Catalytic Asymmetric Inverse‐Electron‐Demand Oxa‐Diels–Alder Reaction of In Situ Generated ortho‐Quinone Methides with 3‐Methyl‐2‐Vinylindoles

Abstract

The first catalytic asymmetric inverse-electron-demand (IED) oxa-Diels-Alder reaction of ortho-quinone methides, generated in situ from ortho-hydroxybenzyl alcohols, has been established. By selecting 3-methyl-2-vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r., 99.5:0.5 e.r.). The utilization of ortho-hydroxybenzyl alcohols as precursors of dienes and 3-methyl-2-vinylindoles as dienophiles, as well as the hydrogen-bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa-Diels-Alder reaction.

Multiple Hydrogen‐Bond Activation in Asymmetric Brønsted Acid Catalysis

“…[17] DFT calculations provided insighti nto the activation mode and nature of the interactions between the N-triflylphosphoramide catalysta nd the generated aza-o-QM. Activation of the aza-o-QM by Hbondingc oordination to the imine group and stabilization of the methylene carbon atom by the catalyst resultsi nm orestable complex A.S ubsequent endo approach of the styrene via an opent ransition state furnishes enantioenriched THQ 3 and regenerates the chiral Brønsted acid catalyst (Scheme 5).…”

Catalytic Asymmetric Inverse‐Electron‐Demand Hetero‐Diels−Alder Reactions

“…With o ‐hydroxybenzyl alcohols 102 as the precursors of o ‐quinone methides, the catalytic asymmetric IEDHDA reactions of 3‐methyl‐2‐vinylindoles 103 with in situ generated o ‐quinone methides were developed by Shi's group in 2015 (Scheme ) . Catalyzed by chiral phosphoric acid 105 , a range of chromans 104 with three adjacent stereogenic centers were obtained in up to 99 % yield, >95:5 d.r., and 99 % ee.…”

Organocatalytic Domino Oxa‐Michael/1,6‐Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds

“…[2] Thepodophyllotoxin analogue NSC 381582 exhibits antineoplastic activity; [3] (+ +)-hematoxylin is used as as tain in histology and is ap otent protein tyrosine kinase inhibitor. [9] Whereas the aforementioned reports have realized high efficiency and stereoselectivity,o nly limited reaction partners,s uch as enamides, [7a] electron-rich olefins, [8,9] and oxonium ylides, [7b] were reacted with o-QMs to construct aryl-substituted chroman frameworks.Therefore,developing additional methods that are not based on o-QM intermediates is still highly desirable. [5] Accordingly,s everal asymmetric reactions to approach this privileged skeleton have been developed over the years.O ne of these,t he strategy based on ortho-quinone methides (o-QMs), [6] has been shown to be very viable and reliable by the research groups of Schneider, [7] Rueping, [8] and Shi.…”