Contents

1.Organocatalysis ..................................................................................................................................... 1
1.1. Principal factors that govern stereoselectivity of the organocatalytic reactions............................ 3
2. Organocatalytic activators in conjugate addition reactions...................................................................3
3. Organocatalytic asymmetric conjugate addition of carbon nucleophile .............................................. 5
3.1. Conjugate addition to aldehydes .................................................................................................... 5
3.1.1 Conjugate addition of aldehydes to , -unsaturated ketones.................................................. 5
3.1.2 Conjugate addition of aldehydes to nitroolefins ...................................................................... 6
3.2. Conjugate addition of ketones ..................................................................................................... 10
3.1.1 Conjugate addition of ketones to ,- unsaturated carbonyl compounds .............................. 11
3.2.2. Conjugate addition of ketones to nitroolefins ....................................................................... 13
3.2.2.1 Mechanism and stereochemical outcomes of Michael addition of ketones. ...................... 15
3.3.1 Conjugate addition of activated methylenes to , -unsaturated aldehydes .......................... 17
4. Conjugate addition of heteroatom nucleophile .................................................................................. 18
4.1 Conjugate addition of nitrogen nucleophiles ................................................................................ 18
4.2 conjugate addition of oxygen nucleophile. ................................................................................... 19
5. Conclusion .......................................................................................................................................... 20
6. References .......................................................................................................................................... 21

1. Organocatalysis:
The adjective organocatalytic is applied to processes in which reagents and catalysts are all small organic
molecules containing only C, H, O, N, S, P, and X.1 The last few years have witnessed a spectacular

advancement in new catalytic methods based on metal free organic molecules. In many cases, these
small compounds give rise to extremely high enantioselectivity. Preparative advantages are notable:
(1) the reaction can be performed under an aerobic atmosphere with wet solvents. (2)The catalysts are
more inexpensive and they are often more stable than enzymes or other bioorganic catalysts. (3)Also,
these small organic molecules can be anchored to a solid support and reused more conveniently than
organometallics / bioorganic analogues and show promising adaptability to high thorough put
screening and process chemistry. The following are the four different domains in which
organocatalysis has major advances2:(a) The activation of the reaction based on the
nucleophilic/electrophilic properties of the catalyst. This type of catalyst has much in common with
conventional Lewis acid /Lewis base activation by metal complexes, (b) transformations in which the
organic catalyst forms a reactive intermediate: the chiral catalyst is consumed in the reaction and
regenerated in parallel catalytic cycles.(c) phase transfer reaction: The chiral catalyst forms a hostguest complex with the substrate and shuttles between the organic solvent and the second phase which
is a solid, aqueous /fluorous phase in which the organic transformation takes place. (d) Molecular
cavity accelerated asymmetric transformation :The catalyst can be selected between competing
substrates depending on the size and structure criteria. The rate acceleration of a given reaction is
similar to the Lewis acid /base activation and is the consequence of the simultaneous action of
different polar functions. The organocatalysis complements with the current methods but not
competes.
Enantioselective synthesis has been one of the increasingly interested areas for the chemists, since
they had recognised that the spatial arrangements within molecules are important for the fundamental
properties of the Substance. The chiral drug industry has become rapidly growing segment of the drug
market and represents close to one thirds of all drug sales worldwide. This has been driven by the
increased regulatory control of enantioselective composition of drug candidate and the potential of
isomerically pure drugs to provide improvements over the previously available reacemates. Undoubtly,
the more elegant and economically most attractive way to introduce chirality into a molecule is by a
catalytic amount of chiral controller to induce the chiral transformation. Methods based exclusively on
metal free chiral organic catalyst have become more significant. For the construction of complex
molecular skeletons these new reactions are becoming powerful tools by good fortune and persistence.
chiral organic molecules have been used from the early days of chemistry to promote reactions.
Page 1

The emergence of homogenous catalysis has a decisive effect on the development of

enantioselective organocatalytic reactions. Thus the concept of asymmetric catalysis has become
almost synonymous with use of metal in chiral environment.
But are metals readily indispensable in these catalytic processes?
Can some of their functions be emulated by an organic system?
In contrast to most synthetic methods, nature provides a subtle balance between metal-free and
metal mediated conditions. Metals certainly have considerable advantages over organic substances.
For example, (1) molecular and structural diversity, (2) large array of reactivity patterns than can
easily be tuned by varying ligands. As well as the tremendous benefits that metal derivatives offer they
are also the source of increasing problems. Such as: high price, toxicity, pollution, waste treatment,
product contamination. A large number of asymmetric transformations are based on organic reagents;
there is an increasing tendency to devise reaction conditions that allow the regeneration of chiral
reagents. This concept will certainly help the development of a number of new organocatalytic
reagents in near future. On the other hand, roles that are typically associated with metals for example
as lewis acid /base and as redox agents can be emulated fairly well organic compounds. During, last
few years there have been a spectacular advancement in new catalytic methods based on organic
molecules. In many cases, these small compounds result in extremely high enantioselectivities. Also
these small organic molecules can be anchored to a solid support and reused more conveniently than
organ metallic/ bioorganic analogues. There is a dichotomy between organic and organ metallic /
bioorganic catalysis, particularly with respect to their reactivity and application.
On the other hand, organocatalytic reactions have evolved essentially from the ligand chemistry of
organometallic compounds. Large arrays of ligands were developed for metalmediated
enantioselective catalytic reactions and are still among the most effective organocatalysts. It is time not
surprising that there are metal-catalysed reactions in which the metal free ligand is known to be active
by itself, even in the same enantioselective transformations. On the other hand, organocatalytic
reactions can be more closely related to enzyme or antibodycatalysed reactions than to
organometallic processes. Indeed these small organic molecules which are often also known as
artificial enzymes or enzyme mimetics. They show some characteristics features of bioorganic
reactions. They often follow saturation or Michaelis-Menten kinetics reminiscent of a mechanism that
involves the reversible formation of an enzymesubstrate complex. However this apparent similarity
hides major differences especially in the mode of action. Enzymes act essentially by stabilizing the
transition state of reaction by the subtle orchestration of a number of functions, where organic
molecules promote the reaction as simple reagents.
Page 2

