Iterative protecting group-free cross-coupling leading to chiral multiply arylated structures

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Materials Science

Background:

• The Suzuki-Miyaura cross-coupling is a cornerstone reaction for synthesizing biaryl and conjugated systems found in pharmaceuticals and materials.
• Current iterative Suzuki-Miyaura coupling often relies on protecting group strategies, limiting efficiency and scope.
• Biaryl and conjugated substructures are prevalent in natural products and small molecules, highlighting the need for streamlined synthetic methods.

Purpose of the Study:

• To develop a novel iterative Suzuki-Miyaura cross-coupling strategy that eliminates the need for protecting groups.
• To enable the use of multiply functionalized coupling partners in sequential cross-coupling reactions.
• To demonstrate the synthesis of valuable chiral, enantioenriched compounds using this protecting-group-free approach.

Main Methods:

• Exploitation of the orthogonal reactivity of different boron substituents in the transmetalation step of the Suzuki-Miyaura reaction.
• Development of a sequential, iterative cross-coupling protocol allowing for the introduction of multiple functional groups without protection.
• Application of the methodology to the synthesis of chiral enantioenriched molecules.

Main Results:

• Successful implementation of iterative Suzuki-Miyaura cross-coupling without the requirement of protecting groups.
• Demonstrated ability to couple multiply functionalized partners in a controlled, sequential manner.
• Efficient preparation of chiral enantioenriched compounds, showcasing the method's utility in synthesizing privileged pharmaceutical structures.

Conclusions:

• This work presents a significant advancement in Suzuki-Miyaura cross-coupling, enabling protecting-group-free iterative synthesis.
• The orthogonal reactivity of boron substituents provides a powerful tool for constructing complex molecular architectures.
• The developed method offers a more efficient and versatile route to valuable chiral compounds for pharmaceutical applications.