Organocatalysts asymmetric reactions

Currently, the chiral phase-transfer catalyst category remains dominated by cinchona alkaloid-derived quaternary ammonium salts that provide impressive enantioselec-tivity for a range of asymmetric reactions (see Chapter 1 to 4). In addition, Maruoka s binaphthyl-derived spiro ammonium salt provides the best results for a variety of asymmetric reactions (see Chapters 5 and 6). Recently, some other quaternary ammonium salts, including Shibasaki s two-center catalyst, have demonstrated promising results in asymmetric syntheses (see Chapter 6), while chiral crown ethers and other organocatalysts, including TADDOL or NOBIN, have also found important places within the chiral phase-transfer catalyst list (see Chapter 8). 

Recently, more efforts have been devoted to the design of novel bifunctional organocatalysts derived from natural cinchona alkaloids, which have been successfully applied in a number of asymmetric reactions. Deng et al. promoted the extensive... 

Other examples of asymmetric reactions involving organocatalysts are (i) Diels-Alder reactions, (ii) Michael reactions, (iii) Mannich reactions and (iv) Shi epoxida-tion and organocatalytic transfer hydrogenation. 

Catalytic enantio- and diastereoselective nitroaldol reactions were explored by using designed guanidine-thiourea brfunctional organocatalysts like 15 (Figure 4.4) under mUd and operationally simple biphasic conditions. These catalytic asymmetric reactions have a broad substrate generality with respect to the variety of aldehydes and nitroalkanes [43]. On the basis of studies of structure and catalytic activity relationships, a plausible guanidine-thiourea cooperative mechanism and a transition state of the catalytic reactions are proposed. 

It is worth mentioning that BNP anions without a metal counterpart, were used as powerful organocatalysts to carry out a variety of asymmetric reactions such as epoxydation of enals reported by List et al The related chiral phosphoric acids HBNP, with bulky functional groups at the 3, 3 positions, are also powerful catalysts. Pioneered by Akiyama et al. and Terada and coworkers, they have recently been applied to a wide range of asymmetric organic transformations.However, this area will not be discussed here since it is beyond the scope of this chapter but the reader may consult the cited references. 

Numerous 2-substituted pyrrolidine organocatalysts have been prepared from L-proline and its derivatives, and have been proven to be highly efficient for many asymmetric reactions. Representative organocatalysts have been selected and categorised on the basis of the 2-substituted group that includes di- and tri-amine (la-m), dithioacetal (2a-f), guanidine (2g-i), sulfonamide (3a-j), amide and thioamide (3k-n), urea (4a and 4e), thiourea (4b-d, f-j) and heterocycles such as tetrazole (5a,b), triazole (5c-g), imidazole (5h-j) and benzoimidazole (5k) (Figure 9.1). 

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). 

In addition, Wang and cowvorkers developed an intramoleeular CDC reaction between tertiary amines and ketones mediated by DDQ (Seheme 2.11). Preliminary attempts towards asymmetric reaction were carried out. Screening of various chiral organocatalysts revealed the simple chiral phosphoric acid (S)-C6 as the most stereoselective eatalyst, giving the cyclization produet 29 with 14% ee. 

The concept of tunable chiral thiourea based organocatalysts, useful for a wide variety of asymmetric reactions, was invented by Jacobsen in 1999 and has been extensively reviewed over the last few years. They have been... 

On the other hand, the asymmetric allylation of aldehydes was also successfully performed in the presence of chiral easily available biheteroaromatic diphosphine oxides, such as tetraMe-BITIOPO, which is the precursor of the industrially produced tetraMe-BITIOP. Using this organocatalyst, the reaction afforded homoallyllic alcohols in fair-to-good yields and with enantio-selectivities of up to 95% ee, as shown in Scheme 2.50. 

