Biocatalytic Atroposelective Synthesis of Axially Chiral Styrenes via Dynamic Kinetic Resolution

Area of Science:

• Biocatalysis
• Organic Chemistry
• Enzyme Engineering

Background:

• Enzymatic synthesis of atropisomers is gaining attention, primarily for biaryls.
• Axially chiral nonbiaryl styrenes represent an underexplored area for atroposelective synthesis.

Purpose of the Study:

• To develop an atroposelective dynamic kinetic resolution (DKR) for nonbiaryl styrenes using enzymes.
• To expand the scope of biocatalytic synthesis for axially chiral compounds.

Main Methods:

• Utilized imine reductases (IREDs) and alcohol dehydrogenases (ADHs) for DKR.
• Employed protein engineering to invert atroposelectivity.
• Applied molecular dynamics (MD) simulations to understand mechanisms.

Main Results:

• Identified IR189 wild type enzyme for high activity and selectivity.
• Achieved inversion of atroposelectivity through protein engineering.
• Discovered two ADHs with enantio-complementary selectivity.
• Synthesized 29 examples of axially chiral styrenes with up to 99% yield and 99:1 e.r.
• Demonstrated synthetic utility via scaled-up reactions and product derivatization.

Conclusions:

• The study presents a novel enzymatic DKR strategy for nonbiaryl styrenes.
• This work significantly advances biocatalytic synthesis of axially chiral compounds.
• The developed methods offer broad substrate scope and high efficiency.