Enzymes are more than just highly evolved catalyst (1) catalytic efficiency, (2) selectivity, (3)
high turnover number are only the part of the peculiar characteristics of the sophisticated system,
which involves built-in feedback and subtle intra and inter molecular cooperation. It offers something
conceptually novel and opens new horizon in synthesis.
1.1. Principal factors that govern stereoselectivity of the organocatalytic reactions.
In metal mediated enantioselective catalytic reactions the metal plays a major role by
translating chiral information and activating the reagent. in the absence of metal the well organized
transition state which is required for the enantioselective transformation can be formed either by
passive or dynamic interactions as is the case in the biological systems. Passive Binding: Refers to
ordinary molecular recognition through hydrophobic, Vander Waals, electrostatic interactions.
Dynamic Binding: Refers to interactions between catalyst and substrates at the reaction centres.
Hydrogen bonding plays a major role in the determination of stereoselctivity of the reaction. Although
this represents an energy contribution of only 1-6 k.cal/mole to interactions hydrogen bonding
influences the conformational preferences by forming rigid 3D structure and contributes to the affinity
and selectivity of molecular recognition. Hydrogen bonding also plays an important role in stabilizing
the reactive intermediates and in modulating the reactivity in a similar way to enzyme catalysis. More
and more evidence is being gathered on the complexity of the enantioselective transformation caused
by the formation of aggregates between substrates and catalysts in the enantioselective path. These
new findings challenge our traditional view which is based essentially on the consideration of
monomers.

2. Organocatalytic activators in conjugate addition reactions

Asymmetric organocatalysis employs small chiral organic molecules to accelerate
asymmetric reactions. This process became very popular as it shows its impact as environmental
friendly and metal-free transformations. Conjugate addition of nucleophiles to electron-poor alkenes is
one of the most frequently used C-C and C-Heteroatom bond forming reactions in organic chemistry.
From mechanistic point of view, interactions between the catalyst and substrate in an asymmetric
organocatalytic conjugate additions are rather different to those implicated in metal-catalysed process.
Organocatalyst provides a chiral environment to the process activating, a) nucleophile, b) electrophile
c) or both the reagents. This happens through: Weak interactions such as a) hydrogen bonding, b) ion
pairing. Strong interactions such as covalent bonding. Weak Interactions: Enantioselective Phase
Transfer Catalysis demonstrates how weak interactions, such as (A) ion pairing, can be used to carry
out enantioface discrimination in conjugate addition reactions.

Page 3

Chiral ion pairs can be formed either by deprotonation with a chiral base or by using a chiral
phase transfer catalyst and are responsible for asymmetric induction in the process electrophile
activation by small molecules bearing hydrogen-bond donor has emerged as an important tool in
enantioselective catalysis. (B) Hydrogen bonding to the conjugate acceptor decreases its electron
density thus activating it towards nucleophile, Strong Interactions: With respect to covalent activation,
(C) The catalyst can either reversibly form a chiral enamine to activate the nucleophile, (D) a chiral
iminium ion to activate the acceptor. Chiral ureas, thioureas, guanidinium, amidinium ions, diols,
biphenyls, hydroxyl acids, amides are amongst the most successfully used chiral hydrogen bond
donors in conjugate addition. The implication of double hydrogen bond has been demonstrated. The
use of N, N-Diphenyl ureas3 was a good example.
NO2

NO 2

NO2
THF

O
N
H

NO 2

N
H

O
N
H

N
H
O

(B)

(A)

Figure 1: N, N-Diphenyl ureas showed the double hydrogen bond in solvent THF

The double hydrogen bond7,8 character of these compounds were characterised by using I.R.
spectra, that showed shift of carbonyl stretching frequency from 1660cm-1in solvents where there is no
hydrogen bond acceptor, to 1720 cm-1in which solvent such as tetrahydrofuran is employed. N, NDiphenyl ureas with Ortho and Para- electron withdrawing and meta-CH3 groups did not form
cocrystals even with strong acceptor like Triphenylphosphineoxide. Urea substituted with m-electron
withdrawing groups such as NO2, CF3, can form complex like those shown in (2). The weakly acidic
ortho C-H protons lie near the carbonyl oxygen. In these, the complete molecule is nearly planar.
In

C H

O,

the actual H

withdrawing groups) H

bond length is about 2.4 , here( C

bond length in C

O,

with meta-electron

is about 2.23 to 2.29 , which when compared

to the simple N, N -Diphenyl ureas was about 2.49 to 2.66 . The carbonyl group forms no inter
molecular hydrogen bonding, in this structure, so the N-H protons are free to bind to guest molecules.
A possible explanation for the highly specific complexation behaviour of this compound is that a weak
C H

interaction takes place with drastically reduced -values (solvatochromic parameters for

proton accepting strength) of the carbonyl group.

