Late-Stage Conversion of a Metabolically Labile Aryl Methyl Ether-Containing Natural Product to Fluoroalkyl Analogues

Abstract

We report the conversion of aryl methyl ethers and phenols into six fluoroalkyl analogues through late-stage functionalization of a natural product-derived FDA-approved therapeutic. This series of short synthetic sequences exploits a combination of both modern and traditional methods and demonstrates that some recently reported methods do not always work as well as desired on a natural product-like scaffold. Nonetheless, reaction optimization can deliver sufficient quantities of each target analogue for medicinal chemistry purposes. In some cases, classical reactions and synthetic sequences still outcompete modern organofluorine transformations, which should encourage the continued search for improved reactions. Overall, the project provides a valuable synthetic roadmap for medicinal chemists to access a range of fluorinated therapeutic candidates with distinct physicochemical properties relative to the original O-based analogue.

Advances in the Development of Trifluoromethoxylation Reagents

“…Generally, fluorination of aromatic substrates bearing amide and nitrile groups as well as heteroaromatic substrates proceeded in higher yield under condition A than under condition B. Recent articles were described the use of the Fluolead (4-tert-butyl-2,6-dimethylphenylsulfur trifluoride) combined with SbCl3 for simple fluorination of aromatic and aliphatic xanthates giving the respective CF3O compounds in high yield [76,77]. Substrates with high level of complexity were also tolerated under reaction conditions, as exemplified by efficient fluorination of xanthate 16 (Scheme 7) delivering aryl trifluoromethyl ether 17.…”

Fluoroalkylation of Dextromethorphan Improves CNS Exposure and Metabolic Stability

“…butanesulfonyl fluoride, NEt3, DCM, -78 °C to rt, 18 h; (q) TMSCF2H, Pd(dba)2, dppf, [SIPr]AgCl, NaO t Bu, PhMe, 110 °C, 18 h, 44% over 2 steps; (r) LiAlH4, THF, 0 °C to rt, 16 h; (s) LiAlD4, THF, 0 °C to rt, 16 h.The fluorinated analogs were synthesized though late-stage functionalization of commercially available DXM•HBr salt, according to our recently published strategy 26. In brief, the basic amine was dealkylated and protected as a carbonate prior to dealkylation of the aryl-methyl ether to reveal phenol 16.…”

“…Finally, phenol 16was converted to a nonaflate and cross-coupled to deliver CF2H analog 24. At this stage, the use of a carbamate protecting group enabled late-stage deprotection/reduction with LiAlH4 or LiAlD4 to afford the target analogs 1-12 (Scheme 1) 9,26.…”

Fluoroalkylation of Dextromethorphan Improves CNS Exposure and Metabolic Stability

“…HBr salt, according to our recently published strategy 26. In brief, the basic amine was dealkylated and protected as a carbonate prior to dealkylation of the aryl-methyl ether to reveal phenol 16 9,26.…”

“…HBr salt, according to our recently published strategy 26. In brief, the basic amine was dealkylated and protected as a carbonate prior to dealkylation of the aryl-methyl ether to reveal phenol 16 9,26. Phenol 16 was triflated, converted to a boronic ester, and subjected to Cu-based perfluoroalkylating reagents to generate CF3 and CF2CF3-derived derivatives (18 and 19).…”