A Mild and Convenient Base-Catalysed Approach to Disubstituted Epidithiodiketopiperazines

Abstract

A novel base-catalysed approach to disubstituted epidithiodiketopiperazines (ETP) is described. The synthetic route involves a multicomponent reaction of a diacetoxyacetamide with a range of different amines and p-methoxybenzylmercaptan to generate the protected ETP core.

Key words

epidithiodiketopiperazine - multicomponent reactions - chaetocin - gliotoxin - chetomin

• References and Notes

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• 8 General Procedures Method A: n-Butylamine (0.18 mL, 1.82 mmol) was added to a solution of diacetate 7 (0.31 g, 0.61 mmol) in MeCN (30.0 mL) followed by addition of p-methoxybenzyl-mercaptan (0.13 mL, 0.91 mmol) and the resulting mixture was stirred for 2 min. DMAP (0.04 g, 0.30 mmol) was added in a single portion and the resulting mixture was heated at reflux for 16 h, cooled to r.t. and the solvent was removed under reduced pressure. Purification via Biotage™ Horizon [petroleum spirit (40–60 °C)–EtOAc, 3:1; snap 25 g] gave protected ETP 8 (0.28 g, 80%) as a colourless solid (see ref. 1). Method B: 3-Chlorobenzylamine (0.13 mL, 1.07 mmol) was added to a solution of diacetate 7 (0.18 g, 0.36 mmol) in MeCN (5.00 mL) followed by addition of p-methoxybenzyl-mercaptan (0.07 mL, 0.53 mmol) and the resulting mixture was stirred for 2 min. DMAP (0.02 g, 0.18 mmol) was added and the mixture was heated in the microwave at 150 °C for 5 min, allowed to cool to r.t. and the solvent was removed under reduced pressure. Purification via Biotage™ Horizon [petroleum spirit (40–60 °C)–EtOAc, 3:1; snap 25 g] gave 1-benzyl-4-(3-chlorobenzyl)-3,6-bis[(4-methoxybenzyl)thio]-piperazine-2,5-dione (0.15 g, 68%) as a colourless solid (see ref. 1). Method C: Ethyl 4-aminobutanoate hydrochloride (0.10 g, 0.61 mmol) was added to a solution of diacetate 7 (0.24 g, 0.47 mmol) in MeCN (3 mL) followed by addition of Et₃N (0.34 mL, 2.45 mmol) and p-methoxybenzylmercaptan (0.10 mL, 0.73 mmol) and the resulting mixture was stirred for 2 min. DMAP (0.04 g, 0.31 mmol) was added and the mixture was heated in the microwave at 130 °C for 30 min, allowed to cool to r.t. and the solvent was removed under reduced pressure. Purification via Biotage™ Horizon [petroleum spirit (40–60 °C)–EtOAc, 3:1; snap 25 g] gave ethyl 4-{4-benzyl-2,5-bis[(4-methoxybenzyl)thio]-3,6-dioxopiperazin-1-yl}butanoate (0.11 g, 28%) as a colourless solid; mp 105–107 °C. IR: 2931, 1730, 1674 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.13 (t, J = 7.1 Hz, 3 H, OCH₂CH ₃), 1.31–1.51 (m, 2 H, CH ₂CO₂CH₂CH₃), 1.93–2.02 (m, 2 H, NCH ₂CH₂), 2.54–2.66 (m, 1 H, NCH ₂CH₂), 3.41–3.54 (m, 2 H, NCH₂Ph), 3.70 (d, J = 12.2 Hz, 1 H, SCH₂), 3.73 (s, 3 H, OMe), 3.76 (s, 3 H, OMe), 3.78–3.83 (m, 1 H, SCH₂), 3.85 (d, J = 13.9 Hz, 1 H, SCH₂), 3.90–4.01 (m, 3 H, CO₂CH ₂CH₃, SCH₂), 4.39 (s, 1 H, CHS), 4.21 (s, 1 H, CHS), 5.08 (d, J = 14.5 Hz, 1 H, NCH₂), 6.61–6.65 (m, 2 H, ArH), 6.77–6.81 (m, 2 H, ArH), 6.80–6.84 (m, 2 H, ArH), 7.03–7.09 (m, 2 H, ArH), 7.11–7.13 (m, 1 H, ArH), 7.23–7.27 (m, 2 H, ArH), 7.30–7.34 (m, 2 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 14.04 (CO₂Et), 21.95 (CH₂), 31.29 (CH₂), 36.10 (SCH₂), 36.80 (SCH₂), 43.13 (CH₂), 46.00 (CH₂), 55.14 (OMe), 55.15 (OMe), 57.23 (CHS), 59.26 (CHS), 60.24 (CO₂Et), 113.96 (ArH), 114.01 (ArH), 127.72 (ArH), 128.46 (ArH), 128.52 (ArH), 128.56 (C), 128.73 (C), 130.60 (ArH), 130.67 (ArH), 134.84 (C), 159.01 (C), 159.03 (C), 164.92 (C), 165.07 (C), 172.26 (C). MS: m/z = 645 (100%) [M + Na]⁺. HRMS: m/z [M + Na]⁺ calcd for C₃₃H₃₈N₂O₆S₂Na: 645.2069; found: 645.2069.