Chiral phosphoric add

Chiral phosphoric add is also effective for aza-Diels-Alder reactions. Danishefsky s diene underwent aza-Diels-Alder reaction with aldimines by means of 21e in the presence of acetic add to give the cycloadduds with high enantios-eledivities (Equation 10.43) [89]. Brassard s diene also partidpated in the aza-Diels-Alder readion under the influence of 21j to give 5-ladams with excellent enantioselectivities [90]. 

Scheme 4.35 Enantioselective Michael addition of p-ketoesters to vinyl ketones catalyzed by chiral phosphoric add 60b.

Recently, a new approach was pursued combining organocatalysis with heterogeneous catalysis [11]. In this case, molecular hydrogen is used as hydrogen source and supported noble metal catalysts for the activation of hydrogen. The implementation of chirahty is affected by a suitable modifier such as chiral phosphoric add esters (P-add) ]55]. 

However, these two procedures have an important limitation, the low enantioselectivities obtained when p,p-dialiphatic enals were used. To overcome this hmitation, list and coworkers applied the AC DC (asymmetric counterion direct catalysis) concept to this reaction [14]. When an achiral amine and a chiral phosphoric add were used together as a catalytic system for this reaction, p,P-dialiphatic enals were reduced with good yields and exceptional levels of enantioconhol. 

N-Boc-protected ethyl trifluoropyruvate imine was effectively used in a F-C reaction with indole derivatives for synthesizing, in high selectivities, quaternary a-amino acids via catalysis with chiral phosphoric acid 26e [64]. A binaphthyl-based chiral sulfonimide [42c] and a chiral squaramide-based hydrogen bond donor [42a] were used as effective catalysts for promoting F-C reaction of indoles with imines. Recently, the F-C alkylation of arenes with glyoxylate imine was described via a chiral phosphoric add (Scheme 35.11) [34]. 

Scheme 35.22 gives an example of Bronsted acid-catalyzed N-acyliminium cycli-zations. Here, chiral phosphoric adds 26e, 26f, or 24b were used to carry out highly... 

SCHEME 9.42 Cascade reaction combining a primary amine and a chiral phosphoric add... 

List has developed the concept of asymmetric counter-ion directed catalysis and applied it in organocatalytic transformations. One of the first pioneering studies in the synergic use of organocatalyst and transition metal was the combination of a Pd(0) catalyst with a chiral phosphoric add in a highly enantioselective Tsuji-Trost type a-allylation of branched aldehydes (Scheme 26.12) [81]. 

Chiral phosphoric add analogs as catalysts in the F-C alkylation reaction of indoles with a,P-unsaturated aromatic enones were also devised [53]. p,y-Unsaturated a-ketoesters were also used as electrophiles in organocatalyzed F-C alkylations of indoles and 2-naphthols. With indoles, chiral addic N-triflylphos-phoramide was successfully employed (Scheme 35.4) [28], whereas in the presence of 2-naphthols a thiourea-based catalyst showed better capadty to mediate a sequential F-C/cycUzation process, giving naphthopyran scaffolds in moderate yields and selectivities (up to 90% ee) [54]. Recently, a,(i-unsaturated acyl phos-phonates were effectively used as hydrogen bond acceptors for F-C alkylations of indole derivatives in the presence of thiourea catalyst ent-19 [55]. 

Whereas a, i-unsaturated aldehydes and enones, nitroolefins, and imines have been used extensively in organocatalyzed enantioselective F-C reactions with various aromatic nucleophiles since 2001, the introduction of new classes of electrophiles in such transformations only started in the last four or five years. In 2007, two independent groups described how N-protected enamines could act as good substrates for preparing, in the presence of chiral phosphoric adds 26e and... 

Chiral phosphoric adds also catalyze [4+2] cydoadditions. Gong and colleagues showed that 99c activates aromatic aldehydes 207, anisidine (119), and cydohex-enone (206) to give the hctero-Diels-Alder products 208 and 209 with good yield and enantioselectivity, along with moderate endo-selectivity (Scheme 42.48) [104]. 

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