Pictet−Spengler Based Synthesis of a Bisarylmaleimide Glycogen Synthase Kinase-3 Inhibitor

Abstract

A practical synthesis of the glycogen synthase kinase-3 (GSK3) inhibitor bisarylmaleimide 1 has been accomplished employing Pictet-Spengler methodology to access the indole 7-position in preparing the benzodiazepine tricyclic fragment. A seven-step linear sequence that starts with commercially available 5-fluoroindole 7 affords the bisarylmaleimide 1 in 33% overall yield.

Biocatalytic Organic Synthesis of Optically Pure (S)-Scoulerine and Berbine and Benzylisoquinoline Alkaloids

“…The synthesis of racemic 1-substituted tetrahydroisoquinolines 1 usually relies on one out of three different strategies: (i) formation of the C1–C8a bond of the isoquinoline core employing either the Pictet–Spengler or the Bischler–Napieralski cyclization, (ii) alkylation at position C1 of the isoquinoline via nucleophilic or electrophilic activation, and (iii) formation of the C4–C4a bond by a Pomeranz–Fritsch reaction (Scheme ) . The first two approaches are particularly appealing since the target molecule is disconnected at central bonds leading to simple starting materials.…”

Bartoli Indole Synthesis

“…A selection of these reactions is shown in Table 4 [31][32][33][34][35][36][37][38]. A selection of these reactions is shown in Table 4 [31][32][33][34][35][36][37][38].…”

Characterization of Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitors as Stimulators of Steroidogenesis

“…Amide coupling of the maleimides with the appropriate carboxylic acids using N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC•HCl) and HOBt as the coupling reagent or treatment with carbamoyl chlorides gave the target compounds 27−31. For the bromo analogue 26 (Scheme 4), 5-bromoindoline 44 was first alkylated with 2chloroethylamine hydrochloride using potassium carbonate as a base in DMF in a pressure tube and treated with aqueous formaldehyde in acetic acid and sulfuric acid, 35 followed by Boc protection. The resultant (tert-butyl 9-bromo-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxylate) 45 was subsequently treated with DDQ, followed by glyoxylation, condensation with benzofuran-3-yl-acetamide, and Boc deprotection to yield the final maleimide 26.…”