMP(14) or BTPP (15).
+
CO2-tBu
Ph2C N
H 2C C
H
7 (0.1 eq)
z
(14)
CH2CH2-Z
14/15, CH2Cl2
13
CO2-tBu
Ph2C N
56-89% ee
N-tBu
N-tBu
N P N
N
Me2N P
NMe2
BTPP (15)
BEMP (14)
In addition to cinchona based alkaloids, ephedra based alkaloids have also been used (Figure 4).
H
3
+ CHCH
N
HO
3
Br
Ph
H
+N Me
X
C12H25 CHCH3
3
Ph
Ph
17
16
Figure 4
Wynberg et. al. reported13 the addition of nitromethane to chalcone using N-dodecyl fluoride
of N-methyl ephedrine (17) to obtain product (18) in 23% ee (eqn. 15).
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O2 N
O
+
CH3NO2
17
toluene
Ph
Ph
O
(15)
Ph
Ph
18 (23% ee)
Loupy et. al. reported14 the addition of diethylacetylamine malonate (19) to chalcone using
N-methyl-N-benzyl ephedrinium bromide (16) to give product (20) in 66% ee (eqn. 16).
O
O
+
Ph
Ph
H
N CO2Et
CO2Et
H
H3C
NHCOCH3
CO2Et
CO2Et
16/KOH
O
Ph
(16)
Ph
19
20 (66% ee)
2.2. Polymer supported catalysts
The principal drawback in the use of alkaloid catalysts is the relative difficulty of separating the
product from the catalyst. One way to overcome this drawback would be to fix the alkaloid on a
solid support in a way that retains the stereochemistry of the alkaloid. To serve this purpose,
various polmer supported alkaloids were prepared (Figure 5).
(CH2-CH) n
(CH-CH2) n
(CH2-CH) n
(CH2-CH)
CN
H OH
CN
N
N
OH
CH2
R
N
21
N
CH3
CH2CH2
HOH2C
N
(CH-CH2) n
H
X CH3
23
22
Figure 5
Burri et. al. carried out15 addition of 1-oxo-2-indane carboxylate to methyl vinyl ketone
using 21 to obtain 24 in 42% ee. The same group reported the addition of dodecanethiol to isopropenyl methyl ketone to obtain 25 in 57% ee (eqn. 17 & 18).
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O
O
CO2CH3
CH2CH2COCH3
21
+
(17)
toluene
CO2CH3
O
24 (42% ee)
+
n-C12H25SH
CH3
21
toluene
O
n-C12H25SCH2CHCOCH3
(18)
25 (57% ee)
Hodge et. al. carried3 out the addition of p-methyl thiophenol to cyclohexenone using 22 and
23 to obtain product (26) in almost quantitative yield (eqn. 19).
SH
S
O
22 / 23
toluene, rt
+
O
(19)
H3C
CH3
26 (58% ee)
2.3. Crown ethers
Crown ethers of wide structural variations have been used for the asymmetric Michael addition
reactions. Since the first report16 by Cram et. al. using chiral crown complexes based on optically
active R/S – BINOL, much progress has been made in this area. Some of the chiral crown ethers
which have been used for this purpose are shown in Figure 6.
CO2CH3
+
O
CO2-tBu
28/KO-tBu
- 78 0C
(20)
O
O
O
up to 99% ee
R
R
PhCHCO2CH3
+
O
27/28, KOtBu
- 78 0C
PhCHCO2CH3
(21)
CH2CH2COCH3
65 - 83% ee
Cram et. al. carried out the addition of methyl-1-oxo-2-indane carboxylate to methyl vinyl
ketone using 20 mol% of crown ether 27/28 (eqn. 20). They also reported16 the addition of
substituted methylphenyl acetate to methyl vinyl ketone (eqn. 21).
