Strychnine as Target, Samarium Diiodide as Tool: A Personal Story

Abstract

Strychnine stands out from the group of classical natural products as one of the first complex compounds to be isolated in pure form and an extreme challenge to be structurally characterized. It has played a central role in natural product total syntheses and the surge in the development of innovative synthetic methods for many decades. Recently, we have accomplished one of the shortest formal total syntheses of strychnine (in ten steps and 14% overall yield or even shorter in eight steps and 10% overall yield). The evolution of a productive synthetic strategy, as well as the synthetic challenges tackled, are described here in detail, including examples of related transformations. The successful synthetic strategy was inspired by the premise that the core structure could be derived from simple aromatic indole precursors by a reductive SmI2 -induced ketyl-aryl coupling. Other key reactions included a diastereoselective reduction and a regioselective elimination protocol. Altogether one of the shortest syntheses of iso-strychnine and hence of strychnine was established.

Diastereoselective Dearomatizing Cyclizations of 5‐Arylpentan‐2‐ones by Samarium Diiodide – A Computational Analysis

“…[35,36] A recent study reports the use of chiral HMPA analogs resulting in highly enantioselective cyclization reactions of indole derivatives, however the generality of this method has still to be demonstrated. [37] Our broad experimental investigations of the cyclizations of indole derivatives [38][39][40][41] were assisted by density functional theory (DFT) calculations which demonstrated the necessity of the incorporation of explicit solvent ligands at the metal center of SmI 2 (THF) 5 . [42] To account for the experimentally observed diastereoselectivity, a chelated complex was proposed where two carbonyl oxygen atoms of the substrate are involved to bind to the samarium center.…”

“…Our broad experimental investigations of the cyclizations of indole derivatives [38–41] were assisted by density functional theory (DFT) calculations which demonstrated the necessity of the incorporation of explicit solvent ligands at the metal center of SmI 2 (THF) 5 [42] . To account for the experimentally observed diastereoselectivity, a chelated complex was proposed where two carbonyl oxygen atoms of the substrate are involved to bind to the samarium center.…”

“For Its Size, the Most Complex Natural Product Known.” Who Deserves Credit for Determining the Structure of Strychnine?

“…Our initial understanding of the chemistry community’s allocation of credit for this achievement comes directly from what has been reported in the literature: some cite Robinson as the sole discoverer; − others cite Woodward, , and yet others cite both , or are ambivalent. − While the patent laws in various countries have their own idiosyncratic rules regarding inventorship, often with policies that have changed over time, there are no such standards for discoverers of scientific phenomena. In contrast, various professional societies have codes dealing with authorship criteria for scientific publications. , …”

A simple and efficient method for constructing azocino[4,3-b]indole

“…1). [9][10][11][12] These structures are two important classes of compounds and have been widely found in biolo-gically active molecules and drug candidates. Moreover, diversely functionalized azocino [4,3b]indoline skeletons have also been versatile synthetics in bioactive molecules.…”