Total syntheses of three structurally complex marine natural products, manzamine A, ircinol A, and ircinal A, are reported. The route pivoted on the construction of a late-stage protecting-group-free pentacyclic enol triflate coupling partner, from which all three family members were accessed divergently via palladium-catalyzed reactions. The rapid synthesis of this key pentacyclic enol triflate was achieved by a highly convergent union of five fragments through a stereoselective Michael addition, a three-component nitro-Mannich lactamization cascade, an unprecedented and highly stereoselective reductive nitro-Mannich cyclization cascade, a stereoselective organometallic addition, and a Z-selective alkene ring-closing metathesis. Altogether this chemistry has allowed the shortest synthetic route to date for manzamine A (18-step longest linear sequence) via a late-stage diversification point that is ideal for future manzamine A analogue synthesis.
A new chemoselective reductive nitro-Mannich cyclization reaction sequence of nitroalkyl-tethered lactams has been developed. Relying on the rapid and chemoselective iridium(I)-catalyzed reduction of lactams to the corresponding enamine, subsequent nitro-Mannich cyclization of tethered nitroalkyl functionality provides direct access to important alkaloid natural-product-like structures in yields up to 81 % and in diastereoselectivities that are typically good to excellent. An in-depth understanding of the reaction mechanism has been gained through NMR studies and characterization of reaction intermediates. The new methodology has been applied to the total synthesis of (±)-epi-epiquinamide in four steps.
The enantioselective synthesis of heavily decorated spirolactams has been accomplished via an arylative or vinylative allene carbocyclisation cascade. Mediated by silver phosphate, a range of allene-linked pro-nucleophiles and aryl or vinyl iodides were reacted in the presence of catalytic Pd(OAc)2 and chiral bis(oxazoline) ligands to afford the spirolactam products in good yields and high enantio- and diastereoselectivities.
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