Ugi Four-Component Reaction with Tandem Deprotection, Cyclization and Pictet–Spengler Reaction: A Concise Route to N-Fused Polycyclic Indoledi­ketopiperazine Alkaloid Analogues

Abstract

Aza-fused polycyclic indolediketopiperazine alkaloids are of potential interest due to their broad range of biological activities. Traditionally, a number of methods have been used to generate N-fused polycyclic indolediketopiperazine skeletons, but the need to develop novel, concise methods with which to modify the substitution pattern continues. Herein, we describe the two-step formation of N-fused polycyclic indolediketopiperazine alkaloid analogues by the application of the Ugi four-component reaction with tandem deprotection, cyclization and Pictet–Spengler reaction.

Key words

alkaloids - Ugi reaction - tandem reactions - deprotection - cyclization - Pictet–Spengler reaction

• References and Notes

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• 8 See the Supporting Information.
• 9 Synthesis of Ugi Products 31a and 31b; General Procedure: To a solution of N-Boc protected l-tryptophan 30 (1 mmol), glycine ester 27 (1 mmol), and paraformaldehyde 29 (1.2 mmol) in methanol (3 mL) was added isocyanide 28 (1 mmol) in a 10 mL reaction glass vial containing a stirring bar. The vial was sealed tightly with a Teflon cap and placed in a microwave cavity (33 W) for 30 min at a pre-selected temperature of 60 °C. After completion of the reaction (indicated by TLC), the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (hexane–EtOAc) to afford the corresponding products. Synthesis of Cyclized Products 33a–i; General Procedure: The Ugi-4CR products (1 mmol) were dissolved in 10% TFA in DCE (3 mL) and the corresponding aromatic aldehydes (1.5 mmol) were added in a 10 mL reaction glass vial containing a stirring bar, the vial was sealed tightly with a Teflon cap and placed in a microwave cavity for 15 min at a pre-selected temperature of 90 °C. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was evaporated and the residue was neutralized with saturated NaHCO₃, extracted with EtOAc (20 mL) and the combined organic layer was washed with water (10 mL) and dried over sodium sulfate. EtOAc was removed under reduced pressure and the crude material was purified by column chromatography (CHCl₃–MeOH) to afford the cyclized products 33a–i in 61–39% yield. Spectroscopic Data for 33a: Yield: 61%; solid. ¹H NMR (300 MHz, CDCl₃): δ = 8.14 (s, 1 H), 7.56 (d, J = 7.2 Hz, 1 H), 7.34–7.15 (m, 7 H), 7.05 (s, 1 H), 5.69 (s, 1 H), 4.55–3.98 (m, 4 H), 3.74–3.51 (m, 2 H), 3.09 (t, J = 12.3 Hz, 1 H), 1.37 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃): δ = 166.5, 166.1, 162.2, 137.0, 136.7, 135.2, 130.4, 129.4, 126.5, 123.2, 120.5, 118.8, 111.5, 109.5, 52.8, 52.2, 51.7, 51.2, 50.4, 29.1, 27.8; HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₈ClN₄O₃: 479.1850; found: 479.1842.