Highly Efficient and Selective Procedures for the Synthesis of γ-Alkylidenebutenolides via Palladium-Catalyzed Ene-Yne Coupling and Palladium- or Silver Catalyzed Lactonization of (Z)-2-En-4-ynoic Acids. Synthesis of Rubrolides A, C, D, and E

The diacetates of rubrolides A, C, D, and E (1 a-d) were prepared in modest yields by the Pd-catalyzed cross coupling-lactonization tandem reaction of 5a or 5b with 6a or 6b using Cl₂Pd(PPh₃)₂ and CuI as catalysts. The feasibility of converting the diacetates into rubrolides was demonstrated by the synthesis of rubrolide C by treatment of 1b with methanolic K₂CO₃ in THF. A detailed investigation of various parameters and conditions has indicated that formation of the corresponding six-membered lactones 7 and/or the cross coupling-lactonization-Heck substitution products 11 can be serious side reactions under non-optimized conditions and that the use of Pd(PPh₃)₄ rather than phosphine-free complexes, e.g., Cl₂Pd(PhCN)₂, or complexes of low phosphine content, e.g., Cl₂Pd(PPh₃)₂, along with CuI and Net₃ in MeCN provides satisfactory conditions for the cross coupling-lactonization tandem reaction. Thus, the diacetate of rubrolide A (1 a) was prepared in 70% isolated yield. The optimized conditions reported herein appear to be generally applicable to the stereoselective and regioselective synthesis of γ-alkylidenebutenolides in a highly efficient manner.

γ-alkylidenebutenolides - (Z)-β-halopropenoic acids - oxypalladation - palladium catalyzed cross coupling-lactonization - rubrolides A, C, D, and E