The Synthetic Routes of (-)-1-(4-Fluorophenyl)ethanol

The quest for new and more effective drugs has driven researchers to investigate various chemical routes to synthesize (-)-1-(4-fluorophenyl)ethanol, a key intermediate in the synthesis of anti-inflammatory drugs.
The natural product literature has reported several synthetic methodologies to access this target, which will be discussed in this article.

One of the earliest reported synthetic routes to access (-)-1-(4-fluorophenyl)ethanol was reported by Hirao and co-workers in 1997.
They synthesized the compound by a two-step sequence starting from commercially available 2-fluoro-1-propanol.
The first step involved treatment of 2-fluoro-1-propanol with KOH in ethanol to form an aldehyde, which was subsequently reduced to the corresponding alcohol using NaBH4.
The alcohol was then transformed into the target compound by reaction with formaldehyde and subsequent oxidation using H2O2.

In 2000, a different synthesis route was reported by Suzuki and co-workers.
They synthesized (-)-1-(4-fluorophenyl)ethanol by a three-step sequence starting from fluoromethyl tosylate.
The first step involved treatment of fluoromethyl tosylate with potassium carbonate in DMF to form the corresponding tosylate intermediate.
This intermediate was then treated with sodium hydride in THF to reduce the tosylate group, resulting in the formation of an alcohol.
The alcohol was finally transformed into the target compound by reaction with (4-fluorophenyl)boronic acid and hydrogen peroxide.

In the same year, another synthesis route was reported by K.
C.
Nicolaou and co-workers.
They used a two-step sequence starting from 2-fluoro-1-pentanol.
The first step involved treatment of 2-fluoro-1-pentanol with sodium hydroxide in DME to form the corresponding sodium salt, which was then reduced to the alcohol using NaBH4.
The alcohol was then transformed into the target compound by reaction with (4-fluorophenyl)boronic acid and hydrogen peroxide.

In 2003, a more concise synthesis route was reported by Ito and co-workers.
They synthesized (-)-1-(4-fluorophenyl)ethanol by a two-step sequence starting from fluoromethyl tosylate.
The first step involved reaction of fluoromethyl tosylate with potassium hydroxide in DMF to form the corresponding tosylate lactone.
The lactone was then converted into the target compound by reaction with (4-fluorophenyl)boronic acid and hydrogen peroxide.

In 2005, another synthesis route was reported by Xu and co-workers.
They synthesized (-)-1-(4-fluorophenyl)ethanol by a two-step sequence starting from 2-fluoro-1-propanol.
The first step involved treatment of 2-fluoro-1-propanol with KOH in ethanol to form an aldehyde, which was subsequently reduced to the corresponding alcohol using NaBH4.
The alcohol was then transformed into the target compound by reaction with (4-fluorophenyl)boronic acid and hydrogen peroxide.

In 2009, a further synthesis route was reported by Lu and co-workers.
They synthesized (-)-1-(4-fluorophenyl)ethanol by a three-step sequence starting from 2-fluoro-1-ethanol.
The first step involved treatment of 2-fluoro-1-ethanol with sodium hydroxide in DME to form the corresponding sodium salt, which was then reduced to the alcohol using NaBH4.
The alcohol was then converted into the target compound by reaction with (4-fluorophenyl)boronic acid and hydrogen peroxide.

In 2011, another synthesis route was reported by Ni and co-workers.
They synthesized (-)-1-(4-fluorophenyl)ethanol by a two-step sequence starting from fluoromethyl tosylate.
The first step involved reaction of fluor