Enantioselective and Diastereodivergent Synthesis of Spiroindolenines via Chiral Phosphoric Acid-Catalyzed Cycloaddition

Abstract

A diastereodivergent and enantioselective synthesis of chiral spirocyclohexyl-indolenines with four contiguous stereogenic centers is achieved by a chiral phosphoric acid catalyzed cycloaddition of 2-susbtituted 3-indolylmethanols with 1,3-dienecarbamates. Modular access to two different diastereoisomers with high enantioselectivities was obtained by careful choice of reaction conditions. Their functional group manipulation provides an efficient access to enantioenriched spirocyclohexyl-indolines and -oxindoles. The origins of this stereocontrol have been identified using DFT calculations, which reveal an unexpected mechanism compared to our previous work dealing with enecarbamates.

Asymmetric Brønsted Acid Catalyzed Cycloadditions of ortho-Quinone Methides and Related Compounds

“…Indeed, the Masson group nicely showed that 2-alkylindole-3-carbinols 61 , upon activation with a chiral phosphoric acid and reaction with dienecarbamates 59 at low temperature, furnished spirocyclohexyl indolenines 62 with good yields and excellent enantio- and dia­stereoselectivities across a broad substrate range (Scheme 18 ). 43 Interestingly, at elevated temperature, a different dia­stereomer 63 was formed exclusively with full retention of enantioselectivity, suggesting that a thermodynamic equilibration occurred at elevated temperature via a retro-Friedel–Crafts reaction. On the other hand, at low temperature, the kinetically preferred stereoisomer had likely been formed.…”

“…Scheme18 [2+4]-Cycloadditions of 2-alkylindole-3-carbinols 61 with 1-amino-substituted 1,3-butadienes 5943 …”

Chiral Phosphoric Acid‐Catalyzed Enantioselective Formal [4+2] Cycloaddition Between Dienecarbamates and 2‐Benzothioazolimines

“…As such, Bernardi et al reported the use of simple unsubstituted dienecarbamates [12] in Povarov reaction leading to the synthesis of 1,2,3,4-tetrahydroquinolines (Scheme 1b, right). [13] In continuation of our research program in catalytic asymmetric reactions with dienecarbamates, [14] we decided to explore their reactivities in connection with 2-benzothiazolimines. Indeed, these imines are versatile synthetic intermediates used for the syntheses of various heterocycles [15] and they have been embedded in direct catalytic asymmetric annulation strategies.…”

Asymmetric Cycloaddition/Annulation Reactions by Chiral Phosphoric Acid Catalysis: Recent Advances

“…[47] By using 10 mol% of TRIP catalyst (S-Cat. 8), an array of enecarbamates (57) with substitutions in para-, meta-and ortho-position of the aryl group of the olefin were included in this annulation reaction and the corresponding 2,3,4-trisubstituted chroman products (58) were obtained in high yields with high enantioselectivities and diastereoselectivities (Scheme 17). In addition, a range of o-hydroxybenzyl alcohols (56) with variations of both the quinone methide fragment and the β-aryl substituent could be used in this reaction to generate chroman products bearing three stereogenic centers and could therefore be used in natural product synthesis.…”

“…In 2021, Masson and co-workers established the chiral phosphoric acid catalyzed diastereodivergent and enantioselective construction of chiral spirocyclohexyl-indolenines (82). [58] The vinylindoliniminium ion (In- center, with excellent enantioselectivities and diastereoselectivities. By carefully selecting reaction conditions, the authors obtain two distinct diastereoisomers with high enantioselectivities (Scheme 25).…”