Synthesis and Biological Evaluation of 12,13-Cyclopropyl and 12,13-Cyclobutyl Epothilones

Nicolaou, K. C.; Namoto, Kenji; Li, Jim; Ritzén, Andreas; Ulven, Trond; Shoji, Mitsuru; Zaharevitz, Dan; Gussio, Rick; Sackett, Dan L.; Ward, Rita D.; Hensler, Anne; Fojo, Tito; Giannakakou, Paraskevi

doi:10.1002/1439-7633(20010105)2:1<69::aid-cbic69>3.0.co;2-8

Cited by 24 publications

References 37 publications

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Hydrozirconation of Alkynes

Milligan,

Hammill,

Crocker

et al. 2023

Organic Reactions

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Since the first preparation of organozirconocenes from alkenes and alkynes in 1972, hydrozirconation has become one of the most commonly used stoichiometric methods to convert readily available starting materials into reactive but stable organometallic intermediates. A broad range of subsequent transformations may be employed to convert organozirconocenes in situ into high‐value functionalized products, often with the strategic formation of one (or several) new carbon–carbon bonds. This chapter focuses on the hydrozirconation of terminal and internal alkynes, and the subsequent synthetic transformations of the resulting alkenylzirconocenes. Zirconocene hydrochloride, Cp 2 Zr(H)Cl, is most frequently employed for the hydrozirconation step and can be used as a reagent or prepared in situ. Subsequent reactions of alkenylzirconocenes include additions to inorganic electrophiles such as halogens, as well as in situ ligand transfers to other metals, such as palladium and zinc, that further expand the range of accessible bond formations. The initial discussion focuses on the mechanism and stereochemical considerations, and on the steric and electronic factors that determine the regiochemistry of the either kinetically or thermodynamically controlled hydrozirconation. The “Scope and Limitations” section presents information on functional group compatibilities and is organized by the type of synthetic transformation of alkenylzirconocenes. Representative applications of the hydrozirconation of alkynes are showcased in syntheses of natural products, comparisons to alternative methods for the hydrometallation of alkynes. The goal of this chapter is to demonstrate the significance of hydrozirconation in organic synthesis, including the utility of the stoichiometric zirconium organometallics obtained from alkyne substrates, and to provide inspiration for the future development of new synthetic methods and strategies.

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Hydrozirconation of Alkynes

Milligan,

Hammill,

Crocker

et al. 2023

Organic Reactions

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Chemistry and Biology of Epothilones

Altmann

Schinzer

2014

Methods and Principles in Medicinal Chemistry

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Design, Synthesis, and Biological Properties of Highly Potent Epothilone B Analogues

et al. 2003

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Owing to their potent cytotoxicity against tumor cells, including taxol (paclitaxel)-resistant cell lines, the epothilones (for example, epothilone A (1) and epothilone B (2)) [1] continue to be the focus of intense chemical, biological, and clinical research efforts around the world. [2,3] Following the findings that cyclopropane-, [4] methylsulfanylthiazole-, [2d, 5] and pyridine- [6] containing epothilone B derivatives (e.g. 3[5a]and 5, [6] ) exhibit outstanding biological profiles as potential antitumor agents, we directed our attention toward the synthesis and evaluation of a small designed library of epothilone B analogues whose members are characterized by such structural motifs. Herein we report the details of these synthetic and biological investigations, which culminated in the discovery of 12,13-cis-cyclopropane methylsulfanyl epothilone B (4) as an extremely potent epothilone B analogue.The design of the present focused epothilone library was based on the current knowledge of structure-activity relationships (SAR), specifically the facts that: 1) epothilone B (2) is considerably more potent than epothilone A (1), 2) a methylsulfanyl replacement for the methyl group on the thiazole moiety enhances the potency, [2d, 5] 3) a heterocycle (e.g. pyridine) [6] replacement for the thiazole ring needs to maintain the proper position (adjacent to the point of

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Synthesis and Biological Evaluation of 12,13-Cyclopropyl and 12,13-Cyclobutyl Epothilones

Cited by 24 publications

References 37 publications

Hydrozirconation of Alkynes

Hydrozirconation of Alkynes

Chemistry and Biology of Epothilones

Design, Synthesis, and Biological Properties of Highly Potent Epothilone B Analogues

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