Exploiting Enzymatic Dynamic Reductive Kinetic Resolution (DYRKR) in Stereocontrolled Synthesis

Abstract

Over the past two decades, the domains of both frontline synthetic organic chemistry and process chemistry and have seen an increase in crosstalk between asymmetric organic/organometallic approaches and enzymatic approaches to stereocontrolled synthesis. This review highlights the particularly auspicious role for dehydrogenase enzymes in this endeavor, with a focus on dynamic reductive kinetic resolutions (DYRKR) to “deracemize” building blocks, often setting two stereocenters in so doing. The scope and limitations of such dehydrogenase-mediated processes are overviewed, as are future possibilities for the evolution of enzymatic DYRKR.

Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N‐Oxide Lewis Base Catalysts

“…Thealdehyde 2awas incubated at 30 8 8Cfor 16 hours with aseries of KREDs in the presence of aglucose/ glucose dehydrogenase (GDH)/NADP cofactor recycling system, [20] and the results are shown in Table 1. Suzuki coupling of the boronate ester 6 with 1-bromoisoquinoline (5)i n8 6% yield was followed by THP ether removal to give 3a in 73 %y ield.…”

Biocatalytic Parallel Interconnected Dynamic Asymmetric Disproportionation of α‐Substituted Aldehydes: Atom‐Efficient Access to Enantiopure (S)‐Profens and Profenols

“…Reductive DKR21a was first developed in a coupled‐substrate approach using ethanol as co‐substrate 18a,21b. While HLADH was limited to low substrate concentration (0.5 mM, Table 1, entry 1), ADH‐10 from Sulfolobus solfataricus was applied on a 5 mM scale and yielded ( S )‐ 2 a in high enantiopurity with only 0.01 eq.…”

Stereoselective Reduction of α‐Fluoro‐β‐keto Esters by NADH and NADPH‐Dependent Ketoreductases

“…After 24 h, the reaction was extracted by EtOAc (2 × 10 mL). Substrate 1a (25,50, 100 or 200 μmol) was mixed with 400 μL 2-propanol and 50 μL methanol, KRED Mix P (29.1 mg in 1.0 mL H 2 O) followed by 1.0 mg KRED P1-H10, P2-C11, or P3-GO9. An in-tube derivatization similar to that previously described was used to synthesize MPTA (α-methoxy-α-trifluoromethylphenylacetic acid) esters of the product alcohols.…”

“…[15] There are numerous reports of KRED-catalyzed enantioselective reductions of -keto esters to -hydroxy esters possessing one chiral center. [22,23] These products form by reduction of the prochiral ketone with epimierzation [24] at the α-carbon, termed dynamic reductive kinetic resolution (DYRKR), [25] to often yield a single stereoisomer. [22,23] These products form by reduction of the prochiral ketone with epimierzation [24] at the α-carbon, termed dynamic reductive kinetic resolution (DYRKR), [25] to often yield a single stereoisomer.…”