Enantioselective first generation

To overcome these problems with the first generation Brmsted acid-assisted chiral Lewis acid 7, Yamamoto and coworkers developed in 1996 a second-generation catalyst 8 containing the 3,5-bis-(trifluoromethyl)phenylboronic acid moiety [10b,d] (Scheme 1.15, 1.16, Table 1.4, 1.5). The catalyst was prepared from a chiral triol containing a chiral binaphthol moiety and 3,5-bis-(trifluoromethyl)phenylboronic acid, with removal of water. This is a practical Diels-Alder catalyst, effective in catalyzing the reaction not only of a-substituted a,/ -unsaturated aldehydes, but also of a-unsubstituted a,/ -unsaturated aldehydes. In each reaction, the adducts were formed in high yields and with excellent enantioselectivity. It also promotes the reaction with less reactive dienophiles such as crotonaldehyde. Less reactive dienes such as isoprene and cyclohexadiene can, moreover, also be successfully employed in reactions with bromoacrolein, methacrolein, and acrolein dienophiles. The chiral ligand was readily recovered (>90%). 

BINAP was introduced by Noyori [18], It has been particularly explored for reduction with ruthenium catalysts. While the first generation rhodium catalysts exhibited excellent performance with dehydroamino acids (or esters), the second generation of hydrogenation catalysts, those based on ruthenium /BINAP complexes, are also highly enantioselective for other prochiral alkenes. An impressive list of rather complex organic molecules has been hydrogenated with high e.e. s. 

These catalysts, 11-13, show good enantioselectivity ranging from 80 to 95% ee in the epoxidation of conjugated cfs-di- and tri-substituted olefins. Epoxidation of "good substrates such as 2,2-dimethylchromene derivatives proceeds with excellent enantioselectivity (>95% ee). Since the results obtained with these first-generation Mn-salen catalysts have been reviewed [21,33], only typical examples are shown in Table 6B.1. These reactions are usually carried out in the presence of donor ligand [34] such as 4-phenylpyridine A -oxide with terminal oxidants such as iodosylbenzene and sodium hypochlorite as described above. However, the use of some other terminal oxidants under well-optimized conditions expands the scope of the Mn-salen-... 

Most of the first-generation Mn-salen complexes such as 16 show poor enantioselectivity (<25% ee) [83]. The Mn-salen complex37, which has a small substituent at theethylenediamine moiety shows moderate enantioselectivity, but chemical yield is poor (Scheme 6B.37). Differing from the oxo-Mn species, the imino-Mn species that is the putative active catalyst species in aziridination has a substituent on its nitrogen atom. It is reasonable to assume that the size of the substituents at the ethylenediamine moiety directs the orientation of the substituent at the nitrogen atom, which influences enantioselectivity,... 

Hyperbranched and dendritic macromolecules have recently been the subject of considerable interest. Bolm developed chiral hyperbranched macromolecules 57 that catalyzed the enantioselective addition of diethylzinc to benzaldehyde [75]. The enan-tiocontrol of the hyperbranched chiral catalysts was slightly lower than for the low-molecular-weight catalyst. TADDOLs linked with dendritic molecules have been synthesized [59]. For example, use of the first generation dendrimer 58 with six terminal TADDOL units resulted in high enantioselectivity. 

The first enantioselective total synthesis of (+)-prelaureatin was achieved by M.T. Crimmins et al. The oxocene core of the natural product was constructed in high yield by a RCM reaction using the first generation Grubbs catalyst. 

Fleming, M., Rigby, J. H., Yoon, T. P., MacMillan, D. W. C. Enantioselective Claisen rearrangements Development of a first generation asymmetric acyl-Claisen reaction. Chemtracts 2001, 14, 620-624. 

Excellent enantioselectivities for all of these dendrimers were observed in the Michael addition reactions of isovaleraldehyde with nitrostyrene. For example, in the presence of 10mol% of the first-generation catalyst, the addition product 2-isopropyl-4-nitro-3-phenyl-butyraldehyde was isolated in 86% yield with 99% ee and moderate diastereoselectivity (diastereomeric ratio (dr) 80 20). Higher diaste-reoselectivities were observed when the meta-substituted dendrimer catalysts were used, but the yields and enantioselectivities were relatively low. In addition, the second-generation dendrimer catalyst could be easily recovered via precipitahon with methanol and reused at least five times, with only a slight loss of catalytic activity. 

A subsequent report describes the evolution of the same enzyme for the hydrolysis of 3-phenylbutyric acid resorufin ester using both a mutator strain and error-prone PCr(2°7] Mutants were screened for improved enantioselectivity based on a microtiter plate assay using the optically pure R- or S-esters. Both mutagenesis methods generated first-generation mutants with higher enantioselectivity ( =6.6 and 5.8 compared to wild-type E=3.5). 

A disadvantage of the first-generation enantioselective hydrogenation catal s was that pure (Z)-enamide had to be used. The ( )-enamide showed a poor turnover and the enantioselectivity was rather low. [84]... 

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