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

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 alpha-amino esters bearing tetrasubstituted alpha-stereogenic centers [3-ethoxycarbonyl-3-(3-indolyl)-2,3-dihydrobenzo[d]isothiazole 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 alpha-tetrasubstituted indolic alpha-amino acids as potential building blocks for peptides and biologically active molecules.