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SIOC developed a novel strategy for asymmetric synthesis of medium-sized rings
Update time: 2016-05-13
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    Cyclic compounds hold a vital position in modern organic chemistry with their ubiquity in nature and serve as one of the most important materials in both academia and industry. Thus the synthesis of cyclic compounds is extremely important in organic chemistry. To date, chemists have plentiful methods for generating small rings with six or fewer members, such as Diels–Alder reaction and other cycloaddition reactions. They also have many ways of constructing large rings with ten or more members, such as Corey-Nicolaou macrolactonization, Keck macrolactonization, and ring-closing metathesis. However, the synthesis of medium-sized rings, especially catalytic asymmetric variants, remains a great challenge because of their unfavorable transannular interactions and entropic factors.

    The You group at the State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry recently developed a novel strategy for enantioselective synthesis of indole-annulated medium-sized-ring compounds (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b02678). First, the nucleophilic attack of the indole C3 position on the π-allyliridium moiety delivers the bridged intermediate II. The reaction is feasible because the substrates are pre-organized by a six- or seven-membered-ring to reduce energetically unfavorable transannular and torsional strain. Subsequently, a ring-opening retro-Mannich reaction affords the ring-expansion intermediate III, from which hydrolysis of the iminium moiety gives the desired product. The proposed mechanism is supported by in situ reduction of the bridged cyclic intermediate. Under mild reaction conditions, various seven-, eight-, or nine-membered rings can be formed smoothly. This novel synthetic strategy opens a window for asymmetric synthesis of medium-sized rings, which are challenging to be accessed by other methods. This method will be important for the medium-sized-ring drugs discovery and development. This work has been highlighted by Chemical & Engineering News with a title of "Asymmetric third ring is a charm for indole-annulated compounds" on May 9, 2016.

    These projects were sponsored by the National Natural Science Foundation of China, Ministry of Science and Technology of PRC, Chinese Academy of Sciences, and Science and Technology Commission of Shanghai Municipality. 

A novel strategy for enantioselective synthesis of indole-annulated medium-sized-ring compounds. (image by YOU Shuli)

 

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