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1. Recent advances in the synthesis and reactivity of azetidines: strain-driven character of the four-membered heterocycle

   https://doi.org/10.1039/d1ob00061f  

   Mughal, Haseeb; Szostak, Michal (April 2021, Organic & Biomolecular Chemistry)

   null (Ed.)

   Azetidines represent one of the most important four-membered heterocycles used in organic synthesis and medicinal chemistry. The reactivity of azetidines is driven by a considerable ring strain, while at the same the ring is significantly more stable than that of related aziridines, which translates into both facile handling and unique reactivity that can be triggered under appropriate reaction conditions. Recently, remarkable advances in the chemistry and reactivity of azetidines have been reported. In this review, we provide an overview of the synthesis, reactivity and application of azetidines that have been published in the last years with a focus on the most recent advances, trends and future directions. The review is organized by the methods of synthesis of azetidines and the reaction type used for functionalization of azetidines. Finally, recent examples of using azetidines as motifs in drug discovery, polymerization and chiral templates are discussed. 

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2. Catalytic Chemo‐ and Regioselective Radical Carbocyanation of 2‐Azadienes for the Synthesis of α‐Amino Nitriles

   https://doi.org/10.1002/anie.202300605  

   Duan, Shengzu; Du, Ya; Wang, Lingling; Tian, Xun; Zi, Yujin; Zhang, Hongbin; Walsh, Patrick J.; Yang, Xiaodong (March 2023, Angewandte Chemie International Edition)

   Abstract α‐Amino nitriles are versatile structural motifs in a variety of biologically active compounds and pharmaceuticals and they serve as valuable building blocks in synthesis. The preparation of α‐ and β‐functionalized α‐amino nitriles from readily available scaffolds, however, remains challenging. Herein is reported a novel dual catalytic photoredox/copper‐catalyzed chemo‐ and regioselective radical carbocyanation of 2‐azadienes to access functionalized α‐amino nitriles by using redox‐active esters (RAEs) and trimethylsilyl cyanide. This cascade process employs a broad scope of RAEs and provides the corresponding α‐amino nitrile building blocks in 50–95 % yields (51 examples, regioselectivity >95 : 5). The products were transformed into prized α‐amino nitriles and α‐amino acids. Mechanistic studies suggest a radical cascade coupling process. 

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3. Copper( i )-catalyzed tandem synthesis of 4,5-functionalized oxazoles from isocyanoacetate and aldehydes

   https://doi.org/10.1039/D2NJ03162K  

   Wan, Yuting; Wu, Jieqing; Ma, Hongfei; Zhu, Hongjun; Walsh, Patrick J.; Li, Yufeng (September 2022, New Journal of Chemistry)

   Oxazoles are among the most important heterocyclic scaffolds in the fields of natural products and medicinal chemistry. Herein is developed a tandem reaction for the synthesis of a diverse array of 4,5-difunctionalized oxazoles utilizing easily-accessible ethyl 2-isocyanoacetate and aldehydes (26 examples, 31–83% yields). This cascade reaction is facilitated by catalytic CuBr and molecular oxygen as the oxidant. The process involves a catalytic cycloaddition oxidative dehydroaromatization mechanism. The broad aldehyde substrate scope, mild reaction conditions, and atom economy make this protocol an attractive alternative to access functionalized oxazoles. 

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4. A One‐Pot Biocatalytic Cascade to Access Diverse l ‐Phenylalanine Derivatives from Aldehydes or Carboxylic Acids

   https://doi.org/10.1002/cctc.202401979  

   Anderson, Shelby_R; Gopal, Madan_R; Spangler, Abigail_P; Jones, Michaela_A; Wyllis, D'Jana_R; Kunjapur, Aditya_M (December 2024, ChemCatChem)

   Abstract Nonstandard amino acids (nsAAs) that arel‐phenylalanine derivatives with aryl ring functionalization have long been harnessed in natural product synthesis, therapeutic peptide synthesis, and diverse applications of genetic code expansion. Yet, to date, these chiral molecules have often been the products of poorly enantioselective and environmentally harsh organic synthesis routes. Here, we reveal the broad specificity of multiple natural pyridoxal 5′‐phosphate (PLP)‐dependent enzymes, specifically anl‐threonine transaldolase, a phenylserine dehydratase, and an aminotransferase, toward substrates that contain aryl side chains with diverse substitutions. We exploit this tolerance to construct a one‐pot biocatalytic cascade that achieves high‐yield synthesis of 18 diversel‐phenylalanine derivatives from aldehydes under mild aqueous reaction conditions. We demonstrate the addition of a carboxylic acid reductase module to this cascade to enable the biosynthesis ofl‐phenylalanine derivatives from carboxylic acids that may be less expensive or less reactive than the corresponding aldehydes. Finally, we investigate the scalability of the cascade by developing a lysate‐based route for preparative‐scale synthesis of 4‐formyl‐l‐phenylalanine, a nsAA with a bio‐orthogonal handle that is not readily market‐accessible. Overall, this work offers an efficient, versatile, and scalable route with the potential to lower manufacturing costs and democratize synthesis for many valuable nsAAs. 

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5. Facile generation of bridged medium-sized polycyclic systems by rhodium-catalysed intramolecular (3+2) dipolar cycloadditions

   https://doi.org/10.1038/s41467-021-25513-7  

   Hou, Bao-Long; Wong, Jonathan J.; Lv, Na; Wang, Yong-Qiang; Houk, K. N.; Li, Chuang-Chuang (December 2021, Nature Communications)

   Abstract Bridged medium-sized bicyclo[m.n.2] ring systems are common in natural products and potent pharmaceuticals, and pose a great synthetic challenge. Chemistry for making bicyclo[m.n.2] ring systems remains underdeveloped. Currently, there are no general reactions available for the single-step synthesis of various bridged bicyclo[m.n.2] ring systems from acyclic precursors. Here, we report an unusual type II intramolecular (3+2) dipolar cycloaddition strategy for the syntheses of various bridged bicyclo[m.n.2] ring systems. This rhodium-catalysed cascade reaction provides a relatively general strategy for the direct and efficient regioselective and diastereoselective synthesis of highly functionalized and synthetically challenging bridged medium-sized polycyclic systems. Asymmetric total synthesis of nakafuran-8 was accomplished using this method as a key step. Quantum mechanical calculations demonstrate the mechanism of this transformation and the origins of its multiple selectivities. This reaction will inspire the design of the strategies to make complex bioactive molecules with bridged medium-sized polycyclic systems. 

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