Organocatalytic addition

Additionally, organocatalytic cross-aldol reactions catalyzed by cyclic secondary amines in aqueous media provide a direct route to a variety of aldols, including carbohydrate derivatives, and may warrant consideration as a prebiotic route to sugars [12a],... 

Scheme 2.24 Three components double Michael addition organocatalytic sequence...

L2909>. An organocatalytic addition of 2-trimethylsilyloxyfuran to aldehydes using 10 mol% of l,3-bis(3-(trifluoromethyl)phenyl)urea provided adducts with modest threo selectivity <06TL8507>. A syn-selective, enantioselective, organocatalytic vinylogous Mukaiyama-Michael addition of 2-trimethylsilyloxyfuran to (E)-3-... 

Scheme 7 Two alternative reaction routes for the organocatalytic Michael-addition of acetylacetone to nitrostyrene...

Enantioselective organocatalytic conjugate additions such as Michael and aldol reactions have been intensely studied under new catalysts. However, only a few organocatalyzed Michael reactions have been developed. The reaction involves construction of a new C-N bond that is very attractive for syntheses of molecules with biological properties. 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

Takemoto and co-workers reported the use of a similarly structured bifunctional catalyst for the first enantioselective organocatalytic Michael addition of malonitrile to... 

Application of an organocatalytic domino Michael addition/intramolecular aldol condensation to the preparation of a series of important heterocycles has recently received much attention [158] with methods being disclosed for the preparation of benzopyrans [159-161], thiochromenes [162-164] and dihydroquinolidines [165, 166]. The reports all use similar conditions and the independent discovery of each of these reactions shows the robust nature of the central concept. A generalised catalytic cycle which defines the principles of these reports is outlined in Fig. 10. Formation of iminium ion 102 is followed by an intermolecular Michael addition of an oxygen, sulfur or nitrogen based nucleophile (103) to give an intermediate... 

Figure 3.8 Organocatalytic Michael addition energy profiles of paths A and B, both leading to (R)-configurated product, as obtained from gas-phase calculations (B3LYP/6-31 lG(d,p)// B3LYP/6-31G(d)).

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 organocatalytic asymmetric Michael addition of 2,2-dimethyl-l,3-dioxan-5-one (143) to various nitroalkenes (144), using a number of proline-based catalysts, afforded... 

Triphenylphosphine was employed as a nucleophilic catalyst for the umpolung addition of azoles (225) to the electron-deficient allenes (226 R1 = H, R2 = OEt, R3 = H, Et) to afford the addition products (227). This organocatalytic methodology has been extended to addition-cyclization reactions between electron-deficient allenes or alkynes and pyrrole-2-carboxaldehyde in the presence of a catalytic amount of tri-butylphosphine, giving the substituted indolizine-7-carboxylates (228 R2 = OEt, Me R3 = H, Et).265... 

An important issue is the right choice of substrate 1 which functions as an anion precursor. Successful organocatalytic conversions have been reported with indanones and benzophenone imines of glycine derivatives. The latter compounds are, in particular, useful for the synthesis of optically active a-amino acids. Excellent enantioselectivity has been reported for these conversions. In the following text the main achievements in this field of asymmetric organocatalytic nucleophilic substitutions are summarized [1, 2], The related addition of the anions 2 to Michael-acceptors is covered by chapter 4. 

There seem to be very few examples of organocatalytic Michael additions of Se-nucleophiles, and these are limited to the addition of selenophenols to enones (Scheme 4.36) [3, 60]. As shown in the scheme, Wynberg and Pluim achieved... 

There appear to be no reports of asymmetric organocatalytic intramolecular Michael additions of N-, S- or Se-nucleophiles. 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

The Lectka group also reported an exciting development in this organocatalytic synthesis of /I-lactams - application of the concept of column asymmetric catalysis [50, 51]. This concept is based, e.g., on two jacketed columns linked together (Scheme 5.32) [50]. The top column is packed with the polymer-supported dehy-drohalogenation agent BEMP, which produces the desired ketenes, in high purity, from acid chlorides. In addition to this in-situ-formed pure ketene, an imine is... 

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