ABSTRACT
Invited for the cover of this issue are Dang Cheng, Fener Chen and co-workers at Fudan University. The image depicts six-step continuous-flow synthesis of diclofenac sodium from commercially available aniline and chloroacetic acid in a desktop microchemical plant. Read the full text of the article at 10.1002/chem.202201420.
Subject(s)
Diclofenac , HumansABSTRACT
Diclofenac sodium is a widely used nonsteroidal anti-inflammatory drug (NSAID) as over-the-counter (OTC) medication for the treatment of inflammatory diseases. Herein, the development of an intensified six-step continuous flow synthesis of diclofenac sodium from commercially available aniline and chloroacetic acid is described. A challenging and unprecedented etherification/Smiles rearrangement cascade of 2-chloro-N-phenylacetamide and 2,6-dichlorophenol into hydroxyacetyldiphenylamine operated with the precise control of reaction conditions in continuous flow was realized as the key step in this multistep synthetic chemistry. The undesired amide hydrolysis in Smiles rearrangement was addressed and the extra installation of N-chloroacetyl group in current industrial batch mode was avoided. Diclofenac sodium was obtained in 63 % isolated yield with an average yield of above 90 % for each step in a total residence time of 205â min.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , DiclofenacABSTRACT
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 32.5â min, corresponding to a throughput of 145â mg/h.
Subject(s)
Alkaloids , Biological Products , Alkaloids/chemistry , Berberine Alkaloids , Biological Products/chemistry , Cyclization , StereoisomerismABSTRACT
A unified strategy for an efficient and high diastereo- and enantioselective synthesis of (-)-chloramphenicol, (-)-azidamphenicol, (+)-thiamphenicol, and (+)-florfenicol based on a key catalytic syn-selective Henry reaction is reported. The stereochemistry of the ligand-enabled copper(II)-catalyzed aryl aldehyde Henry reaction of nitroethanol was first explored to forge a challenging syn-2-amino-1,3-diol structure unit with vicinal stereocenters with excellent stereocontrol. Multistep continuous flow manipulations were carried out to achieve the efficient asymmetric synthesis of this family of amphenicol antibiotics.
Subject(s)
Thiamphenicol , Anti-Bacterial Agents , Catalysis , Chloramphenicol/analogs & derivatives , Heterocyclic Compounds, 3-Ring , Nitro Compounds , Thiamphenicol/analogs & derivativesABSTRACT
Development of efficient and stereoselective synthesis of prostaglandins (PGs) is of utmost importance, owing to their valuable medicinal applications and unique chemical structures. We report here a unified synthesis of PGs cloprostenol, bimatoprost, PGF2α, fluprostenol, and travoprost from the readily available dichloro-containing bicyclic ketone 6a guided by biocatalytic retrosynthesis, in 11-12 steps with 3.8-8.4% overall yields. An unprecedented Baeyer-Villiger monooxygenase (BVMO)-catalyzed stereoselective oxidation of 6a (99% ee), and a ketoreductase (KRED)-catalyzed diastereoselective reduction of enones 12 (87 : 13 to 99 : 1 dr) were utilized in combination for the first time to set the critical stereochemical configurations under mild conditions. Another key transformation was the copper(ii)-catalyzed regioselective p-phenylbenzoylation of the secondary alcohol of diol 10 (9.3 : 1 rr). This study not only provides an alternative route to the highly stereoselective synthesis of PGs, but also showcases the usefulness and great potential of biocatalysis in construction of complex molecules.
ABSTRACT
A concise asymmetric total synthesis of a group of tetrahydroprotoberberine alkaloids, (-)-canadine, (-)-rotundine, (-)-sinactine, and (-)-xylopinine, has been accomplished in three steps from the commercially available corresponding disubstituted phenylethylamine and disubstituted benzaldehyde. Our synthesis toward these four alkaloids took advantage of the following strategy: in the first step, we achieved an efficient and sustainable synthesis of secondary amine hydrochlorides via a fully continuous flow; in the second step, we developed a Pictet-Spengler reaction/Friedel-Crafts hydroxyalkylation/dehydration cascade for the construction of the dihydroprotoberberine core structure (ABCD-ring); and in the last step, Ir-catalyzed enantioselective hydrogenation was employed for the introduction of the desired stereochemistry at the C-14 position in the tetrahydroprotoberberine alkaloids. This work significantly expedites the asymmetric synthesis of the entire tetrahydroprotoberberine alkaloid family as well as a more diverse set of structurally related non-natural analogues.
Subject(s)
Hydrogenation , Berberine/analogs & derivatives , Berberine Alkaloids , Catalysis , StereoisomerismABSTRACT
A time-economical TfOH-catalyzed N-H insertion between anilines and α-alkyl and α-aryl-α-diazoacetates provides a straightforward approach to access unnatural α-amino esters, which readily undergo various transformations and can thus be used for the synthesis of pharmaceutically relevant molecules. The α-amino esters were obtained in moderate to excellent yields.