Highly Enantioselective Hydroxylation of 3-Arylpropanenitriles to Access Chiral β-Hydroxy Nitriles by Engineering of P450pyr Monooxygenase

Abstract

Direct enzymatic hydroxylation of prochiral alkylnitriles represents a green and efficient synthesis of chiral β-hydroxy nitriles, but reported examples are very inefficient and limited. Here we describe the development of an evolved P450pyr monooxygenase for enantioselective benzylic hydroxylation of alkylnitriles. By the use of an engineered P450pyr-D5M3 mutant, a variety of pharmaceutically relevant chiral aryl-substituted β-hydroxy nitriles were prepared from prochiral 3-arylpropanenitriles in moderate yields with excellent enantioselectivities.

Biocatalytic Synthesis of Chiral Benzylic Alcohols via Enantioselective Hydroxylation by a Self-Sufficient Cytochrome P450 from Deinococcus gobiensis

“…Derivatives substituted with an electron-withdrawing group (R 1 = F, Br) on the phenyl ring can provide better yields than those substituted with an electron-donating group (methyl). Interestingly, a similar phenyl substituent effect on the yield was also reported for P450BM3, 16 P450PL2, 17 P450pyr, 18 and P450DA. 19 Besides alkane and olefin substrates, an alkyne substrate was also tolerated.…”

Dehydroxylative Cyanation of Alcohols Promoted by Triphenyphosphine/1,2-Diiodoethane

“…6 Therefore, the installation of a CN group into organic molecules has received considerable attention. 7 Traditional methods include dehydration of primary amides, 8 nucleophilic cyanide addition 9 or substitution, 10 the Sandmeyer reaction 11 and the Rosenmund von Braun protocol. 12 The Sandmeyer reaction and Rosenmund von Braun reaction, both of which use stoichiometric CuCN as a key reagent, have been later evolved into catalytic versions utilizing transition metal as catalysts, including Pd, 13 Cu, 14 and Ni metals.…”

Current Advances in the Enzyme Engineering of O2‐Dependent Enzymes – Boosting the Versatility and Applicability of Oxygenases and Oxidases

“…The crucial modification in all these mutants was the shorter distance between the heme‐oxygen and C4‐ para position of substrates compared to the wild type [34] . Furthermore, increasing the enantioselectivity from 96 % ee to >99 % was possible by a single exchange [35] …”