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H 3C
CH3
O
O
O
O
O
O
O
O
O
O
O
O
H 3C
CH3
27
28
O
O
O
O
R
O
O
R
N
O
O
n
OR
30
O
29
OR
O
OMe
H
O
O
O
O
O
O
O
OR
OR'
OR
O
O
O
O
O
N R
O
H
O
O
O
RO
31
'
RO
OR
O
O
OR'
RO
'
RO
32
OR
RO
OR
O
O
OR
O
OR'
O
O
O
O
OR'
OR
O
O
O
OR
O
O
O
O
O
O
O
33
OR
O
O
O
O
O
.
34
Figure 6
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Koga et al. reported17 the addition of methylphenyl acetate to acrylates using the crown ether
29 (eqn. 22).
CO2CH3
CO2CH3
29/KOtBu
+
O
R
CO2CH3
(22)
R
up to 88% ee
18
Penandes et. al. prepared several bis lacto-18-crown-6 ethers (32-34) and examined their
efficiency for the enantioselective addition of methyl phenyl acetate to methyl vinyl ketone (eqn.
23).
O
O
Ph
OMe
Ph
(32-34)/KO-tBu
+
OMe
(23)
CH2CH2COCH3
O
7-44% ee
19
Camphor derived crown ether 30 was used by Brunet et. al. for the addition of alkyl phenyl
acetate to methyl acrylate to obtain the product 35 up to 85% yield (eqn. 24).
CO2R
Ph
CO2R
OMe
+
27/KO-tBu
O
Ph
(24)
CO2CH3
35 (83% ee)
20
Toke et. al. reported the addition of nitroalkanes to chalcone using crown 31 (eqn. 25).
O
Ph
Ph
+
NO2
31/NaOtBu
Ph
O 2N
(25)
Ph O
60% ee
2.4. Chiral diamines
Mukaiyama et. al. reported21 the enantioselective addition of thiols to cyclohexenone using chiral
diamines. The best results were obtained using (2S,4S)-2-anilinomethyl-1-ethyl-4-hydroxy
pyrrolidine (36) as the catalyst to realize the product in up to 67% optical purity and in 24-90%
yield (eqn. 26).
It was proposed that the product formation takes place via formation of an ammonium
thiolate complex where the ammonium counterpart has a 5,5-fused ring structure (Figure 7).
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HO
NRR'
N
O
PhSH
+
CHR''
O
36
toluene
(26)
SPh
up to 67% ee
Such rigid structure was supposed to be a crucial factor in the enantioselection because the
enantioselectivity decreased when the substituent of the amine was replaced by bulkier groups
and therefore this structure no longer remained a preferred one. Also in a solvent like toluene, the
thiolate anion is stabilized by the π-π interaction and the freedom of its location is further limited
by the interaction with the aromatic ring of the catalyst. Approach of cyclohexenone to complexA takes place with a hydrogen-bond interaction between the carbonyl group and the hydroxyl
group of the catalyst. In a protic solvent like ethanol this interaction is reduced resulting in no
enantioselection. It was also postulated that the attack of thiolate anion to the enone occurs where
two pathways B and C are possible (Figure 7). In case of the pathway C, the steric congestion of
the aniline group and the cyclohexenone ring prevents the complex-A and the enone from
reaching a favorable transition state leading to a preferential attack on the Re face of the
cyclohexenone through pathway B resulting in the predominant formation of the [R]-enantiomer.
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Et
N
H
N
H
N
+
HO
H
S
N
Et
A
O
O H
H
O
O
O
Et
Et
+
H
N
H
N
S
H
N
H
S
N
B
Re-face attack
C
Si- face attack
O
O
S
S
Figure 7
2.5. Amino acid and their derivatives
Taguchi et. al.22 used [S]-N-(2-pyrrolidylmethyl)-N,N,N-trimethylammonium hydroxide (37) for
the addition of soft nucleophiles to enones giving product with moderate to high optical purity
(eqn. 27).
