Asymmetric reactions Michael reaction

Figure 1.15 Supramolecular catalysts for organocatalysis (a) Route to catalyst libraries (b) asymmetric nitro-Michael reaction.

Hechavarria Fonseca MT, List B (2004) Catalytic asymmetric intramolecular Michael reaction of aldehydes. Angew Chem Int Ed Engl 43 3958-3960... 

Roush, W. R. An asymmetric intramolecular Michael reaction. Construction of chiral building blocks for the synthesis of several alkaloids. Chemtracts Org. Chem. 1988,1, 233-235. 

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

The utihty of Cu(II)-box complex 96 for asymmetric Mukaiyama-Michael reaction has been intensively studied by Evans et al. (Scheme 10.91) ]248]. In the presence of HFIP fhe 96-catalyzed reaction of S-t-butyl thioacetate TMS enolate with alkylidene malonates provides fhe Michael adducts in high chemical and optical yield. HFIP plays a crucial role in inducing catalyst turnover. Slow addition of the silyl enolate to a solution of 96, alkylidene malonates, and HFIP is important in achieving high yields, because fhe enolate is susceptible to protonolysis with HFIP in fhe presence of 96. The glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Quite recenfly, Sibi et al. reported enantioselective synthesis of t -amino acid derivatives by Cu( 11)-box-catalyzed conjugate addition of silyl enolates to aminomefhylenemalonates ]249]. 

Palomo et al. have extended the range of nucleophiles amenable in asymmetric organocatalysed Michael reactions of nitronates and malonates to oc,P-unsaturated aldehydes Inspired by the prolinol motif, they proposed a series of derivatives, among which 21 was the most efficient catalyst for the nitro-Michael reaction of Scheme 1.11 and the Michael reaction of Scheme 1.12. These reactions required the use of benzoic acid as co-catalyst to optimize results. 

Asymmetric nitro-Michael reactions of methyl vinyl ketone (MVK) in the presence of bicyclic guanidine with a benzhydryl group led, disappointedly, to low asymmetric induction (9-12%) [21a] Trials for the reaction of 0 ,p-unsaturated y- or 8-lactones with pyrrolidine in the presence of the conjugate acids of a bicyclic guanidine [50] or the Murphy s guanidine [24a] (R = Me in Scheme 4.7) resulted in the production of racemic compounds. The latter phase transfer catalyst (PTC) catalyses the nitro-Michael addition of chalcone but with limited range (70% yield, 23% ee) [24c]. 

A 2,2-disubstituted chromane system was asymmetrically constructed by application of intramolecular oxa-Michael addition reaction through 6-exo-trig mode cyclization [57]. Good asymmetric induction at the quaternary carbon was observed when Z-alkene was treated with the same guanidine 17 used in asymmetric carba-Michael reaction in Table 4.5 (Scheme 4.18). 

Kumamoto, T., Rhine, K., Endo, M. et al. (2005) Guanidine-catalysed asymmetric addition reactions Michael reaction of cyclopentenone with dibenzyl malonates and epoxidation of chalcone. Heterocycles, 66, 347-359. 

For a leading review on the asymmetric phospha-Michael reaction see D. Enders, A. Saint-Dizier, M.-I. Lannou and A. Lenzen, Eur. J. Org. Chem., 2005, 29. 

Anilide 2a catalysed asymmetric intramolecular Michael reaction of formyl enones to chiral cyclic keto-aldehydes in excellent yields with good stereoselectivity (eqn. (1) in Scheme 6.3). The intramolecular Michael addition of a ketosulfone to an unsaturated ketone (eqn. (2) in Scheme 6.3) catalysed by 15e has heen used as a key step in the synthesis of the carbon tricyclic framework of Lycopodine. The same sulfonylprolinamide served as catalyst in the construction of all-carhon substituted quaternary stereocentre via Robinson-type annulation process (eqn. (3) in Scheme 6.3). 

Scheme 11.31 Asymmetric Mukaiyama-Michael reactions of silyloxy-furans and a,p-unsaturated aldehydes using pyrrolidine 33. 4-NBA = 4-nitro-benzoic acid.

The reaction has heen expanded to an asymmetric thio-Michael reaction by the addition of aiylmethyl mercaptans to cyclohex-2-enone in the presence of 10 mol% of triphenylmethyl-L-cysteine (9 examples, 44-86%, ee 8-58%). Maleimides undergo Michael addition with a,a-disubstituted aldehydes (Scheme 12.10). Several catalytic systems have been tested to promote the reaction, including a- or p-amino acids, potassium salts of amino acids... 

In the total synthesis of (+)-Greek tobacco lactone (14SL1888), the authors utilized the previously reported asymmetric Mukaiyama—Michael reaction of acrolein with a 2-siloxyfuran to prepare the key aldehyde intermediate in one step (14CEJ5983). This process was catalyzed by tmns-2,5-diphenylpyrrolidine via an iminium intermediate, with high enantioselectivity. The natural product was obtained from the aldehyde intermediate in a remarkable 34% overall yield in only four steps. 

Merging chemical synthesis and biosynthesis as a strategy of the total synthesis of natural products and natural product libraries 12AG(E)4012. Palladium-mediated total synthesis ofbioactive natural products 13S1271. Recent contributions from the asymmetric aza-Michael reaction to alkaloids total synthesis 13NPR1211. 

First studies in the direct asymmetric organocatalytic Michael reactions of a,a-disubstituted aldehydes with nitrostyrenes were carried out by Barbas et al. [51] employing 30 mol% of diamine/TFA bifunctional catalyst 31, which afforded... 

More recent studies on asymmetric PTC Michael reactions involving ketones, have sown that the A-alkylated cinchonidinium cation 61 mediates the enantioselective conjugate addition of acetophenone to chalcones (Scheme 2.34) [103]. In the proposed transition state of the reaction, the acetophenone enolate and the a,P-enone are contact... 

Tan and coworkers reported an asymmetric sulfa-Michael reaction, in which the enantioselective step is a protonation. Although the optimal solvent reported was Et20 (a highly hazardous solvent, rank 6,... 

Recently, Cobb and co-workers [110] developed the organocatalytic asymmetric intramolecular Michael reaction of nitronates to conjugated esters (Scheme 5.52). By... 

A strategy for the desymmetrization of cyclohexadienones via asymmetric aza-Michael reaction using cinchonine-derived thiourea 52 was developed by You s group (Scheme 11.33) [113]. A series of highly enantioenriched bicyclic pyrrolidine and morpholine derivatives were obtained in excellent yields and enantioselectivities. 

Another diarylprolinol ether has been used to catalyse several asymmetric domino Michael reactions. Therefore, Jorgensen et al. have demonstrated its efficiency for the asymmetric synthesis of 1,4-dihydropyridines, which are closely related to the NADH system, a biological system of utmost importance, and moreover these molecules are important drugs used in the treatment of a number of diseases, such as cardiovascular diseases and Alzheimer s disease. Thus, a series of chiral 1,4-dihydropyridines were prepared on the basis of a one-pot multicomponent reaction between a a,p-unsaturated aldehyde, a P-diketone... 

Other-than-proline derivatives have been successfully employed to catalyse a great number of asymmetric nitro-Michael reactions. Therefore, excellent... 

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