This review provides a comprehensive coverage of the history, biology and chemistry of tetrodotoxin (TTX). It traces the origin of this remarkable molecule all the way back to the ancient Chinese medicine records. The discovery of biological activity, isolation, and a brief overview of structure elucidation are summarized. Next, the biology of TTX is discussed, primarily in the context of its activity in the sodium channels, its anesthetic properties, and its potential use in cancer treatment or drug addiction. Biosynthesis of TTX is covered before the discussion of the total syntheses. All total, formal or partial syntheses are covered but those total syntheses that have been discussed in previous reviews are only briefly summarized. Finally, the synthesis of natural and unnatural derivatives is surveyed, and a conclusion and outlook are provided for this very extensive field of endeavor. To the best of our knowledge the literature coverage is complete up to December 2018.

Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method. Various substituents are tolerated on the amidine and the isocyanide, providing efficient access to a broad range of diversely substituted 4-aminoquinazolines of significant pharmaceutical interest.

This Review traces the discovery of the Wittig-Still rearrangement and its applications in organic synthesis. Its relationship to Wittig rearrangements is discussed along with detailed analysis of E/Z- and diastereoselectivity. Modifications of the products arising from the Wittig-Still rearrangement are reviewed in the context of increased complexity in intermediates potentially useful in target-oriented synthesis. Early applications of the Wittig-Still rearrangement to modifications of steroids are reviewed as are applications to various terpene and alkaloid natural product targets and miscellaneous compounds. To the best of our knowledge, the literature is covered through December 2016.

Graphical abstract

Selagibenzophenone A (1) and its isomer selagibenzophenone B (2) were recently described as natural products from Selaginella genus plants with PDE4 inhibitory activity. Herein, we report the first total syntheses of both compounds. By comparing spectroscopic data of the synthetic compounds with reported data for the isolated material, we demonstrate that the structure of one of the two natural products was incorrectly assigned, and that in fact isolated selagibenzophenone A and selagibenzophenone B are identical compounds. The synthetic strategy for both 1 and 2 is based on a cross-coupling reaction and on the addition of organometallic species to assemble the framework of the molecules. Identifying a suitable starting material with the correct substitution pattern is crucial because its pattern is reflected in that of the targeted compounds. These syntheses are finalized via global deprotection. Protecting the phenols as methoxy groups provides the possibility for partial control over the selectivity in the demethylation thanks to differences in the reactivity of the various methoxy groups. Our findings may help in future syntheses of derivatives of the biologically active natural product and in understanding the structure–activity relationship.