Enantioselective synthesis of γ-butenolides through Pd-catalysed C5-selective allylation of siloxyfurans

Metal-catalysed asymmetric allylic alkylation reactions have played a pivotal role in the construction of chiral compounds. When applied to the synthesis of butenolides, a common moiety present in many biologically active compounds, this reaction has always provided the C3-allylated products and only traces of the C5-allylated analogues. Here we report a Pd-catalysed C5-selective method that provides direct and highly enantioselective (up to >99% e.e.) access to a wide range of substituted butenolides using 2-substituted allyl acetates as the allylic partner. Mechanistic studies supported by density functional theory calculations have shown that the C5-selectivity observed is the result of a steric constraint induced by the substituent on the central carbon of the π–allyl complex forcing the reactive dienolate intermediate to expose its C5-reactive centre. The practicality, scalability and synthetic utility of the process was demonstrated through the total synthesis of three O-terpenoidal natural products: excavacoumarin B, D and E. The construction of C–C bonds with regio- and stereoselectivity is paramount in natural product synthesis and metal-catalysed asymmetric allylic alkylation reactions have played a key role, with high C3 selectivity demonstrated in butenolide synthesis. Now, a palladium-catalysed C5-selective method is reported, providing direct and highly enantioselective access to a range of diversely substituted butenolides.