An Efficient Synthetic Method to Nonnatural α‐ and β‐Tryptophan Analogues via Friedel‐Crafts Alkylation of Indoles with Nitroacrylates

Abstract

The Friedel-Crafts alkylation of indoles with nitroacrylates could provide α-and β-tryptophan nitro-precursors, respectively, in moderate to good yields under Lewis acid catalysis. The diastereoselectivities of the reaction were enhanced by using 2-substituted indoles. The alkylation products could be easily transformed to nonnatural tryptophan derivatives.

Asymmetric Synthesis of β2-Tryptophan Analogues via Friedel–Crafts Alkylation of Indoles with a Chiral Nitroacrylate

“…The Friedel–Crafts alkylation of β-nitroacrylate ( R )- 2 with N -methylindole 10a (R 1 = CH 3 and R 2 = H), used as representative indole, was first carried out according to the protocol described by Chen et al, i.e., room temperature using copper(II) triflate, Cu(OTf) 2 (5 mol %) as Lewis acid (Scheme ). We used dry dichloromethane as solvent because of the low solubility of the β-nitroacrylate ( R )- 2 in diethyl ether.…”

“…To select the Lewis acid, which is assumed to form a 1,3-metal bonding species with the nitro functional group during Friedel–Crafts alkylation of nitroalkenes, , we evaluated other metal and lanthanide triflates.…”

“…Concerning β-tryptophan analogues 5 , the racemic 5-methoxy analogue (R 1 = R 3 = H and R 2 = 5-OCH 3 ) presents antihypertensive activity and has previously been obtained from the corresponding 3-indolylacetonitrile. More recently, the Friedel–Crafts alkylation of various indoles with the ( E )-methyl-3-nitroacrylate has been developed to provide racemic nitro precursors 6 of β-tryptophan derivatives 5 . The preparation of optically active compounds via ring-opening of chiral methyl N -Z-2-aziridine carboxylate with indoles has been reported to afford a mixture of optically active β-tryptophan methyl esters analogues 7 and the corresponding α-regioisomers 8 .…”

“…More recently, the FriedelÀCrafts alkylation of various indoles with the (E)-methyl-3-nitroacrylate has been developed to provide racemic nitro precursors 6 of β-tryptophan derivatives 5. 10 The preparation of optically active compounds via ring-opening of chiral methyl N-Z-2-aziridine carboxylate with indoles has been reported 11 to afford a mixture of optically active β-tryptophan methyl esters analogues 7 and the corresponding R-regioisomers 8. These two series of compounds were separated by repeated column chromatography.…”

Synthetic Approaches to 3-(2-Nitroalkyl) Indoles and Their Use to Access Tryptamines and Related Bioactive Compounds

“…Interaction of nitroalkenes with Lewis acids is by far the most exploited way of activation in their reaction with indoles. A suitable tuning of the Lewis acidity of the catalyst is possible so that a large variety of reaction conditions can be adopted for a successful FC process (Table ). − Among these catalysts, lanthanide salts have been proved to be rather efficient in promoting this reaction since their “hard” acidity make them particularly effective in the interaction with the negatively charged oxygen atoms of nitroalkenes.…”