Retrosynthetic strategies and their impact on synthesis of arcutane natural products.

Retrosynthetic analysis is a cornerstone of modern natural product synthesis, providing an array of tools for disconnecting structures. However, discussion of retrosynthesis is often limited to the reactions used to form selected bonds in the forward synthesis. This review details three strategies for retrosynthesis, focusing on how they can be combined to plan the synthesis of polycyclic natural products, such as atropurpuran and the related arcutane alkaloids. Recent syntheses of natural products containing the arcutane framework showcase how these strategies for retrosynthesis can be combined to plan the total synthesis of highly caged scaffolds. Comparison of multiple syntheses of the same target provides a unique opportunity for detailed analysis of the impact of retrosynthetic disconnections on synthesis outcomes.

Total Synthesis of the Diterpenoid Alkaloid Arcutinidine Using a Strategy Inspired by Chemical Network Analysis.

Arcutinidine and other arcutinidine-type diterpenoid alkaloids feature an intricate polycyclic, bridged framework with unusual connectivity. A chemical network analysis approach to the arcutane skeleton enabled the identification of highly simplifying retrosynthetic disconnections, which indicated that the caged structure could arise from a simpler fused ring system. On this basis, a total synthesis of arcutinidine is reported herein, featuring an unprecedented oxopyrrolium Diels-Alder cycloaddition which furnishes a key tetracyclic intermediate. In addition, the synthesis utilizes a diastereoselective oxidative dearomatization/cycloaddition sequence and a SmI2-mediated C-C coupling to forge the bridged framework of the natural products. This synthetic plan may also enable future investigations into the biosynthetic relationships between the arcutanes, the related diterpenoid atropurpuran, and other diterpenoid alkaloids.

Recent advances in acetylcholinesterase Inhibitors and Reactivators: an update on the patent literature (2012-2015).

INTRODUCTION: Acetylcholinesterase (AChE) is the major enzyme that hydrolyzes acetylcholine, a key neurotransmitter for synaptic transmission, into acetic acid and choline. Mild inhibition of AChE has been shown to have therapeutic relevance in Alzheimer's disease (AD), myasthenia gravis, and glaucoma among others. In contrast, strong inhibition of AChE can lead to cholinergic poisoning. To combat this, AChE reactivators have to be developed to remove the offending AChE inhibitor, restoring acetylcholine levels to normal. Areas covered: This article covers recent advances in the development of acetylcholinesterase modulators, including both inhibitors of acetylcholinesterase for the efforts in development of new chemical entities for treatment of AD, as well as re-activators for resurrection of organophosphate bound acetylcholinesterase. Expert opinion: Over the past three years, research efforts have continued to identify novel small molecules as AChE inhibitors for both CNS and peripheral diseases. The more recent patent activity has focused on three AChE ligand design areas: derivatives of known AChE ligands, natural product based scaffolds and multifunctional ligands, all of which have produced some unique chemical matter with AChE inhibition activities in the mid picomolar to low micromolar ranges. New AChE inhibitors with polypharmacology or dual inhibitory activity have also emerged as highlighted by new AChE inhibitors with dual activity at L-type calcium channels, GSK-3, BACE1 and H3, although most only show low micromolar activity, thus further research is warranted. New small molecule reactivators of organophosphate-inhibited AChE have also been disclosed, which focused on the design of neutral ligands with improved pharmaceutical properties and blood-brain barrier (BBB) penetration. Gratifyingly, some research in this area is moving away from the traditional quaternary pyridinium oximes AChE reactivators, while still employing the necessary reactivation group (oximes). However, selectivity over inhibition of native AChE enzyme, effectiveness of reactivation, broad-spectrum reactivation against multiple organophosphates and reactivation of aged-enzyme continue to be hurdles for this area of research.