Page 4

(B)

(A)

X
R*

O
Nu- +cation

R1

N
O

R*

Nu -

Hydrogen bonding as
electrophilic activator

Nucleophile activation by
ion pair formation

(C)

(D)
+
NR 2
NR 2 *

Nu

Activation of nucleophile by
formation of chiral enamines

R'

Chiral iminium ion to

activate the acceptor

Figure 2: Organocatalytic activators in conjugate addition

3. Organocatalytic asymmetric conjugate addition of carbon nucleophile

3.1. Conjugate addition to aldehydes:
A wide variety of carbon nucleophile have been successfully used in the organocatalytic
asymmetric inter- and intramolecular Michael additions to different , -unsaturated systems. Among
them, the conjugate addition of aldehydes to (a) , -unsaturated ketones, (b) alkylidenemalonates,
(c)nitroolefins.

3.1.1 Conjugate addition of aldehydes to , -unsaturated ketones

The

catalyst

(S)-2-bis-(3,5-dimethyl

phenyl)

methyl

pyrrolidine4(1)catalysed

the

enantioselective Michael addition of aldehydes to vinyl ketones was found to show modest
enantioselectivities. Most stable anti-enamine (A) was formed, whose Re-face was shielded by the
bulky groups present at the 2-substituent of the catalyst, leaving Si-face available for electrophile
approach. A diphenyl prolinol derived catalyst diphenylprolinolmethylether (catalyst 2) catalyzed the
intermolecular Michael addition of a wide variety of aldehydes with different vinyl ketones with the
highest enantioselectivity about 95-99% ee employing significantly lower catalytic loading (1-5 mol
%) than those reported with other organocatalysts (20- 30 mol %) .This catalyst acts as a nucleophilie
activators rather than the electrophilie activators reacting with aldehydes to form the corresponding
enamine intermediate, which suffered conjugate addition to vinyl ketones.
Page 5

Scheme1. Conjugate addition of aldehydes to , -unsaturated ketones catalysed by (1) & (2).
O
Ph

O
catalyst 1, 2

H
Bn

Catalyst (mol%)
1(20)
2(5)

Solvent

Temp

THF/HF IP
neat

rt
4C

Yield(%)
78
82

ee(%)
65
>95

Ph
N
H

N
H

Ph
OMe

Catalyst 2
Catalyst 1

N
H

H
R

R
(A)

(B)

Enamine intremediate for the Michael additon of aldehydes to vinyl ketones

3.1.2 Conjugate addition of aldehydes to nitroolefins

Chiral nitroalkanes are highly versatile synthetic intermediates, due to the ability to transform
the nitro group into other useful intermediates.Here the catalyst used was diphenylprolinol derivative,
simple introduction of siloxy group into the proline structure leads to an increase in catalytic activity,
thus allowing a decrease in catalytic loading and shorter reaction times, without compromising the
enantioselectivity and is accomplished by broadening of substrate scope. The higher reactivity of these
compounds relative to the earlier parent compound can be attributed to effective formation of the
corresponding enamine without generation of aminal, which would be formed in the case of diphenyl
prolinol. Commercial preparation of siloxyether of diphenylprolinol from diphenyl prolinol is one of
the advantages in the use of this catalyst. The high diastereoselectivity and excellent enantioselectivity
can be explained as follows: The anti-enamine, with its double bond oriented away from the
diphenylsiloxymethyl group, would be formed selectively and react with nitrostyrene via an acyclic
synclinical transition state.
Page 6

Scheme 2: Asymmetric Michael addition of aldehydes to nitrostyrenes

R3

R2
CHO

NO2

R3

Catalyst (mol%) R1
3 (10)
Prn
4 (5)
Prn

catalyst

R2
H
H

Time
2d
20h

Solvent
Hexane
CH2 CL2

NO2

solvent, T (C)

R R

Temp
0C
0C

Yield (%)
74
90

syn/ anti
95/5
99/1

ee (%)
99
>99

Catalyst 4

Catalyst 3

HO

Ph
N
H

Ph
OTMS

N
H

Ph

O
Ph

siloxyether
of diphenyl
prolinol

tr ans-4-Hydroxy
prolylamide derivative

TMSOPh2 C

O
N
+
-O N
H
Ph

Proposed transition state model f or

Michael addition of aldehydes to nitrostyrenes

An electrostatic interaction between nitro group and nitrogen atom of the enamine would be
operating. The bulky diphenylsiloxymethyl group on the pyrrolidine ring would play two important
roles towards the excellent enantioselectivity, a) Promotion of the selective formation of anti-enamine,
b) selective shielding of Reface of the enamine double bond. A variety of orgnanocatalysts were
developed for improving the efficiency of the process. These systems were commercially available
and/or easily prepared from the chiral pool through very simple chemical transformations, usually
consisting of chiral secondary amines, probably due to the favourable imine-secondary enamine
equilibrium, although primary amine catalysts have also been developed. Both primary and secondary
chiral amines fill the gap left by proline catalyst that, while still playing a central role in
aminocatalysis, providing modest enantioselectivities in this process under different reaction
conditions.

