Nickel-catalyzed reactions natural products synthesis

Tubular Fixed-Bed Reactors. Bundles of downflow reactor tubes filled with catalyst and surrounded by heat-transfer media are tubular fixed-bed reactors. Such reactors are used most notably in steam reforming and phthaUc anhydride manufacture. Steam reforming is the reaction of light hydrocarbons, preferably natural gas or naphthas, with steam over a nickel-supported catalyst to form synthesis gas, which is primarily and CO with some CO2 and CH. Additional conversion to the primary products can be obtained by iron oxide-catalyzed water gas shift reactions, but these are carried out ia large-diameter, fixed-bed reactors rather than ia small-diameter tubes (65). The physical arrangement of a multitubular steam reformer ia a box-shaped furnace has been described (1). 

While transition metal-catalyzed hydroboration is a well-established reaction, the same cannot be said for the transition metal-catalyzed hydroalumination. The synthetic utility of this reaction is only just beginning to emerge. Lautens has led the way in the use of hydroaluminations as the key step in the total synthesis of complex natural products. The synthesis of the anti-depressant sertraline130 involved the formation of the tetrahydronaphthalene core, and this is best achieved using the nickel-catalyzed hydroalumination of oxabicyclic alkenes (Table 16). 

In 2012, Yamaguchi, Itami, and coworkers [43] reported the first nickel-catalyzed decarboxylation C-H biaryl coupling of azoles with aryl esters. No stoichiometric oxidants or expensive catalysts were needed to perform this reaction. This methodology was successfully applied for the convergent formal synthesis of Muscoride A (a natural product with antibacterial activity) (Scheme 3.26). The flexibility of this approach will likely enable the preparation of a series of analogs of the Muscoride family [44]. 

Other important molecules that are useful intermediates in the synthesis of natural products are chiral diols. anli-l,2-Diols of type 30 were obtained in good yields (75-85%) and moderate to good diastereoselectivity (76-96% de) by a nickel-catalyzed three-component addition of a-silyloxy aldehydes 27, alkynyl silanes 28a, and reduction with triisopropyl silane (29a) (Scheme 11.11) [31]. The diastereoselectivity of this process could be explained by the Felkin model. Alternatively, a chiral alkynyl derivative can control the outcome of the reaction. Thus, the coupling of optically active, oxazolidinone-derived ynamides, aldehydes, and silane as reducing agent led to the formation of y-siloxyenamide derivatives with diastereoselectivities up to 99% [32]. 

The [2 -I- 2 -I- 2] cycloaddition reaction was used successMly in the synthesis of the sesquiterpene alkaloid illudinine (Scheme 2.6) [5], The terminal diyne 27 bearing a gm-dimethyl group in the backbone successfully undergoes a nickel-catalyzed cycloaddition reaction with protected homopropargyl amine 28 to afford cycloadduct 29. This intermediate (29) was converted successfully to the natural product illudinine 30 in five simple steps. 

Azanickelacycle formation with partial replacement of the heterocyclic moiety substance by the nickel catalyst was also employed for the synthesis of indoles, an important class of heterocycles found in natural products and pharmaceuticals. Maizum et al. demonstrated a nickel-catalyzed decarbonylative cycloaddition by which anthranilic acid derivatives 39, which are readily available, react with alkynes to afford substituted indoles 41 (Scheme 12.17) [20]. The reaction is supposed to proceed via oxidative addition and decarbonylation to afford azanickelacycle 40, followed by alkyne insertion, 1,3-acyl migration, and reductive elimination, to afford A-pivaloyl-protected indole 41. Deprotected indole 42 was obtained as the final product upon workup, that is, treatment of the reaction crude reaction mixture with NaSMe in MeOH. 

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