Malonates enantioselective Michael addition

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

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... 

The catalytic enantioselective addition of aromatic C - H bonds to alkenes would provide a simple and attractive method for the formation of optically active aryl substituted compounds from easily available starting materials. The first catalytic, highly enantioselective Michael addition of indoles was reported by Jorgensen and coworkers. The reactions used a,fl-unsaturated a-ketoesters and alkylidene malonates as Michael acceptors catalyzed by the chiral bisoxazoline (BOX)-metal(II) complexes as described in Scheme 27 [98,99]. 

Rasappan R, Hager M et al (2006) Highly enantioselective michael additions of indole to benzylidene malonate using simple bis(oxazoline) ligands importance of metal/ligand ratio. Org Lett 8 6099-6102... 

Enantioselective Michael Additions. Amine 1 has also been used as an effective ligand for enantioselective Michael reactions of ketone lithium enolate donors with various benzylidene acceptors. As representative examples, the lithium enolates of aryl methyl ketones were reacted with dimethyl benzylidene-malonate in the presence of 1 (eq 9). The lithium enolate was generated from the corresponding ketone by treatment with hex-amethyldisilazide in the presence of lithium bromide in toluene. The resulting enolate was then exposed to 1 and allowed to stir for 30 min to form the desired ternary complex. After addition of the benzylidene acceptor, the desired products were isolated in acceptable yields and with high % ee. 

Figure 11.4 Enantioselective Michael addition of malonates to cyclic enones.

A catalytic enantioselective Michael addition of diisopropyl malonate to a,p-unsaturated ketones and aldehydes has been achieved using 5 mol% of the... 

Scheme 4.5 68a-catalyzed enantioselective Michael addition of malonates to nitroalkenes and application to the total synthesis of (R)-(-)-baclofen. 

Scheme 4.11 Enantioselective Michael addition of malonic acid half-thioesters to nitroalkenes catalyzed by 70b.

Similarly, Yoshida developed an enantioselective Michael addition of malonates to enones by using a primary p-amino acid, O-tert-butyldiphe-nylsilyl (TBDPS) (S)-p-homoserine, lithium salt 15 (Scheme 2.10). ... 

In 2003, Takemoto and coworkers published the enantioselective Michael addition of malonates to nitro-olefins catalysed by the first bifunctional thiourea 15, providing the corresponding products in high yields and enantioselectivities. The proposed mechanism involved a bifunctional transition state, where activation of the nitro-olefin is promoted by the thiourea group, while the activation of the malonate occurred by the tertiary amine (Scheme 19.18). ... 

Subsequently, the highly enantioselective Michael addition of malonates and 1,2,4-triazole to cyclic and acyclic enones, as well as the first phospha-Michael reaction of cyclic enones and diaryl phosphine oxides was reported using a similar catalyst.In 2012, Huang, Wang and coworkers demonstrated that primary amine-thiourea 39 can efficiently catalyse the... 

Ley et al. have demonstrated that the pyrrolidinyl tetrazole catalyst, depicted in Scheme 1.13, could be used to efficiently induce the enantioselective Michael addition of malonates to oi,p-unsaturated enones. Cyclic, acyclic and aromatic enones could be involved in this process, and the reaction with the most efficient ethyl malonate provided, in the presence of piperidine as an additive, the corresponding Michael products in high yields with good to excellent enantioselectivities, as shown in Scheme 1.13. 

In addition, several organocatalysts other than cinchona alkaloid derivatives have been developed very recently. As an example, a chiral bicyclic guanidine was found by Tan et al. to be an excellent catalyst for enantioselective Michael additions of malonates or ethyl benzoylacetates to cyclopentenone or... 

Recently, the mechanism of enantioselective Michael addition of malonic esters and keto esters to cyclic conjugated enones catalyzed by Ru bifunctional complexes 1 was studied in detail. ... 

Feng, Liu, and coworkers reported a highly enantioselective Michael addition of malonates to /3,y-unsaturated a-ketoesters catalyzed by a chiraLV,iV -dioxide-yttrium(III) complex (eq 7). The chiral catalyst was prepared from Y(OTf)3 and afforded Michael adducts with an enantiomeric excess as high as 99%. 

