Total Synthesis of Taxol Enabled by Inter‐ and Intramolecular Radical Coupling Reactions

Imamura, Yusuke; Takaoka, Kyohei; Komori, Yuma; Nagatomo, Masanori; Inoue, M.

doi:10.1002/anie.202219114

Cited by 13 publications

(5 citation statements)

References 78 publications

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“…Without doubt, many more currently unimaginable innovations in taxane synthesis will be reported from laboratories worldwide in the future. 217…”

Section: Discussionmentioning

confidence: 99%

“…It is also important to note that the hundreds of taxoids and other cyclooctanoids recently isolated have provided an opportunity to evaluate the strategies and lessons learned in the construction of Taxol. Without doubt, many more currently unimaginable innovations in taxane synthesis will be reported from laboratories worldwide in the future …”

Section: Discussionmentioning

confidence: 99%

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Strategies and Lessons Learned from Total Synthesis of Taxol

et al. 2023

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Taxol (paclitaxel), the most well-known taxane diterpenoid, is the best-selling natural-source anticancer drug ever produced and one of the most common prescriptions in the treatment of breast, lung, and ovarian cancers, saving countless lives around the world. Structurally, Taxol possesses a highly oxygenated [6−8−6−4] core bearing 11 stereocenters, seven of which are contiguous chiral centers. Moreover, the extremely strained bicyclo[5.3.1] undecane ring system with a bridgehead double bond is a unique structural feature. All these features make Taxol a highly challenging synthetic target. Tremendous synthetic efforts from more than 60 research groups around the world have already culminated in ten total syntheses and three formal syntheses, as well as more than 60 synthetic model studies of Taxol. This review is intended to provide a long-overdue appraisal of the great achievements in the total syntheses of Taxol reported in the last few decades. In doing so, we summarize the development of synthesis toward Taxol from 1994 to 2022, including the evolution of synthetic strategy for accessing this complex molecular scaffold and key lessons learned from such endeavors. Finally, we briefly discuss the future of the research in this area.

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“…Without doubt, many more currently unimaginable innovations in taxane synthesis will be reported from laboratories worldwide in the future. 217…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Strategies and Lessons Learned from Total Synthesis of Taxol

et al. 2023

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“…Thus, a combination of radical and ionic chemistry was employed for the synthesis of this intricate structural network of taxol ( 9.7 ) (Scheme 10). [55] …”

Section: Radical Chemistry In Total Synthesis Of Pharmaceuticalsmentioning

confidence: 99%

Growing Utilization of Radical Chemistry in the Synthesis of Pharmaceuticals

Gupta

Laha

2023

The Chemical Record

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Our current unhealthy lifestyle and the exponential surge in the population getting affected by a variety of diseases have made pharmaceuticals or drugs an imperative part of life, making the development of innovative strategies for drug discovery or the introduction of refined, cost‐effective and modern technologies for the synthesis of clinically used drugs, a need of the hour. Ever since their discovery, free radicals and radical cations or anions as reactive intermediates have captivated the chemists, resulting in an exceptional utilization of these moieties throughout the field of chemical synthesis, owing to their unprecedented and widespread reactivity. Sticking with the idea of not judging the book by its cover, despite the conventional thought process of radicals being unstable and difficult to control entities, scientists and academicians around the globe have done an appreciable amount of work utilizing both persistent as well as transient radicals for a variety of organic transformations, exemplifying them with the synthesis of significant biologically active pharmaceutical ingredients. This review truly accounts for the organic radical transformations including radical addition, radical cascade cyclization, radical/radical cross‐coupling, coupling with metal‐complexes and radical cations coupling with nucleophiles, that offers fascinating and unconventional approaches towards the construction of intricate structural frameworks of marketed APIs with high atom‐ and step‐economy; complementing the otherwise employed traditional methods. This tutorial review presents a comprehensive package of diverse methods utilized for radical generation, featuring their reactivity to form critical bonds in pharmaceutical total synthesis or in building key starting materials or intermediates of their synthetic journey, acknowledging their excellence, downsides and underlying mechanisms, which are otherwise poorly highlighted in the literature. Despite great achievements over the past few decades in this area, many challenges and obstacles are yet to be unraveled to shorten the distance between the academics and the industry, which are all discussed in summary and outlook.

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“…In 2023, we developed a new radical-based strategy for stereoselective assembly of ABC-ring 2 and achieved a total synthesis of 1 in 34 steps from 2,2-dimethylcyclohexane-1,3-dione ( 6 ) (0.0095% overall yield) . A photoinduced intermolecular radical reaction in the presence of Pt-doped TiO 2 forged the C8–C9 bond of 3 , leading to the coupling of A-ring fragment 5 and C-ring fragment 4 . , After installation of the C8-quaternary stereocenter, the reductive radical reaction was induced with a low-valent titanium reagent to cyclize the central B-ring by linking the C1–C2 bond of 2 .…”

Section: Introductionmentioning

confidence: 99%

Total Synthesis of Taxol Enabled by Intermolecular Radical Coupling and Pd-Catalyzed Cyclization

Watanabe,

Oga,

Matoba

et al. 2023

J. Am. Chem. Soc.

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Taxol (1) is a clinically used antineoplastic diterpenoid. The tetracyclic ring system comprises a 6/8/6-membered carbocycle (ABC-ring) and a fused oxetane ring (D-ring) embedded with a bridgehead double bond and decorated with multiple oxygen functionalities. Here, we report a convergent total synthesis of this exceedingly complex natural product. The C-ring fragment was designed to possess a bromocyclohexenone and an extra tetrahydrofuran ring to control the reactivity and selectivity, as well as to minimize functional group manipulations en route to 1. The α-alkoxyacyl telluride of the A-ring served as a radical precursor, and intermolecular radical coupling with the C-ring realized the installation of the C2- and C3-stereocenters and reductive removal of the bromide. After the C8-quaternary stereocenter was constructed by exploiting the three-dimensional shape of the intermediate, the C11-vinyl triflate of A-ring and the C8-methyl ketone of C-ring were utilized for Pd(0)-catalyzed cyclization of the central eight-membered B-ring with the bridgehead olefin. Adjustment of the oxidation level and attachment of the oxetane D-ring completed the total synthesis of 1 (28 steps, as the longest linear sequence). The fragment design principle and implementation of the powerful radical coupling reaction described in the present synthesis provide valuable information for planning and executing syntheses of diverse densely oxygenated terpenoids.

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Total Synthesis of Taxol Enabled by Inter‐ and Intramolecular Radical Coupling Reactions

Cited by 13 publications

References 78 publications

Strategies and Lessons Learned from Total Synthesis of Taxol

Strategies and Lessons Learned from Total Synthesis of Taxol

Growing Utilization of Radical Chemistry in the Synthesis of Pharmaceuticals

Total Synthesis of Taxol Enabled by Intermolecular Radical Coupling and Pd-Catalyzed Cyclization

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