The use of the solvent engineering has been applied for controlling the resolution of lipase-catalyzed synthesis of β-aminoacids via Michael addition reactions. The strategy consisted of the thermodynamic control of products at equilibrium using the lipase CalB as a catalyst. The enzymatic chemo- and enantioselective synthesis of (R)-(−)-N-benzyl-3-(benzylamino)butanamide is reported, showing the influence of the solvent on the chemoselectivity of the aza-Michael addition and the subsequent kinetic resolution of the Michael adduct; both processes are catalyzed by CalB and both are influenced by the nature of the solvent medium. This approach allowed us to propose a novel one-pot strategy for the enzymatic synthesis of enantiomerically enriched β-aminoesters and β-aminoacids.

Recent progress of the catalytic promiscuity of enzymes have invigorated the use of biocatalysis in organic chemistry. Explorations of biocatalysis for the synthesis of esters are critical since up to now, existing traditional methods are complicated, which usually require long reaction times, microwaves or even toxic reagents. This paper presents a versatile biocatalytic methodology to obtain benzyl esters through a transesterification reaction of methyl esters with Candida antarctica lipase B (CaLB) and benzyl alcohol in the absence of solvent. In addition, the effect of the nucleophile size and the substituent directly attached to the carbonyl group was studied. The results show that, in some cases, using a vacuum shifts the equilibrium of the reaction towards the products. Based on these results, molecular docking studies were carried out, where specific regions in the CaLB catalytic cavity were analyzed.

The kinetic resolution of N‐tert‐butoxycarbonyl γ‐amino methyl esters bearing different stereocenters at alpha (γ2), beta (γ3), or gamma (γ4) positions was carried out by enantioselective hydrolysis with Candida antarctica lipase B (CaLB) in 2‐methyl‐2‐butanol solvent. The results show that the process is significantly less enantioselective for the γ2‐amino methyl ester (E=2.5), the γ3‐amino methyl ester (E=7.6), and the γ4‐amino methyl ester (E=8.3) when compared with the kinetic resolution of analogous N‐protected β3‐amino esters (E>80). Based on these results, molecular docking studies were carried out, through which particular regions in the CaLB catalytic cavity were analyzed. The steric exclusion region composed of Ile189 and Val190 residues, together with the amino bonding region that induces a hydrogen bond with the Asp134 residue, appear to be responsible for the high selectivity in the resolution of carboxylic acid derivatives with beta stereocenters. This interaction is well preserved for β‐amino esters as substrates. By contrast, γ‐amino esters exhibit greater conformational diversity, so the effectiveness of the interaction is reduced, which apparently is responsible for the loss of enantioselectivity in the resolution process.

A general chemo-enzymatic approach to synthesize both enantioenriched trans-3-alkoxyamino-4-oxy-2-piperidones, which are important scaffold for various naturally occurring alkaloids, is reported. To this end, a selective transition-metal-free dual C−H oxidation of piperidines mediated by the TEMPO oxoammonium cation (TEMPO+) was used, followed by enzymatic resolution of the corresponding alkoxyamino-2-piperidones with Candida antarctica lipase (CAL-B), to yield the title compounds in high enantiomeric excess (ee). The absolute configuration of both enantioenriched compounds was determined using chemical correlation and circular dichroism (CD) spectroscopy. The former method highlights the oxidative ring contraction of the trans-alkoxyamine-2-piperidone ring into its corresponding 2-pyrrolidinone.