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Owing to its associated advantages such as the generation of two stereocenters in 100% maximum theoretical yield, mild reaction conditions and environmentally friendliness, ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) is a versatile and appealing synthetic approach to access valuable chiral alcohols containing two or more stereocenters. Despite the considerable progress that has been made in this research field, previous studies mostly focused on ketone substrates with relatively simple structures. In the present study, ketoreductases YDR368w and YGL039w were identified through enzyme screening and applied to the KRED-catalyzed DYRKR of sterically hindered 2-aryl-1,5-benzothiazepin-3,4(2H,5H)-diones (1). Eleven structurally diverse chiral cis-(2S,3S)-2,3-dihydro-3-hydroxy-2-aryl-1,5-benzothiazepin-4(5H)-ones (cis-(2S,3S)-2), including the critical synthetic intermediates to the calcium channel blockers diltiazem and clentiazem, were prepared in 50–90% isolated yields with excellent stereoselectivities (all >20 : 1 dr and ≥99% ee). Finally, the successful execution of a gram scale synthesis and the demonstrated excellent recyclability of the immobilized ketoreductase (up to 20 cycles) both underscored the good application potential of the currently established DYRKR method. [ABSTRACT FROM AUTHOR]

An asymmetric allylation of cyclic ketimine esters with vinylethylene carbonates was accomplished through a Pd/Cu dual catalysis system under a mild condition, providing a range of trisubstituted allylic 2H‐pyrrole analogues bearing a chiral quaternary stereogenic center in high yields (up to 92% yield) and with excellent regioselectivities and enantioselectivities (up to 96% ee). A gram‐scale operation was also conducted in high efficiency without erosion of enantioselectivity and stereoselectivity. [ABSTRACT FROM AUTHOR]

Cyclohexylamine oxidase CHAOCCH12‐C2 was previously discovered and utilized in the chemo‐enzymatic synthesis of (S)‐1‐(4‐methoxybenzyl)‐1,2,3,4,5,6,7,8‐octahydroisoquinoline ((S)‐1 a), the key precursor for the industrial production of antitussive dextromethorphan. Herein, structure‐guided semi‐rational engineering and random mutagenesis were applied to CHAOCCH12‐C2, resulting in an evolved variant WXF‐FM which possessed five point mutations: H68Q/E198G/L200V/I201L/V209S and displayed >15‐fold higher kcat and improved stereoselectivity towards (R)‐1 a relative to the WT enzyme. WXF‐FM‐catalyzed deracemization of 200 mM of rac‐1 a was achieved at gram‐scale under Turner's deracemization conditions, affording (S)‐1 a in 76 % isolated yield with 97 % ee, demonstrating the effectiveness and great potential of this enzyme in the practical, green synthesis of dextromethorphan. Two bulky analogues of (S)‐1 a were also afforded with much higher optical purities in WXF‐FM‐catalyzed reactions than those obtained in WT enzyme‐catalyzed reactions. Through conducting complete deconvoluting experiments, presence of strong cooperative effect was revealed, and the mutational effect of H68Q on (R)‐1 a was suggested to be possibly applicable to related cyclohexylamine oxidases. Molecular dynamics (MD) simulations indicated the enlargement of binding and entrance cavities, and the formation of a new hydrogen‐bonding between FAD and (R)‐1 a both likely contributed to the enhanced catalytic activity. [ABSTRACT FROM AUTHOR]

A palladium‐catalyzed bisallylation of vinylethylene carbonates with β‐ketophosphonates to access to (Z)‐trisubstituted dihomoallylic phosphonates bearing a quaternary carbon center with good regio‐ and stereoselectivity is reported. This operationally simple protocol exhibits excellent functional group tolerance to deliver valuable dihomoallylic phosphonates. [ABSTRACT FROM AUTHOR]

We report here the discovery of a novel ketoreductase (KRED), named KmCR2, with a broad substrate spectrum on bioreduction of sterically bulky diaryl‐ and aryl(heteroaryl)methanones. The position of the substituent on aromatic rings (meta versus para or ortho) was revealed to control the stereospecificity of KmCR2. The stereoselective preparation of both enantiomers of diaryl‐ or aryl(heteroaryl)methanols using strategically engineered substrates with a traceless directing group (bromo group) showcased the potential application of this substrate‐controlled bioreduction reaction. The combined use of substrate engineering and protein engineering, was demonstrated to be a useful strategy in efficiently improving stereoselectivity or switching stereopreference of enzymatic processes. [ABSTRACT FROM AUTHOR]

