Synthesis and Neurotrophic Activity Studies of Illicium Sesquiterpene Natural Product Analogues.

Neurotrophic natural products hold potential as privileged structures for the development of therapeutic agents against neurodegeneration. However, only a few studies have been conducted to investigate a common pharmacophoric motif and structure-activity relationships (SARs). Here, an investigation of structurally more simple analogues of neurotrophic sesquiterpenes of the illicium family is presented. A concise synthetic route enables preparation of the carbon framework of (±)-Merrilactone A and (±)-Anislactone A/B on a gram scale. This has allowed access to a series of structural analogues by modification of the core structure, including variation of oxidation levels and alteration of functional groups. In total, 15 derivatives of the natural products have been synthesized and tested for their neurite outgrowth activities. Our studies indicate that the promising biological activity can be retained by structurally simpler natural product analogues, which are accessible by a straightforward synthetic route.

Synthesis of Lactones via C-H Functionalization of Nonactivated C(sp3)-H Bonds.

An electron-deficient amide is utilized as a directing group to functionalize nonactivated C(sp3)-H bonds through radical 1,5-hydrogen abstraction. The γ-bromoamides formed are subsequently converted to γ-lactones under mild conditions. The method described is not limited to tertiary and secondary positions but also allows functionalization of primary nonactivated sp3-hybridized positions in a one-pot sequence. In addition, the broad functional group tolerance renders this method suitable for the late-stage introduction of γ-lactones into complex carbon frameworks.

Synthesis of ramariolide natural products and discovery of their targets in mycobacteria.

Ramariolides A-D are natural products with antibacterial activity. To exploit their cellular mechanism, we here devise the first total synthesis and prepare a photoprobe for target identification. Antibacterial testing against several pathogenic strains including Mycobacterium tuberculosis revealed the highest potency for ramariolide A. Chemical proteomics unraveled binding to essential proteins for amino acid anabolism.

A six-step total synthesis of α-thujone and d6-α-thujone, enabling facile access to isotopically labelled metabolites.

The short synthesis of α-thujone relies on the functionalization of the readily available dimethylfulvene. Furthermore, the three main metabolites of the natural product were also synthesized. Since d6-acetone can be used as a starting material, the route developed allows for the facile incorporation of isotopic labels which are required for detecting and quantifying trace amounts via GC/MS analysis.