Page 7

Controls the equillibrium

between conformers and
blocks one enamineface

H
H

H
N
H

H O

R
N H
H

H
Hydrogen bond donor that activates
the acceptor and directs its approach
from less hindered enamine face

(a)

R1

(b)

Figure 3: Approach in the design of trans-4-hydroxyprolylamide derived catalyst

The basic proposal stems from the observation that in the majority of the above catalyst
systems a hydrogen-bond donor at the -position of the pyrrolidine nitrogen atom (a) is introduced to
help the catalytic reaction to proceed. This observation can be corrected to the amine catalyzed
aldoladditions wherein a hydrogen-bond motif arising from the same position is involved in a halfchair, six- membered transition state during the catalytic cycle, thus suggesting that the self-aldol
reaction in competition with Michael addition could be the reason for most of the observed problems
of latter. The hypothesis was that if design5 outlined in (b), wherein the -hydrogen bond donor is
omitted, could be operative. The aldol reaction might be kept at a minimum whilst the Michael
reaction should proceed with a high degree of diastereo- and enantiocontrol. One of the main problems
associated with organocatalysis is the high catalyst loading, usually in the range of 1030mol%,
required to perform the desired transformation. This is a problem when expensive chiral materials are
used to prepare the organocatalysts, especially when they are employed in large scale syntheses.
Among the advantages that organic catalysts present over enzymes and metal-based catalysts should
be emphasized the possibility of ready immobilization on a solid support with the aim of facilitating
catalyst recovery and recycling. Catalysts were recently demonstrated to efficiently promote the
asymmetric Michael addition of a wide range of aldehydes to nitroolefins at rt with excellent levels of
enantio- and diastereoselectivity.
n-C 8F 17

N
H

n-C 8F 17

N
H

NHSO2 -n-C4 F9

OTMS

Figure 4: Recyclable organocatalysts for the conjugate addition of aldehydes to nitroolefins

Page 8

Catalysts could be easily recovered by fluorous solid-phase extraction and precipitation in

MeOH, respectively, and reused several times, while still retaining a high catalytic activity. On the
other hand, fluorous (S)-pyrrolidine sulfonamide promoted the Michael addition of aldehydes to
nitrostyrene in water, and could be easily recovered by fluorous solid-phase extraction and reused. A
preliminary study regarding the use of chiral ionic liquids as asymmetric organocatalysts in the
Michael addition of aldehydes to nitrostyrene was presented very recently. Catalyst, which consisted
of a chiral pyrrolidine covalently tethered to an imidazoliumcation, was demonstrated to be an effcient
organocatalyst for the reaction of and -substituted aldehydes to nitrostyrene under neat conditions
in the presence of TFA as a cocatalyst. This result was very interesting since Michael additions of
aldehydes to - nitrostyrenes in ionic liquids such as (bmim) PF6 employing different organocatalysts
afforded very low diastereo- and enantioselectivities.
NBu
N
N
H

BF4 -

Figure 5: Chiral ionic liquid, tetrabutyl imidazolium

Asymmetric catalyzed domino reactions produce chiral structures elaborate in a rapid, atomeconomic, and competent manner. An efficient chemo-, diastereo-, and enantioselective three
component domino synthesis of tetrasubstituted cyclohexenecarboxaldehydes was done using prolinolderived catalyst.The catalytic cascade consisted of a three component reaction, comprising of linear
aldehyde, nitroalkene, , unsaturated aldehyde, and catalyst, which was capable of catalyzing each
step of the process. The four stereogenic centres were generated in three consecutive C C bond
formations with good diastereocontrol and complete enantiocontrol.. The firststep of the catalytic cycle
consisted of a stereoselective Michael addition of the linear aldehyde to the nitroalkene via enamine
formation. This step was responsible for the high stereoselectivity of the process, the selectivity being
kept or enhanced in the second step, the conjugate addition of nitroalkane formed to the activated
chiral iminium of the ,-unsaturated aldehydes. A final intramolecular aldol condensation via
enamine with subsequent hydrolysis released the desired tetra substituted cyclohexenecarboxaldehyde.
This protocol allowed the synthesis of a wide variety of polyfunctionalized cyclohexene building
blocks, since different substituents were tolerated in the starting material.

Page 9

O
R1

NO2

R2

CHO

Catalyst A

CHO

R3

R1

R2

R3
NO2

R 1 =Me, R 2=Ph,
40%, dr = 78/22.
>99% ee
O
R1
R

+ H 2O

Ph

NO2

R2

R2

NO2

R1

Ph

CHO

R2

OTM S

R1

OTM S

Ph
O-

CHO

Ph

N
H
H 2O

R1

NO2

R3
NO2
R3

CHO + A

Ph
O

R1

Ph
OTM S

R2

H 2O

R3
NO2

R1 = alkyl, R2 = aromatic, heteroaromatic, R3 = H, alkyl, aromatic.

Scheme 3: Three component double michael addition organocatalytic sequence.

