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Alkenes are found in many biologically active molecules, and there are a large number of chemical transformations in which alkenes act as the reactants or products (or both) of the reaction. Many alkenes exist as either the E or the higher-energy Z stereoisomer. Catalytic procedures for the stereoselective formation of alkenes are valuable, yet methods enabling the synthesis of 1,2-disubstituted Z alkenes are scarce. Here we report catalytic Z -selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and of allylic amides, used until now only in E -selective processes. The corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. These transformations, promoted by catalysts that contain the highly abundant and inexpensive metal molybdenum, are amenable to gram-scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. The utility of this method is demonstrated by its use in syntheses of an anti-oxidant plasmalogen phospholipid, found in electrically active tissues and implicated in Alzheimer’s disease, and the potent immunostimulant KRN7000. Catalytic route to Z-selective olefins The Z-alkene bond is one of the most important chemical bonds in nature. Many natural products contain one or several Z alkenes, consisting of a double bond with two substituents at each end pointing in the same direction. The potency or function of these natural products disappears or changes significantly if the two substituents point in opposite directions — a structure called an E alkene. Convenient methods for the stereoselective synthesis of 1,2-disubstituted Z alkenes are scarce. Amir Hoveyda and colleagues now describe catalytic Z-selective cross-metathesis reactions of terminal enol ethers and allylic amides, previously used only in E-selective processes. The potential of this reaction is demonstrated by its use in syntheses of antioxidant plasmalogen phospholipids found in electronically active tissues and implicated in Alzheimer's disease, and the potent immunostimulant and antitumour agent KRN7000. There are a large number of chemical transformations in which alkenes act as the reactants and/or the products of the reaction, but methods enabling the facile synthesis of 1,2-disubstituted Z alkenes are scarce. This paper describes catalytic Z -selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously,and allylic amides, used thus far only in E -selective processes. The utility of this methodology is demonstrated by its use in syntheses of anti oxidant C18 (plasm)-16:0 (PC), found in electrically active tissues and implicated in Alzheimer's disease, and the potent immunostimulant KRN7000.

Boron functional groups are often introduced in place of aromatic carbon–hydrogen bonds to expedite small-molecule diversification through coupling of molecular fragments 1 – 3 . Current approaches based on transition-metal-catalysed activation of carbon–hydrogen bonds are effective for the borylation of many (hetero)aromatic derivatives 4 , 5 but show narrow applicability to azines (nitrogen-containing aromatic heterocycles), which are key components of many pharmaceutical and agrochemical products 6 . Here we report an azine borylation strategy using stable and inexpensive amine-borane 7 reagents. Photocatalysis converts these low-molecular-weight materials into highly reactive boryl radicals 8 that undergo efficient addition to azine building blocks. This reactivity provides a mechanistically alternative tactic for sp 2 carbon–boron bond assembly, where the elementary steps of transition-metal-mediated carbon–hydrogen bond activation and reductive elimination from azine-organometallic intermediates are replaced by a direct, Minisci 9 -style, radical addition. The strongly nucleophilic character of the amine-boryl radicals enables predictable and site-selective carbon–boron bond formation by targeting the azine’s most activated position, including the challenging sites adjacent to the basic nitrogen atom. This approach enables access to aromatic sites that elude current strategies based on carbon–hydrogen bond activation, and has led to borylated materials that would otherwise be difficult to prepare. We have applied this process to the introduction of amine-borane functionalities to complex and industrially relevant products. The diversification of the borylated azine products by mainstream cross-coupling technologies establishes aromatic amino-boranes as a powerful class of building blocks for chemical synthesis. Selective borylation of azines—nitrogen-containing aromatic heterocycles used in the synthesis of many pharmaceuticals—is made possible by forming a radical from an aminoborane using a photocatalyst.

Human spermine oxidase (hSMOX) plays a central role in polyamine catabolism. Due to its association with several pathological processes, including inflammation and cancer, hSMOX has garnered interest as a possible therapeutic target. Therefore, determination of the structure of hSMOX is an important step to enable drug discovery and validate hSMOX as a drug target. Using insights from hydrogen/deuterium exchange mass spectrometry (HDX-MS), we engineered a hSMOX construct to obtain the first crystal structure of hSMOX bound to the known polyamine oxidase inhibitor MDL72527 at 2.4 Å resolution. While the overall fold of hSMOX is similar to its homolog, murine N 1-acetylpolyamine oxidase (mPAOX), the two structures contain significant differences, notably in their substrate-binding domains and active site pockets. Subsequently, we employed a sensitive biochemical assay to conduct a high-throughput screen that identified a potent and selective hSMOX inhibitor, JNJ-1289. The co-crystal structure of hSMOX with JNJ-1289 was determined at 2.1 Å resolution, revealing that JNJ-1289 binds to an allosteric site, providing JNJ-1289 with a high degree of selectivity towards hSMOX. These results provide crucial insights into understanding the substrate specificity and enzymatic mechanism of hSMOX, and for the design of highly selective inhibitors. Rational engineering of human spermine oxidase yields crystallizable structures and the design of an allosteric inhibitor.

The synthesis of functionalized nitrogen heterocycles is integral to discovering, manufacturing and evolving high-value materials. The availability of effective strategies for heterocycle synthesis often biases the frequency of specific ring systems over others in the core structures of bioactive leads. For example, while the six- and five-membered piperidine and pyrrolidine are widespread in medicinal chemistry libraries, the seven-membered azepane is essentially absent and this leaves open a substantial area of three-dimensional chemical space. Here we report a strategy to prepare complex azepanes from simple nitroarenes by photochemical dearomative ring expansion centred on the conversion of the nitro group into a singlet nitrene. This process is mediated by blue light, occurs at room temperature and transforms the six-membered benzenoid framework into a seven-membered ring system. A following hydrogenolysis provides the azepanes in just two steps. We have demonstrated the utility of the strategy with the synthesis of several azepane analogues of piperidine drugs. While saturated N-heterocycles are widespread motifs in drug discovery, the seven-membered ring azepane is highly underrepresented. Now nitroarenes have been validated as competent substrates for azepane synthesis through conversion into singlet nitrenes for ring enlargement via N insertion and hydrogenolysis. This enables a highly versatile access towards polysubstituted azepanes in just two steps.

Alkenes are found in a great number of biologically active molecules and are employed in numerous transformations in organic chemistry. Many olefins exist as E or higher energy Z isomers. Catalytic procedures for stereoselective formation of alkenes are therefore valuable; nonetheless, methods for synthesis of 1,2-disubstituted Z olefins are scarce. Here we report catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and allylic amides, employed thus far only in E-selective processes; the corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. Transformations, promoted by catalysts that contain the highly abundant and inexpensive molybdenum, are amenable to gram scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. Utility is demonstrated by syntheses of anti-oxidant C18 (plasm)-16:0 (PC), found in electrically active tissues and implicated in Alzheimer’s disease, and the potent immunostimulant KRN7000.