Michael addition, acidic chiral imines

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

Hypothesizing that primary amine catalysts, due to their reduced steric requirements, might be suitable for the activation of ketones, we studied various salts of a-amino acid esters. (For pioneering use of primary amine salts in asymmetric iminium catalysis involving aldehyde substrates, see Ishihara and Nakano 2005 Sakakura et al. 2006 for the use of preformed imines of a, 3-unsaturated aldehydes and amino acid esters in diastereoselective Michael additions, see Hashimot et al. 1977.) We have developed a new class of catalytic salts, in which both the cation and the anion are chiral. In particular, valine ester phosphate salt 35 proved to be an active catalyst for the transfer hydrogenation of a variety of a, 3-unsaturated ketones 36 with commercially available Hantzsch ester 11 to give saturated ketones 37 in excellent enantiose-lectivities (Scheme 28 Martin and List 2006). 

Chiral amines have been transformed into chiral imines RCH=NG, which are usually in equilibrium with the tautomeric enamines. These enamines undergo asymmetric alkylations, and the best results are often obtained with ethers 1.58 or with valine derivatives 1.59 (R = i-Pr, R = tert-Bu) [169, 173,253] in the presence of bases. Enamines, lithioenamines and zinc enamines derived from imines are very potent Michael donors that often participate in highly stereoselective reactions [161, 162, 169, 173, 254, 257, 260, 262, 267], Chiral imines can suffer very selective addition reactions of organomagnesium reagents [139, 253, 254] and allyl-metals [154, 258]. They also suffer stereoselective Ti-catalyzed silylcyanation [268], Strecker reaction [266], and [2+2] or [4+2] cydoadditions [131, 256, 263], When the reaction produces an imine product, the chiral auxiliary is recovered after acidic hydrolysis. However, when an amine is obtained as the product, as is often the case from phenethylamine derivatives, the chiral residue is cleaved by hy-drogenolysis. In such cases, the chiral amine is not, strictly speaking, a chiral auxiliary. But these processes will be discussed anyway because of their importance in asymmetric synthesis. 

In conclusion, chiral heterobimetallic lanthanoid compexes LnMB, which were recently developed by Shibasaki et al., are highly efficient catalysts in stereoselective synthesis. This new and innovative type of chiral catalyst contains a Lewis acid as well as a Bronsted base moiety and shows a similar mechanistic effect as observed in enzyme chemistry. A broad variety of asymmetric transformations were carried out using this catalysts, including asymmetric C-C bond formations like the nitroaldol reaction, direct aldol reaction, Michael addition and Diels-Alder reaction, as well as C-0 bond formations (epoxidation of enones). Thereupon, asymmetric C-P bond formation can also be realized as has been successfully shown in case of the asymmetric hydrophosphonylation of aldehydes and imines. It is noteworthy that all above-mentioned reactions proceed with high stereoselectivity, resulting in the formation of the desired optically active products in high to excellent optical purity. 

Chiral tetronic acids.2 The key step in a synthesis of chiral 5,5-disubstituted tetronic acids (4-hydroxybutenolidcs) involves Michael addition to acrylates of a chiral imine (2) derived from a dihydrofuran-3-onc and (R)-l-phenylethylamine (1). After... 

A broad range of enantiomericaUy pure 4,5-dihydrobenzo[r [l,3]diox-epines 177 have been prepared via a four-component Mannich reaction and subsequent intramolecular oxo-Michael reaction (14CC2196). The reactions proceeded with both high enantio- and diasteroselectivity, utilizing a dual catalytic system of Rh2(OAc)4 and a chiral phosphoric acid 178. The rhodium catalyst forms the protic oxonium ylide 174 from a diazo compound 171 and this subsequently adds to imine 175, formed in situ. The resulting enantiomericaUy enriched intermediate 176 then undergoes an intramolecular and diastereoselective oxo-Michael addition to form the final product 177. 

Chiral oxazaborolidine catalysts were applied in various enantioselective transformations including reduction of highly functionalized ketones/ oximes or imines/ Diels-Alder reactions/ cycloadditions/ Michael additions, and other reactions. These catalysts are surprisingly small molecules compared to the practically efficient chiral phosphoric acids, cinchona alkaloids, or (thio)ureas hence, their effectiveness in asymmetric catalysis demonstrates that huge substituents or extensive hydrogen bond networks are not absolutely essential for successful as5unmetric organocatalysis. 

Enantioselective Friedel-Crafts reactions using metal-based chiral catalysts or chiral organocatalysts have been investigated extensively because the reactions directly provide alkylated arenes, a pharmacologically important substructure, in optically active forms. The chiral phosphoric acid catalyzed Friedel-Crafts reaction was first accomplished via the activation of imines but, currently, the scope of the electrophilic components has been broadened to include the Michael addition to nitroalkenes, a, 3-unsaturated carbonyl compounds, and so on. 

After great success in the reduction of imines, quinolines, and pyridines. Rueping et al. designed a chiral phosphoric acid-catalyzed cascade reaction, in which enamines and enones are heated with Hantzsch ester la and (R)-6, then a Michael addition, cyclization, isomerization and hydride transfer reaction take place successively to afford chiral tetrahydropyridine 59 and azadecaUnone 60 products in excellent enantioselectiYities (Scheme 32.11) [33]. Remarkably,... 

Diastereoselective preparation of a-alkyl-a-amino acids is also possible using chiral Schiff base nickel(II) complexes of a-amino acids as Michael donors. The synthetic route to glutamic acid derivatives consists of the addition of the nickel(II) complex of the imine derived from (.S )-,V-[2-(phenylcarbonyl)phenyl]-l-benzyl-2-pyrrolidinecarboxamide and glycine to various activated olefins, i.e., 2-propenal, 3-phenyl-2-propenal and a,(f-unsaturated esters93- A... 

Protected glycine derivatives have been used as the nucleophilic partner in enantioselective syntheses of amino acid derivatives by chiral PTC (Scheme 10.9). Loupy and co-workers have reported the addition of diethyl acetylaminomalonate to chalcone without solvent with enan-tioselectivity up to 82% ee [44]. The recent report from the Corey group, with catalyst 8a used in conjunction with the benzophenone imine of glycine t-butyl ester 35, discussed earlier, results in highly enantioselective reactions (91-99% ee) with various Michael acceptors (2-cyclo-hexenone, methyl acrylate, and ethyl vinyl ketone) to yield products 71-73 [21], Other Michael reactions resulting in amino acid products are noted [45]. 

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