Ethers prolinol silyl

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. ... 

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... 

Figure 8.1 The most common diaryl prolinol silyl ether organocatalysts Cla and C2a.

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... 

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). ... 

Various cycloaddition reactions can be efficiently catalysed by prolinol silyl ethers.Dienamines generated from a,(3-unsaturated aldehydes participated in the Diels-Alder reaction with quinones. Nitrolefins can also function as dienophiles in organocatalytic Diels-Alder reaction. Reyes, Vicario and coworkers found that unconjugated 2,5-dienals are more reactive substrates than the corresponding conjugated aldehydes (Scheme 8.35). The reaction proceeded with clean p,E-selectivity and the corresponding products were obtained in high diastereomeric and enantiomeric purities. 

Chen and coworkers reported organocatalytic asymmetric [4 + 2] formal cycloadditions of cyclohexenylidene malononitriles with enals. This reaction afforded chiral bicyclo[2.2.2]octanes. Higher-order cycloadditions can also be catalysed by prolinol silyl ethers. Intramolecular [6 + 2] additions of fulvenes substituted at the exocyclic 6-position with a 5-formylalkyl group afforded synthetically useful linear triquinane derivatives in good yields and excellent enantioselectivities. ... 

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). 

A closely related synthesis of tricyclic oxazines and oxazolidines was reported shortly afterward by Ye s group when the internal nucleophile is a hydroxyl function from a benzyhc alcohol or a phenol, respectively [18]. Enamides have also been proposed by Wang and collaborators [19] as functionalized pronucleophiles in a similar organocascade with unsaturated aldehydes promoted by diphenyl prolinol silyl ether in the presence of phenylacetic acid to give cychc hemiaminals. Recently, we proposed the first example of activation of 7V-tosyl-l,3-ketoamides under thiourea-based bifimctional catalysis for an enantioselective domino Michael/spirolactamiza-tion sequence leading to chiral scaffolds of high synthetic interest [20]. 

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%... 

On the other hand, diaryl prolinol silyl ethers have been applied as orga-nocatalysts for the asymmetric Mannich reaction of acetaldehyde with N-benzoyl-, iV-Boc- and iV-Ts-imines in the presence of para-aiirobtnzoic acid in THF. The generated (3-amino aldehyde products were isolated in good to high yields and excellent enantioselectivities (95-98% ee) after conversion into the corresponding alcohols by reduction with L1A1H4 (Scheme 3.10). 

As a final method for the enantioselective synthesis of tetrahydropyrans, we will mention the discovery by Hayashi that diphenyl prolinol silyl ether 41 catalyzes the formation of 3-nitrotetrahydropyrans 68 from nitrostyrenes, aldehydes, and ethyl glyoxylate in enantiomeric excesses higher than 90% (Scheme 3.17) [54]. This... 

Diamination was first reported in 2007 by Jprgensen and coworkers with a combination of enamine and iminium-ion activation modes catalyzed by the diaryl prolinol silyl ether 3 (10 mol%) [18]. The sequential addition of succinimide as the nucleophile and diethyl azodicarboxylate as the electrophile afforded the syn-diaminated products 32 and 33 in promising overall yield (40%) with high levels of stereoselectivities (dr up to 8/2, ee 99%) (Scheme 12.14). 

Using tV-(benzylthio)succinimide, Cdrdova and coworkers described a highly enantioselective aminosulfenylation of a,p-unsaturated aldehydes [20], The domino process was catalyzed by the diphenyl prolinol silyl ether 5 (20 mol%) and was initiated by adding a small amount of succinimide (10 mol%) (Scheme 12.17). The syn- and tmti-p-amino-a-mercaptoaldehydes 37 and 38 were obtained as a separable mixture of diastereomers in high yields (60-83%) and with diastereomeric ratios ranging from 49 51 to 77 23. The enantiocontrol of the one-pot sequence was excellent leading to the products in 93-99% ee. 

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