Regio‐ and Enantioselective (3+3) Cycloaddition of Nitrones with 2‐Indolylmethanols Enabled by Cooperative Organocatalysis

Abstract

The regio‐ and enantioselective (3+3) cycloaddition of nitrones with 2‐indolylmethanols was accomplished by the cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA). Using this approach, a series of indole‐fused six‐membered heterocycles were synthesized in high yields (up to 98 %), with excellent enantioselectivities (up to 96 % ee) and exclusive regiospecificity. This approach enabled not only the first organocatalytic asymmetric (3+3) cycloaddition of nitrones but also the first C3‐nucleophilic asymmetric (3+3) cycloaddition of 2‐indolylmethanols. More importantly, theoretical calculations elucidated the role of the cocatalyst HFIP in helping CPA control the reactivity and enantioselectivity of the reaction, demonstrating a new mode of cooperative catalysis.

Green Efficient One-Pot Synthesis and Separation of Nitrones in Water Assisted by a Self-Assembled Nanoreactor

“…Nitrones are 1,3-dipoles of the allyl anion type, used to synthesize isoxazolidines by reaction with dipolarophiles, such as alkenes and acetylenes [ 9 , 10 ]. Generally, nitrones are obtained in dry conditions and purified employing a chromatographic column [ 11 ]. The tetrahedral capsule as a confining nanoreactor allowed us to synthesize these substrates using water as a solvent and separate them by extractions with organic solvents.…”

Organocatalytic Asymmetric [2 + 4] Cycloadditions of 3-Vinylindoles with ortho-Quinone Methides

“…To fulfill this task and in continuation of our ongoing efforts in the enantioselective synthesis of indole-based chiral heterocycles [32][33][34][35], we designed a chiral phosphoric acid [36][37][38][39][40][41][42][43][44] (CPA)-catalyzed asymmetric [2 + 4] cycloaddition of 3-vinylindoles with ortho-quinone methides (o-QMs) and their precursors (Figure 4). The o-QMs were selected To fulfill this task and in continuation of our ongoing efforts in the enantioselective synthesis of indole-based chiral heterocycles [32][33][34][35], we designed a chiral phosphoric acid [36][37][38][39][40][41][42][43][44] (CPA)-catalyzed asymmetric [2 + 4] cycloaddition of 3-vinylindoles with ortho-quinone methides (o-QMs) and their precursors (Figure 4). The o-QMs were selected as suitable reaction partners because of their high reactivity as oxa-dienes in catalytic asymmetric cycloadditions [45][46][47][48][49][50][51][52][53][54][55][56][57][58]…”

“…This dual activation mode of CPA facilitates regioselective and enantioselective [2 + 4] cycloaddition between 3-vinylindoles 1 and o-QMs 2, thus affording the chiral indole-containing chroman derivatives 3. To fulfill this task and in continuation of our ongoing efforts in the enantioselective synthesis of indole-based chiral heterocycles [32][33][34][35], we designed a chiral phosphoric acid [36][37][38][39][40][41][42][43][44] (CPA)-catalyzed asymmetric [2 + 4] cycloaddition of 3-vinylindoles with ortho-quinone methides (o-QMs) and their precursors (Figure 4). The o-QMs were selected as suitable reaction partners because of their high reactivity as oxa-dienes in catalytic asymmetric cycloadditions [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63].…”

Simple amino silyl ether organocatalyst for asymmetric hetero Diels–Alder reaction of isatins with enones

“…Recently, asymmetric cooperative catalysis has attracted immense interest, in which two catalysts work simultaneously to form products which cannot be accomplished by the use of a single catalyst alone. [23][24][25][26][27][28] Most recently, we have also reported a simple two catalysts component system consisting of a primary β-amino alcohol B as a catalyst and N-protected amino acid C as a cocatalyst for this asymmetric hDA reaction. 29 This dual component system showed efficient catalytic activity affording the chiral spirooxindole-tetrahydropyranone Z, which acts as a synthetic precursor for many biologically active compounds.…”

“…Recently, asymmetric cooperative catalysis has attracted immense interest, in which two catalysts work simultaneously to form products which cannot be accomplished by the use of a single catalyst alone 23–28 . Most recently, we have also reported a simple two catalysts component system consisting of a primary β‐amino alcohol B as a catalyst and N ‐protected amino acid C as a co‐catalyst for this asymmetric hDA reaction 29 .…”