Total Syntheses of Lyconadins A–C

Abstract

The total synthesis of the Lycopodium alkaloid lyconadin A was accomplished and it was applied to the total syntheses of the related congeners, lyconadins B and C. Lyconadin A has attracted attention as a challenging target for total synthesis due to the unprecedented pentacyclic skeleton. Our synthesis of lyconadin A features a facile construction of the highly fused tetracyclic skeleton through a combination of an aza-Prins reaction and an electrocyclic ring opening, followed by formation of a C-N bond. Transformation of the bromoalkene moiety of the tetracycle to a key enone intermediate was extensively investigated, and three methods via sulfide, oxime, or azide intermediates were established. A pyridone ring was constructed from the key enone intermediate to complete the synthesis of lyconadin A. A dihydropyridone ring could also be formed from the same enone intermediate, leading to a synthesis of lyconadin B. Establishment of the conditions for an electrocyclic ring opening without formation of the C-N bond resulted in completion of the total synthesis of lyconadin C.

Morphological Evaluation of Nonlabeled Cells to Detect Stimulation of Nerve Growth Factor Expression by Lyconadin B

“…The total synthesis of lyconadin B has recently been described; this molecule is a member of the lycopodium alkaloid family of compounds, which are related in that they regulate various biological responses. [10][11][12] NGF, the molecule stimulated by lyconadin B, regulates the differentiation, survival, and growth of neurons and plays central role in neurological diseases such as Alzheimer and Parkinson diseases. Rescuing cholinergic neurons by inducing NGF is a promising strategy for the treatment of Alzheimer disease.…”

From Amino Acids to Nature-Inspired Molecular Scaffolds: Incorporation of Medium-Sized Bridged Heterocycles into a Peptide Backbone

“…In this research article, we report the synthesis of diverse bridged molecular scaffolds (XV-XIX) using seven-membered endocyclic N-acyliminium ions (XIV) as the key intermediates in a complexity-generating synthetic route that is compatible with the traditional Merrifield synthesis of peptides on solid supports ( Figure 2). These bridged scaffolds possess complex 3D structures contained in several natural products such as gelsemoxonine (XX), 35 lyconadins (XXI), 36 and indol alkaloids such as geleganimine (XXII) 37 and actinophyllic acid (XXIII). 38 Target molecular scaffolds were prepared from acyclic precursors containing an acetal-protected aldehyde attached via a three-carbon spacer to an amide nitrogen and an internal nucleophile present on various amino acids (XIII, Figure 2).…”

Divergent Total Syntheses of Lyconadins A and C

“…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 space and identify new molecules for anti-neurodegenerative agent development.…”

“…We were able to convert 16 to lyconadin A following a slightly modified Fukuyama-Yokoshima pyridone synthesis protocol. [14] …”