Organocatalytic reactions, enantioselection enantioselectivity

The required chiral sulfur ylide of type 59 is formed in a reaction with a diazo compound in the presence of an achiral metal catalyst. Subsequently, asymmetric reaction of the chiral ylide 59 with the C=N double bond of the imine proceeds diastereoselectively and enantioselectively, giving the optically active aziridine 57. The chiral sulfide catalyst released is then used for the next catalytic cycle. The cat-alytically active species in the asymmetric process is the sulfide, so this concept can also be regarded as an organocatalytic reaction. 

In summary, several reports have shown that asymmetric modified aldol reactions using y-dienolates, nitroalkanes, or nitrones as donors can (in principal) be performed by use of organocatalysts. Often, however, enantioselectivity is moderate only, and must still be improved. Because these organocatalytic reactions give important intermediates, e.g. for synthesis of pharmaceuticals, it can be expected that this field of modified aldol reactions with organocatalysts will gain further synthetic importance in the future. 

Another key event in the history of organocatalytic reaction was the discovery of efficient r-proline-mediated asymmetric Robinson annulation reported during the early 1970s. The so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction (an intramolecular aldol reaction) allowed access to some of the key intermediates for the synthesis of natural products (Scheme 1.4) [37, 38], and offered a practical and enantioselective route to the Wieland-Miescher ketone [39]. It is pertinent to note, that this chemistry is rooted in the early studies of Langenbeck and in the extensive investigations work of Stork and co-workers on enamine chemistry... 

Furthermore, many organocatalytic reactions are already known that proceed with both high conversion and enantioselectivity. There is a range of organocatalytic reactions known to give the desired products with excellent enantioselectivities of more than 99% ee (Berkessel and Groger 2005). 

Chiral N heterocyclic carbenes (NHCs), as Lewis basic organocatalysts, have been synthesized and applied to enantioselective organocatalytic reactions in recent years. Encouraged by Sheehan and Hunneman s first report of chiral thiazolium salts as NHC precursors for organocatalytic reactions [37], Leeper, Enders, Rovis, Glorius, Herrmann, and others have synthesized series of novel chiral NHCs with mono cyclic, bicyclic, or tricyclic backbones [38]. Recently, a series of bifunctional NHCs were synthesized and applied to aza BMH reaction of cyclopent 2 enone with... 

Electrophihcity The dark-side of indole chemistry 13OBC5206. Enantioselective organocatalytic reactions with isatin 13COC1957. Indoles in multicomponent processes 12CRV3508. 

In the previons section, secondary chiral amines were employed that give rise to enamine formation npon reaction with ketones or aldehydes. Chiral tertiary amines, unable to form enamines, are nevertheless capable of inducing enantioselectivity in case substrates are used that contain sufficiently acidic protons such as aldehydes, ketones or active methylene compounds [33]. The cinchona alkaloids, by far the most versatile source of Brpnsted base catalysts, have played a prominent role in various types of asymmetric organocatalytic reactions [34], which is also true for the Mannich reaction. 

In the late 1990s, several research groups worked on the development of chiral DMAP analogs. The works of Fu [23], Vedejs [24], and Fuji [25] led to the synthesis of powerful catalysts and the development of enantioselective organocatalytic reactions such as Steghch rearrangements, kinetic resolutions of secondary alcohols, kinetic resolution of amines, and so on (Scheme 1.8). 

As mentioned in the introductory chapter, historically the first asynunetric organocatalytic reaction can be dated back to Breeling s quinine (2)- or quinidine (3)-mediated addition of HCN to benzaldehyde (1) at the beginning of the last century (Scheme 1) (7), a reaction that was later on reinvestigated by Prelog (75). hi addition, one of the first highly enantioselective reactions ever was reported in the 1950s by Pracejus, who carried out the addition of methanol to methyl phenyl... 

Epoxides can also be accessed asymmetrically using hypervalent iodine reagents in combination with imidazolidinone catalysts 78 (Scheme 30). The methodology developed by MacMillan et al. includes participation of hypervalent iodine reagent in a 1,4-heteroconjugate addition reaction for the organocatalytic, asymmetric epoxidation of a,p-unsaturated aldehydes 77. This organocatalytic reaction allows for the enantioselective formation of epoxides 78 from a wide array of electronically and sterically diverse a,p-unsaturated aldehydes [92]. 

In addition, Erase et al. have studied the thermal elfects in the L-proline-catalysed asymmetric a-amination of disubstituted aldehydes with azodi-carboxylates, demonstrating that this reaction was accelerated under micro-wave conditions at 60 Compared to the results previously obtained at room temperature, both the yield and the enantioselectivity could be significantly increased and the reaction time considerably reduced. As shown in Scheme 5.15, this improved protocol allowed the fast and efficient synthesis of chiral a,a-disubstituted amino aldehydes with enantioselectivities of up to 90% ee, providing the best results for the a-amination of a-branched aldehydes to date. Significantly, the amination of branched aldehydes is one of the few organocatalytic reactions where good to moderate levels of enantioselection can be achieved at high temperatures (60-70 °C). 

Chapter three Mechanism of enantioselection in organocatalytic reactions 185... 

Besides these organocatalytic methods, enantioselective Biginelli reactions can be induced by means of chiral Lewis acids. Indeed, the first synthesis of a highly enantioenriched dihydropyrimidine (compound 46) via Biginelli chemistry was developed by Zhu and coworkers in 2005 [46] and was based on the use of the chiral ytterbium species 47 as a Lewis acid catalyst. This reaction gave very good chemical yields and enantioselectivities and showed excellent functional group tolerance. In the proposed transition state, coordination of the catalyst with intermediate 48 leads... 

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