Enantioselective Michael addition catalyzed by chiral aluminum Lewis acid is one of the most important methods to obtain enantiomerically pure compounds. As an early work in this fleld, in 1986, Shibasaki and coworkers reported catalytic enantioselective Michael addition of malonates to cyclic enones catalyzed by Li-Al bimetallic catalyst (72) (ALB) derived by premixing LiAlH4 and 2 equivalent of (R)-BINOL in THF (Scheme 6.86) [106, 107]. The structure of (R)-ALB was confirmed by X-ray crystallographic analysis of ALB-cyclohexenone complex. One notable advantage of ALB catalyst is that it works nicely in the tandem Michael-aldol sequence. 

Enantioselective Michael addition of malonates to a,p-unsaturated carbonyls with Al(salen) complex was firstly reported by Jha and Joshi in 2001. They reported the formation of Al-Na bimetallic Al(salen) complex (73b) from (R,R)-salen and NaAlH2(OCH2CH20Me), and catalytic activity for catalytic enantioselective Michael addition of malonic diesters to cyclic a,P-enones (Scheme 6.93) [111]. In the reaction of cyclopentenone with various malonates, this catalyst resulted in good chemical yield and moderate enantioselectivity. 

Scheme 22.32 Enantioselective Michael additions of dialkyl malonates to substituted...

A practical and highly enantioselective Michael addition of malonates to enones catalysed by bifunctional primary amine-thiourea (5) derived from 1,2-diaminocyclohexane has been reported. The addition of weak acids and elevated temperature improved the efficiency of the Michael reaction. This approach enables the efficient synthesis of 1,5-ketoesters with good yields, excellent enantioselectivities (up to 99% ee), and low loading (0.5-5 mol%) of catalysts. A related bifunctional cinchona-thiourea catalyst has been involved in asymmetric organocatalysed conjugate addition reactions of monoth-iomalonates to nitroolefins. ... 

When cyclic enones were used as Michael acceptors, both malonates and acetoacetates gave impressive yields and enantioselectivities of the desired Michael addition products (Scheme 5.2Q) NMR spectra and single-crystal X-ray data supported the following ruthenium intermediate (Scheme 5.21) and transition state (Figure 5.8). 

A chiral phase transfer catalyst was dissolved in ionic liquid media for the enantioselective Michael reaction of dimethyl malonate with l,3-diphenylprop-2-en-l-one with K2CO3 203). The phase-transfer catalyst was a chiral quininium bromide (Scheme 20). The reaction proceeded rapidly with good yield and good enantioselectivity at room temperature in all three ionic liquids investigated, [BMIM]PF6, [BMIM]BF4 and [BPy]BF4. In the asymmetric Michael addition, the enantioselectivity or the reaction in [BPy]Bp4 was the same as in conventional organic solvents. 

Significant improvement in the catalytic activity of ALB was realized without any loss of enantioselectivity by using the second-generation ALB [27] generated by the self-assembled complex formation of ALB with alkali metal-malonate or alkoxide. This protocol allowed the catalyst loading to be reduced to 0.3 mol %, for example, the Michael addition of methyl malonate to cyclohexenone catalyzed by the self-assembled complex of (ff)-ALB (0.3 mol %) and KO Bu (0.27 mol %) in the presence of MS 4A gave the adduct in 94% yield and 99% ee [28]. This reaction has been successfully carried out on a 100-g scale wherein the product was purified by recrystallization. The kinetic studies of the reactions catalyzed by ALB and ALB/Na-malonate have revealed that the reactions are second-order to these catalysts (the rate constant ALB = 0.273 M 1h 1 ALB/Na-maionate = 1-66 M 1h 1) [27]. This reaction was used as the first key step for the catalytic asymmetric total synthesis of tubifolidine (Scheme 8D. 11) [28]. 

Cobalt(II) complexes prepared in situ from (AcO Co and two novel chiral spiro nitrogen-containing ligands, 7,7/-bis(2-pyridinecarboxamido)-l,l/-spirobiindane (SIPAD) and 7,7/-bis(2-quinolinecarboxamido)-l,l/-spirobiindane (SIQAD), are efficient cata- lysts for the asymmetric Michael addition of malonates to chalcone derivatives. The alkylation products were obtained in high yields with moderate enantioselectives.169... 

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