Divergent Total Syntheses of Lyconadins A and C

Abstract

Divergent and concise total syntheses of two lycopodium alkaloids, lyconadins A and C have been developed. The synthesis of lyconadin A with potent neurotrophic activity features an efficient ketal deprotective formal aza-[4+2] cyclization to form the cage-like core structure. A ketal deprotective Mannich reaction was developed to build the tricyclic structure of lyconadin C. Both lyconadins A and C were synthesized from pivotal intermediate 14. Each step to the synthesis of intermediate 14 was conducted on gram-scale. Keywords total synthesis; lycopodium alkaloid; lyconadin; neurodegenerative disease; formal [4+2] cyclizationWhile advances in therapeutic methods and strategies for the treatment of neurodegenerative diseases have been relatively limited in the past several decades, there is increasingly strong evidence to suggest that naturally-occurring polypeptide neurotrophic factors, [1] such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) may be of significant therapeutic benefit in treating neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and Huntington's disease. [2] Unfortunately, these natural neurotrophic factors suffer from poor bioavailability and pharmacokinetics. In addition, direct administration to the brain is usually required. [3] Recently, small-molecule natural products have been identified to show activity for promoting the production of natural neurotrophic factors or functioning similarly as them for neuron growth and maintenance. [4] In comparison, small molecules are more likely to cross the blood brain barrier. Their potency, selectivity and pharmacological properties can be readily optimized through structural editing. [5] They may serve as valuable chemical probes as well. [6] In this context, we took note of the family of lycopodium alkaloids, which are enriched with molecules having neurotrophic activities. [7] Among them, lyconadins A (1) and B (2) (Figure 1), isolated by Kobayashi and co-workers, have been shown to enhance the mRNA expression for neurotrophic growth factor biosynthesis in 1321N1 human astrocytoma cells, suggesting that they may serve as promising lead compounds for anti-neurodegenerative drug discovery. [8] Structurally, lyconadin C (3) [9] and dihydrolycolucine (4) [10] share common motifs with lyconadins A (1) and B (2). In addition, lyconadin A has shown modest in vitro anti cancer cell proliferation activity. Their intriguing structural features and important biological activity have motivated many synthetic efforts directed toward their synthesis, [11] culminating in the elegant total syntheses of the lyconadins by Smith (lyconadins A and B), [12] Sarpong (lyconadin A), [13] Fukuyama (lyconadins A, B and C), [14] and Waters (lyconadin C). [15] In addition to the total syntheses of these challenging natural molecules, we are particularly interested in creating a focused small-molecule library based on these privileged structures in order to explore the related chemical sp...

Cutting-Edge and Time-Honored Strategies for Stereoselective Construction of C–N Bonds in Total Synthesis

“…In 2014, Dai and co-workers reported the concise total syntheses of two Lycopodium alkaloids, lyconadins A and C, featuring a tandem reductive amination/formal [4 + 2] cycloaddition (Scheme 153b). 635 Ketone 153-6 was treated with ammonium acetate and sodium cyanoborohydride to afford the primary amine, which was subsequently reacted with formaldehyde under acidic conditions to provide polycyclic ketone 153-9 in 68% yield. A stepwise approach to ketone 153-9 from 153-6 was pursued to probe the mechanism of this cascade reaction.…”

One-Carbon Insertion and Polarity Inversion Enabled a Pyrrole Strategy to the Total Syntheses of Pyridine-Containing Lycopodium Alkaloids: Complanadine A and Lycodine

“…Our interest in the chemical synthesis and biological study of natural products with neurotrophic activities led us to these Lycopodium alkaloids. In 2014, we reported the total syntheses of lyconadins A and C. 9 Herein we report our total syntheses of complanadine A (1) and lycodine (4).…”

Diversity-oriented synthesis of Lycopodium alkaloids inspired by the hidden functional group pairing pattern

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