Synergistic Pd/Cu-Catalyzed 1,5-Double Chiral Inductions.

Area of Science:

• Organic Chemistry
• Asymmetric Catalysis
• Stereoselective Synthesis

Background:

• Existing methods primarily focus on creating single or adjacent chiral centers.
• Asymmetric construction of two nonadjacent stereocenters remains a significant challenge due to limited remote chiral induction strategies.
• Development of new methodologies is crucial for accessing complex chiral molecules.

Purpose of the Study:

• To develop a novel catalytic system for the asymmetric synthesis of molecules with two nonadjacent stereocenters.
• To establish a 1,5-double chiral induction model using a C═C bond relay strategy.
• To achieve divergent synthesis of all four stereoisomers of target products.

Main Methods:

• Synergistic palladium/copper-catalyzed reaction.
• Application of a C═C bond relay strategy for 1,5-double chiral induction.
• Utilizing two chiral catalysts with different configurations for divergent stereoisomer synthesis.
• Mechanistic investigations using control experiments and Density Functional Theory (DFT) calculations.

Main Results:

• Successful demonstration of a 1,5-double chiral induction model.
• Divergent synthesis of all four stereoisomers of products containing 1,5-nonadjacent stereocenters, including allenyl axial and central chirality.
• Identification of key mechanistic steps: 1,5-oxidative addition, contra-thermodynamic η³-allyl palladium shift, and conjugate nucleophilic substitution.
• Detailed understanding of the factors controlling reactivity, regio-, enantio-, and diastereoselectivity.

Conclusions:

• The developed C═C bond relay strategy provides an effective method for constructing two distant stereocenters.
• The synergistic Pd/Cu-catalyzed system offers precise control over stereochemistry, enabling access to all stereoisomers.
• This approach is expected to serve as a general protocol for synthesizing complex molecules with remote stereocenters.