Phosphoric novel catalysts

Scheme 3.4 Novel structural motifs of chiral phosphoric acid catalysts.

In 2008, Du and coworkers designed and synthesized novel double axially chiral phosphoric acid catalysts based on BINOL [28]. Subsequently, these catalysts have been successfully applied in asymmetric transfer hydrogenation of 2 substitued (Table 10.8) and 2,3 disubstitued quinolines (Scheme 10.26). They found that ether was the best solvent. For 2 substitued quinolines, up to 98% ee was obtained when the substitutent of catalyst was cyclohexanyl. 

Zhu and co-workers [77] have successfully developed the first organocatalytic enantioselective three-component Povarov reaction for the efficient synthesis of enantiomerically enriched (2,4-cis)-4-amino-2-aryl(alkyl)-tetrahydroquinolines. To illustrate the power of this novel catalytic enantioselective three-component Povarov reaction, they applied this methodology to the short and efficient synthesis of torcetrapib (188), a potent cholesteryl ester transfer protein (CETP) inhibitor (Scheme 17.31). Reaction of 4-trifluoromethylaniline 184, propionaldehyde 18, and enecarbamate 185 using phosphoric acid catalyst 186 afforded tetrahydroquino-line 187 in 57% yield with 93% ee. Ethoxycarbonylation, deprotection/acylation, and benzylation provided torcetrapib (188) in four steps with 32% overall yield. 

A novel chiral imidazoline-substituted phosphoric acid catalyst (274) has been successfully applied for highly enantioselective desymmetrisa-tion of aziridines (273) with trimethylsilyl isothiocyanate (TMSNCS) (Scheme 74). ... 

An enantioselective Friedel-Crafts alkylation of pyrroles with /V-acylimincs has been reported <070L4065>. The reactions were run in the presence of chiral phosphoric acids. A novel C-H bond activation procedure was developed for the preparation of heteroarylamides including pyrrole-3-carboxamides <07CL872>. The reactions involved imine-substituted pyrroles, isocyanate electrophiles, and a rhenium catalyst. 

In the same year, Zhou and List reported a novel one-pot tandem reaction which, for the first time, combined chiral Bronsted acid catalysis with enamine and iminium catalysis. Later, on the basis of control experiments and ESI-MS/MS analysis, a reasonable mechanism was proposed (Scheme 2.2). The initial step of this tandem reaction was mediated by achiral /j-ethoxyaniline (PEP-NH2) and chiral phosphoric acid (R)-TRIP either reagent alone was inefficient in promoting this aldol condensation to afford the first iminium intermediate. The following step was a conjugate reduction which was also Bronsted acid and amine co-catalysed, and no further conversion took place in the absence of either catalyst. The final step was an acid-catalysed reductive amination. This novel sequence allowed the highly enantioselective synthesis of pharmaceutically active chiral ds-3-substituted cyclohejyl or heterocyclohexyl amines in high diastereo- and... 

A highly enantioselective kinetic resolution of protected homoaldols via a catalytic asymmetric transacetalization reaction could be achieved with a novel phosphoric acid STRIP (6) (Table 1) [25]. A catalyst loading of 1 mol% could be routinely used at 20°C, and even 0.1 mol% of the catalyst can give very similar enantiomeric ratios. The method is applicable to the resolution of a wide range of secondary and, most remarkably, of tertiary homoaldols. In most cases, both acyclic homoaldols 7 and cyclic homoaldols 8 could be obtained in enantiomeric ratios exceeding 95 5. Although chemical kinetic resolutions of secondary alcohols by other methods are well developed [26], these are not readily applicable to kinetic resolutions of tertiary alcohols [27-34]. 

Methyl, ethyl, benzyl, benzhydryl, p-nitrobenzyl, p-methoxy-benzyl, 4-picolyl, j3j -trichloroethyl, j3-methylthioethyl, /J-p-toluenesulphonylethyl, and -p-nitrophenylthioethyl esters may be prepared directly from the acid and alcohol. TTie most usual method [4, 5] consists of heating the acid and an excess of the alcohol with an acid catalyst (e.g., Fischer-Speier, hydrochloric or sulphuric acid). The extent of reaction is improved if the water formed is removed by azeotropic distillation with an inert solvent (benzene, carbon tetrachloride, or chloroform). Considerable variation is possible in the natvire of the acid catalyst thus phosphoric acid [6], aryl sulphonic acids [7, 8, 9], alkyl sulphates [10], and acidic ion-exchange resins [11] may be employed. Removal of the water by azeotropic distillation during the formation of methyl esters is difficult and Brown and Lovette [12] introduced the novel reagent acetone dimethyl acetal (7) for the direct formation of methyl esters. In the presence of a trace of methanol and an acid catalyst the reagent acts as a scavenger of water formed by esterification and liberates further methanol for reaction. 

The last few years have witnessed spectacular advancement in chiral Bronsted acid catalysis. Thiourea and phosphoric acids, in particular, have emerged as novel chiral catalysts of choice in a number of synthetic reactions. A number of chiral alcohols and nitrogen containing materials have been obtained with excellent optical purity in a simple protocol. The scope of the catalysts will be expanded by further study. They are considered to be artificial enzymes. One of the advantages of chiral Bronsted acid over chiral Lewis acid is the stability toward moisture and... 

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