Enantioselective Total Synthesis of (-)-Caldaphnidine O via a Radical Cyclization Cascade.

The synthetically challenging, diverse chemical skeletons and promising biological profiles of the Daphniphyllum alkaloids have generated intense interest from the synthetic chemistry community. Herein, the first and enantioselective total synthesis of (-)-caldaphnidine O, a complex bukittinggine-type Daphniphyllum alkaloid, is described. The key transformations in this concise approach included an intramolecular aza-Michael addition, a ring expansion reaction sequence, a Sm(II)/Fe(III)-mediated Kagan-Molander coupling, and the rapid formation of the entire hexacyclic ring skeleton of the target molecule via a radical cyclization cascade reaction, which was inspired by an unexpected radical detosylation observed in our recent dapholdhamine B synthesis.

Total Synthesis of Dapholdhamine B and Dapholdhamine B Lactone.

The intriguing structural complexity and bioactivities of the Daphniphyllum alkaloids have long attracted much attention. Herein, we report the first and enantioselective total synthesis of Daphniphyllum alkaloid dapholdhamine B and its lactone derivative. The chemical structure of dapholdhamine B contains a unique aza-adamantane core skeleton and eight contiguous stereocenters, including three contiguous fully substituted stereocenters, which present a formidable synthetic challenge. This concise approach used to achieve the first synthesis of an aza-adamantane natural product features a vinylogous Mannich reaction, an optimized α-bromo-α,ß-unsaturated ketone synthesis, a substrate-dependent intramolecular aza-Michael addition, a key annulation via amide activation, an SN2'-type lactonization, and a facile Horner-Wadsworth-Emmons reaction that converts the hemiacetal moiety to the corresponding homologated carboxylic acid.

Triptolide derivatives as potential multifunctional anti-Alzheimer agents: Synthesis and structure-activity relationship studies.

Owning to the promising neuroprotective profile and the ability to cross the blood-brain barrier, triptolide has attracted extensive attention. Although its limited solubility and toxicity have greatly hindered clinical translation, triptolide has nonetheless emerged as a promising candidate for structure-activity relationship studies for Alzheimer's disease. In the present study, a series of triptolide analogs were designed and synthesized, and their neuroprotective and anti-neuroinflammatory effects were then tested using a cell culture model. Among the triptolide derivatives tested, a memantine conjugate, compound 8, showed a remarkable neuroprotective effect against Aß1-42 toxicity in primary cortical neuron cultures as well as an inhibitory effect against LPS-induced TNF-α production in BV2 cells at a subnanomolar concentration. Our findings provide insight into the different pharmacophores that are responsible for the multifunctional effects of triptolide in the central nervous system. Our study should help in the development of triptolide-based multifunctional anti-Alzheimer drugs.