Nitriles enantioselective biotransformations

Optically active a-hydroxy carboxylic acids are useful intermediates in medicinal chemistry and asymmetric synthesis (Coppola and Schuster 1997). Enantioselective biotransformations of a-hydroxy nitriles (cyanohydrins) are important because they can lead to a dynamic kinetic resolution from readily available starting material. 

Wang, M.X. 2005. Enantioselective biotransformations of nitriles in organic synthesis. Topics in Catalysis, 35 117-30. 

The addition of HCN to aldehydes or ketones produces cyanohydrins (a-hydroxy nitriles). Cyanohydrins racemize under basic conditions through reversible loss of FiCN as illustrated in Figure 6.30. Enantiopure a-hydroxy acids can be obtained via the DKR of racemic cyanohydrins in the presence of an enantioselective nitriletransforming enzyme [86-88]. Many nitrile hydratases are metalloenzymes sensitive to cyanide and a nitrilase is usually used in this biotransformation. The DKR of mandelonitrile has been extended to an industrial process for the manufacture of (R)-mandelic acid [89]. 

Biotransformations of hve-membered alicyclic trani-A-protected-amino nitriles proceeded faster than in case of six-membered compounds. The products of the trani-A-protected-amino nitriles (amides and acids) were formed preferentially than the products of the c A-counterparts (only amides). Enantioselectivities were strongly dependent on the structure the trani-hve-membered substrates gave exclusively amides with excellent optical purity (94-99%), in contrast to the tran -six-membered substrates resulted in the formation of the acid with excellent enantiopurity (87-99%). The corresponding c A-compounds yielded much lower enantiomeric excesses. Nitrile precursor of a-methylene-P-amino acids was analogously investigated (Winkler et al., 2005) (Table 17.13). 

These data and considerations on structural features of substrates have suggested the hypothesis that a readily reachable reactive site is embedded within a spacious pocket of the enantioselective nitrile hydratase, while the amidase comprises a relatively deep-buried and size-limited enantioselective active site. This hypothesis has been supported by the results obtained studying the biotransformations of differently configured 2,2-dimethyl-3-arylcyclopropanecarbonitriles catalyzed by... 

Ma, D.Y, Wang, D.X., Pan, J., et al. 2008b. Nitrile biotransformations for the synthesis of enantiomer-ically enriched P -, and P -hydroxy and alkoxy acids and amides, a dramatic O-substituent effects of the substrates on enantioselectivity. Tetrahedron Asymmetry, 19 322-29. 

Wang, M.X., Deng, G., Wang, D.X., et al. 2005. Nitrile biotransformation for highly enantioselective synthesis of oxiranecarboxamides with tertiary and quaternary sterocenters efficient chemoenzymatic approaches to enantiopur a-methylated serine and isoserine derivatives. Journal of Organic Chemistry, 70 2439-44. 

Nifrilases catalyze the conversion of organonitriles directly to the corresponding carboxylic acids. Synthetic hydrolysis of nitriles into the corresponding amides and carboxylic acids requires severe reaction conditions. A typical synthetic approach would require the use of 70% H2SO4 and heat (13). Such a reaction condition is not compatible when selectivity and the conservation of other hydrolysable functional groups in a substrate are desired. Biotransformation of nitrites can be accomplished under mild conditions, in an aqueous environment (13). Additionally, enantioselectivity of the biocatalytic conversion of nitriles to chiral acids has been demonstrated (14-16). Therefore, nifrilases provide an alternative route for synthetic processes that require conversion of nitriles to corresponding acids. 

Figure 11.6 Biotransformations of racemic p-aminonitriles by nitrile hydratase and amidase in whole cells of Rhodococcus erythropolis A4 [38]. The enantiomeric excess is only specified for the reactions which proceeded with significant enantioselectivities.

Wang, M.-X. and Lin, S.-J. (2001) Highly efficient and enantioselective synthesis of L-arylglycines and D-arylglycine amides from biotransformations of nitriles. Tetrahedron Lett., 42, 6925-6927. 

M. Gao, D.-X. Wang, Q.-Y. Zheng, M.-X. Wang, An unusual p-vinyl effect leading to high efficiency and enantioselectivity of the amidase, nitrile biotransformations for the preparation... 

Nitrile hydratases (NHases) exhibit broader substrate specificities than nitrilases, and they are more tolerant of sterically demanding substrates. In contrast, NHases mainly exhibit lower enantioselectivities than nitrilases, although biotransformations of a few specific nitriles by NHase proceeded with excellent enantioselectivities [5,6]. Low NHase enantioselectivity, however, can be compensated for by using enantiose-lective amidases in the next step. NHases are usually less thermostable than nitrilases, but a few of them are resistant to increased temperatures or organic solvent concentrations [8, 9]. The majority of characterized NHases are Fe or Co type, except for a new NHase with three metal ions (Co, Cu, Zn) reported in Rhodococcus jostii [85]. 

Wang, M.-X. (2009). Progress of enantioselective nitrile biotransformations in organic synthesis. CHIMIA International Journal for Chemistry, 63,331-333. 

Rhodococcus rhodochrous NCEMB 11216 bears an enantioselective nitrilase, which is active toward a wide range of aliphatic nitriles with C-2 group substitutions [29]. The highest stereoselectivity was reached during biotransformation of (/ ,5)-2-methylhexani-... 

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