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N
O
H
1
+
R
2
R
() +
n NMe
3
H2C(CO2R)2
OH
37
1
R
CH(CO2R)2
2
HFIP, Toluene
R
O
3
R
(27)
R3
up to 71% ee
A test reaction done between dibenzyl malonate and cyclohexenone using the catalyst 37
gave the product in 88% yield with 3.5% ee. Taguchi et. al. concluded that due to strong basicity
of the catalyst direct attack of malonate to the enone causes lowering of the enantioselectivity.
HFIP (1,1,1,3,3,3-hexafluoro-2-propanol) was therefore added to reduce basicity and to control
the imminium intermediate formation which resulted in product with up to 70% ee. These results
suggested that the face selective attack on enone was controlled through the reversible imminium
intermediate.
Hanessian et. al. reported23 the conjugate addition of nitroalkanes to cycloalkenones
using L-proline as the catalyst (eqn. 28).
CO2H
O
H
+
R1R2CHNO2
O
N
(3 - 7 mol%)
(28)
( )n
CHCl3 , rt
( )n
R
R
NO2
69 - 93% ee
24
List et. al. reported the addition of cyclohexanone to 2-phenyl-1-nitroethane also using
L-proline (eqn. 29).
O
O
+
Ph
NO2
Ph
NO2
L-proline (15 mol%)
(29)
DMSO, 94%
>20:1 dr
20% ee
2.6. Chiral oxazoline
Ahn et. al. reported25 the Michael addition catalyzed by chiral tripodal oxazoline (38) in
conjuction with KOtBu (eqn. 30).
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Ph
CO2CH3
CO2CH3
38 (10 - 20 mol%)
+
CO2CH3
Ph
51 - 86%
(30)
CO2CH3
31 - 82% ee
O
R
N
R
N
O
O
N
R
38 - (S,S,S)- BTO
3. Organometallic Catalysts
3.1. Metal salts of amino acids
Yamaguchi et. al. reported26 the first catalytic asymmetric Michael addition of a simple maolnate
to prochiral enones and enals employing readily available rubidium salt of L-proline (eqn. 31).
CO2Rb
O
N
+
CH
H2C(CO2-iPr)2
H
O
(5 mol%)
CHCl3
(31)
HC R
CH(CO2-iPr)2
R
35 - 76% ee
The catalyst was found to be associated with water of hydration and the reaction rate was
considerably lowered in the presence of molecular sieves 4A. In fact, small amount of water was
found to promote the reaction. Rubidium salts of N-methyl-proline, pyrrolidine or trimethyl
amine were found to be ineffective for the reaction showing that the secondary amine and the
metal carboxylate moieties of the catalyst are essential for high catalytic activity. It was proposed
that the asymmetric induction takes place through enantioface differentiation of the Michael
acceptor (Figure 8).
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CH(CO2-iPr)2
+
NR2
H
NR2 =
R ''
R'
N
CO2
H
Figure 8
The same group later reported27 the addition of nitroalkanes to enones and enals by using
rubidium salt of L-proline to obtain the product in up to 84% ee (eqn. 32). [R]-adducts were
obtained from cyclic [Z]-enones and [S]-adducts from acyclic [E]-enones.
CO2Rb
O
R
+
H
R1
R
N
2
3
O
NO2
H (5 mol%)
CHCl3
(32)
R
R
R
NO2
up to 84% ee
3.2. Metal-diamine complexes
Michael reaction catalyzed by inorganic salts is widely reported.28-35 Along with these reports,
the use of metal-diamine complexes36 is also known. Brunner et. al. reported37 the first transition
metal catalyzed Michael addition using cobalt(II)-diamine complex. It was postulated that an
octahedral complex involving Co(II), diamine and 2-indane carboxylates first formed, which
then undergoes stereoselective Michael addition to methyl vinyl ketone (eqn. 33 & 34).
