Catalytic, enatioselective Michael addition reactions

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 NO 2 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.


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).
( 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).
(c).Both the reactants i.e.Michael donor and Michael acceptor are achiral however the catalyst used for the reaction is chiral (eqn.4) 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).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 reported 1 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 Various chiral cinchona alkaloids which have been used for Michael addition reaction are shown in Figure 2. Addition of aromatic thiols to conjugated cycloalkenones was also reported.Quinine or N-(p-nitrobenzyl) quininium chloride (6) showed comparable catalytic activity (eqn.6).

R' R
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 proposed 4 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).

Figure 3
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. reported 5 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).Mukaiyama et.al. reported 7 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 0 C. However reaction at 20 0 C gave product (11) in 92% yield and in 55% ee (eqn.9).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).

Scheme 1
Recently Skarzewski et.al. reported 10 enantioselective addition of thiophenols to chalcones in the presence of cinchonine to give Michael adduct (12) in up to 80% ee (eqn.11).

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).Burri et.al. carried out 15 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).

Crown ethers
Crown ethers of wide structural variations have been used for the asymmetric Michael addition reactions.Since the first report 16 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.   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).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 complex-A 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.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. reported 23 the conjugate addition of nitroalkanes to cycloalkenones using L-proline as the catalyst (eqn.28).

-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).

Figure 8
The same group later reported 27 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.

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. Extensive studies showed [47][48][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).However for cyclic enones of different ring-size, the gallium-sodium complex (GSB) (48)  and the aluminium lithium complex (49) proved 50  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).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 adduct 53

-90% ee
The same group later reported 54,55 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 free lanthanum catalyst (50b) displayed perfect enantioselection in the addition of malonates to cyclic enones (eqn.49

Scheme 3
We have recently reported 58 a new aluminium-salen complex for the enantioselective addition of various alkylmalonates to cycloalkenones (Scheme-4).

Na
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.

Chiral N,N-dioxides
The N-oxide functional group is known to form complexes with a variety of metals 59 due to its strong electron donating ability.1][62][63][64][65][66][67] Nakajima et.al. developed 68 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).The same group also reported 69 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).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.

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 Figure 1
Figure 9 Figure 10 Tomioka et.al. reported71 the addition of thiols to acrylate derivatives in the presence of chiral ligand(59) and lithium phenolate (eqn.54).
The existence of bicyclo[3.3.0]complex (60) as active species in the reaction was postulated.
© ARKAT USA, Inc 51 be the catalyst of choice (eqn.45).Feringa et.al.demonstrated51that 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).