Imines Mukaiyama type Mannich reaction

Scheme 3.3 Mukaiyama type Mannich reaction of imines with ketene silyl acetals.

The catalytic, enantioselective, vinylogous Mannich reaction has recently emerged as a very powerful tool in organic synthesis for the assembly of highly functionalized and optically enriched 6 amino carbonyl compounds. Two distinctly different strategies have been developed. The first approach calls for the reaction of preformed silyl dienolates as latent metal dienolates that react in a chiral Lewis acid or Bronsted acid catalyzed Mukaiyama type reaction with imines. Alternatively, unmodified CH acidic substrates such as a,a dicyanoalkenes or 7 butenolides were used in vinylo gous Mannich reactions that upon deprotonation with a basic residue in the catalytic system generate chiral dienolates in situ. 

The development of a catalytic, enantioselective Mannich-type reaction of si-lyl ketene acetals lagged far behind the now-well-established enantioselective Mukaiyama directed aldol addition. The major consideration for the invention of such a transformation is obviously the selection of an appropriate Lewis acid activator. This is a challenging problem in view of the basicity of the imine nitrogen, the ambiguity in complexation geometry, and most importantly the release of the catalyst to effect turnover. Thus, it is not surprising that the first successful catalytic, enantioselective Mannich reaction was reported only in 1997. 

Three-component coupling reaction of a-enones, silyl enolates, and aldehydes by successive Mukaiyama-Michael and aldol reactions is a powerful method for stereoselective construction of highly functionahzed molecules valuable as synthetic intermediates of natural compounds [231c]. Kobayashi et al. recently reported the synthesis of y-acyl-d-lactams from ketene silyl thioacetals, a,/l-urisalu-rated thioesters, and imines via successive SbCl5-Sn(OTf)2-catalyzed Mukaiyama-Michael and Sc(OTf)3-catalyzed Mannich-type reactions (Scheme 10.87) [241]. 

In recent years, catalytic asymmetric Mukaiyama aldol reactions have emerged as one of the most important C—C bond-forming reactions [35]. Among the various types of chiral Lewis acid catalysts used for the Mukaiyama aldol reactions, chirally modified boron derived from N-sulfonyl-fS)-tryptophan was effective for the reaction between aldehyde and silyl enol ether [36, 37]. By using polymer-supported N-sulfonyl-fS)-tryptophan synthesized by polymerization of the chiral monomer, the polymeric version of Yamamoto s oxazaborohdinone catalyst was prepared by treatment with 3,5-bis(trifluoromethyl)phenyl boron dichloride ]38]. The polymeric chiral Lewis acid catalyst 55 worked well in the asymmetric aldol reaction of benzaldehyde with silyl enol ether derived from acetophenone to give [i-hydroxyketone with up to 95% ee, as shown in Scheme 3.16. In addition to the Mukaiyama aldol reaction, a Mannich-type reaction and an allylation reaction of imine 58 were also asymmetrically catalyzed by the same polymeric catalyst ]38]. 

Finally, Mukaiyama-Mannich-type reactions can also be induced and mediated by proton activation of the imine component, which thereby obtains a sufficient degree of reactivity to be attacked by highly nucleophilic silicon enolates. Thus, Wenzel and Jacobsen have shown that the specific protection by N-aryl substituents with a pendant ortho-hydioxy or ortho-methoxy chelating group is not required, if the acetate-derived sHyl ketene acetals 362 are reacted with simply BOC-protected aryl and hetaryl imines 361. Thus, P-amino esters 364 are obtained in excellent enantiomeric excess, if the reaction is catalyzed by the chiral urea derivative 363 that is assumedto act by activation through hydrogen bonding (Scheme 5.95) [181]. 

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