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CO2CH3
39 (5 mol%)
+
CO2CH3
- 50 OC, 64 hr
O
CH2CH2COCH3
O
(33)
O
66% ee
39 (5 mol%)
+
CO2CH3
(34)
O
CO2CH3
O
O
CH2CH2COCH3
39% ee
NH2
Ph
+
39 =
Ph
Co(acac)2
NH2
Botteghi et. al. prepared38 Ni(II) complexes with chiral chelating nitrogen ligands such as
2,2’-bipyridines, 1,10-phenanthroline and 1,2-diamines for the addition of nitromethane to
benzalacetone, chalcone and 2-cyclohexenone. Catalyst derived from Ni(acac)2 and (+)-(S)-2(anilinomethyl)-pyrrolidine (40) showed good catalytic activity providing up to 24% ee (eqn. 35
& 36).
NO2
O
CH3NO2
+
40 (5 mol%)
O
(35)
R
Ph
Ph
Ph
up to 24% ee
O
O
CH3NO2
40 (5 mol%)
+
(36)
NO2
up to 24% ee
N
H
40 =
N
H
+
Ni(acac)2
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Recently Christoffers et. al.39 created quaternary chiral centers using catalyst derived from
Ni(OAc)2.2H2O and (R,R)-1,2-cyclohexane diamine (eqn. 37).
O
O
O
O
OR
Ni(II) + diamine
+
( )n
O
(37)
CO2R
CHCl3
( )n
up to 99% ee
3.3. Transition metal complexes
Ito et. al. reported40 the addition of N-methoxy-N-methyl-2-cyanopropionamide (41) to vinyl
ketones or acrolein using 0.1-1 mol% of rhodium catalyst prepared in situ from Rh(acac)(CO)2
and dipsosphine ligand (S,S)-(R,R)-PhTRAP (42) (eqn. 38).
O
CN
N
CH3
42 + Rh(acac)(CO)2
+
CH3
O
O
O
OMe
R
C6H6
R
H3 C
41
OMe
N
CN CH3
(38)
89 - 94% ee
Ph2P
CH3
H
Fe
Fe
H3C
Ph2P
H
42 (S,S)-(R,R)-PhTRAP
They also reported41 the addition of alkyl-2-cyano carboxylate to vinyl ketones using Rh(S,S)-(R,R)-PhTRAP complex giving the product in more than 90% yield and up to 89% ee (eqn.
39).
O
NC
OR '
+
O
O
O
Rh-(S,S)-(R,R)-PhTRAP
R
CH3
C6H6 , 6 - 24 hr
OR
H 3C
(39)
CN
72 - 89% ee
42
Nozaki et. al. used chiral bisphosphine ligand (43) and prepared a chiral Rh(I) complex
which was used for the addition of α-cyano esters to vinyl ketones (eqn. 40).
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CN
R
1
CO2R
O
O
+
43 + Rh(acac)(CO)2
2
R
R
Ph2P
CO2R1
2
(40)
R
CN
up to 73% ee
OMe
OMe
Ph2P
43
Suzuki et. al. prepared rhodium complex43
carboxylate to methyl vinyl ketone (eqn. 41).
NHSO2Ar
Ph
O
CO2CH3
+ 44
Ph
+
O
for the addition of methyl-1-oxo-2-indane
O
O
NH2
(41)
CH2Cl2 , - 30 oC
CO2CH3
75% ee
Cl
Cl
Rh
Cl
Rh
Cl
44
Kanemasa et. al. reported44 the asymmetric conjugate addition of thiols to 3-(2-alkenoyl)-2oxazolidinone (45) catalyzed by chiral cationic Ni(II) complex (46) (eqn. 42).
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R-SH
+
CH3
N
O
O
46( 10 mol%)
O
O
45
46 =
N
O
CH3
O
(42)
SR
55 - 96% ee
O
O
N
M
Ln
Ph
O
N
Ph
MLn = Ni(ClO4)2 . x H2O
3.4. Heterobimetallic complexes
Heterobimetallic complex in which each metal plays a different role in the enantiodifferentiation
represents another class of potent catalyst for enantioselective Michael reaction. The development
of the multifunctional alkalimetal lanthanide-BINOL catalyst by Shibasaki et al.45, 46 marked the milestone
in this area enabling efficient catalytic conjugate additions of malonates to acyclic as well as cyclic
substrates with high enantioselectivities. These complexes are depicted in Figure 9.
