Asymmetric Construction of Remote Vicinal Quaternary and Tertiary Stereocenters via Direct Doubly Vinylogous Michael Addition

Abstract

An asymmetric direct doubly vinylogous Michael addition has been developed for the generation of sterically congested vicinal quaternary and tertiary stereocenters. This doubly vinylogous Michael addition of β,γ-unsaturated butenolides to 3-methyl-4-nitro-5-alkenyl isoxazoles, powered by a bifunctional squaramide, affords a broad range of densely functionalized enantioenriched γ,γ-disubstituted butenolides in high yields with excellent diastereo- and enantioselectivities in most cases. Moreover, the strategy highlights the first application of β,γ-unsaturated butenolides in an asymmetric 1,6-conjugate addition.

Cinchona Derivatives as Bifunctional H‐bonding Organocatalysts in Asymmetric Vinylogous Conjugate Addition Reactions

“…Our research group reported the first use of vinylogous deconjugated butenolides 8 in a 1,6‐conjugate addition reaction in 2018 [44a] . Cinchonidine‐derived catalyst C18 was employed to carry out this highly selective reaction between butenolides 8 and 3‐methyl‐4‐nitro‐5‐alkenylisoxazoles 52 (Scheme 30).…”

Stereoselective Organocatalytic Synthesis of γ,γ‐Disubstituted Butenolides

“…Previously, the group of Jørgensen, has described the organocatalytic doubly vinylogous 1,6‐Michael addition of alkylidene lactones to 2,4‐dienals and later Dixon has explored the addition of γ ‐butyrolactam to cyclic dienones (Scheme ). The organocatalytic direct doubly vinylogous addition of γ ‐substituted butenolides to 1,6‐Michael acceptor such as 3‐methyl‐4‐nitro‐5‐alkenyl‐isoxazoles is rarely reported . The γ ‐substituted butenolides and 3‐methyl‐4‐nitro‐5‐alkenyl‐isoxazoles are attractive vinylogous partner as their heterocyclic cores are found in large number of bioactive natural products and pharmaceuticals ,,.…”

Synthesis of γ,γ‐Disubstituted Butenolides through a Doubly Vinylogous Organocatalytic Cycloaddition

“…[2] Therefore, much attentionh as been given to the development of synthetic methods allowing for their preparation, in particulari nas tereocontrolled manner. [3][4][5][6] The most commona pproachr elies on the application of dienolates A for their preparation.I th as been demonstrated that silyloxy furans serve as their synthetic equivalents readily participating in the vinylogous Mukayama-aldol or Mukayama-Michael and related reactions proceeding in ar egioselective fashion in the 5-position of the furan ring. [4,5] It is also possible to generated ienolates A from 5-substituted-3H-furan-2-ones (a-Angelica Lactone and relateds ystems) or 5-substituted-5H-furan-2-ones under Brønstedb ase catalysis conditions.…”

“…[4,5] It is also possible to generated ienolates A from 5-substituted-3H-furan-2-ones (a-Angelica Lactone and relateds ystems) or 5-substituted-5H-furan-2-ones under Brønstedb ase catalysis conditions. [6,7] Within this research area, the asymmetrico rganocatalysis [8] has provenh ighly useful, providing valuable solutions leading to enantiomerically enriched g,g-disubstituted butenolides. [5,6] Given the importance of g,g-disubstitutedb utenolides, we becamei nterested in the development of an alternative synthetic strategy for their preparation.…”

“…[6,7] Within this research area, the asymmetrico rganocatalysis [8] has provenh ighly useful, providing valuable solutions leading to enantiomerically enriched g,g-disubstituted butenolides. [5,6] Given the importance of g,g-disubstitutedb utenolides, we becamei nterested in the development of an alternative synthetic strategy for their preparation. It was envisioned that it may rely on the application of 5-alkylidenefuran-2(5H)-ones 1 [9] as their precursors (Scheme 1, middle).…”