Bimetallic Relay Catalyzed Asymmetric Ring Isomerization/[4+2] Cyclization Tandem Reaction of Cyclopropenone

• Cyclopropenones can diversify into oxygen-containing heterocyclic compounds. Among them, under the catalysis of transition metals (such as silver, gold, copper, etc.), cyclopropenone can produce highly active cyclobutane-condensed furan intermediates through cycloisomerization (Figure 1a), and then undergo a series cyclization reaction; However, strong background reactions often make stereoselectivity difficult to control. Coupled with the linear coordination characteristics of silver or gold, asymmetric reactions involving silver or gold are difficult to achieve. Based on the previous work (Angew. Chem. Int. Ed., 2017, 56, 885; Angew. Chem. Int. Ed., 2016, 55, 6075), the research group of Professor Feng Xiaoming of Sichuan University used metal relay catalysis strategy. Under the catalysis of achiral AgⅠ, cyclopropenone undergoes cycloisomerization to generate active furan intermediates, which are then reacted with unsaturated alkenes under the catalysis of a chiral nitroxide metal complex (Feng catalyst) [4 +2] cyclization reaction, a series of multi-substituted chiral furopyran compounds were synthesized (Figure 1b).
  

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• Figure 1. Introduction to the reaction involving cyclopropenone

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  The authors first optimized the reaction conditions using cyclopropenone 1a and 2,3-dioxapyrrolidine 2a as model substrates. Through a series of screening of catalysts, additives, solvents, temperatures, metal ligand ratios and other conditions, chirality was finally obtained with a yield of 93%, an enantioselectivity of 90%ee and a diastereoselectivity of >19:1. Furopyran derivative 3aa (Figure 2).

  
  

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• Figure 2. Screening of reaction conditions

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  Substrate expansion under optimal conditions shows that it has good functional group compatibility for various aryl-substituted 2,3-dioxapyrrolidines and differently substituted cyclopropenones (Figure 3). The author also tried a cycloisomerization cyclization series reaction involving alkenyl indolone and cyclopropenone, and achieved good results (Figure 4). Gram-scale scale-up showed that the yield and stereoselectivity remained almost unchanged (Figure 5).

  
  
  

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• Figure 3. Investigation on the universality of cyclopropenone and 2,3-dioxapyrrolidine substrates
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• Figure 4. Investigation on the universality of cyclopropenone and alkenyl indolinone substrates
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• Figure 5. Amount of enlargement
• Finally, the author showed in the control experiment (Figure 6): (1) AgⅠ is crucial to the formation of the intermediate; (2) the addition of chiral dinitroxide ligand (Feng ligand) can effectively inhibit the formation of [4+ 4] The generation of by-product 6aa, the chiral Lu(OTf)3 system controls the enantioselectivity of the tandem cyclization; (3) The ligand is partially coordinated with AgOTf, showing the ligand deceleration effect of cycloisomerization ; (4) The formation of by-product 6aa is related to Lu(OTf)3. Based on the above experiments and catalyst and product single crystals, the author proposed a possible transition state model (Figure 7).
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• Figure 6. Control experiment
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• Figure 7. Transition state model

• In summary, Feng Xiaoming's research group used a bimetallic catalytic strategy to achieve the cycloisomerization of cyclopropenone and the [4+2] cyclization of 2,3-dioxapyrrolidine and indolone enester. Through the series reaction, multi-substituted chiral furopyran compounds are obtained with high yield, excellent diastereoselectivity and good enantioselectivity. Relevant results were recently published in Science China Chemistry.