Chemoenzymatic Dynamic Kinetic Resolution: A Powerful Tool for the Preparation of Enantiomerically Pure Alcohols and Amines

Abstract

Chemoenzymatic dynamic kinetic resolution (DKR) constitutes a convenient and efficient method to access enantiomerically pure alcohol and amine derivatives. This Perspective highlights the work carried out within this field during the past two decades and pinpoints important avenues for future research. First, the Perspective will summarize the more developed area of alcohol DKR, by delineating the way from the earliest proof-of-concept protocols to the current state-of-the-art systems that allows for the highly efficient and selective preparation of a wide range of enantiomerically pure alcohol derivatives. Thereafter, the Perspective will focus on the more challenging DKR of amines, by presenting the currently available homogeneous and heterogeneous methods and their respective limitations. In these two parts, significant attention will be dedicated to the design of efficient racemization methods as an important means of developing milder DKR protocols. In the final part of the Perspective, a brief overview of the research that has been devoted toward improving enzymes as biocatalysts is presented.

Stereoselective Access to 1-[2-Bromo(het)aryloxy]propan-2-amines Using Transaminases and Lipases; Development of a Chemoenzymatic Strategy Toward a Levofloxacin Precursor

“…Finally, the pyridine ketone 3f led to the (S)-4f in 95-97% ee and high to excellent conversion values (88-97%, entries [15][16][17]. Unfortunately, none of the commercially available TAs gave good activities for the preparation of the (R)-amines, the synthesis of (R)-4c and (R)-4d in enantiopure form being achieved with 91% and 57% conversion, respectively, when using the At-TA (entries 5 and 10).…”

“…Lipase-catalyzed acylation is a common strategy for the resolution of racemic amines and alcohols under mild reaction conditions, 17 mainly using esters as acyl donors. 18 So at this point, an initial screening of the reaction conditions was performed with the less hindered substrate, 1-(2-bromophenoxy)propan-2-amine (4a) as the model substrate (Table 3).…”

Tandem Reactions Combining Biocatalysts and Chemical Catalysts for Asymmetric Synthesis

“…In fact, more than half of the drugs currently in use are chiral compounds. In order to fulfill the increasing demand for enantiopure compounds, significant advances in asymmetric synthesis and catalysis have been achieved [9,10]. Dynamic kinetic resolution (DKR) catalyzed by transition-metal racemization complexes and kinetic resolution enzymes, have been employed as efficient methods to prepare chiral alcohols and amines that constitute important synthetic building blocks of various chemical products, such as agrochemicals, food additives, fragrances and pharmaceuticals [11].…”

“…Since the pioneering work of William [13], Bäckvall [14] and Kim [15] on developing practical systems that combined metal catalysts with lipases or serine proteases for DKR of alcohols and amines, a variety of studies have been performed to improve these systems, such as discovering catalysts that could efficiently racemize alcohols and amines at mild conditions, improving the stability and catalytic efficiency of enzymes, and expanding the substrate scopes [9,10]. To date, immobilized Candida antarctica lipase B (CALB) [16] and C. antarctica lipase A (CALA) [3] have been the most common enzymes of choice to prepare R-or S-enantiomers of alcohols respectively, owing to their robustness and activity in organic solvents at temperatures up to 100 • C. …”

“…Other more cost-effective and readily accessible metal complexes, such as iridium, aluminum and vanadium complexes, have also been investigated for DKR of secondary alcohols [9]. Akai and co-workers have demonstrated that the oxyvanadium (V) complex [VO(OSiPh3)3] in tandem with various lipases allowed for DKR of a wide range of linear and cyclic allylic secondary alcohols [30,31] (Scheme 2).…”