On the other hand, Hayashi et al. have reported the highly enantio-selective formal [3 + 3] cycloaddition of a,p-unsaturated aldehydes with ene-carbamates catalysed by diphenylprolinol silyl ether as an organocatalyst. This reaction consisted of four consecutive reactions including an asymmetric ene reaction, an isomerisation from an imine into an enecarbamate, a hydrolysis and a hemiacetal formation in one pot to afford synthetically important chiral piperidine derivatives with excellent enantioselectivities of up to 99% ee, good yields and moderate to good diastereoselectivities, as shown in Scheme 6.22. 

Y. Qiao, A.D. Headley, Ionic liquid immobilized organocatalysts for asymmetric reactions in aqueous media. Catalysts 3 (2013) 709-725. 

In 2003, Rawal reported the use of TADDOLs 177 as chiral H-bonding catalysts to facilitate highly enantioselec-tive hetero-Diels-Alder reactions between dienes 181 and different aldehydes 86 (Scheme 6.29A) [82], and also BINOL-based catalysts 178 were found to facilitate this reaction with excellent selectivities [83]. TADDOLs were also successfully used as organocatalysts for other asymmetric transformations like Mukaiyama aldol reactions, nitroso aldol reactions, or Strecker reactions to mention a few examples only [84]. In addition, also BINOL derivatives have been employed as efficient chiral H-bonding activators as exemplified in the Morita-Baylis-Hilhnan reaction of enone 184 with different carbaldehydes 86 [85]. The use of chiral squaramides for asymmetric reactions dates back to 2005 when Xie et al. first used camphor-derived squaric amino alcohols as ligands in borane reductions [86]. The first truly organocatalytic application was described by Rawal et al. in 2008 who found that minute amounts of the bifunctional cinchona alkaloid-based squaramide 180 are... 

The asymmetric reaction of nitromethane with aldehydes as well as activated ketones (e.g., trifluoroacetophenone and a-ketoesters) is possible with various chiral metallic complexes or organocatalysts under atmospheric pressure with good yield and enantioselectivity. However, the Henry reaction of aryl alkyl ketones still remains problematic and challenging. Matsumoto s group also tested the very difficult reaction of acetophenone and nitromethane with quinidine. No product was observed under Ibar and only traces at 7 kbar, but application of 10 kbar resulted in a significant improvement in yield (31%) -unfortunately, no enantioselectivity was detected (Scheme 21.3). 

The IL medium is most beneficially appUed for asymmetric reactions promoted by hydrophilic amino acid organocatalysts, in particular proline. Amino acids, being poorly soluble in hydrocarbon or ether solvents, are not washed out to the organic phase during products isolation, which allows the catalyst-IL system... 

The O-TMS-diphenylprolinol 103/BzOH catalytic system is also applicable as an organocatalyst of Michael reactions of nitroalkanes with a, i-enals in aqueous medium [117]. However, functionalized task-specific ionic liquids incorporated in the chiral-pyrrolidine unit, apart from being very efficient and versatile organo-catalysts of Michael and some other asymmetric reactions, show much worse behavior in asymmetric aldol reactions, where their performance is inferior to IL-supported catalysts bearing the a-amino acid fragment [118]. 

The coupling of enzyme-catalyzed resolution with metal-catalyzed racemization constitutes a powerful DKR methodology for the synthesis of enantioenriched alcohols, amines, and amino acids. In many cases, the metalloenzymatic DKRs provide high yields and excellent enantiopurities, both approaching 100%, and thus provide useful alternatives to the chemical catalytic asymmetric reactions employing transition metals (complexes) or organocatalysts. The wider applications of a metalloenzymatic DKR method, however, are often limited by the low activity, narrow substrate specificity, or modest enantioselectivity of the enzyme employed. The low activities of metal-based catalysts, particularly in the racemization of amines and amino acids, also limit the wider applications of DKR. It is expected that fm-ther efforts to overcome these limitations with the developments of new enzyme-metal combinations will make the metalloenzymatic DKR more attractive as a tool for asymmetric synthesis in the future. 

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