Enantioselective Construction of Spirooxindole‐Fused Cyclopenta[c]chromen‐4‐ones Bearing Five Contiguous Stereocenters via a Stepwise (3+2) Cycloaddition

Abstract

The bifunctional quinine-catalyzed stepwise (3 + 2) cycloaddition for the enantioselective construction of spirooxindole-fused cyclopenta[c] chromen-4-ones is developed. The reactions of 3homoacylcoumarins and alkylidene oxindole electrophiles generate aforementioned spirooxindolechromenone adducts bearing five contiguous stereocenters, of which one is the spiro all-carbon quaternary stereocenter in high yields (up to 99%) with excellent stereoselectivities (up to > 20:1 dr and 99% ee). This methodology was investigated for three different alkylidene oxindole electrophiles and could also be practically demonstrated on a gram scale. Mechanistic investigations revealed that the (3 + 2) cycloaddition for the enantioselective synthesis of spirooxindole-fused cyclopenta[c]chromen-4-ones is proceeding via a stepwise reaction pathway.

Squaramide Catalyzed Asymmetric Synthesis of Five‐ and Six‐Membered Rings

“…Lin and co‐workers showed an elegant protocol to synthesize spirooxindole linked cyclopenta[c]chromen‐4‐ones through squaramide C catalyzed formal (3+2) annulation [77] . The cyclization involved 3‐homoacyl coumarin 194 and 3‐alkylidene oxindole 192 as starting substrates which afforded the products 195 bearing five contiguous stereocenters through double Michael cascade.…”

“…Lin and co-workers showed an elegant protocol to synthesize spirooxindole linked cyclopenta[c]chromen-4-ones through squaramide C catalyzed formal (3 + 2) annulation. [77] The cyclization involved 3-homoacyl coumarin 194 and 3-alkylidene oxindole 192 as starting substrates which afforded the products 195 bearing five contiguous stereocenters through double Michael cascade. The reaction was well compatible with ester and ketone substituted 3-alkylidene oxindoles to deliver the products with moderate to excellent chemical yields and high stereocontrol.…”

Enantioselective Synthesis of Spirocyclopentane Oxindoles Bearing Five Consecutive Stereocenters through Secondary Amine‐Catalyzed [3+2] Cycloaddition

“…[10] Soon afterward, the group of Lin reported an [3 + 2] cyclization between alkylidene oxindole derivatives and 3-homoacylcoumarins to give the enantioen- riched spirocyclopentane oxindoles in the presence of quininederived squaramide catalyst (Scheme 1c). [11] It is worth noting that the above-mentioned synthetic advancements were explored based on bifunctional hydrogenbonding catalysis, organocatalytic cascade reactions using other covalent catalysis are currently less explored and highly desirable in assembling such spiro architectures with five contiguous chiral centers. As part of our continual interest in developing elegant organocatalytic asymmetric cascade reactions to synthesize spirooxindole skeletons, [12] in this work, we disclosed a secondary amine-catalyzed [3 + 2] cycloaddition between C3-substituted oxindoles and α,β-unsaturated aldehydes to afford optically active densely functionalized spirocyclopentane oxindole derivatives.…”

“…In a report published by Liu and co‐workers in 2019, quinidine‐derived thiourea‐catalyzed [3+2] annulation between C3‐saturated oxindoles and nitroolefins has successfully led to the formation of cyclopentane‐spirooxindoles with five contiguous chiral centers (Scheme 1b) [10] . Soon afterward, the group of Lin reported an [3+2] cyclization between alkylidene oxindole derivatives and 3‐homoacylcoumarins to give the enantioenriched spirocyclopentane oxindoles in the presence of quinine‐derived squaramide catalyst (Scheme 1c) [11] …”

Recent Advances in Squaramide-Catalyzed Asymmetric Cascade Reactions for the Synthesis of Spirooxindoles

“…2020 年, 林文伟课题组[25] 以 3-苯乙酰基香豆素 34 为启动串联反应试剂, 以方酰胺 C1 为催化剂, 二氯甲 烷为溶剂, 30 ℃条件下开发了与 3-亚甲基氧吲哚 2 的不 对称 Michael/Michael 串联反应, 高产率、高立体选择性 地构建了具有连续五个立体手性中心, 三个连续季碳手 性中心的螺环氧吲哚 35. 该策略底物适应性广泛, 作者 尝试了三种类型的 3-亚甲基氧吲哚, 当取代基 R 3 为酯 基和苯甲酰基时, 都能获得出色的收率以及立体选择 性; 当取代基 R 3 为苯基时, 反应的对映选择性有所下 降, 可获得 61%～90%的 ee 值(Eq.…”