Use of Fluorine in the Medicinal Chemistry and Chemical Biology of Bioactive Compounds—A Case Study on Fluorinated Taxane Anticancer Agents

Abstract

Scheme 1. Synthesis of fluorine-containing taxanes by means of the b-lactam synthon method. HMDS = hexamethyldisilazide.

Importance of Fluorine and Fluorocarbons in Medicinal Chemistry and Oncology

“…Thereby, thanks to the development of safe and selective fluorinating agents, more than 50% of the marketed drugs are fluorinated, including many anti-cancer agents such as fluorinated taxane anticancer agents and 5-Fluorouracil (5-FU) (Figure 1), this later being an anti-cancer compound employed for several decades since its discovery in 1957 by Charles Heidelberger et al [12,13,[19][20][21][22].…”

Synthesis of 3‐Trifluoro‐2‐hydroxy/amino‐1‐fluoropropylphosphonates†

“…2 As demonstrated by us, optically active trifluoromethylated aminophosphonic acids could be obtained conveniently by a base-catalyzed [1,3]-proton shift reaction. 3,4 In the meantime, the basicity of the reagent plays a predominant role in this reducing agent free biomimetic reductive amination process.…”

“…1 The [1,3] proton shift reaction (PSR) was shown as an useful methodology for the synthesis of α,β-disubstituted fluorinated β-aminoacid.…”

“…Generally speaking, fluorine atom located on the α-carbon atom as an electron withdrawing group is very sensitive to base forming an ethylenic linkage via HF elimination. Therefore, we are interested to explore the chemical behaviors of compound 3 under [1,3]-proton shift reaction conditions with various bases. Herein we wish to describe our study on the reaction involved in the preparation of the titled molecule.…”

“…

Reaction of diethyl 2,2-difluoro-3-(α-methylbenzyl)imino-4,4,4-trifluoropropanephosphonate (3) with triethylamine afforded a mixture of normal [1,3]-proton shift reaction product 5 and its HF-eliminated compound 6Z in 1∶ 1 ratio. Upon hydrolysis, this reaction mixture gave solely 1,3,3,3-tetrafluoro-2-dioxypropanephosphonate (9).

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