3.2. Conjugate addition of ketones

The asymmetric organocatalytic conjugate addition of ketones has been performed by using the
following Michael acceptors, a) , - unsaturated carbonyl compounds, b) Alkylidene malonates,
c)Nitroolefins. The process has been studied under homogeneous and Phase Transfer Catalytic
conditions using a wide variety of chiral organocatalysts such as a) Cinchona alkaloid derivatives, b)
Small peptides, c) Chiral primary and secondary amines, derived from the chiral pool or obtained
synthetically. This methodology has led to the preparation of different enantiomerically enriched
compounds, such as 1,5-dicarbonylcompounds, functionalized cyclopropanes, and nitroketones.

Page 10

3.1.1 Conjugate addition of ketones to , - unsaturated carbonyl compounds:

L-proline derivatives, as well as chiral quaternary ammonium salts, are employed for the
enantioselective addition of ketones to enones under either homogeneous or Phase Transfer Catalytic
conditions. L-proline derived organocatalyst was proven to be highly enantioselective in Michael
addition of ketones to chalcones. The reaction was carried out under mild conditions to obtain
synthetically useful 1,5-dicarbonyl compounds in high yields and with high to excellent levels of
enantio- and diastereoselectivity in the case of using six-membered ring ketones as nucleophiles
These results werent seen with use of cyclopentanone and cycloheptanone as nucleophiles. High level
of stereoslectivity for cyclohexanones could be rationalised with the proposed transition state model
Scheme4: Enantioselective organocatalytic Michael addition of ketones to chalcones.

O
+

Ar1

Ar 2

CH2
CH 2

Ar 1

Ar2

4-ClC 6 H4 Ph
4-NO 2 C6 H 4 Ph

O
Ar 2

PrOHi , rt

Ar 1

catalyst 3 (10 mol%)

Yield(%)
80
87

Time(d)
4
4

sy n/ anti

ee( %)

>98/2
>98/2

90
92

N O
S
H
CF3
O HO
i
OPr

Ar 2
NHSO2 CF 3
N
H
catalyst 3: pyrrolidine sulfonamide

Ar 1
Proposed transition state for
Michael addition of ketones to chalcones

.
The NH proton of the triflamide group provides stabilization through a hydrogen bonding
interaction with the chalcones carbonyl group. The triflamide group has pKa value of 6.3. The sulfonyl
group has an acidifying effect on an adjacent N-H. In triflamide6 group might participate in an
additional hydrogen bonding interaction with the carbonyl group through the solvent, synergistically
bringing about a tighter transition state .The triflamide moiety also produced a high facial preference
for the approaching enone. A model inspected supported that the process would take place by the
preferential enamine addition to the less hindered Si-face of nitro-olefins.

Page 11

The bifunctional nature of catalyst has acidic sulphonamide and basic pyrrolidine which shows
that high catalytic activity can be shown by this even in the absence of the acidic additives.
The use of ammonium salts derived from cinchona alkaloid catalysts such as [4(trifluromethyl)benzyl] cinchoninium bromide for the PTC conjugate addition of 2-alkylindanones to
methyl vinyl ketones9 was carried out in a two phase toluene /50% aqueous NaOH system, yielding
higher enantioselectivities (up to 80% ee) of the corresponding Michael adduct which is a key
intermediate in drug synthesis.10
Scheme 5:Asymmetric Michael addition to methyl vinyl ketone catalyzed by 4.
Cl

Cl

O
O

Cl
Pr n
MeO

catalyst 4 (5.6 mol%)

50% aqueous NaOH/toluene, rt

Cl

Pr n

MeO

O
95%, 80% ee

Br-

OH
N
N

H
CF3

catalyst 4: [4-(trifluromethyl) benzyl] Cinchoninium bromide

N-Alkylated cinchonidinium cation mediated the enantioselective conjugate addition of

actophenones to chalcones under PTC conditions. In the proposed transition state of the reaction, the
acetophenone enolate and the , - enone are contact ion paired with the ammonium nitrogen of the
catalyst. The phenyl group of the nucleophile is positioned to - stack with the 9-anthracenyl subunit
of the catalyst, which definitely confers rigidity and a proper chiral atmosphere onto the system. The
catalyst also promoted the enantioselective dimerisation, under the same chiral phase-transfer catalysis
conditions, of , -enones able to generate dienophiles by deprotonation of a - hydrogen to yield
chiral 1,5-dicarbonyl compounds through an enantioselective Michael additiondouble bond
isomerisation sequence. At low temperatures, this dimerisation reaction generally afforded good yields
and high enantioselectivities, the best being for -electron-deficient enones and those having bulkier
substituents at the -position. The product of the dimerisation is useful intermediates for the synthesis
of chiral -keto acids, important chiral building blocks for peptide isostere.

Page 12

Scheme 6:Cinchonidinium-catalyzed Michael addition of ketones to chalcones.