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O
O
Ga
O
O
Na
M
O
48
O
O
La
O
M
O
M
O
O
O
Al
O
O
Li
47 a (M = Na)
b (M = K)
49
O
O
O
La
O
O
M
50 a (M = K)
b (M = H)
Figure 9
Extensive studies showed47-49 that the lanthanum-sodium-BINOL complex (LSB) (47a) is
very selective in the addition of prochiral β-keto esters to methyl vinyl ketone (eqn. 43 & 44).
O
O
CO2ET
COCH3
47a (5 mol%)
+
(43)
CO2Et
O
91% ee
O
O
CO2Bn
COCH3
47a (5 mol%)
+
(44)
CO2Bn
O
89% ee
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However for cyclic enones of different ring-size, the gallium-sodium complex (GSB) (48)
and the aluminium lithium complex (49) proved50 to be the catalyst of choice (eqn. 45).
O
O
48 / 49 (10 mol%)
+
H2C(CO2Bn)2
(45)
CH(CO2Bn)2
( )n
( )n
88 - 99% ee
Feringa et. al. demonstrated51 that the conjugate addition reactions catalyzed by (49) can be
extended to α-nitro esters as nucleophiles to get the product in up to 80% ee (eqn. 46).
CO2Bn
NO2
49 (5mol%)
+
CH3
COCH3
BnO2C
H 3C
O
(46)
NO2
up to 80% ee
By the use of 20 mol% of 47b as catalyst, Shibasaki et al.52 were able to obtain the addition
product of nitromethane to chalcone in 97% ee (eqn. 47).
O2N
O
Ph
Ph
+
CH3NO2
O
47b + t-BuOH (20 mol%)
Ph
Ph
(47)
97% ee
Besides carbon nucleophiles, thiols were also subjected to 1,4-addition to cyclic enones
furnishing the corresponding Michael adducts with good yields and high enantioselectivities.
Amongst various heterobimetallic complexes, the lanthanum catalyst 47a showed the highest
level of stereoselectivity. Thus the reaction of benzylmercaptan and cyclohexenone in the
presence of 10 mol% of 47a afforded the Michael adduct53 in 90% ee (eqn. 48).
O
O
+
PhCH2SH
46a (10mol%)
(48)
SCH2Ph
56 - 90% ee
The same group later reported54,55 the structurally modified catalyst 50 in which two BINOLmoieties were linked by an ether group. This heterobimetallic complex (50a) gave only moderate
selectivities in the conjugate addition of dibenzyl malonate to cyclic enones whereas alkali metal
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free lanthanum catalyst (50b) displayed perfect enantioselection in the addition of malonates to
cyclic enones (eqn. 49 & 50).
O
O
CH2(CO2Bn)
50a (10 mol%)
+
(49)
( )n
( )n
CH(CO2Bn)
>99% ee
O
O
CO2Et
50b (10mol%)
+
COCH3
(50)
CO2Et
O
75% ee
Sundarajan et. al. used56 chiral amino diol (51) for preparing the heterobimetallic complex
with lithium aluminium hydride (Scheme-2).
Ph
Ph
Ph
N
+
OH
OH
LiAlH4
52
51
O
O
CO2R
CO2R
52, THF
+
rt
H
CO2R
CO2R
up to 94% ee
Scheme 2
Kumaraswamy et. al. reported57 a new calcium-BINOL (53) catalyst for asymmetric addition
of malonates to chalcone and cycloalkenones (Scheme-3).
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+
H2C(CO2R)
53 (15 mol%)
ee: 40%
O
O
H2C(CO2R)
Ph
Ph
Ph
Ph
CH(CO2R)
O
O
53 (15 mol%)
+
O
( )n
( )n
CO2R
ee: 21 - 48%
O
CO2R
O
Ca . 2KCl
O
53
Scheme 3
We have recently reported58 a new aluminium-salen complex for the enantioselective
addition of various alkylmalonates to cycloalkenones (Scheme-4).
