Dipeptides asymmetric hydrogenation

Following the success in producing amino acids by asymmetric hydrogenation, this research has been extended to dipeptides. Using rhodium complexes of the same or similar ligands to those above, the hydrogenation of dehydrodipeptides is also possible in optical yields in the range of 90-98% (equation 51).261"264... 

Poulin and Kagan have shown that a double asymmetric hydrogenation can be carried out on the same dipeptide precursor with excellent optical selectivity (equation 52). [Rh(cod)(jR,R-DIPAMP)]+ was used as catalyst. The major diastereoisomer of the product, which had the S,S-configuration, showed an optical purity of better than 95%.265... 

Efficient asymmetric hydrogenation of alkenes other than the amino acid and dipeptide precursors described above has met with only limited success. This appears to be at least in part due to the inability of many alkenes to function as bidentate chelates. Ethyl 2-acetoxyacrylate was hydrogenated with an enantiomer excess of 89% using [Rh(cod)(R,R-DIPAMP)]+, giving the S-enantiomer (equation 53). The ligands CHIRAPHOS, PROPHOS, DIOP, BPPM and CAMP were less effective.266... 

Fig. 27. Asymmetric hydrogenation routes to dipeptides and related compounds...

Conjunction of the newly created asymmetric center with an existing one offers applications e.g., high stereoselectivity for production of all diastereomers of chiral dipeptides are achieved by means of asymmetric hydrogenation of dehydrodipeptides that have the proper choice of chiral ligands . 

Asymmetric hydrogenation of precursors of dipeptides has mainly been studied by Kagan, Ojima and coworkers [154, 752]. Double diastereodifferentia-tion comes into play ( 1.6), and excellent selectivities are obtained when the ligands of rhodium are diop 3.31 (Ar = Ph), dipamp 3.31 or bppm 3.36 (R = Ph, R = NHAr). A few examples of dipeptide hydrogenations are shown in Figure 7.4. 

Synthesis of Chiral Dipeptides by Means of Asymmetric Hydrogenation of Dehydrodipeptides... 

Table III summarizes typical results for the asymmetric hydrogenation of a variety of N-acyldehydrodipeptides with pyrrolidino-diphosphines and diPAMP. As Table III shows, (R, ), (S S) ( >1.) or (R,R)-dipeptides in high optical purities can be readily synthesized by using these chiral ligands, and, in one recrystalliza-tion easily lead to optically pure dipeptides.

In connection with these studies, the asymmetric hydrogenation catalyzed by Raney nickel modified with dipeptide should be mentioned. In the hydrogenation of methyl acetoacetate [Eq. (5)], Izumi and his co-workers (70) found that the... 

Table 2. Asymmetric hydrogenation of methyl acetoacetate catalyzed by Raney nickel modified with dipeptide and amino acid (JO)...

A comprehensive review of asymmetric hydrogenation, mainly 2-oxo-carboxylic acids and their esters, over heterogeneous catalysts of Pt-alumina modified with alkaloids was presented in Chapter 5 of this book. Here some practical aspects of these catal5i ic systems will be considered. Thus, ethyl (i )-4-phenyl-2-hydroxybutyrate is an important intermediate for the synthesis of the angiotensin-converting enzyme inhibitor Benazepril (Scheme 7.20.) and other carboxyalkyl dipeptides like Enalapril (Scheme 7.21.)... 

Fig. 21. Synthesis of a dipeptide by asymmetric hydrogenation of an azo-methine. Replacing benzylamine with S-a-methylbenzylamine produced an increase in the relative amount of B,S product, but with R-a-methylbenzyla-mine the S,S product predominated.

Further studies were carried out mainly with glycine, since here the group R is simply hydrogen, so that no side reactions take place. In addition, glycine does not have an asymmetric carbon atom, so that chirality problems cannot occur (see Sect. 9.4). Steinman and Cole (1967) used dicyandiamide as a condensa-tion/dehydration agent a dipeptide was formed in about 1.2% yield. 

The heterogeneous hydrogenation of dehydrodioxopiperazines (e.g., 55) has been described as a stereocontrolled route to dipeptides. The principle involved has been applied to several related problems in amino acid synthesis 5 b. It is much more difficult to achieve stereoselectivity in the hydrogenation of linear dehydrodipeptides with heterogeneous catalysts, which indicates that it is the orientation of the existing asymmetric center on the catalyst surface with the alkyl substituent remote from palladium that is responsible for the selectivity. 

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