Total Synthesis of Tagetitoxin

Abstract

The intriguing structure of tagetitoxin (1), a long-standing challenge in natural product synthesis, has been the subject of multiple revisions and has been confirmed through total synthesis. The route commences from a renewable furan starting material and features a number of unusual transformations (such as rearrangements, bromocyclization, and P(V)-based phosphate installation) to arrive at the target in 15 steps. As the route was designed to enable access to both enantiomers, the absolute configuration of the natural product could be assigned using a bioassay on (+)-1 and (−)-1.

Nature Chose Phosphates and Chemists Should Too: How Emerging P(V) Methods Can Augment Existing Strategies

“…Specifically, the synthesis of the highly complex and polar natural product tagetitoxin, a decades-old unanswered puzzle for the field, was enabled by Ψ reagents. 74 Some of the most difficult aspects of this synthesis were the incorporation of phosphorus at the right stage, the determination of the absolute configuration of the natural product, and the purification of noncrystalline intermediates ( Figure 5 B). The use of conventional P(III) and P(V) reagents for this purpose were only met with failure due to either a lack of chemoselectivity or reactivity.…”

“…As a result, the synthesis could be completed and the absolute configuration could be assigned using a biochemical assay. 74 The lessons learned in these strikingly different scenarios led to more daring applications of the P(V) platform.…”

Nucleophilic Ring‐Opening of 1,6‐Anhydrosugars: Recent Advances and Applications in Organic Synthesis

“…tagetis, the structure of tagetitoxin has been conclusively settled through total synthesis by the group of Baran, explaining in part why the natural product proved elusive to synthesis for so many years. [26] In 2009, the synthetic strategy reported by the group of Porter [27] focusing on the construction of a 9-oxa-3-thiabicyclo[3.3.1] nonane skeleton was designed on the basis of the incorrect structure assignment proposed by Mitchell et al in 1989. [28] Attempts to synthesize tagetitoxin and its non-natural decarboxy analogue hinged on the acetylide ring-opening of 2,4-di-O-triethylsilyl derivatives of 1,6-anhydro-5-C-vinylglucose and 1,6-anhydroglucose, respectively (Scheme 8b).…”

“…In 2020, almost forty years after its isolation from Pseudomonas syringae pv. tagetis , the structure of tagetitoxin has been conclusively settled through total synthesis by the group of Baran, explaining in part why the natural product proved elusive to synthesis for so many years [26] . In 2009, the synthetic strategy reported by the group of Porter [27] focusing on the construction of a 9‐oxa‐3‐thiabicyclo[3.3.1]nonane skeleton was designed on the basis of the incorrect structure assignment proposed by Mitchell et al.…”

Mild and Chemoselective Phosphorylation of Alcohols Using a PSI-Reagent

“…11 However, like all known methods it suffers from a lack of chemoselectivity (in this case free amines are not tolerated). The recently disclosed P(V)-based -platform for the construction of P-linkages has been applied to the simplified synthesis of an ever growing, diverse range of compounds such as: cyclic dinucleotides, 12,13 stereopure anti-sense oligonucleotides, 12 methylphosphonates, 14 chiral phosphines, 14 DNA 5 and protein bioconjugates, 16 complex alkaloids, 17 and fully chemically modified oligonucleotides using a commercial automated synthesizer. 18 As part of the ongoing -platform development,  O (1) was identified as a suitable reagent for forging phosphodiester bonds.…”