Total synthesis of (–)-dihydroprotolichesterinic acid via a diastereoselective conjugate addition, development of enantioselective halocyclization reactions, and progress towards the total synthesis of jiadifenolide



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In an effort to develop a unified route to functionalized succinic acid derivatives, a new diastereoselective conjugate addition of monoorganocuprates, Li[RCuI], to a chiral fumarate was developed. The conjugate addition proceeded with good yields and a high degree of diastereoselectivity for a variety of alkyl and aryl nucleophiles. Application of this new methodology culminated in the shortest total synthesis of (–)-dihydroprotolichisterenic acid to date. The novel organocatalyst developed by the Martin group was applied to enantioselective iodolactonization reactions. Reaction conditions were optimized and the resulting halolactones were obtained in high yields and enantioselectivities for a number of olefinic acids. Of particular note is the disclosure of the first iodolactonization reactions forming a C–I bond at a stereogenic center. The utility of this catalyst was further extended to kinetic resolution reactions. Additionally, this catalyst was found to promote the first enantioselective halolactamization reaction with moderate enantioselectivity. Finally, the catalyst was modified in an effort to enhance the enantioselectivity and verify the proposed bifunctional nature of the catalyst. Lastly, an enantiospecific total synthesis of the neurotrophic sesquiterpenoid natural product (–)-jiadifenolide was progressed. The stereochemistry was introduced by the use of commercially available (+)-pulegone as the starting material. The first diastereoselective decarboxylative allylation on a cyclopentanone was developed A samarium diiodide mediated radical annulation was planned to forge two of the rings, and late stage oxidation manipulation could then lead to the completion of the synthesis.