Efficient One-step Synthesis Of ?-alkylidene Butenolides

As an important skeletal motif,?-alkylidene butenolides widely distribute in natural products with important biological activities and diversified structures.It can also serve as a key building blocks in the total synthesis of related natural products,and widely applied to the complex structure of the synthesis of multifunctional compound.Especially,Fused?-alkylidene butenolides are common in the natural products and still have good reactivity.The fused?-alkylidene butenolides has great significance in organic chemistry and drug design.In view of the disadvantages of the traditional synthesis strategy,this study took fused?-alkylidene butenolides as the research object and a one-step strategy for efficient construction of fused?-alkylidene butenolides was developed based on TiCl₄-Et₃N-mediated condensation of ketones with methyl pyruvate.The reaction conditions were optimized systematically and the results showed that the optimum combination of the catalytic system is 1.5 equiv TiCl₄ and 3.0 equiv Et₃N.The applicability of the substrates were evaluated and the results showed that the strategy was suitable for cycloalkanones,acyclic ketones,halogen substituted ketones and aromatic ketones,and the corresponding?-alkylidene butenolides could be obtained with medium to high yield?55%⁸0%?.Meanwhile,different?-ketone esters can also be applied to this strategy.Furthermore,this strategy has a good tolerance to acid sensitive group-OTBS.The application of the methodology to the straightforward synthesis of elem-1,3,7,8-tetraen-8,12-olide,chloranthalactone A,and dehydromenthofurolactone is demonstrated.Finally,the reaction mechanism was studied in detail,and the structure of key intermediate 4 was successfully separated and identified by controlling the reaction conditions.Based on the results of literature investigation,the reaction mechanism was reasonably predicted and the pathway of by-products was explained.