Enhancement Of The Traditional Fischer Indole Synthesis And Its Applications In Total Synthesis

Indoles are a type of widespread heterocycles in nature, which are of vital importance to human life. Indole alkaloids, a group of natural products that contain either indole itself or indole derived motifs, are often the active ingredients in traditional medicines or work as critical signaling molecules in living cells. The Fischer indole synthesis is a highly efficient and practical method of synthesizing indoles. It represents one of the most critical ways in indole synthesis.In the past50years, numerous complex indole alkaloids have been synthesized. The application of the Fischer indolization in these syntheses has been a main focus. However, it could not be successfully applied in most cases. One of the main reasons is the lack of regioselectivity in the traditional Fischer indole synthesis, when unsymmetrical ketones are taken as substrates. It has been well known that the regioselectivity of the Fischer method is affected by many factors including the acidity of the catalyst, the electronic effect of the aromatic hydrazine and the steric hindrance of the ketone. The predictability of regioselectivity was low, which limits the use of Fischer indolization in synthesizing indole alkaloids.To solve the regioselectivity issue, we proposed a C-N coupling strategy to form the ene-hydrazine intermediate with a fixed double bond and eventually achieved regioselective Fischer indole synthesis. We used the Ullmann coupling reaction to couple acyl aromatic hydrazines with vinyl halides to form the ene-hydrazine intermediate which upon treatment with ZnCl2afforded indoles in a regioselective fashion in one-pot. Applying this method, we were able to synthesize many types of indole structures with different ring sizes, substituents on the benzene rings as well as functional groups such as free hydroxyls, free amines and esters.The superb functional group tolerance of our method enabled us to develop interrupted Fischer indole synthesis to further extend our method into the synthesis of indole alkaloids with complex core structures. For example, we were able to achieve highly efficient total synthesis of esermethole and desoxyeseroline in one step without the need for any further functional group manipulation. In our total synthesis of minfiensine, we discovered that the substituents on our substrate could control the stereochemistry of the newly formed core structure, which provides an idea for a substrate-controlled asymmetric Fischer indole synthesis leading to an asymmetric total synthesis of minfiensin.In summary, our modified Fischer indole synthesis reveals great potential in the total synthesis of complex indole alkaloids. We firmly believe that many total syntheses of alkaloids with similar structures, such as vincorine and aspidophylline A, could benefit from this method. It provides an alternative approach and a new perspective for bond disconnection in the synthesis of indole alkaloids.