Divergent access to E- or Z-trisubstituted medium-sized cycloalkenes by Pd-catalysed cycloaddition

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Medium-sized rings (9-11 members) are crucial in natural products but scarce in pharmaceuticals due to synthetic challenges.
• Stereoselective synthesis of macrocyclic alkenes (E- or Z-isomers) is difficult, often requiring pre-existing geometric purity in starting materials.

Purpose of the Study:

• To develop an efficient and stereoselective catalytic method for constructing 11-membered heterocyclic alkenes.
• To enable the divergent synthesis of E- or Z-trisubstituted cycloalkenes from common terminal alkene precursors.

Main Methods:

• Palladium-catalyzed formal cycloaddition of two readily available building blocks.
• Ligand-controlled divergent synthesis to achieve E- or Z-alkene stereochemistry.
• Density functional theory (DFT) calculations to elucidate reaction mechanisms.

Main Results:

• Successful construction of 11-membered heterocyclic alkenes via Pd-catalysis.
• Ligand-induced control over E/Z stereochemistry of trisubstituted cycloalkenes.
• DFT studies revealed ligand-dependent coordination (η¹ or η³) of a key Pd-π-allyl intermediate, directing allylic substitution.

Conclusions:

• A novel Pd-catalyzed cycloaddition provides efficient access to medium-sized heterocyclic alkenes.
• This method offers a stereoselective and divergent route to E- or Z-alkenes, valuable for pharmaceutical development.
• Mechanistic insights explain the stereochemical outcome based on ligand effects on palladium coordination.