New Ugi/Pictet-Spengler Multicomponent Formation of Polycyclic ­Diketopiperazines from Isocyanides and α-Keto Acids

Abstract

A new four-component 1,4-diketopiperazine formation is described via an Ugi/Pictet-Spengler two-step procedure. The use of α-ketocarboxylic acids and homoveratryl isocyanide allows the formation of α-keto amides along with cyclised 6-hydroxy­piperazines. The mixtures are not separated but directly treated with trifluoroactic acid to afford a tricyclic 2,5-diketopiperazine in a ­Pictet-Spengler-type cyclisation.

Key words

diketopiperazine - isocyanide - multicomponent reaction - Ugi - Pictet-Spengler

References and Notes

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12

Typical Procedure (Given for 6a):
To a solution of 124 mg of o-nitrobenzaldehyde 2a (0.82 mmol, 1 equiv)and 60 mg of butylamine 3a (0.82 mmol,
1 equiv) in MeOH (800 µL, 1 M) were added 157 mg of homoveratryl isocyanide(4a) (0.82 mmol, 1 equiv) and
57 µL of pyruvic acid (1a, 0.82 mmol, 1 equiv) under inert argon atmosphere. The mixture was then stirred at r.t. during 2 h. After concentration under reduced pressure, the crude product was dissolved in 4 mL of TFA (0.2 M) and stirred at r.t. for 1 h. Flash chromatography (50-100% Et₂O-petroleum ether gradient) afforded the desired diketo-piperazine in a 69% overall yield as a mixture of two diastereomers in a 1:1.2 ratio.
Spectroscopic Data for DKP 6a:
Major diastereomer: ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (d, J = 7.8 Hz, 1 H), 7.78 (s, 1 H), 7.40 (dt, J = 3.8, 7.6 Hz, 2 H), 6.74 (d, J = 7.6 Hz, 1 H), 6.55 (s, 1 H), 6.25 (s, 1 H), 4.69 (q, J = 7.8 Hz, 1 H), 4.11 (q, J = 7.8 Hz, 1 H), 3.92 (s, 3 H), 3.86 (s, 3 H), 3.22 (dt, J = 4.3, 12.6 Hz, 1 H), 2.79-2.64 (m, 2 H), 2.60 (d, J = 10.6 Hz, 1 H), 2.02 (s, 3 H), 1.67-1.57 (m, 2 H), 1.39-1.27 (m, 2 H), 0.91 (t, J = 7.3 Hz). ¹³C NMR (100.6 MHz, CDCl₃): δ = 167.8, 163.8, 150.6, 148.8, 147.8, 133.3, 133.1, 132.2, 129.7, 129.6, 126.1, 125.7, 111.9, 109.3, 62.8, 58.1, 56.4, 56.2, 46.2, 37.8, 31.5, 29.0, 27.7, 20.4, 14.2.
Minor diastereomer: ¹H NMR (400 MHz, CDCl₃): δ = 7.91 (d, J = 7.8 Hz, 1 H), 7.74 (s, 1 H), 7.64 (dt, J = 1.2, 7.8 Hz, 1 H), 7.53 (dt, J = 1.2, 7.8 Hz, 1 H), 7.26 (d, J = 7.8 Hz, 1 H), 6.50 (s, 1 H), 6.20 (s, 1 H), 4.65 (q, J = 7.8 Hz, 1 H), 4.05 (q, J = 7.8 Hz, 1 H), 3.99 (s, 3 H), 3.94 (s, 3 H), 3.05 (q, J = 9.8 Hz, 1 H), 2.79-2.64 (m, 2 H), 2.60 (d, J = 10.6 Hz, 1 H), 1.98 (s, 3 H), 1.67-1.57 (m, 2 H), 1.39-1.27 (m, 2 H), 0.83 (t, J = 7.3 Hz). ¹³C NMR (100.6 MHz, CDCl₃): δ = 168.7, 163.73, 150.9, 148.8, 147.5, 133.2, 133.1, 131.5, 129.9, 129.1, 126.7, 126.1, 111.6, 111.3, 62.8, 58.4, 56.5, 56.2, 46.1, 37.8, 31.6, 29.0, 28.5, 20.3, 14.0. IR: ν = 2928, 2312, 1653, 1513, 1424, 1354, 1256 cm^-1. HRMS: m/z calcd for C₂₅H₂₉O₆N₃: 467.2056; found: 467.2052.