Synthesis of 2,6-trans-Tetrahydropyrans Using a Palladium-Catalyzed Oxidative Heck Redox-Relay Strategy

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Natural Product Synthesis

Background:

• The C-aryl-tetrahydropyran motif is a key structural feature in numerous biologically active natural products.
• Synthesizing these complex architectures presents significant challenges in organic chemistry.
• Novel and efficient synthetic methodologies are crucial for accessing these valuable compounds.

Purpose of the Study:

• To develop a novel synthetic strategy for constructing functionalized 2,6-trans-tetrahydropyrans.
• To demonstrate the utility of a stereoselective Heck redox-relay approach.
• To apply this strategy to the total synthesis of a biologically relevant natural product.

Main Methods:

• A stereoselective Heck redox-relay strategy was employed.
• The synthesis involved a novel exo-cyclic migration mechanism.
• Starting material was an enantiopure dihydropyranyl alcohol.

Main Results:

• The Heck redox-relay strategy successfully synthesized functionalized 2,6-trans-tetrahydropyrans with excellent stereoselectivity in a single step.
• The novel exo-cyclic migration was key to the reaction's success.
• The strategy was validated through the total synthesis of a trans-epimer of the natural product centrolobine in high yield and stereoselectivity.

Conclusions:

• The developed Heck redox-relay strategy offers an efficient and stereoselective route to C-aryl-tetrahydropyran motifs.
• This methodology provides a powerful tool for the synthesis of complex natural products containing this scaffold.
• The approach overcomes previous synthetic challenges associated with this important structural motif.