Prolinol silyl ethers Michael additions

Michael additions are among the most important organocatalytic transformations.The ability of prolinol silyl ethers to form enamines, diena-mines, trienamines or iminium ions makes them appealing in a number of chemical transformations based on addition of a nucleophile to an a,p-unsaturated carbonyl compound or other Michael acceptor. The first example of Michael addition catalysed by a prolinol silyl ether was published by Hayashi and coworkers. Aliphatic aldehydes added to a range of aryl-substituted nitroalkenes. Prolinol silyl ether Cla presumably formed chiral enamines with aldehydes. The F-anh-enamine was formed and it reacted with nitroalkene via an acyclic synclinal transition state, originally proposed... 

Detailed mechanistic studies of this reaction have been undertaken hy several teams. Michael addition of the simplest enolisahle aldehyde, acetaldehyde, poses a significant challenge due to high auto-aldol reactivity of acetaldehyde. List and coworkers used prolinol silyl ether eatalysts to promote enantioselective Michael addition of acetaldehyde to nitroalkenes.The key to successful accomplishment of this transformation was slow addition of acetaldehyde via a syringe pump. 

Cordova and coworkers showed that prolinol silyl ethers can also operate as iminium catalysts. The Michael addition of 1-fluorobis-(phenylsulfonyl)methane to a,p-unsaturated aldehydes proceeded with high enantioselectivity (Scheme 8.6). The primary Michael adducts were transformed to aldehydes, carbo>g7lic acids, or the sulfonyl groups could... 

Other compounds with sufficiently acidic C-H protons can serve as pronucleophiles in Michael additions to a,p-unsaturated aldehydes. Li, Wang and coworkers showed that arylmethanes bearing electron-withdrawing substituents underwent Michael addition to various enals mediated hy prolinol silyl ethers. Catalyst screening revealed that triethylsilyl catalyst Clb was the most efficient one (Scheme 8.10). Independently, Jorgensen and coworkers have also described benzylation of unsaturated aldehydes with toluenes. ... 

Heteroaromatic compounds are also suitable nucleophiles in the Michael additions to enals catalysed by prolinol silyl ethers. Hayashi and coworkers demonstrated that oxazolinones can add effectively to enals (Scheme S.lSa)." Indole also added effectively to a,p-unsaturated aldehydes (Scheme 8.13b). Also, enantioselective Michael addition of simple 3(2H)-furanones to a,(3-unsaturated aldehydes has been described (Scheme 8.13c). ... 

Heteroatom nucleophiles were described less often. Ye and coworkers published a phospha-Michael addition catalysed by prolinol silyl ether catalyst. Another method for constructing a new C-N bond is the aza-Michael addition, that is the addition of nitrogen-based nucleophiles to a,(3-unsaturated aldehydes. Several groups published these type of reactions using diatylprolinol silyl ether as catalyst. " Fustero and coworkers used this reaction as a key step in the synthesis of biologically active chiral heterocycles. Recently, the authors showed the synthesis of quinolizidine alkaloids, such as (-l-)-myrtine, (-)-lupine and (-l-)-epiquinamide. Vicario applied 5-mercaptotetrazoles as nucleophiles towards a range of unsaturated aldehydes. The reaction proceeded via the iminium activation. The... 

S.2.3.2. 0L, -Unsaturatecl Aldehydes as Acceptors. As an alternative strategy for the synthesis of y-nitro aldehyde compounds, the asymmetric Michael addition of nitroalkanes to a,(3-unsaturated aldehydes was also investigated in recent years. Due to the high reactivity of aldehydes, the competitive 1,2-addition reaction is the major limitation for the development of such a reaction. Disubstituted prolinol silyl ether derivatives [72] proved to be effective catalysts to tackle this synthetic challenge, and excellent results were obtained with 7 in the presence of acid or base additive (Scheme 5.35). 

One year later, the same group achieved the four-component conpling of enals, protecting hydroxylamine (A -methoxycarbmate), aryamines, and acetone by a combination of (5)-prolinol silyl ether and (5)-proline [18], affording orthogonally protected 1,3-diamine motif efficiently with excellent stereochemical control (Scheme 9.17). Mechanistically, the reaction proceeds via a (S)-prolinol silyl ether-catalyzed aza-Michael addition of protected hydroxylamines to a,p-unsaturated enals followed by an (S)-proline-promoted Mannich reaction of the p-amino aldehyde... 

Later, the same group succeeded in achieving a cascade Michael/nitro-Mannich/ acetalization reaction by the combination of covalent enamine catalysis and noncovalent bifunctional base/Br0nsted acid catalysis [32]. The fuUy substituted piperidines with diverse substitution patterns were prepared efficiently starting from simple aliphatic aldehydes, Ts-protected imines, and trani -P-nitro alkenes (Scheme 9.36). This finding effectively incorporated prolinol silyl ether-catalyzed Michael addition of aldehyde 65 to nitroalkene 75 and valine-derived bifunctional thiourea-mediated nitro-Mannich reaction of y-nitro aldehyde 106 to imine 105 in the cascade process, providing a complementary contribution to the well-known single catalyst-promoted triple cascade reactions and two catalyst-promoted reaction cascades. 

---