O
Ph

Ph

Ph

O
Ph

catalyst 5 (10 moi%)

50% aqueousKOH/toluene,-10c

R = MeO, 72%, 80% ee

Br -

H
N
N

OH

R
O
O
N

catalyst 5

HO

3.2.2. Conjugate addition of ketones to nitroolefins:

The first organocatalytic addition of ketones to trans--nitrostyrene using L-proline as a
catalyst and with good yields but very disappointing enantioselectivities (0-23% ee). The solvent effect
was considered to be one of the major factors in increasing the enantioselectivities.In MeOH, the
enantioselectivity increased to about 76% for the major syn diastereomer in the reaction between 3pentanone and trans-nitrostyrene employing 20mol% of L-proline as a catalyst. Hydrochloride salt
of N- isopropyl -2, 2-bipyrrolidine as catalyst in CHCl3 as the solvent was used. In this study the
highest obtained enantioselectivity was 81% for the addition of cyclohexanone to nitrostyrene with a
very high diastereoselectivity (syn /anti: 94/6).
The observed syn selectivity was in accordance with the Seebach- Golinski model. Interestingly Nisopropyl -2, 2-bipyrrolidine mediated anti-selective Michael addition when -hydroxyketones were
employed as nucleophiles. The reversal of diastereoselectivity was ascribed to the putative formation
of the Z-enamine intermediate, which was favoured through formation of hydrogen bonds between the
OH of the nucleophile and the tertiary nitrogen atom of the catalyst. The dependence of the
organocatalyst on the nucleophilic substrate is a general phenomenon in organocatlysis. Some of the
catalysts developed for the asymmetric addition of aldehydes to nitroolefins were very efficient for the
addition of six-membered ring ketones to -nitrostyrene and derivatives.
Page 13

Scheme 7: Conjugate addition of -hydroxyketones to -nitrostyrenes by catalyst 7

O
R

OH

NO2

Ph

catalyst 7(15mol%)

Ph
NO 2

CHCl3

OH

Catalyst

R
Pr n

Temp

Yield (%) syn/ anti

rt

21

ee (%)

8 /92

98

-O
H
N
Pri

catalyst (7)
N- isopropyl -2, 2'-bipyrrolidine

O
R

H
N
H

H
Ph
N
O
Pr 1
Proposed transition state of
conjugate addition of ketones to nitroolef ins

The chiral ionic liquids showed above performed much better than other chiral pyrrolidinederived catalyst in ionic liquids as the reaction media. Catalyst (d) showed best activity and selectivity
under neat conditions, while imidazolium-supported organocatalyst (e) showed a better catalytic
performance in [bmim] PF6 in terms of productivity and enantioselectivity. These catalysts are
recycled and reused without any loss of acivity and stereoselectivity.

NEt

NBu
N
N
H

BF4-

(d)

N
N
H

Br

(e)

Figure 6: Chiral ionic liquids which have shown better enantiselectivities

Number of other models of catalyst were prepared and most of then showed major action
towards the conjugate addition of cyclic six-membered ketones. Most of the catalysts developed were
suitable for the cyclic six membered ketones but not for the conjugate addition of aliphatic ketones. To
explore this area the organocatalyst was developed. It was the Jacobsons thiourea that was most
efficient for this process and was assuming only the very mild reaction conditions. These catalysts
were not only used for conjugate addition of different aliphatic ketones with nitrostyrenes, but also
nitroalkenes bearing -substituents with very high regio- , anti-diastereo and enantioselectivities.

Page 14

Very small changes in an organocatalyst structure may often alter its catalytic activity
especially in terms of enantioselectivity. These modifications of the catalyst structure are mostly
performed through organic transformations leading to new chiral organocatalyst.
O

H
N

H
N

NH
Prolinamide-derivative

N
H

Pyridinone

NH

N
H
O

H
N

H
N

Figure 7: Asymmetric Michael addition of cyclohexanones to -nitrostyrene catalysed by self-assembled organocatalyst.

However, very recently the catalytic activity of prolinamide-derived organocatalyst could be

modulated in the presence of achiral additives, such as pyridinone This methodology which was based
on self-assembling of the components through complementary hydrogen bonding. By this approach a
small catalytic library was developed using a single chiral catalyst and different achiral additives. By
employing different pyridinones catalytic activity of the prolinamide-derived organocatalyst was used
for the conjugate addition of cyclohexanones to -nitrostyrenes without needing to prepare new chiral
catalysts. In fact, the presence of the achiral hydrogen-bonding additive not only fine-tuned the
enantioselectivity of the catalyst, but also transformed it into a highly effective promoter for the
reaction.

3.2.2.1 Mechanism and stereochemical outcomes of Michael addition of ketones.

When primary or secondary amines are used as catalysts, the reaction clearly involves, a
catalytic energetically favoured, enamine mechanism. The existence of the enamine intermediate in the
Michael addition is confirmed by employing techniques such as the ESI-MS method on different
catalysts, such as Jacobsons thiourea. In the case of the proline derived organocatalyst, an acyclic
synclinical transition state assembly explain the usually obtained syn-diasteroselectivity and absolute
configuration. Depending on the catalyst employed, two potential models for the stereochemical
outcome of the reaction have been postulated. Both models propose an electrostatic interaction
between the nitro group and the nitrogen of the pyrrolidine ring. However, it has been suggested that
facial bias is induced by steric factors or through hydrogen-bonding interactions.
Page 15

The first possibility involves the generation of a syn-enamine, while hydrogen-bonding

transition state engage the generation of the anti-enamine. The different solvents, additives, and co
solvents present in the reaction media can assist in the stabilization of the transition state and favour
one facial preference for the approach the substrate as depicted in proposed transition state. Proline
sulphonamide derivative catalysed Michael addition of ketones to nitrostyrenes. In this case, a
cooperative hydrogen-bond solvent participation takes place resembling the oxyanion hole commonly
found in enzymes for stabilizing transition state. It seems then very clear that intra- and intermolecular
hydrogen bonding interactions play a key role in the organocatalytic cycle.
O
O
+N N R2 N
O
Ar

