Diphenylprolinols silyl ether

Diphenylprolinol silyl ethers (17) have been found to be efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. 

The diphenylprolinol silyl ether 45a catalyst was developed by the Hayashfs group for the addition of a-unbranched aldehydes to aryl and alkyl substituted nitroolefins [35]. This catalyst, as well as the perfluoroalkyl derivative 45b [36],... 

Enders et al. elegantly applied diphenylprolinol silyl ether 6a as a catalyst for triple cascade reactions (Scheme 10.18), wherein 6a played the roles ofboth enamine catalyst and iminium catalyst. It should be noted that the four stereocenters were completely controlled[36].Theproposedcatalyticcycleofthe triplecascade isshownin Scheme 10.2. 

Hayashi and co-workers took advantage of the organocatalyzed reaction for the stereoselective synthesis of the cyclohexane structure. Diphenylprolinol silyl ether ent-6a proved to be effective for the domino Michael reaction/Horne-Wardsworth-Emmons reaction. They synthesized (-)-oseltamivir by three one-pot operations, with a total yield of 57% (Scheme 10.4) [38]. 

Cordova " and Wang showed new variants of cyclopropanation reaction using diphenylprolinol silyl ether catalysts. The reaction required... 

The 0-TBS-hydro>y-diphenylprolinol silyl ethers 14, analogues of the Jorgensen-Hayashi catalyst 3a, were tested in 2008 by List and coworkers for the challenging catalytic asymmetric Michael reactions of acetaldehyde with nitroalkenes. While 4-hydroxy-proline derivative 14a displayed diminished activity, but slightly better enantioselectivity with respect to 3a, the 3-hydroxy-proline derivative 14b gave in this case very poor results (Scheme 11.12). 

An early example of an asymmetric domino Michael/Knoevenagel reaction was reported by Jorgensen et al. [167] in 2006, providing the synthesis of chiral cyclohexenones from the reaction of tert-butyl 3-oxobutyrate and a, 3-unsaturated aldehydes catalyzed by chiral diphenylprolinol silyl ether derivative. Soon after, the... 

As is well known, quinones are easily converted to the corresponding phenol compounds. By using the enantioselective Michael addition of aldehydes to quinones, J0rgensen and co-workers [21] developed the first organocatalytic a-arylation of aldehydes. In the presence of diphenylprolinol silyl ether 7, the a-arylation proceeds well under environmentally friendly conditions (EtOH and H2O as solvent), affording the optically active a-arylated products with high yields and excellent enantioselectivities (Scheme 5.10). 

Hayashi and co-workers [85] discovered the first enantioselective organocatalytic intermolecular ene reaction of cyclopentadiene 7 and 2-enals 8 as the enophile. The reaction is catalyzed by diphenylprolinol silyl ether 141 and affords chiral cyclopentadienes 142 as a mixture of regioisomers in good yield and ee with low to... 

Nitroethanol was recently employed as C/O bis-nucleophile by Hayashi and coworkers [38] for the synthesis of optically active functionalized tetrahydropyrans by reaction with enals using diphenylprolinol silyl ether as the organocatalyst (Scheme 16.18). The diastereoselectivity of the Michael/acetalization sequence was improved by isomerization to the thermodynamically more stable trans isomers upon basic treatment. 

Chromene derivatives where also accessed by a slightly different strategy by Kim and co-workers [40], who developed a diphenylprolinol silyl ether-catalyzed Michael/acetalization reaction from malonates and 2-hydroxycinnamaldehydes. 

ThefoUowingdominoreactiondevelopedbyj0rgensenandco-workers [44a] involves enamine activation of aldehydes by diphenylprolinol silyl ether promoting an enantioselective Michael addition onto quinones, followed by an intramolecular hemiacetaliza-tion (Scheme 16.22). The resulting dihydrobenzofiirans were obtained with high yields... 

Among the selected examples, we can cite the remarkable Hayashi s syntheses of (-)-oseltamivir [94] and ABT-341 [95] both catalyzed by diphenylprolinol silyl ether (R)-124 (Scheme 2.69). In both cases, a highly substituted cyclohexane moiety B (obtained via an asymmetric Michael addition and a domino Michael reaction/Homer-Wadsworth-Emmons... 

Riguet reported a methodology involving an enantiose-lective organocatalytic Friedel-Crafts alkylation followed by an Ugi 4-center 3-component reaction [57]. In the first reaction, the Friedel-Crafts reaction, 5-hydroxyfuran-2(5F/)-one (53) was used as an electrophile to alkylate indoles 52 to give the intermediate 54, using a diphenylprolinol silyl ether 56 as catalyst (Scheme 7.22). Then, adducts 54—obtained from Friedel-Crafts reaction—were used in a one-pot manner... 

A number of highly efficient asymmetric domino nitro-Michael additions of C-nucleophiles catalysed by organocatalysts were described in 2008. One of the most employed organocatalysts for these types of reactions is diphenylprolinol silyl ether. This catalyst was used by Hong et al. to develop a highly diastereo-and enantioselective domino reaction occurring between 7-oxohept-2-enoate and nitroalkenes (Scheme 1.61). ° The reaction afforded highly functionalised... 

