Total Synthesis of (±)-Lycojaponicumin D and Lycodoline-Type Lycopodium Alkaloids

Abstract

Lycopodium alkaloids with structural diversity and biological significance have been stimulating an increasing interest in the synthetic and medicinal communities, in which inspiration and exploration of their related biogenetic relationship generally constitute one of the major concerns. Driven by the plausible biogenetic entry to lycojaponicumin D as the first member of Lycopodium alkaloids having a structurally unusual C3-C13-linked scaffold, a new connection with lycodoline has been proposed and discovered on the basis of the design of an unprecedented bioinspired tandem fragmentation/Mannich reaction. Initiated by expeditious assembly of bridgehead heterofunctionalization in the [3.3.1] bicyclic system of lycodoline, a novel tandem palladium-mediated oxidative dehydrogenation/hetero-Michael reaction has been developed for the strain-driven formation of the C-heteroatom bond, leading to a new approach to conformationally rigid bridgehead heteroquaternary carbons. The present unified strategy provides a scenario for the divergent total syntheses of nine natural Lycopodium alkaloids and four unnatural C12 epimers, wherein (±)-lycojaponicumin D and six lycodoline-type alkaloids have been synthetically achieved for the first time.

Recent Development in Palladium-Catalyzed Domino Reactions: Access to Materials and Biologically Important Carbo- and Heterocycles

“…A different approach, which can be considered a pseudo-domino process, was employed as key step in the asymmetric synthesis of (−)-α-lycorane, (−)-zephyranthine, and a formal total synthesis of (+)-clivonine . Using a different approach, the synthesis of the [3.3.1]-bicyclic system of Lycopodium alkaloids was achieved by a complex domino palladium-mediated oxidative dehydrogenation/​hetero-Michael . Another general method for the synthesis of 1-difluoroalkyl isoquinolines took place in the palladium-catalyzed radical cascade difluoroalkylation-cyclization of vinyl isocyanides with bromodifluoroacetic derivatives …”

“…131 Using a different approach, the synthesis of [3.3.1]-bicyclic system of Lycopodium alkaloids was achieved by a complex domino palladium-mediated oxidative dehydrogenation/hetero-Michael. 132 Another general method for the synthesis of 1-difluoroalkyl isoquinolines took place in the palladium-catalyzed radical cascade difluoroalkylation-cyclization of vinyl isocyanides with bromodifluoroacetic derivatives. 133…”

“…131 Using a different approach, the synthesis of the [3.3.1]-bicyclic system of Lycopodium alkaloids was achieved by a complex domino palladium-mediated oxidative dehydrogenation/hetero-Michael. 132 Another general method for the synthesis of 1difluoroalkyl isoquinolines took place in the palladiumcatalyzed radical cascade difluoroalkylation-cyclization of vinyl isocyanides with bromodifluoroacetic derivatives. 133 This palladium-promoted addition of boronic acids to nitriles was also employed in a novel and efficient protocol for the synthesis of various 2,4-disubstituted, 1,2,4-trisubstituted, and 1,2,4,5-tetra-substituted imidazoles, which are common motifs in many molecules with interesting bioactivities.…”

Manganese-Catalyzed Intermolecular Oxidative Annulation of Alkynes with γ-Vinyl Aldehydes: An Entry to Bridged Carbocyclic Systems

“…Bridged carbocyclic systems, including bridged bicyclic and tricyclic carbocycles, are unique structural motifs that widely exist in numerous natural products, pharmaceuticals, and other bioactive molecules (Scheme ). , For example, trichagmalin A and xyloccensins, − which were isolated from the leaves of Cedrela odorata or the fruits of the Chinese mangrove plant, are constituted by an octahydro-1 H -2,4-methanoindene skeleton. Other natural products, including spirovibsanin A, , hyperforin, − α-cedrene, (−)-huperzine A, − and lycodoline, , all feature a bicyclo[2.3.2]­nonane ring system.…”

“…Other natural products, including spirovibsanin A, , hyperforin, − α-cedrene, (−)-huperzine A, − and lycodoline, , all feature a bicyclo[2.3.2]­nonane ring system. Furthermore, bridged carbocyclic systems have a multitude of applications in the organic and medicinal community, including use as chiral ligands and versatile synthetic intermediates. , Efficient construction of a bridged dicarbocyclic or tricarbocyclic framework is therefore in demand and has attracted ongoing interest from scientific researchers. ,, However, the majority of strategies for selectively building such frameworks are restricted to the intramolecular fashion with unavailable limited substrates via multiple synthetic steps, and an alternative one-step entry that allows the divergent construction of different bridged cyclic systems from simple starting materials is very challenging.…”