4-hydroxyproline-derived

Uozumi has explored a series of (25, 4/ )-4-hydroxyproline-derived 2-aryl-6-hydroxy-hexahydro-lFf-pyrrolo[l,2-c]imidazolones as potential alternatives to cinchona alkaloid-based catalysts for the alcoholative ASD of meio-anhydrides (Fig. 16) [226]. Uozumi screened a small library of catalysts prepared by a four-step, two-pot reaction sequence from 4-hydroxyproline in combination with an aldehyde and an aniline. The most selective member, compound 67, mediated the methanolytic ASD of cw-hexahydrophthalic anhydride in 89% ee when employed at the 10 mol% level for 20 h at -25 °C in toluene [226]. 

Surprisingly few studies have been directed towards the development of noncinchona alkaloid-based catalysts for the alcoholative ASD of meso-anhydrides, or indeed any of the enantioselective alcoholysis processes. Uozumi has reported a series of (2S, 4R)-4-hydroxyproline-derived 2-aryl-6-hydroxyhexahydro-lfi-pyr-rolo[l,2-c] imidazolones which mediate the methanolytic ASD of ds-hexa-hydrophthalic anhydride in up to 89% ee when employed at the 10 mol% level for 20 h at —25 °C in toluene [186]. Additionally, Nagao has described the use of a bifunctional chiral sulfonamide for the thiolytic ASD of meso-cyclic anhydrides in up to 98% ee when employed at the 5 mol% level for 20 h at rt in ether [187]. 

Insertion of carbon monoxide into aryl halides prepared by condensation of ortho-halogenoanilines with 4-hydroxyproline derivatives leads to the 1,4-benzodiazepine skeleton. This methodolgy has been applied to the first synthesis of prothracarcin,... 

Hydroxyproline derivatives 29-33 wherein a silylojg -, sulfonylo - or a carbamoyloxy group is attached to position four of the pyrrolidine ring appeared very useful organocatalysts for various asymmetric reactions (Figure 10.3). 

Hydroxyproline-derived prolinamides represent a very useful class of organocatalysts as they commonly exhibit higher activity and better stereoinduction than the corresponding amino acids due to a significant... 

Different 4-hydroxyproline derivatives have been prepared by modification of the hydroxy group in order to improve their efficiencies and to facilitate their recovery and recyclability properties (Fig. 4.11). 

Given the overall positive effect of the tertiary hydroxyl group on stereoselectivity, other amino acid derivatives were also evaluated [39, 40]. Notably, 4-hydroxyproline derivative 16 furnished the desired aldol in 95% yield, even for the most difficult substrate, 4-methoxybenzaldehyde [39]. 

Recently, and co-workers [41] Zhang reported the first highly efficient protocol for the synthesis of a-amino esters with prolinol-derivated catalyst. The (9-pivaloyl 7ra 5-4-hydroxyproline derivative (Cat. 10) achieved best results. Crucial for efficiency was the addition of small quantities of pentanoic acid. Through this approach, a broad range of chiral a-amino esters were synthesized in good yields (up to 97%) and with high levels of enantioselectivity (up to 93%) (Scheme 15.14). 

NCC6H4) did not exceed 10% at 11% ee, in the case of 4-hydroxyproline-derived catalyst 51a the yield was 59% and the ee 72%. The results highlight an important role of the auxiliary carboxy group in asymmetric catalysis and has been taken into account in further studies on the synthesis of immobilized versions of proline-derived organocatalysts. 

Extensive molecular dynamic simulations of proline-catalysed asymmetric aldol condensation of propionaldehyde in water have revealed that the stereoselectivity can be attributed to differences in transition-state solvation pattems. " The hydrogen bond concept has been applied to design new proline-based organocatalysts. " 4-Hydroxyproline derivatives bearing hydrophobic groups in well-defined orientations have been explored as catalysts in water an advantage of aromatic substituents syn to the carboxylic acid moiety has been attributed to a stabilizing transition-state hydrophobic interaction and this is supported by quantum mechanics (QM) calculations. " Catalysts and solvents were screened for reaction between cyclohexanone andp-nitrobenzaldehyde. 

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