Chiral pyrrolidines constitute the first class of organocatalysts which have been successfully used to catalyse various domino Michael addition reactions involving other-than-C-nucleophiles. As an example, Wang et al. have reported highly enantio- and diastereoselective domino aza-Michael-Michael reactions of ot,p-unsaturated aldehydes with a trans 4-amino protected cx,p-unsaturated ester catalysed by diphenylprolinol silyl ether combined with NaOAc as a base. As summarised in Scheme 1.75, the corresponding trisubstituted synthetically useful, highly functionalised chiral pyrrolidines were produced in high yields and diastereoselectivities of up to 94% de combined with almost complete enantioselectivity in all cases of substrates. 

On the other hand, Hayashi et al. have reported the highly enantio-selective formal [3 + 3] cycloaddition of a,p-unsaturated aldehydes with ene-carbamates catalysed by diphenylprolinol silyl ether as an organocatalyst. This reaction consisted of four consecutive reactions including an asymmetric ene reaction, an isomerisation from an imine into an enecarbamate, a hydrolysis and a hemiacetal formation in one pot to afford synthetically important chiral piperidine derivatives with excellent enantioselectivities of up to 99% ee, good yields and moderate to good diastereoselectivities, as shown in Scheme 6.22. 

The continuing controversy over the mechanism of the stereoselective Michael addition as catalysed by diphenylprolinol silyl ether is the subject of a short review (12 0 references). 0... 

In 2013, Li et al. reported a novel synthesis of chiral six-memhered spir-ocyclic oxindoles bearing five consecutive stereocentres on the basis of an enantioselective three-component domino Michael-Michael-aldol reaction catalysed hy a combination of a chiral diphenylprolinol silyl ether and a chiral bifunctional quinine thiourea. " As shown in Scheme 2.26, the reaction between iV-substituted oxindoles, nitrostyrenes, and enals led to the corresponding highly substituted spirocyclic oxindoles in high yields, moderate diastereoselectivities of up to 44% de, and enantioselectivities of up to >99% ee. A large variety of substrates could be used well in this... 

Three-component domino Michael-Michael-aldol reaction catalysed by a combination of chiral diphenylprolinol silyl ethers and a chiral bifunctional quinine thiourea. 

As an alternative to the ambident reactivity of nitroso partners, the dual nucle-ophilicity of hydroxylamines has been exploited for the seleetive construction of valuable functionalized hydro-oxazoles. Efficient entries to these heterocyclic building blocks have been developed following two eomplementary direetions involving either aza- or oxa-Miehael addition in the first step. Thus, Cordova and coworkers proposed a simple and effieient chemo and enantioseleetive aeeess to 5-hydroxyisoxazolidines 58 based on i minium activation of unsaturated aldehydes with diphenylprolinol silyl ether as the organoeatalyst (Scheme 2.16). The domino reaetion is initiated by an aza-Michael addition of N-protected hydroxylamines 56 to the iminium ions, and... 

Urushima, T., Sakamoto, D., Ishikawa, H., Hayashi, Y. (2010). Enantio- and diastereose-lective synthesis of piperidines by coupling of four components in a one-pot sequence involving diphenylprolinol silyl ether mediated Michael reaction. Organic Letters, 12, 4588-4591. 

Ishikawa, H., Sawano, S., Yasui, Y, Shibata, Y, Hayashi Y. (2011). Asymmetric one-pot four-component coupling reaction synthesis of substituted tetrahydropyrans catalyzed by diphenylprolinol silyl ether. Angewandte Chemie International Edition, 50, 3774-3779. 

Hayashi, Y., Gotoh, H., Hayashi, T., Shoji, M. (2005). Diphenylprolinol silyl ethers as efficient organocatalysis for the asymmetric Michael reaction of aldehydes and nitroalkenes. Angewandte Chemie International Edition, 44, 4212-4215. 

Prior to the work on prostaglandins, Hayashi and coworkers found a new route to effectively produce the dipeptidyl peptidase IV-selective inhibitor ABT-341 (Scheme 14.6) [14]. The strategy also comprised a Michael addition and HWE reaction, but these were in this case used to generate disubstituted cyclohexene carboxylates instead. After a diphenylprolinol silyl ether (10 mol%)-promoted asymmetric Michael addition of acetaldehyde (2.0 equiv) to nitroalkene 38 (97% ee) in 1,4-dioxane in 5 h, another Michael addition was initiated by addition of vinyl phosphonate 40 (1.2 equiv) under basic conditions (CS2CO3, 2.0 equiv) at 0 °C in dichloromethane. The subsequent intramolecular HWE reaction in ethanol at room temperature afforded the cyclohexene in 15 min., which was isomerized in situ by the addition of DiPEA (10 equiv) to yield trans-43. 

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