Organocatalytic reactions, enantioselection reaction

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

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... 

Considerable effort has been devoted to the development of enantiocatalytic MBH reactions, either with purely organic catalysts, or with metal complexes. Paradoxically, metal complex-mediated reactions were usually found to be more efficient in terms of enantioselectivity, reaction rates and scope of the substrates, than their organocatalytic counterparts [36, 56]. However, this picture is actually changing, and during the past few years the considerable advances made in organocatalytic MBH reactions have allowed the use of viable alternatives to the metal complex-mediated reactions. Today, most of the organocatalysts developed are bifunctional catalysts in which the chiral N- and P-based Lewis base is tethered with a Bronsted acid, such as (thio)urea and phenol derivatives. Alternatively, these acid co-catalysts can be used as additives with the nucleophile base. 

Ahrendt KA, Borths CJ, MacMillan DWC (2000) New strategies for organic catalysis The first highly enantioselective organocatalytic Diels-Alder reaction. J Am Chem Soc 122 4243-4244 Akiyama T (2004) Preparation of chiral Bronsted catalysts in asym. synthesis and asym. Mannich, aza-Diels-Alder reaction, hydrophosphorylation therewith. PCT Int Appl WO 200409675, 2004-11-11... 

Brown SP, Goodwin NC, MacMillan DWC (2003b) The first enantioselective organocatalytic Mukaiyama-Michael reaction a direct method for the synthesis of enantioenriched gamma-butenolide architecture. J Am Chem Soc 125 1192-1194... 

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). 

MacMillan DWC, Ahrendt KA, Borths CJ (2000) New strategies for organic catalysis the first highly enantioselective organocatalytic diels-Alder reaction. J Am Chem Soc 122 4243-4244... 

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... 

Another example of organocatalytic AFC alkylation reaction with p,y-unsaturated a-keto esters was reported by Wang and co-workers in 2012. In the presence of 10 mol% rosin-derived tertiary amine-thiourea 96, a variety of p,y-unsaturated a-keto esters reacted with 1-naphthol smoothly to afford the modified chromanes 97 in good yields (79-86%) with up to 96% ee (Scheme 6.39). Again, the hydrogen bonding between substrates and catalyst was proposed to be a key element for the enantioselective control. 

In 2008, Zhang, Ying, and co-workers reported an organocatalytic p-amination reaction of a,p-unsaturated aldehydes with nitrosobenzene catalyzed by an NHC. Specifically, the addition of NHC to a,p-unsaturated aldehyde generates a homoenolate intermediate that reacts with nitrosobenzene to afford Af-phenylisoxazolidin-5-ones, followed by an acid-catalyzed esterification and Bamberger-type rearrangement to produce Af-PMP-protected p-amino esters. A preliminary study on the enantioselective reaction of... 

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

Pihko and co-workers reported asymmetric organocatalytic Diels-Alder reactions on solid support (JandaJel -supported or n-propyl-functionalized silica gel) with the advantage of easy recovery and reuse, Scheme 3.22 [36]. For example, synthesized polymer- and siUca-supported chiral imidazolidinone catalysts 55 and 56 were demonstrated to be efficient catalyst for the enantioselective Diels-Alder reactions of cyclopentadiene and cinnamaldehyde. 

Scheme 3.67 Enantioselective organocatalytic [3+2] reaction between 2-acylaminomalonates and a, 3-unsaturated aldehydes...

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