Michael addition prolinol catalysts

Lattanzi and coworkers disclosed that L-diaiyl prolinols served as suitable catalysts in one of the most popular Michael addition reaction, i.e. the reaction of malonate esters and cyclic p-ketoesters to nitroalkenes to generate functionalised products amenable to further manipulation (Scheme 7.7). 

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. ... 

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). 

Other nucleophiles, such as dicyanoolefins, have been submitted to orga-nocatalysed Michael additions with a,p-unsaturated aldehydes by Loh et al., in 2008. Therefore, a pool of water-compatible catalysts, namely dialkyl-(. -prolinols, was developed for the enantioselective direct vinylogous Michael addition of vinylmalononitriles to a,p-unsaturated aldehydes in aqueous medium. In all the reactions tested, only the ufM/i-Michael addition products were obtained. Notably, the best results in both yields and enantioselectivities were obtained by using the catalyst bearing a hexyl group, as shown in Scheme 1.11. 

Finally, a remarkable four-component tandem Michael-aza-Henry-hemi-aminalisation-dehydration tandem reaction was recently developed by Lin and co-workers on the basis of a dual organocatalysis involving a chiral diaryl prolinol trimethylsilyl ether and a chiral cinchona alkaloid." As shown in Scheme 2.37, the reaction began with the Michael addition of an aldehyde to a nitroalkene catalysed by the L-proline-derived catalyst, giving the corresponding intermediate aldehyde. The latter intermediate... 

In addition to pyrrolidine-based structure, prolme-based catalysts were also investigated. Two examples of supported prolinamide-based catalysts for the Michael reaction are 86 and 87 (Figure 24.29). Prolinamide-bridged silsesquioxane 86 was prepared from a bis-sUylated prolinamide by sol-gel methodology and used in water. This catalytic material was also used in aldol reactions [108]. The prolyl-prolinol catalyst 87 was anchored to a polystyrene backbone and used in a dichloromethane/water mixture [22a]. 

The group of Enders recently disclosed an original use of prolinol TMS ether as organocatalyst to promote the Michael addition of oxindoles to nitroolefins (Scheme 34.25) [65]. The reaction proceed through Bronsted base activation despite the fact that such a catalyst structure, chiral pyrrolidine, was usually employed in... 

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. 

The modified prolinol derivative (324) has been developed as a readily recyclable catalyst for the Michael addition of malonates CH2E2 (E = C02RO to enals RCH=CHCH=0, which proceeds at 10mol% loading in the presence of PhC02H (40%) as the Brpnsted acid cocatalysts in a mixture of H2O and Pr OH (3 2). The Michael adducts RCH(CHE2)CHCH=0 were thus obtained in <97% ee ... 

The analogue of 0-TMS prolinol (325) with CH3(CH2)n groups instead of the typical aryls, activated by a Brpnsted base, has been employed as catalyst for the Michael addition of N-Boc-protected oxindoles to nitroalkenes and exhibited >98 2 dr and 82 to >99% 0... 

Proline and proline derivatives have been utilized extensively as chiral catalysts for a wide range of asymmetric transformations [40, 132]. Gelman has documented a remarkable case in which enolizable aldehydes undergo selective Michael additions to enone acceptors (Equation 28) [133]. Diphenylpro-linol methyl ether (165) proved superior to other prolinol derivatives in terms of enantioselectivity and reactivity. As an example, the addition of oc-tanal (163) to ethyl vinyl ketone (164) in the presence of 5 mol% of 165 was carried out without solvent to furnish 166 in 87% yield and >95% ee. 

Since the Michael adducts 24 possess a stereogenic sp -center in the a-position, conjugate addition can be conducted asymmetrically in the presence of chiral catalysts, for example, with a,P-unsaturated aldehydes in the presence of diphenyl-(S)-prolinol-trimethylsilyl-ether/NEt3 [142]. 

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