1,3-Dicarbonyl compounds enantioselective Michael addition

The axially chiral guanidine catalyst (155) (0.4-5 mol%) has been developed to facilitate the highly enantioselective Michael addition of 1,3-dicarbonyl compounds (g to a broad range of conjugated nitroalkenes (<98% ee).211... 

A highly enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes has been reported that employs a newly developed Ni(II)-(bis)diamine-based catalyst (174). The reaction scope includes substituted and unsubstituted malonates, /3-keto esters, and nitroalkenes bearing aromatic and aliphatic residues.202... 

Scheme 4.6 68a-catalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to nitrostyrenes. 

In 2002, Itoh and Kanemasa found that the combined use of both amine and chiral Lewis acid (R,R)-DBFOX-Ph complex of Ni(II) can be an active catalyst for enantioselective Michael addition of nitromethane or malononitrile to unsaturated carbonyl compounds [37a,b]. Recently, they have reported a new enol ketone synthesis through the reactions between cyclic 1,3-dicarbonyl donors and a,p-unsaturated carbonyl acceptors under the double catalytic activation conditions (10mol% each) of Ni(11)-perchlorate hexahydrate and (2,2,6,6-tetramethylpiperidine (TMP) (114))(Scheme 16.33) [38a,b]. Thus, 1,3-cyclohexanedione (112) is allowed to react with 4-bromo-l-crotonoyl-3,5-dimethylpyrazole (113), in THF at room temperature in the presence of both catalytic amounts to give 4,7,7-trimethyl-3,4,5,6,7,8-hexahy-drobenzopyran-2(H),5-diones (115) in good yields along with high enantioselectivity up to 99% ee. 

Subsequently, several groups have studied related squaramide-catalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes. High enantioselectivities have been achieved using pyrrolidine-cinchonine-squaramide catalyst 14 [81], quinine-squaramide catalyst 15 [82, 83], and Cs-symmetrical cinchonine-squaramide catalyst 16 (Figure 10.4) [84]. Notably, the reaction time... 

CATALYTIC ENANTIOSELECTIVE MICHAEL ADDITION OF 1,3-DICARBONYL COMPOUNDS TO CYCLIC ENONE FOR THE SYNTHESIS OF THE STRYCHNOS ALKALOIDS AND MAGNOLIONE ANALOGS... 

A chiral quinine-derived squaramide catalysed the highly enantioselective Michael addition of malononitrile to chalcones. The reactions take place at a very low catalyst loading (0.5 mol%) and provide the Michael adducts with high yields and good enan-tioselectivities (up to 96% ee). Chiral bifunctional squaramides have also been used as multiple hydrogen-bond donor-acceptor organocatalysts for the asymmetric Michael addition of nitroolefins to 1,3-dicarbonyl compounds. ... 

On the other hand, the enantioselective 1,4-addition of carbanions such as enolates to linear enones is an interesting challenge, since relatively few efficient methods exist for these transformations. The Michael reaction of p-dicarbonyl compounds with a,p-unsaturated ketones can be catalysed by a number of transition-metal compounds. The asymmetric version of this reaction has been performed using chiral diol, diamine, and diphosphine ligands. In the past few years, bidentate and polydentate thioethers have begun to be considered as chiral ligands for this reaction. As an example, Christoffers et al. have developed the synthesis of several S/O-bidentate and S/O/S-tridentate thioether... 

The asymmetric Michael addition of 1,3-dicarbonyl compounds to nitrostyrene is promoted by chiral alkaloid catalysts to give the addition products in good chemical yield, but the enantioselectivity is rather low (Eq. 4.47).62... 

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

Allylic C-H insertions have been used in key steps of the enantioselective synthesis of the pharmaceuticals (+)-ceitedil (26) [21] and (+)-indatraline (27) [22] (Scheme 11). The allylic C-H insertion reaction is an exciting alternative to the Claisen rearrangement as a rapid method for the synthesis of y,c>-unsaturated ester [23 ]. Similarly, the allylic C-H insertion with vinyl silyl ethers generates protected 1,5-dicarbonyl compounds, a complimentary reaction to the Michael addition [24]. Both types of C-H insertion can be achieved with high diastereoselectiv-ity and enantioselectivity [23, 24]. 

In recent years, many chiral catalysts for the enantioselective synthesis of optical active 1,5-dicarbonyl compounds have been developed, such as chiral crown ethers with potassium salt bases and chiral palladium complexes, including bimetallic systems. Nakajima and coworkers reported on enantioselective Michael reactions of S-keto esters to a,/3-unsaturated carbonyl compounds in the presence of a chiral biquinoline N,N dioxide-scandium complex, which catalyzed the additions in high yields and with enan-tioselectivities up to 84% ee . Kobayashi and coworkers found that the combination of Sc(OTf)3 with the chiral bipyridine ligand 149 (equation 41) was also effective as a chiral catalyst for asymmetric Michael additions of 1,3-dicarbonyl compounds 147 to a,/3-unsaturated ketones 148. The corresponding Michael adducts 150 were obtained in good to high yields with excellent enantiomeric excesses in most cases (Table 10). 

A more simple thiourea catalyst with amino functionality catalyses the asymmetric Michael addition of 1,3-dicarbonyl compound to nitroolefin [29,30]. In the reaction of malonate to nitrostyrene (Table 9.11) the adduct is satisfactorily obtained when A-[3,5-bis(trifluor-omethyl)phenyl]-A -(2-dimethylaminocyclohexyl)thiourea is used as a catalyst (ran 1), whereas the reaction proceeds slowly when the 2-amino group is lacking (ran2). In addition, chiral amine without a thiourea moiety gives a poor yield and enantioselectivity of the product (run 3). These facts clearly show that both thiourea and amino functionalities are necessary for rate acceleration and asymmetric induction, suggesting that the catalyst simultaneously activates substrate and nucleophile as a bifunctional catalyst. 

Based on the elegant work from the group of Studer on redox activation of a,p-unsaturated aldehydes/ the You group realized enantioselective NHC-catalyzed Michael addition reactions to a,p-unsaturated aldehydes by redox oxidation. With 10 mol% of camphor-derived triazolium salt, developed by the authors group, the reactions of various dicarbonyl compounds... 

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