Regio‐ and Enantioselective (3+3) Cycloaddition of Nitrones with 2‐Indolylmethanols Enabled by Cooperative Organocatalysis

Abstract

The regio‐ and enantioselective (3+3) cycloaddition of nitrones with 2‐indolylmethanols was accomplished by the cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA). Using this approach, a series of indole‐fused six‐membered heterocycles were synthesized in high yields (up to 98 %), with excellent enantioselectivities (up to 96 % ee) and exclusive regiospecificity. This approach enabled not only the first organocatalytic asymmetric (3+3) cycloaddition of nitrones but also the first C3‐nucleophilic asymmetric (3+3) cycloaddition of 2‐indolylmethanols. More importantly, theoretical calculations elucidated the role of the cocatalyst HFIP in helping CPA control the reactivity and enantioselectivity of the reaction, demonstrating a new mode of cooperative catalysis.

Organocatalytic Enantioselective Synthesis of Axially ChiralN,N′‐Bisindoles

“…The addition of 5 Å molecular sieve (MS) and hexafluoroisopropanol (HFIP) to the reaction improved the yield and enantioselectivity of 3 aa to some extent. The action of 5 Å MS might be associated with dehydration in the formal (3+2) cycloaddition, and the effect of HFIP is largely due to the cooperative catalysis with CPA [31c] . Finally, by slightly modulating the reagent ratio and extending the reaction time from 12 to 48 h, the yield of 3 aa considerably improved to 87 % with an excellent enantioselectivity of 93 % ee.…”

Organocatalytic Csp2–O Amination of Quinolin-4(1H)-ones with 3-Alkynyl-3-hydroxyisoindolinones

“…The advancement in asymmetric organocatalysis is continually gaining momentum, making it a more prevalent and impactful tool in the field of organic synthesis . Recently, we successfully established an organocatalytic formal C sp2 –O bond amination of 1-methylnaphthalen-2-ols with 3-alkynyl-3-hydroxyisoindolinones as nitrogen sources, which features a cascade reaction, high atomic economy, and mild conditions, together with obvious substrate dependence and generally moderate yields (Scheme B) .…”