Enantio‐ and Diastereoselective Synthesis of Chiral Syn‐Aryl β‐Hydroxy α‐Amino Esters via Biocatalytic Dynamic Reductive Kinetic Resolution

Abstract

Development of an efficient, stereoselective, sustainable synthesis of chiral aryl β-hydroxy α-amino acids and their derivatives is of paramount importance, owing to the broad utility of these molecules in pharmaceutical application and asymmetric synthesis. We report a systematic study on ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) of aryl α-amino β-keto esters 6, furnishing 20 structurally diverse chiral syn-aryl βhydroxy α-amino esters (syn-(2S,3R)-7) in moderate-toexcellent isolated yield (up to 93%), along with moderateto-excellent diastereoselectivity (up to > 99 : 1 dr) and excellent enantioselectivity (mostly > 99% ee). The practical synthesis potential of our developed method was showcased by the asymmetric, chemo-enzymatic total synthesis of thiamphenicol (1).

Ketoreductase-catalyzed dynamic reductive kinetic resolution of sterically hindered 2-aryl-1,5-benzothiazepin-3,4(2H,5H)-diones: asymmetric synthesis of a key diltiazem precursor and its analogues

“…Among them, 13 KREDs originated from Saccharomyces cerevisiae (baker's yeast), which was previously shown to be able to mediate the efficient DYRKR on 1a. 20,21 Ketoreductases such as SsCR, KmCR2, and KRED-Bt capable of catalyzing DYRKR on other ketone substrates 9,11 were also included in the present study. As a common practice in the field, a glucose dehydrogenase (GDH, originating from Thermoplasma acidophilum, WP_010901307.1) was employed for the regeneration of the expensive cofactor NADPH by using glucose as the sacrificial co-substrate.…”

“…[1][2][3][4][5][6][7] Within this context, in the past two decades, ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) has been rapidly developed and applied to the asymmetric synthesis of two or more stereocenter-containing valuable chiral alcohols, for instance, the veterinary antibiotic florfenicol and α-substituted-β-hydroxy phosphonates of anti-bacteria activities. [4][5][6][7][8][9][10][11][12] When combined with protein engineering, small molecular activation, or photoredox catalysis, racemic ketone starting materials with high α-C-H pK a or a static β-ketostereocenter could be tuned as a viable substrate for KRED-catalyzed DYRKR, achieving the straightforward, stereoselective synthesis of the corresponding alcohol product, a mission difficult, if not impossible, to accomplish via traditional synthetic means. [13][14][15] Diltiazem (Fig.…”

Biocatalytic dynamic reductive kinetic resolution of aryl α-chloro β-keto esters: divergent, stereocontrolled synthesis of diltiazem, clentiazem, and siratiazem

“…7 Furthermore, direct displacement of the chlorine atom of 1 by an appropriate nitrogen nucleophile would ultimately give rise to b-phenylserine derivatives (5) with activities of inhibiting the influenza virus. 8,9 In recent years, ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) has been increasingly invoked for asymmetric synthesis, [10][11][12][13][14] mainly owing to its capability of onestep installation of two stereogenic centers with a maximum theoretical yield of 100%, and of harnessing the inherent advantages of enzyme catalysis like environmental friendliness and mild reaction conditions. 15 In this regard, we envisioned that chiral aryl a-chloro b-hydroxy esters 1 could be prepared in a concise and sustainable way through KRED-catalyzed DYRKR of aryl a-chloro b-keto esters 6 (Scheme 1), given the configurational lability of the a-carbons of the latter molecules.…”