Photochemical Deracemization of Chromanes and its Application to the Synthesis of Enantiopure Bioactive Compounds

TL;DR

A new photochemical method efficiently produces enantiopure chromanes, which are important in pharmaceuticals, using a chiral photocatalyst and a thiol additive.

Contribution

A novel photochemical deracemization method for enantiopure chromane synthesis using a chiral photocatalyst and thiol additive.

Findings

The method achieved 71%–90% yield and 80%–99% ee for 21 examples of chromane deracemization.

A chiral photocatalyst selectively abstracts hydrogen from one enantiomer to establish a photostationary state.

The method was applied to synthesize five enantiopure pharmaceuticals efficiently.

Abstract

Chromanes are frequently encountered as chiral structure elements in active pharmaceutical ingredients (APIs). We have now discovered an access to enantiopure chromanes, which employs a 1:1 mixture of their enantiomers (racemate) in a photochemical deracemization reaction (21 examples, 71%–90% yield, 80%–99% ee). A chiral photocatalyst (10 mol%) acts by selective hydrogen abstraction at one chromane enantiomer and establishes a photostationary state in which the other enantiomer prevails. A thiol additive (20 mol%) was found to improve the enantioselectivity of the process. The mechanism of the reaction was investigated by experimental and quantum‐chemical studies. The oxygen atom of the chromane locks the rotation around the exocyclic C─C bond to the amide by forming an intramolecular hydrogen bond. Forward hydrogen atom transfer (HAT) occurs exclusively in one diastereomeric complex via a readily accessible transition state. Reasonable pathways for back HAT were identified which are in line with deuterium labeling experiments. The method was applied to the concise preparation of five chromane‐containing drugs (Doxazosin, Fidarestat, Nebivolol, Repinotan, Sarizotan) as single enantiomers.

Various substituted chromane‐2‐carboxamides were successfully deracemized by employing a chiral benzophenone (BP, 10 mol%) as photocatalyst and an achiral thiol as additive (20 mol%). The method was applied to the concise enantioselective synthesis of five active pharmaceutical ingredients.

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