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Flow chemistry has many advantages over batch synthesis of organic small-molecules in terms of environmental compatibility, safety and synthetic efficiency when scale-up is considered. Herein, we report the 10-step chemo-biocatalytic continuous flow asymmetric synthesis of cyproterone acetate (4) in which 10 transformations are combined into a telescoped flow linear sequence from commercially available 4-androstene-3, 17-dione (11). This integrated one-flow synthesis features an engineered 3-ketosteroid-Δ1-dehydrogenase (ReM2)-catalyzed Δ1-dehydrogenation to form the C1, C2-double bond of A ring, a substrate-controlled Co-catalyzed Mukaiyama hydration of 9 to forge the crucial chiral C17α-OH group of D ring with excellent stereoselectivity, and a rapid flow Corey-Chaykovsky cyclopropanation of 7 to build the cyclopropyl core of A ring. By strategic use of these three key reactions and fully continuous-flow operations, cyproterone acetate (4) is produced in an overall yield of 9.6% in 3 h of total reaction time, this is the highest total number of chemical transformation performance in any other continuous-flow synthesis reported to date. Flow chemistry has many advantages over batch synthesis of organic small molecules in terms of environmental compatibility, safety and synthetic efficiency when scale-up is considered. Herein, the authors report a 10-step chemobiocatalytic, continuous-flow asymmetric synthesis of cyproterone acetate in which 10 transformations are combined into a telescoped flow linear sequence from commercially available 4-androstene-3,17-dione. [ABSTRACT FROM AUTHOR]

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]

Covering: up to 2023 Huperzine alkaloids are a group of natural products belonging to the Lycopodium alkaloids family. The representative member huperzine A has a unique structure and exhibits potent inhibitory activity against acetylcholine esterase (AChE). This subfamily of alkaloids provides a great opportunity for developing synthetic methodologies and asymmetric synthesis. The efforts towards the synthesis of huperzine A have cultivated dozens of total syntheses and a rich body of new chemistry. Impressive progress has also been made in the synthesis of other huperzine alkaloids. The total syntheses of huperzines B, U, O, Q and R, structure reassignment and total syntheses of huperzines K, M and N have been reported in the past decade. This review focuses on the synthetic organic chemistry and the biosynthesis and medicinal chemistry of huperzines are also covered briefly. [ABSTRACT FROM AUTHOR]

A catalytic asymmetric total synthesis of avibactam and relebactam, two marketed diazabicyclooctane (DBO) β-lactamase inhibitors (BLIs), has been accomplished. An important feature of this study is the creation of a stereogenic center by using Rh-catalysed asymmetric hydrogenation, affording the crucial α-amino acid ester derivative with high-level enantiocontrol (99% ee). Furthermore, the adoption of flow technologies for the assembly of a majority of intermediates significantly achieves a faster preparation and greater synthetic efficiency than corresponding batch procedures. [ABSTRACT FROM AUTHOR]

Continuous flow synthetic technologies had been widely applied in the total synthesis in the past few decades. Fully continuous flow synthesis is still extremely focused on multi‐step synthesis of complex natural pharmaceutical molecules. Thus, the development of fully continuous flow total synthesis of natural products is in demand but challenging. Herein, we demonstrated the first fully continuous flow approach towards asymmetric total synthesis of natural tetrahydroprotoberberine alkaloids, (−)‐isocanadine, (−)‐tetrahydropseudocoptisine, (−)‐stylopine and (−)‐nandinine. This method features a concise linear sequence involving four chemical transformations and three on‐line work‐up processing in an integrated flow platform, without any intermediate purification. The overall yield and enantioselectivity of this four‐step continuous flow chemistry were up to 50 % and 92 %ee, respectively, in a total residence time of 32.5 min, corresponding to a throughput of 145 mg/h. [ABSTRACT FROM AUTHOR]

We disclose an asymmetric total synthesis of prostaglandin C2 TBS ether, a derivative of an extremely sensitive natural prostaglandin C2. The key to the synthesis is a SmI2-mediated ketyl–enoate reaction that leads to the formation of the functionalized cyclopentane ring with high-level stereochemical control. Access to the crucial alkene system is realized late in the synthesis by the implementation of a Grignard addition/dehydration/metathesis sequence. [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]

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 β‐hydroxy α‐amino esters (syn‐(2S,3R)‐7) in moderate‐to‐excellent isolated yield (up to 93%), along with moderate‐to‐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). [ABSTRACT FROM AUTHOR]

With the rapid development of genomic DNA sequencing, recombinant DNA expression, and protein engineering, biocatalysis has been increasingly and widely adopted in the synthesis of pharmaceuticals, bioactive molecules, fine chemicals, and agrochemicals. In this review, we have summarized the most recent advances achieved (2018–2020) in the research area of ketoreductase (KRED)‐catalyzed asymmetric synthesis of chiral secondary alcohol intermediates to pharmaceuticals and bioactive molecules. In the first part, synthesis of chiral alcohols with one stereocenter through the bioreduction of four different ketone classes, namely acyclic aliphatic ketones, benzyl or phenylethyl ketones, cyclic aliphatic ketones, and aryl ketones, is discussed. In the second part, KRED‐catalyzed dynamic reductive kinetic resolution and reductive desymmetrization are presented for the synthesis of chiral alcohols with two contiguous stereocenters. [ABSTRACT FROM AUTHOR]

We have developed the chloramphenicol base urea-catalyzed intramolecular Michael addition of γ -hydroxy- α , β -unsaturated enones. The oxidation of the resulting products provided facile access to the corresponding α -hydroxy chiral alcohols with good efficiency and enantioselectivity, with the reaction displaying broad substrate scope. The utility of this methodology was further demonstrated by the synthesis of ( R )-2-hydroxy-4-phenylbutanoate, which is a key building block for the construction of the ACE inhibitor benazepril hydrochloride. [ABSTRACT FROM AUTHOR]

A novel approach to synthesize pitavastatin calcium ( 1 ), an effective HMG-CoA reductase inhibitor, based on readily available and attractively functionalized ( R )-3-chloro-1,2-propanediol is reported. This work highlights an intermolecular diastereoselective bromine-induced cyclization of homoallylic carbonate to meet stereochemical challenges in the synthesis of statins. An efficient route to a new triphenylphosphonium tetrafluoroborate salt of a quinoline core is also presented. [ABSTRACT FROM AUTHOR]