Is There No End to the Total Syntheses of Strychnine? Lessons Learned in Strategy and Tactics in Total Synthesis

Abstract

From the 19th century to the present, the complex indole alkaloid strychnine has engaged the chemical community. In this review, we examine why strychnine has been and remains today an important target for directed synthesis efforts. A selection of the diverse syntheses of strychnine is discussed with the aim of identifying their influence on the evolution of the strategy and tactics of organic synthesis.

R. B. Woodward, A Great Physical Organic Chemist

“…), as stated by Carl Djerassi in 1954 following the publication of the strychnine synthesis, was pronounced years before most of Woodward's greatest accomplishments. After Woodward, it took an additional nearly 40 years before the next total synthesis of strychnine was reported . What an amazing compliment to Woodward's synthetic achievement!…”

Metallacycle-mediated cross-coupling in natural product synthesis

“…175–185 Moving forward with the development of methods for Co-mediated [2+2+2] annulation between enynes and alkynes, Vollhardt’s group demonstrated the ability to employ an indole double bond in the annulation process and highlighted the application of this coupling chemistry in the context of a formal total synthesis of strychnine. 186, 187 As illustrated in Figure 59B, union of 149 with acetylene ( 71 ) delivered the tetracyclic product 150 in 46% yield.…”

Synthesis of the Strychnos Alkaloid (−)‐Strychnopivotine and Confirmation of its Absolute Configuration

“…However, to date, the absolute configuration of strychnopivotine has been uncertain, due to the absence of X‐ray crystal structure analyses of the natural compound. Despite its unusual structure and, unlike others alkaloids from this family, such as strychnine 2 , strychnopivotine has received little attention from the scientific community. Indeed, its biological activity has not been evaluated, and although some efforts towards the construction of its core structure have been reported, only one total synthesis of (±)‐strychnopivotine has been achieved, by the leading group of Padwa in 2008 .…”