Synthesis of Chiral Tryptamines via a Regioselective Indole Alkylation

Abstract

A practical synthesis of chiral tryptamines from simple, unprotected indoles has been developed. Indole nucleophiles prepared with MeMgCl in the presence of CuCl reacted with chiral cyclic sulfamidates almost exclusively at the C-position of indole to form a variety of α- and/or β-substituted chiral tryptamines in good yield with excellent regioselectivity. The utility of this simple alkylation process has been demonstrated with the practical synthesis of two biologically active targets, cipargamin and TIK-301, which were completed in three steps, starting from the corresponding indole starting materials.

Efficient Manufacturing Process for the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) via a Crystallization-Driven Diastereoselective Pictet–Spengler Condensation

“…Several approaches to the synthesis of tryptamine 11 were investigated, including chiral resolution of racemic tryptamine 13 , regioselective CuCl-mediated alkylation of indole ( 14 ) with cyclic sulfamidate 15 , and Larock indolization of 2-bromoaniline ( 17 ) and alkyne 18 (Scheme ).…”

“…We also attempted to develop a synthesis of tryptamine 11 that employs the indole alkylation chemistry that we discovered previously . Cyclic sulfamidate 15 was readily synthesized from amino alcohol 19 in 57% yield in two steps, cyclization with SOCl 2 and RuCl 3 -catalyzed oxidation.…”

Catalyst-Controlled Regioselective Chlorination of Phenols and Anilines through a Lewis Basic Selenoether Catalyst

“…The NMR spectra match the literature precedence. 46 The product was dissolved in anhydrous DCM (∼50 mL, 0.5 M). Et 3 N was syringed (4.8 mL, 34.5 mmol, 1.5 equiv) into the solution, and the reaction was cooled down to 0 °C.…”

Microwave-Assisted Synthesis of 2-Methyl-1H-indole-3-carboxylate Derivatives via Pd-Catalyzed Heterocyclization

“…For instance, 3-nitroindoles are essential structural moiety for the development and synthesis of novel antidiabetic agents [19], whereas halogenated indoles represent a key structural moiety of human 15-lipoxygenase-1 inhibitors [20], and indole-3-carboxylic acids, along with their related esters, are key moieties for mast cell tryptase inhibitors [21]. As part of chiral-indole-based skeletons, there are chiral tryptamines that constitute bioactive molecules acting in the central nervous system [22], while many axially chiral indoles have proved potent anticancer activity [23]. An efficient route to obtain indole-3-carboxylate derivatives from several substituted anilines has been developed by Wurtz et al by performing palladium-catalyzed intramolecular oxidation [24].…”