Prolinol silyl ether catalysts

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... 

Prolinol silyl ether catalysts were also able to control the Mannich reaction of acetaldehyde. Xu and coworkers utilised Michael adducts of aldehydes with nitroalkenes in the subsequent Mannich-type reaction with imines followed by cyclisation. Highly substituted chiral piperidines were formed. Suitable imines for organocatalytic Mannich reactions can also be generated in situ from amido sulfones (Scheme 8.34). ... 

An alternative catalyst design consists of the introduction of bulky groups at the pyrrolidine ring, which would exert their stereochemical influence via steric shielding of one of the diastereotopic faces of the enamine intermediate. In this context, a wide variety of different proline derivatives have been employed in this transformation, including prolinol silyl ether homoprolinol silyl... 

Prolinol silyl ethers were introduced independently by Jorgensen and Hayashi in 2005 (Figure 8.1) and this catalyst type quickly became one of the privileged structures in the asymmetric organocatalysis. ... 

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... 

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). 

Diphenyl prolinol silyl ether (123a) has been employed as a catalyst for the Michael-Michael cascade reaction of the /3-dicarbonyl Michael donor (155) and Q, /i-unsaturated aldehydes (156), giving rise to functionalized cyclic keto esters (157) with <32 1 dr and <99%... 

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. 

Iminium catalysis is one of the most powerful methods for the introduction of a nucleophile in -position of an a,(3-unsaturated carbonyl. Various nucleophiles can be entered such as N, O, C, aryl, and heteroaryl nucleophiles in usually high levels of stereoselectivity. To obtain these high enantioselectivities, two catalysts have seemed to be more general as soon as aldehydes are involved. Diaryl-prolinol silyl ethers and MacMillan imidazolidinones have found applications in numerous processes (Scheme 11.3). These catalysts are... 

On more complex natural product synthesis, Pansare and co-workers exploited the well-studied addition of cyclohexanone to nitroolelin to introduce the requisite functionalities of pancranine (Scheme 11.22). As mentioned, the diaryl prolinol silyl ethers, general catalysts for aldehyde, do not work in the case of ketones because of the steric constraint of the requisite transition state. A good 89% ee and >19 Ur was obtained using catalyst 89. Interestingly, the final construction of the complex... 

Hong and co-workers entirely exploited the ability of amine catalysts to promote cascade reactions by different mechanisms. They applied a one-pot oxa Michael-Michael-Michael-aldol reaction for the synthesis of conicol, a marine terpenoid isolated from Aplidium conicum (Scheme 11.32). Using diphenyl prolinol silyl ether 12,... 

Chiral tetrahydrothiophenes are compounds displaying important biological activities. They were obtained also through an enantioselective domino sulfa-Michael-Michael process of a,(3-unsaturated aldehydes with ethyl 4-mercapto-2-butenoate [47]. While catalyst 17a turned out to be ineffective, the diarylprolinol silyl ether 17b afforded cyclic products with high to excellent enantio- and diastereoselectivity (Scheme 14.16a). A closely related sulfa-Michael aldol process was developed by using 3-mercapto a-carbonyl esters as reaction partners. The best stereoselectivity and yield were obtained with diaryl prolinol 17c in the presence of small amounts of H2O (Scheme 14.16b) [48]. 

Non-catalyzed aldol reactions via hypervalent silicon species have also been studied. An aldol reaction between aldehydes and silyl enol ethers of amides was reported by Myers [105]. The reaction can be conducted under mild conditions to produce anti aldol without Lewis acid or base catalysts (Sch. 62). Asymmetric induction was particularly high when the (Z)-silyl ketene A/,0-acetal derived from prolinol was used. 

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