Synergistic [4 + 1] Spiroannulation and Selective Ring-Opening Strategy toward γ-Spirolactams

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• The synthesis of complex heterocyclic compounds is crucial in medicinal chemistry.
• Spirocyclic compounds, particularly spiro-fused lactams, are prevalent in natural products and pharmaceuticals.
• Developing efficient and regioselective synthetic routes to these structures remains a significant challenge.

Purpose of the Study:

• To develop a novel and efficient synthetic strategy for constructing γ-spirolactams.
• To explore a Rh(III)-catalyzed [4 + 1] spiroannulation reaction between 2-aryl-4H-benzo[d][1,3]oxazines and maleimides.
• To elucidate the reaction mechanism, including the role of water in regioselective C-O bond cleavage.

Main Methods:

• Rh(III)-catalyzed spiroannulation reaction.
• Consecutive ring closing and ring opening reactions.
• Regioselective C-O bond cleavage promoted by *in situ* generated water.
• Mechanistic studies involving isotopic labeling and computational analysis.

Main Results:

• Successful synthesis of diversely substituted γ-spirolactams with pendant benzyl alcohol groups.
• Formation of new C-C, C-N, and C-O bonds in a single synthetic operation.
• Identification of the reaction pathway involving initial coordination, C-H activation, migratory insertion, and subsequent ring-opening/closing steps.
• Demonstration of the crucial role of water in the regioselective cleavage of the benzoxazine C4-O bond.

Conclusions:

• A unique and efficient Rh(III)-catalyzed [4 + 1] spiroannulation strategy has been established.
• The methodology provides access to structurally orchestrated isoindoline-1-one spirosuccinimides.
• The detailed mechanistic investigation offers insights into the reaction's unique features, including the water-promoted C-O bond cleavage.