Chiral Phosphoric Acid-Catalyzed Enantioselective Construction of 2,3-Disubstituted Indolines

Abstract

Highly enantio-and regioselective selective (3 + 2) formal cycloaddition of b-substituted ene-and thioenecarbamates as well as cyclic enamides with quinone diimides catalyzed by a BINOL-and SPINOL-derived phosphoric acid has been reported. A wide variety of 2-amino 2,3-disubtituted indolines, including polycyclic ones, were prepared in generally high yields (up to 98%) with moderate to complete diastereoselectivities and in most cases excellent enantioselectivities (up to 99% ee).Chiral 2,3-disubstituted indolines are privileged heterocyclic rings frequently encountered in various natural bioactive alkaloids (such as (-)-physostigmine, (+)-aspidospermidine and pircrinine, Figure 1) 1 and biologically active drugs (such as pentopril and relcovaptan). 2 In addition, they have been successfully employed as chiral auxiliaries and organocatalysts in asymmetric synthesis. 3 As a result, several asymmetric catalytic approaches have been established for the construction of indoline rings. 4 Despite these elegant achievements, the development of novel asymmetric synthetic routes of 2,3disubstituted indolines is still highly desirable.

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

“…Masson and co-workers developed the organocatalytic asymmetric construction of 2,3-disubstituted indolines by enantio-and regioselective [3 + 2] formal cycloaddition of βsubstituted ene-and thioenecarbamates (31) and of cyclic enamides (32) with quinone diimides (30) in 2021. [41] Using CPA, a wide range of quinone diimides, enecarbamates and thioenecarbamates were accommodated in the enantioselective formal (3 + 2) cycloaddition to provide highly enantio-and diastereoselective 2,3-disubstituted indolines (33 or 34) in generally high yields (up to 98 %) with moderate to complete diastereoselectivities and in most circumstances excellent enantioselectivities (up to 99 % ee) (Scheme 10). The authors used crude 1 H NMR spectra of aldehyde traces resulting from the hydrolyzed imine intermediate to confirm the mechanistic pathway, and they explained that the mechanism of the reaction involves Michael addition to form In-10, isomerization to form In-11, and subsequently underwent intramolecular aminalization to generate a desired product 33 (Scheme 10).…”

“…Masson and co‐workers developed the organocatalytic asymmetric construction of 2,3‐disubstituted indolines by enantio‐ and regioselective [3+2] formal cycloaddition of β‐substituted ene‐ and thioenecarbamates ( 31 ) and of cyclic enamides ( 32 ) with quinone diimides ( 30 ) in 2021 [41] …”

Enamides and dienamides in phosphoric acid-catalysed enantioselective cycloadditions for the synthesis of chiral amines

“…Very recently, we further extended the developed (3 + 2)cycloaddition reactions to the quinone diimines 64, 64 providing an efficient manner to a wide range of 2,3-disubstituted indolines 65 and 66. 65 In the presence of chiral phosphoric acid catalysts with BINOL or SPINOL backbones, quinone diimines 64 reacted with β-substituted enecarbamates 1 and with cyclic enamides 50 to produce a diversity of highly enantiomerically enriched indolines in high yield with moderate to excellent diastereoselectivity.…”

Organocatalytic cycloaddition–elimination cascade for atroposelective construction of heterobiaryls

“…However, several challenges were still imbedded in this strategy, including (1) finding a feasible leaving group with catalytic sites to activate arylethylene substrates; (2) selecting powerful catalysts to increase the reactivity and promote elimination of the leaving group as well; (3) efficiently inducing stereocontrol in the sequential cycloaddition and elimination steps. To address these challenges, the alkoxycarbonylamino group was selected as the leaving group because enecarbamates have long served as a reactive dipolarophile to deliver enantioenriched compounds bearing contiguous chiral centers, 16 especially upon activation by chiral phosphoric acid (CPA). 16 c–i In addition, the elimination of carbamate has proven to be feasible under strong acidic conditions; 17 here CPA is expected to serve as an acid to realize the elimination.…”