Prolinol ether catalysts

Using a similar approach, but assisted by Jprgensen/Hayashi prolinol ether catalysts, Fustero et al. [103] and Carter and co-workers [104] have independently documented additional innovative applications of this intramolecular reaction providing a practical route to enantioenriched piperidines from the corresponding co-amino a,p-unsaturated aldehydes (Scheme 11.28). This methodology has been later expanded successfiiUy to the synthesis of quinoUzidine alkaloids such as... 

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). ... 

Subsequently, the same group developed an AFC reaction of 4,7-dihydroindoles with a,p-unsaturated aldehydes promoted by diphenyl-prolinol ether (S)-118 in the presence of 20 mol% of triethylamine as the co-catalyst. C2-Substituted 4,7-dihydroindoles 119 were obtained in high yields (61-93%) and excellent enantioselectivity (up to 99% ee). After... 

In 2008, the groups headed by Jprgensen and Rueping contemporaneously reported the use of 1,3-diketones reacting as bis-nucleophiles with a,p-unsaturated aldehydes under iminium catalysis with a diaryl prolinol sdyl ether catalyst (Scheme 16.13) [27, 28]. This domino reaction allowed the formation of 3,4-dihydropyrans with good yields and enantioselectivities but variable diastereoselectivities in favor of the 1,3-trans derivatives, precursors of indoloquinoUzidines [29]. 

N- unsubstituted Rs-substituted indoles of type 218 (R4 = H, 1.20 equiv) and P-substituted a,P-unsaturated aldehydes (213, 1.0 equiv) in the presence of diphenyl prolinol TMS ether catalyst 212 (5-20 mol %) in ethereal solvents such as TBME at 25 "C to -20 "C could afford adducts 219 in very good yields (66-95%) and enantioselectivities (92-98%). 

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. 

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... 

In contrast to the plethora of methodologies showing stereoselective applications of the Jorgensen-Hayashi catalyst (Chapter 8), a few reports have addressed the catal3dic ability of prolinol carbon-ethers in asymmetric synthesis. These procedures focused on the employment of commercially available (5)- or (R)-2-metho3qmiethylpyrrolidine, a scaffold originally... 

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). 

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]. 

A wide-ranging enantio- and diastereo-selective reaction of imines and aldehydes gives anP-Mannich product. For example, PhCH2CH2CH=NTs reacts in brine with both aliphatic and aromatic aldehydes. A simple diaryl prolinol TMS ether serves as chiral catalyst A-nosyl imines can also be employed. ... 

Branched enals have been aziridinated enantioselectively using a diaryl prolinol TMS ether as catalyst, giving IV-tosyl aziridines with a quaternary centre." ... 

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%... 

When nitrostyrenes and dimethylmalonate were reacted with a,p-un-saturated aldehydes in the presence of a combination of chiral diphenyl-prolinol triethylsilyl ether and a chiral cinchona alkaloid catalyst through a three-component reaction, Xu et al. showed that they afforded, according to a Michael-Michael-aldol domino reaction, the corresponding chiral functionalised cyclohexanes in moderate to good yields, good to excellent enantioselectivities of up to >99% ee, albeit moderate diastereoselectivities... 

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... 

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]. 

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. 

---