Enantioselective Construction of Cyclic Indolyl α‐Amino Esters via a Friedel–Crafts Alkylation Reaction

Abstract

An enantioselective Friedel-Crafts alkylation reaction of indoles with cyclic N-sulfonyl ketimino esters was developed. Under the optimized conditions using a chiral copper(II) triflate-bisoxazoline complex as the catalyst, a range of N-sulfonyl ketimino ester derivatives and indoles reacted smoothly to afford indole-containing chiral cyclic aamino esters bearing tetrasubstituted a-stereogenicisothiazole 1,1-dioxides] in excellent yields and with high enantioselectivities (up to 99% ee). Pyrrole and N,N-dimethylaniline were also investigated as aromatic substrates to afford the corresponding products with good results. An asymmetric induction model was then proposed on the basis of the observed absolute configuration of the product 3-ethoxycarbonyl-3-(5-bromo-3-indolyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. Synthetic transformations to convert the products into cyclic chiral N-sulfonamido alcohols and the deprotection of the sulfonamides were performed. This study provides an efficient approach to chiral a-tetrasubstituted indolic a-amino acids as potential building blocks for peptides and biologically active molecules.

Construction of Benzylic Stereogenic Carbon Centers through Enantioselective Arylation Reactions

“…This reaction yielded cyclic indolylic α-amino esters in excellent enantioselectivities and good to excellent yields (Scheme 10). 17 Of note, an aniline and pyrrole were also successfully involved as substrates in this reaction leading to the desired adducts 16k and 16l in good to excellent enantioselectivities.…”

The Co(ii)/spiroBox-catalyzed enantioselective Mukaiyama-Mannich reaction for the synthesis of quaternary α-amino acid derivatives

“…The alkoxycarbonyl group of the cyclic N -sulfonyl imine was observed to be critical for high catalytic efficiency ( 1aa and 1ia vs. 1ja ), presumably due to the coordination of the oxygen atom of the carbonyl group and the nitrogen atom of the imine with the metal center having formed a five-membered intermediate, which enhanced the nucleophilic addition of enol silyl ether to the imine. 12 The stereochemical outcome can be explained using the proposed model shown in Scheme 6. First according to this model, intermediate a was generated as a result of the coordination of the imino ester and the spiroBox to Co( ii ) in an octahedral arrangement, which minimized any unfavorable steric interaction between the sulfonyl moiety of the imino ester and indane group on the oxazoline ring.…”

Zn (II)/spiroQuinox catalyzed asymmetric Friedel–Crafts alkylation of indoles with cyclic N‐sulfonyl ketimino esters

“…The benzosultam derivatives functionalized with C‐3 indole substituents are interesting targets for medicinal chemistry. [ 5b ] In recent years, two examples of asymmetric F–C alkylation have been reported by the research groups of Jia [ 9a ] and Lin. [ 9b ] High yields and excellent enantioselectivities were obtained by using of Cu/bisoxazoline complex or chiral phosphoric acid catalysts, respectively.…”

“…[ 5b ] In recent years, two examples of asymmetric F–C alkylation have been reported by the research groups of Jia [ 9a ] and Lin. [ 9b ] High yields and excellent enantioselectivities were obtained by using of Cu/bisoxazoline complex or chiral phosphoric acid catalysts, respectively. In this context, we report on a development of the benzosultam derivatives by catalyzed asymmetric F–C reaction of indoles and cyclic N ‐sulfonyl ketimino esters by newly created catalytic system based on a complex of Zn (II) and spiroQuinox ligand.…”