H
H
Al Na+
N
N
OH
HO
+
O
O
O
O
N
N
Al
O O O O
Na
THF
0 0C
O O
O
O
R'
CO2R
CO2R
54
54 (10 mol%)
+
( )n
THF, 0 0C
( )n
H
CO2R
CO2R
33 - 58% ee
Scheme 4
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We postulate that sodium phenoxide moiety acts as a Bronsted base abstracting the proton
from the Michael donor while central aluminium metal complexes with the carbonyl
functionality of the Michael acceptor due to its Lewis acidic nature.
3.5. Chiral N,N-dioxides
The N-oxide functional group is known to form complexes with a variety of metals59 due to its
strong electron donating ability. However only a limited number of attempts to employ N-oxides
as chiral catalysts have been reported.60-67 Nakajima et. al. developed68 a cadmium catalyst
containing (S)-3,3’-dimethyl-2,2’-bisquinoline-N,N’-dioxide (55) as a chiral ligand. With this
system, the conjugate addition of thiophenol to enones was carried out to obtain the desired
products in 61-81% ee (eqn. 51).
O
O
PhSH
55 + CdI2
(10 mol%)
+
(51)
( )n
( )n
SPh
61 - 77% ee
55 =
+N
N+
O
O
The same group also reported69 the enantioselective Michael addition of β-ketoesters to
methyl vinyl ketone employing 55 along with scandium triflate. The Michael adduct was
obtained in 90% yield with up to 80% ee (eqn. 52).
O
CO2-tBu
55 + Sc(OTf)3
(5 mol%)
+
O
O
CO2-tBu
O
(52)
80% ee
The predominant formation of [R] adduct was explained by the transition state model (Figure
9). The bulky tert-butyl ester moiety should be located on the si-face of the keto ester plane in
order to avoid steric repulsion with the quinoline moiety which leads the attack of MVK at the
re-face preferentially.
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MVK
(re attack)
O
N+
O
N+
O
Sc
O
O
Figure 10
3.6. Miscellaneous catalysts
Koga et. al. examined70 various chiral lithium-2-amino alkoxides(56-58) for catalyzing
enantioselective Michael addition of methyl phenyl acetate and methyl acrylates. Product with as
high as 84% ee was obtained. However the chiral alkoxides were effective only in
stoichiometric amount (eqn. 53).
R
H 2N
O
H3C
Ph
H2N
O
Li
H3C
O
R 1 R2 N
Li
Li
58
57
56
Ph
CO2CH3
Ph
CO2CH3
OMe
+
56- 58 (100 mol%)
Ph
THF
O
CO2CH3
(53)
84% ee
71
Tomioka et. al. reported the addition of thiols to acrylate derivatives in the presence of
chiral ligand (59) and lithium phenolate (eqn. 54).
R
SLi
HS
R
CO2CH3
+
+
59
CO2CH3
S
(54)
R
R
R
up to 71% ee
Ph
Ph
Me2N
O
59 =
MeO
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The existence of bicyclo[3.3.0] complex (60) as active species in the reaction was postulated.
Ph
Ph
Me2N
O
Li
PhS
O
CH3
60
4. Conclusions
Catalysts with wide structural variations have been used for asymmetric Michael addition
reactions. Organocatalyst include chiral diamines, chiral crown ethers, chiral alkaloids, chiral
aminoacids and chiral oxazolines. Organometallic catalysts include salts of amino acids, metaldiamine complexes, schiff base-metal complexes, transition metal complexes, heterobimetallic
complexes and metal-N,N-dioxide complexes. There is no single catalyst discovered so far, that
is good for the entire range of Michael reaction. However some recent developments have made
it possible to select an efficient catalyst for a particular series of transformation
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