An array of hybrid catalysts incorporating a chloramphenicol base moiety linked to another chiral scaffold through a squaramide linker were developed and successfully used in the Michael addition of 2,3-dihydrobenzofuran-2-carboxylates to nitroolefins. Control experiments suggested that the hybrid catalysts were more reactive than nonhybridized bifunctional catalysts, and matching of the chirality between the two scaffolds was crucial for high reactivity and stereoselectivity. These hybrid organocatalysts could be used with a variety of substrates. At a 0.5 mol-% catalyst loading, a range of 2,3-dihydrobenzofuran-2-carboxylates derivatives bearing quaternary and tertiary stereogenic centers were obtained in high yields (up to 98 %) with excellent enantioselectivities (up to 99 % ee) and moderate diastereoselectivities (up to 8:92 dr). [ABSTRACT FROM AUTHOR]

Keywords: Allylation; -Quaternary; Pd/Cu Catalyzed; Trisubstituted; Vinylethylene Carbonates EN Allylation -Quaternary Pd/Cu Catalyzed Trisubstituted Vinylethylene Carbonates 1775 1775 1 06/09/22 20220607 NES 220607 The front cover image, provided by Fener Chen, illustrates an asymmetric allylation of cyclic ketimine esters with vinylethylene carbonates through a Pd/Cu dual catalysis system under a mild conditions. Allylation, -Quaternary, Pd/Cu Catalyzed, Trisubstituted, Vinylethylene Carbonates Front Cover Picture: Synergistic Pd/Cu Catalyzed Allylation of Cyclic Ketimine Esters with Vinylethylene Carbonates: Enantioselective Construction of Trisubstituted Allylic 2H-Pyrrole Derivatives (Adv. [Extracted from the article]

A robust and practical method has been developed for the synthesis of florfenicol ( 1 ) starting from commercial available 4-(methylsulfonyl) benzoic acid. The key step in this synthesis was the Ru-chloramphenicol base catalyzed asymmetric transfer hydrogenation of N -Boc α-amino-β-ketoester 5 through a dynamic kinetic resolution, which afforded the key chiral building block, anti -(2 S ,3 S )-α-Boc-amino-β-hydroxyl ester 4 , with high diastereoselectivity (92% de) and enantioselectivity (78% ee). The synthesis of a series of novel chloramphenicol base ligands L1–L10 is also included. This protocol could also be used for the asymmetric synthesis of fully synthetic analogs of florfenicol. [ABSTRACT FROM AUTHOR]

• An efficient, stereoselective ketoreductase for the enantioselective synthesis of a key (R)-α-lipoic acid precursor evolved. • High space-time yield (391 g∙L−1∙d−1) accomplished. • Mechanistic insights gained via complete deconvolution experiments and molecular dynamics (MD) simulations. Methyl (R)-8-chloro-6-hydroxyoctanoate ((R)-MCHO, (R)- 2a) is a key precursor that can be utilized in the production of (R)-α-lipoic acid ((R)-LA) of pharmaceutical and dietary significance. Owing to its high atom economy, maximum theoretical yield of 100%, and environmentally friendliness, ketoreductase (KRED)-catalyzed stereoselective reduction of methyl 8-chloro-6-oxooctanoate (MCOO, 1a), an ε-keto ester, represents an efficient yet challenging approach to the synthesis of (R)- 2a. We report herein the development of a versatile KRED, referred to as Ss CR L211H/V127A/L135I, through enzyme screening followed by structure-guided protein engineering, which was assisted by comparative analysis of enzyme-/substrate- binding modes in prereaction-state and free-state molecular dynamics (MD) simulations. This enzyme variant displayed 2.8-fold increased k cat (16.77 s−1) towards 1a relative to the wild-type Ss CR, improved stereoselectivity (98.0% ee), and no substrate inhibition. Insights were gained on the origin of the enhancement of enzyme's catalytic activity and stereoselectivity, by conducting complete deconvolution experiments and MD simulations. In the presence of 60 g∙L−1 of wet E. coli cells coexpressing Ss CR L211H/V127A/L135I and glucose dehydrogenase (GDH), and 0.05 mM NADP+, complete reduction of 260 g∙L−1 of 1a was achieved furnishing (R)- 2a with 98.0% ee with a space-time yield of 391 g∙L−1∙d−1, thereby showcasing the promising potential of this ketoreductase in the asymmetric synthesis of (R)- 2a. [Display omitted] [ABSTRACT FROM AUTHOR]