R1

R2

R1

R2

N
N Ar
H
H
O
N+ O

Ar

O
HO
H N
NN O H
O
Ph

N
H
O
F3C
H
N 1
R
R2
O O
H
Ar
S

Scheme 8: Proposed transition state model for the conjugate addition of ketones to -nitrostyrenes

Chiral primary amine-thiourea catalysts showed an opposite sense of relative stereoinduction in

the conjugate addition of acyclic ketones to nitroolefins . These anti-selective catalyst stands in
contrast to the usually obtained results which lead to selective formation of the syn-diastereomers. This
unexpected situation suggested the participation of a Z-enamine intermediate moreover with respect to
the electrophilic activation by urea-type catalyst. It was demonstrated that only one oxygen of the nitro
group is bound to the thiourea moiety in an out-of-plane arrangement.

3.3. Conjugate addition of active methylenes:

The asymmetric conjugate addition of activated methylenes is one of the most studied
organocatalytic reaction. A wide variety of Michael acceptors, such as enals, enones, ,-unsaturated
nitriles, nitroolefins,

,-unsaturated imides, vinyl sulfones, are successfully employed as

electrophiles with a high degree of stereocontrol. Conjugate addition of activated methylenes to ,unsaturated aldehydes was studied with wide range of nucleophiles such as 1,3-diketones, malonates,
and malononitriles.
Page 16

3.3.1 Conjugate addition of activated methylenes to , -unsaturated aldehydes

R1
EWG

organocatalyst

R1

EWG

CHO

CHO

EWG

EWG

EWG=COR, CO 2R, CN

Figure 9: Asymmetric conjugate addition of activated methylenes to , -unsaturated aldehydes

Michael addition of 2-carboxycyclopentanones to acrolein where there was a significant

improvement in the selectivity of the reaction was achieved by using just 2 mol% of chiral quaternary
ammonium salt under PTC conditions (K2CO3, toluene). Bifunctional cinchona alkaloids were used for
high efficient and general asymmetric conjugate addition of carbonyl donors to , -unsaturated
aldehydes. Marine toxin (+)-tanikolide was synthesized by this approach. The organocatalytic
enantioselective addition of malonates to aromatic ,-unsaturated aldehydes employing iminium ion
activation with proline-derived catalyst. The reaction which was solvent dependent was applied to the
enantioselective synthesis of (+) and (-) paroxetine11 as well as (+)- femoxetine, proceeded especially
well for benzyl and methyl malonates, being non-diasteroselective for unsymmetrical malonates. With
regards to the ,-unsaturated aldehydes partner, the process was quite general tolerating many
functional groups with excellent enantioseleectivies for the substrate studied. Owing to the steric
interactions, ortho-substituent in the aromatic ring of the electrophile led to the very low yields

Scheme 9: Conjugate addition of malonates to , -unsaturated aldehydes catalysed by 8

R1 O2 C

O
Ar

R 1OOC

COOR 2

catalyst 8

CO2R 2

(10 mol%)

EtOH, 0C, 96 h

Ar

CHO

F3C
CF 3
N
H

OTMS

Ar
Ph

R 1 R 2 Yield(%)
Me Me
85

ee(%)
91

CF3
F 3C
catalyst 8

Page 17

Scheme 10: Asymmetric formal synthesis of (-)-Paroxetine

F3 C
CF3

BnO 2C

CO2 Bn

N
H

OTM S

F3 C

CF3
(10 mol%)

O
O
OBn

0C, EtOH,
80%, 91% ee

OBn

PhCH2 NH2
NaBH(OAc) 3
Diioxane,
70%

Ph

Ph

N
LiALH4 , THF, , 85%

OH

CO2 Bn

2 Steps

O
O
O

(-)-Paroxetine

4. Conjugate addition of heteroatom nucleophile

Different nitrogen, oxygen, sulphur nucleophilic species can undergo organocatalytic
asymmetric Michael addition reactions to different electrophilic olefins are very popular reactions.
They lead to enantiomerically enriched hetero functionalized derivatives.
4.1 Conjugate addition of nitrogen nucleophiles
The asymmetric organocatalytic michael addition of nitrogen nucleophiles to , -unsaturated
carbonyl compounds is a very important reaction since it allows the preparation of optically active amino acids.12 The tripeptide catalyst (1a) was employed in the enantioselective conjugate addition of
the azides ion to , -unsaturated carbonyl compounds.
Page 18

Conformational studies of the catalyst led to the conclusion that decreasing the conformational
freedom of the N-terminal histidine of the peptide residue with a -substituent should be should be
beneficial for the catalyst. The - methylated peptide (2a) effected the addition TMS-N3 to several
unsaturated imides with better enantioselectivities than (1a). Typically 2.5 mol% peptide catalyst (1a)
or (2a) were used and with 92% of enantioselectivity is achieved. The -azido imides were readily
converted to N-Boc protected -amino acids by hydrogenation and hydrolysis.
Scheme 11: Addition of TMS-N3 to several unsaturated imides catalysed by tripeptide (1a) and (2a)

O
N

catalyst (1a),(2a) (2.5mol%)

R

TMSN 3
ButCO 2H, toluene

N3

1. H2, Pd/C, EtOAc, Boc2O

NHBoc
HO2 C

2. LiOH, MeOH

O
N

HN

BocHN

O
N

Bu t

HN

catalyst

2a

Me

Temp(C) Yield (%)

25

90

ee(%)
78

N
Bn

(1a), R = H
(2a), R=Me

4.2 conjugate addition of oxygen nucleophile.

