Catalytic Asymmetric (4+3) Cyclizations of In Situ Generated ortho‐Quinone Methides with 2‐Indolylmethanols

Abstract

The first catalytic asymmetric (4+3) cyclization of in situ generated ortho‐quinone methides with 2‐indolylmethanols has been established, which constructed seven‐membered heterocycles in high yields (up to 95 %) and excellent enantioselectivity (up to 98 %). This approach not only represents the first catalytic asymmetric (4+3) cyclization of o‐hydroxybenzyl alcohols, but also enabled an unprecedented catalytic asymmetric (4+3) cyclization of 2‐indolylmethanols. In addition, a scarcely reported catalytic asymmetric (4+3) cyclization of para‐quinone methide derivatives was accomplished.

Cooperative Catalysis for the Highly Diastereo‐ and Enantioselective [4+3]‐Cycloannulation of ortho‐Quinone Methides and Carbonyl Ylides

“…Enantioselective [4+3]‐cycloadditions of o ‐QMs were first described independently by the groups of Scheidt and Ye under chiral NHC catalysis to produce benzoxopinones . Very recently, the first example of a phosphoric acid catalyzed enantioselective reaction of o ‐QMs with 2‐indolylmethanols as 1,3‐dipoles toward indolylbenzoxepins was established by Shi et al . An interesting study by the Lautens group described a purely Brønsted acid catalyzed diastereoselective synthesis of oxa‐bridged oxazocines through cycloaddition with isomünchnones …”

New Perspectives in the Indole Ring Functionalization using 2‐Indolylmethanols

“…The utilization of hydroxylated derivatives such as alcohols and phenols as nucleophilic reagents in the reaction with 2‐indolylmethanols has seldom been observed and is currently of very limited practical interest. In a very recent paper, the substitution of the hydroxy group in 2‐indolylmethanols 33 by a phenolic system is the last step of a catalytic asymmetric cyclization leading to optically active benzoxepine derivatives 115 and 116 in good yields and satisfactory enantioselectivities (Scheme ) . Reactions with 2‐hydroxybenzyl alcohols 113 involve the initial formation of o ‐quinone methides XLVI which in the presence of a chiral phosphoric acid 55b lead to the corresponding Friedel–Crafts adducts XLVII .…”

Catalytic Asymmetric (4+3) Cyclizations of In Situ Generated ortho‐Quinone Methides with 2‐Indolylmethanols

“…The absolute configuration of 3aa was determined to be S by single-crystal X-ray analysis. [18] (13)],w hich indicates that the two (4+ +3) cyclizations have similar mechanisms. Based on the control experiments and the absolute configurations of products, [18] we suggested apossible reaction pathway to explain the chemistry and stereochemistry of the reaction (Scheme 9).…”

“…As shown in Table 1, this reaction could be applicable to awide range of 2-indolylmethanols 1 (entries [1][2][3][4][5][6][7][8] and o-hydroxybenzyl alcohols 2 (entries 9-22) bearing different substituents,g enerating products 3 with regiospecificity in high yields and excellent enantioselectivity.Itisworth noting that 2-indolylmethanol 1h bearing two alkyl groups (i-Pr) could serve as asuitable substrate to give product 3ha in an acceptable yield and good enantioselectivity (entry 8). Notably,apart from aromatic groups (entries [13][14][15][16][17][18][19][20], aliphatic groups such as methyl and iso-propyl groups could successfully serve as suitable R 3 groups for substrates 2,w hich participated in the (4+ +3) cyclization in good yields and high enantioselectivity (entries 21-22).…”