Enantioselective Synthesis of Axially Chiral Spiro[3.3]heptanes by Site-Selective C-H Functionalization

Area of Science:

• Organic Chemistry
• Asymmetric Synthesis
• Catalysis

Background:

• Enantioselective synthesis of axially chiral 2,6-disubstituted spiro[3.3]-heptanes is challenging due to distant functionalities.
• Existing enantioselective methods often rely on enzymatic processes.
• A need exists for efficient, non-enzymatic routes to these complex chiral structures.

Purpose of the Study:

• To develop a highly regio-, diastereoselective, and enantioselective method for synthesizing 2,6-disubstituted spiro[3.3]-heptanes.
• To achieve this synthesis via desymmetrization of 2-substituted spiro[3.3]-heptanes using rhodium-catalyzed C-H functionalization.
• To explore the mechanism and scope of this novel catalytic approach.

Main Methods:

• Utilized rhodium-catalyzed C-H functionalization employing donor/acceptor carbenes derived from aryldiazoacetates and styryldiazoacetates.
• Employed a D4-symmetric dirhodium catalyst, dirhodium tetrakis-(4,4'-(3,5-ditertbutylphenyl)-6,6'-dichlorobinaphthylphosphate) (Rh2(S-MegaBNP)4).
• Investigated the role of the N-phthalimido group on the spiro[3.3]-heptane substrate and performed computational studies.

Main Results:

• Achieved highly regio-, diastereoselective (>20:1 rr, >20:1 dr), and enantioselective (99% ee) synthesis of target compounds.
• Optimized conditions yielded products in up to 92% yield.
• Computational studies revealed catalyst rigidity and substrate/carbene orientation control via hydrophobic interactions, and diastereoselectivity through conformation sorting.

Conclusions:

• The study presents an effective non-enzymatic strategy for enantioselective synthesis of axially chiral spiro[3.3]-heptanes.
• Bowl-shaped dirhodium catalysts demonstrate subtle site selectivity influenced by noncovalent interactions.
• The N-phthalimido group is suitable for further derivatization into amine and amide products.