Production of (S)‐β‐Nitro Alcohols by Enantioselective C−C Bond Cleavage with an R‐Selective Hydroxynitrile Lyase

Abstract

Hydroxynitrile lyase (HNL)‐catalysed stereoselective synthesis of β‐nitro alcohols from aldehydes and nitroalkanes is considered an efficient biocatalytic approach. However, only one S‐selective HNL—Hevea brasiliensis (HbHNL)—exists that is appropriate for the synthesis of (S)‐β‐nitro alcohols from the corresponding aldehydes. Further, synthesis catalysed by HbHNL is limited by low specific activity and moderate yields. We have prepared a number of (S)‐β‐nitro alcohols, by kinetic resolution with the aid of an R‐selective HNL from Arabidopsis thaliana (AtHNL). Optimization of the reaction conditions for AtHNL‐catalysed stereoselective C−C bond cleavage of racemic 2‐nitro‐1‐phenylethanol (NPE) produced (S)‐NPE (together with benzaldehyde and nitromethane, largely from the R enantiomer) in up to 99 % ee and with 47 % conversion. This is the fastest HNL‐catalysed route known so far for the synthesis of a series of (S)‐β‐nitro alcohols. This approach widens the application of AtHNL for the synthesis not only of (R)‐ but also of (S)‐β‐nitro alcohols from the appropriate substrates. Without the need for the discovery of a new enzyme, but rather by use of a retro‐Henry approach, it was used to generate a number of (S)‐β‐nitro alcohols by taking advantage of the substrate selectivity of AtHNL.

Hydroxynitrile Lyase Discovery, Engineering, and Promiscuity towards Asymmetric Synthesis: Recent Progress

“…Recently, AtHNL was studied in the synthesis of (S)-β-nitroalcohols using retro-Henry reaction. [54] Under optimized biocatalytic reaction conditions ten different racemic aromatic βnitroalcohols were converted to their corresponding (S)-βnitroalcohols (Scheme 12). At least half a dozen aromatic (S)-βnitroalcohols were synthesized showing 99 % ee and 47 % conv.…”

“…However the enantioselectivity of these mutants in the preparation of anticipated ( R )‐β‐nitroalcohols has not been investigated. Recently, At HNL was studied in the synthesis of ( S )‐β‐nitroalcohols using retro‐Henry reaction [54] . Under optimized biocatalytic reaction conditions ten different racemic aromatic β‐nitroalcohols were converted to their corresponding ( S )‐β‐nitroalcohols (Scheme 12).…”

One‐Pot Enzyme Cascade Catalyzed Asymmetrization of Primary Alcohols: Synthesis of Enantiocomplementary Chiral β‐Nitroalcohols

“…AtHNL protein expression and purification were done as per the protocol explained earlier. [14] BmHNL protein expression and purification was carried out according our standardized protocol (ESI, 2.3). [50]…”

“…Lipase, esterase, halohydrin dehalogenase, and HNL catalyzed retro-Henry reaction are used in the kinetic resolution of a racemic β-nitroalcohol or an epoxide. [12][13][14][15][16] Alcohol dehydrogenase catalyzed asymmetric reduction, [17][18][19][20] and HNL catalyzed nitroaldol reaction [21][22][23][24][25] are the other two routes. Both kinetic resolution and asymmetric reduction requires an additional step of substrate preparation, while the former could provide a maximum 50% theoretical yield.…”

Structure-Guided Tuning of a Hydroxynitrile Lyase to Accept Rigid Pharmaco Aldehydes

“…Despite the development of numerous chemical methods, enzymatic C–C bond formation has emerged as a greener process and an attractive complementary approach that often affords high enantioselectivity . Currently, lyases (e.g., EC 4.1.x.x) are used for enzymatic C–C bond formation, , among which only hydroxynitrile lyase (HNL) catalyzes both C–C and C–X (X = O or N) bond formation in hydrocyanation or nitro-aldol reactions . The vicinal C–O or C–O/C–N functional groups generated from the method provide an indispensable tool in the construction of key structural motifs with pharmaceutical significance .…”