Enantioselective addition consecutive reactions

The first asymmetric autocatalysis with amplification of was observed in the automultiplication of a 5-pyrimidyl alkanol 80 (Figure l)169. When (5)-5-pyrimidyl alkanol 80 with as low as 2% is used as the asymmetric autocatalyst for enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde 88, the of the produced pyrimidyl alkanol (and the initial asymmetric autocatalyst) 80 increases to 10% (Figure 1, 1st run). Consecutive asymmetric autocatalyses using 5-pyrimidyl alkanol 80 with 10% have increased its to 57%, 81% and 88% , successively. During the reactions, the major (S)-enantiomer in the initial asymmetric autocatalyst has automultiplied by a factor of 238, while the slightly minor (R)-enantiomer has automultiplied by a factor of only 16. 

The major advantage of the use of CuHY as a catalyst for this reaction is the ease with which it can be recovered from the reaction mixture by simple filtration if used in. a batch reactor (alternatively it can be used in a continuous flow fixed bed reactor). We have carried out the heterogeneous asymmetric aziridination of styrene until completion, filtered and washed the zeolite then added fresh styrene, PhI=NTs and solvent, without further addition of chiral bis(oxazoline), for several consecutive experiments. The yield and the enantioselectivity decline slightly on reuse we have found that adsorbed water can build up within the pores of the zeolite on continued use and we believe that this is the cause of loss of activity and enantioselection. However, full enantioselectivity and yield can be recovered if the catalyst is simply dried in air prior to reuse, or alternatively the catalyst can be recalcined and fresh oxazoline ligand added. 

In 2013, the Hui group developed an efficient NHC-catalyzed stereoselective aza-Michael-Michael-lactonization cascade reaction of 2-amino phenyl-enones and 2-bromoenals. Functionalized tetrahydroquinolines with three consecutive stereogenic centers were obtained in high yields with excellent diastereo- and enantioselectivity. This approach is attractive due to the mild reaction conditions and the potential application of the products in medicinal chemistry. In addition, this strategy extends the scope of NHC catalysis and provides a simple protocol for the NHC-catalyzed cascade reaction (Scheme 7.100). 

In 2011, Moreau, Greek and coworkers reported a multicatalytic process [6] merging two consecutive enamine catalytic cycles based on a Michael addition/a-amination cascade reaction [7]. The Michael addition of aldehydes to p-nitrostyrene followed by the electrophilic amination were catalyzed, respectively, by the diphenylprolinol silylether 5 and the 9-amino-(9-deoxy)-cpf-cinchonine 6 (Scheme 12.4), both previously described by Hayashi and coworkers [8] and Melchiorre and coworkers [9]. One interesting feature of this reaction is that diphenylprolinol silylether 5 can specifically catalyze the Michael addition, while 9-amino-(9-deoxy)-ep/-cinchonine 6 is required to promote the electrophilic amination. The Michael addition of propionaldehyde to p-nitrostyrene was achieved by using only 5 mol% of catalyst 5 in chloroform at 0 C. After completion of the reaction, dibenzyl azodicarboxylate (DEAD, 1.5 equiv), trifluoroacetic acid (15 mol%) and the second catalyst 6 (5 mol%) were added. The expected product 7 was obtained as a single diastereomer in good yield (80%) and with excellent enantioselectivity (ee 96%). Various nitroalkenes bearing electron-rich and electron-deficient aryl... 

In addition to conventional Diels-Alder reactions, consecutive [4-1-2] reactions have been subjected to extensive investigation through the iminium-enamine catalytic sequence. Wang, Rios, and others simultaneously described enantioselective cascade sulfa-, oxa-, and aza-Michael/aldol/dehydration reactions promoted by chiral secondary amines. An initial strategy for a one-pot synthesis of chiral thiochromenes with good to high enantioselectivities was reported (Schemes 1.46 and 1.47) [71]. 

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