Catalytic Asymmetric Aza-ene Reaction of 3-Indolylmethanols with Cyclic Enaminones: Enantioselective Approach to C3-Functionalized Indoles

Abstract

The catalytic asymmetric aza-ene reactions of 3-indolylmethanols with cyclic enaminones and the highly enantioselective aza-ene reactions utilizing cyclic aza-ene components have been established, which directly assemble isatin-derived 3-indolylmethanols and dimedone-derived enaminones into C3-functionalized chiral indoles with one all-carbon quaternary stereogenic center in high yields and excellent enantioselectivities (up to 99% yield, up to 95:5 er).

Reaction of indoles with aromatic fluoromethyl ketones: an efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K2CO3/n-Bu4PBr in water

“…(1H-Indol-3-yl)methanols have emerged as versatile pre-electrophiles for C-C functionalization at the position 3 of indoles [1][2][3][4]. Friedel-Crafts alkylation of (1H-indol-3-yl)methanols with indoles has proven to be a powerful strategy for the preparation of biologically important 3,3′-diindolylmethanes (DIMs) [5][6][7][8][9][10][11][12][13][14].…”

“…Friedel-Crafts alkylation of (1H-indol-3-yl)methanols with indoles has proven to be a powerful strategy for the preparation of biologically important 3,3′-diindolylmethanes (DIMs) [5][6][7][8][9][10][11][12][13][14]. Additionally, (1H-indol-3-yl)methanols have been used as key precursors for the construction of complex indole derivatives that would be useful in pharmaceuticals as drugs and agrochemicals [2][3][4][5][6][7][8][9][10][11][12][13][14]. The simple (1H-indol-3-yl)methanol, a break-down product of glucobrassicin, which can be found in cruciferous vegetables [15], has a wide range of biomedical applications as an anticancer [16], antioxidant, and antiatherogenic agent [17].…”

Enantioselective synthesis of mixed 3,3′-bisindoles via a phosphine-catalyzed umpolung γ-addition of 3′-indolyl-3-oxindoles to allenoates

“…From a synthetic viewpoint, preparation of optically enriched mixed 3,3 0 -bisindole structures is a long-standing and challenging task, especially in view of the presence of an all-carbon quaternary stereogenic center at the indole C 3 -position [15][16][17][18][19][20]. In recent years, various synthetic strategies have been developed for their asymmetric synthesis, including: 1,4-conjugate additions or epoxide-opening via Friedel-Crafts reactions of indoles [21][22][23][24], Rh-or Ru-mediated multicomponent tandem reactions [25][26][27], as well as nucleophilic substitutions of various 3-indolylmethanols and their structural analogues [28][29][30][31][32][33][34][35][36]. Undoubtedly, given the extreme synthetic value of the mixed 3,3 0 -bisindole motifs, there still exists an urgent need to devise efficient approaches for their enantioselective synthesis, especially those methods amenable for the preparation of a broad spectrum of natural products.…”

“…The 3 0 -indolyl-3-oxindoles appear to be ideal prochiral pronucleophiles, the hydrogen atom at the oxindole 3-position is sufficiently acidic for basic abstraction, thus allowing for subsequent reactions to take place. The reactivity inversion of substrates is appealing: 3 0 -indolyl-3oxindoles serve as a nucleophilic partner, as opposed to many existing methods [28][29][30][31][32][33][34][35][36] employing leaving group-bearing 3,3 0bisindoles as an electrophile. Moreover, in addition to allenoates, other electrophilic partners could also be utilized, therefore greatly broadening the reaction scope, making a diverse range of target molecules synthetically accessible.…”

Formal Asymmetric Organocatalytic [3+2] Cyclization between Enecarbamates and 3‐Indolylmethanols: Rapid Access to 3‐Aminocyclopenta[b]indoles

“…[3+ +2] cycloaddition reactiono f3 -indolylarylmethanols and 3vinylindole, which could concisely furnish cyclopenta [b]indole in one synthetic operation, albeit with moderate selectivity (enantiomeric excess( ee) < 10 %). [4c] Subsequent to this, Shi et al developed an efficient asymmetric [ 3 + + 2] cyclization of 3hydroxy-3-indolyl-oxindoles with 3-methyl-2-vinylindoles [4d] or 3-methyl-7-vinylindoles [4e] in the presence of chiral phosphoric acid, leadingt os pirocyclic compounds with good enantioselectivity.D espite thesee legant achievements, there is no convenient enantioselective [3+ +2] cycloaddition for the preparation of cyclopenta [b]indoles.I nc ontinuation of our research program in catalytic asymmetric cycloaddition with enamides, [5] we envisaged that the combination of ac hiral phosphoric acid catalyst [6] and a3 -indolylarylmethanol would result in the formation of an alkylideneindoleninium ion, [3,7,8] which would then undergo enantioselective [3+ +2] cycloaddition with the polarized enamide double bond (Scheme 1). [9] Herein, we report ah ighly diastereo-and enantioselective one-pot [3+ +2] cycloaddition route to the synthesis of 3-aminocyclopenta[b]indoles with ab road scope (Scheme 1).…”