The asymmetric O-Michael addition was employed in the synthesis of chiral benzopyranes.13
The benzopyrane unit was constructed through a domino reaction involving the oxo-Michael attack of
salicylic acid derivatives onto the ,- unsaturated aldehydes activated through an iminium ion with
catalyst (a) , followed by an intramolecular aldol reaction and subsequent elimination of water . This
overall reaction sequence provided benzopyranes with aromatic C-2 substituents in up to 60% yield
and 60%ee, while C-2 aliphatic analogues were obtained in 90% ee, but in low yields 20%.
Scheme 12: Organocataylzed asymmetric synthesis of chiral benzopyranes
MeO

catalyst(a) (10mol%)
+

Pr

OH
Ph

CH 2Cl2

MeO

O
O

Pr

yield 21%,
ee
90%

Ph
OTMS
catalyst (a)
N
H

Page 19

5. Conclusion.
Even though the asymmetric conjugate addition reaction catalyzed by a chiral organic molecule is one
of the earliest examples of a catalytic asymmetric transformation, it has reached to a spectacular
advancement during recent years. Conjugate additions of hydrogen, as well as carbon and heteroatom
nucleophiles, to a wide variety of Michael acceptors such as ,-unsaturated carbonyl compounds,
nitroolefins, can be efficiently performed employing readily available organocatalysts with excellent
levels of asymmetric induction and in short reaction times. This has provided a wide range of Michael
adducts in enantiomerically pure form, which have been employed as chiral building blocks in the total
synthesis of different natural products. Despite the considerable progress that has been made in the
elucidation of transition states, there is still much scope available for the new organocatalytic
transformations and especially, to the rational design of general catalysts based on all of the aspects
that control the reactivity and selectivity of these reactions.

Page 20

6. References.
(1) Gabriela, G.; Carmen, N.; Ramon, D. J. Enantioselective direct aldol reaction: The blossoming
of modern organocatalysis. Tetrahedron: Asymmetry 2007, 18, 2249-2293.
(2) Dalko, I. P.; Lionel, M. Enantioselective organocatalysis. Angew. Chem. Int. Ed. 2001, 40,
3726-3748.
(3) Etter, C. M.; Panunto, T. W. 1,3-Bis (m-nitro phenyl) urea: An exceptionally good complexing
agent for proton acceptors. J. Am. Chem. Soc. 1988, 110, 5897-5898.
(4) Almasi, D.; Alonso, A. D.; Najera, C. Organocatalytic asymmetric conjugate additions.
Tetrahedron: Asymmetry 2007, 18, 299-365.
(5) Palomo, c.; Vera, S. Highly efficient asymmetric Michael addition of aldehydes to nitroalkanes
catalyzed by a simple trans-4-hydroxy prolylamides. Angew. Chem. Int. Ed. 2006, 45, 59845987.
(6) Wei Wang.; Jian Wang.; and Hao li. Direct highly enantioselective pyrrolidine sulphonamide
catalysed Michael addition of aldehydes to nitrostyrenes. Angew. Chem. Int. Ed. 2005, 44,
1369-1371.
(7) Taylor, M. S.; Jacobsen, E. N.; Asymmetric catalysis by chiral hydrogen bond donors. Angew.
Chem. Int. Ed. 2006, 45, 1520-1543.
(8) Pikho, M. P.; Activation of carbonyl double hydrogen bonding: An emerging tool in
asymmetric catalysis. Angew. Chem. Int. Ed. 2004, 43, 2062-2064.
(9) Conn, R. S. E.; Lovell, A. V. Chiral Michael additions: methyl vinyl ketone addition catalysed
by Cinchona alkaloid derivatives. J. Org. Chem. 1986, 51, 4710-4711.
(10) Dolling, H. U.; Paul Davis.; Grabowski, J. J. E. Efficient catalytic asymmetric alkylation 1.
Enantioselective synthesis of (+) -Indacrenone via Chiral Phase transfer catalyst. J. Am. Chem.
Soc. 1984, 106, 446-447.
(11) Brandau, S.; Landa, A.; Franzen, J.; Marigo, M.; Jorgensen, A. K. Organocatalytic conjugate
addition of malonates to ,-unsaturated aldehydes: Formal synthesis of (-)- Paroxetine, Chiral
Lactams, and Lactones. Angew. Chem. Int. Ed. 2006, 45, 4305-4309.
(12) Horstmann, T. E.; Guerin, D. J.; Miller, S. J. Asymmetric Conjugate additions of Azides to ,unsaturated carbonyl compounds catalysed by small peptides. Angew. Chem. Int. Ed. 2000, 39,
3635-3638.
(13) Govender, T.; Hojabri, L.; Mogaddam, F. M.; Arvidsson, P. I. Organocatalytic synthesis of
chiral benzopyrans. Tetrahedron: Asymmetry 2006, 17, 1763-1767.

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