Aldol Condensations on a 3-Alkylidene-2,5-diketopiperazine: Synthesis of Two Marine Natural Products

Published as part of the Special Section 9^th EuCheMS Organic Division Young Investigator Workshop

This work is dedicated to Prof. Leiv K. Sydnes on the occasion of his 70th birthday.

Abstract

The synthesis of two marine natural products containing a 3-alkylidene-6-arylidene-2,5-diketopiperazine scaffold by employing two consecutive aldol condensations starting with 1,4-diacetyl-2,5-diketopiperazine is reported. The target compounds contain a phenol or an imidazole group as aryl substituents, respectively, and suitable conditions for the aldol condensation of 1-acyl-3-alkylidene-2,5-diketopiperazine with the required functionalised aromatic aldehydes were developed. Provided the optimal base was used, introduction of the phenol group did not require use of a protecting group. Boc-protection was beneficial for introduction of the imidazole group, and conditions for carrying out the aldol condensation and Boc-deprotection in one step were identified. The stereochemistry of the target compounds was confirmed by NMR analysis.

Key words

2,5-diketopiperazine - natural product - total synthesis - ­aldol condensation

• References and Notes

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• 13 Experimental procedure and characterization data for 6 are in accordance with reference 6d.
• 14 Experimental procedure for the condensation of 6 with 4-hydroxybenzaldehyde: Compound 6 (100 mg, 0.5 mmol), 4-hydroxybenzaldehyde (58 mg, 0.5 mmol) and Cs₂CO₃ (163 mg, 0.5 mmol) were mixed in anhydrous degassed DMF (3 mL) and the reaction mixture was stirred at 80 °C for 6 h. After cooling to room temperature, crushed ice was added and the resulting white precipitate was isolated by filtration and washed with water. The solid material was dried in vacuo to give the title compound (57 mg, 42%) as a white solid. Characterisation data for 3 are in accordance with reference 9. See the Supporting Information for comparison. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.24 (s, 1 H), 9.80 (s, 1 H), 9.78 (s, 1 H), 7.36 (d, J = 8.6 Hz, 2 H), 6.79 (d, J = 8.6 Hz, 2 H), 6.67 (s, 1 H), 5.67 (d, J = 10.4 Hz, 1 H), 2.94 (dhept, J = 10.4, 6.5 Hz, 1 H), 0.97 (d, J = 6.5 Hz, 7 H); ¹³C NMR (101 MHz, DMSO-d ₆): δ = 158.1, 157.6, 157.6, 131.0, 125.4, 125.1, 124.01, 123.96, 115.6, 115.1, 23.9, 22.3. HRMS (ESI): m/z [M+Na]⁺ calcd for C₁₅H₁₆N₂O₃Na⁺: 295.1053; found: 295.1057.
• 15 Experimental procedure for the condensation of 6 with N-Boc-protected imidazole-5-carbaldehyde: Compound 6 (168 mg, 0.8 mmol), N-Boc imidazole-5-carbaldehyde (392 mg, 2.0 mmol), t-BuOK (185 mg, 1.65 mmol) and t-BuOH (1.7 mL) were added to a dried round-bottomed flask. The flask was evacuated, back-filled with argon and sealed with a septum before anhydrous DMF (6 mL) was added. The mixture was stirred at 80 °C for 8 h and then cooled to room temperature before the reaction mixture was partitioned between ethyl acetate (15 mL) and saturated aqueous NH₄Cl (15 mL). The aqueous layer was extracted further with ethyl acetate (2 × 15 mL) before the combined organic layers were dried over anhydrous Na₂SO₄, filtered and evaporated in vacuo until ca. 1 mL of an oily residue remained (containing residual DMF). The oily residue was purified by flash column chromatography, eluting with EtOAc, to give the title compound as a pale-yellow amorphous solid (116 mg, 59%). R_f  = 0.58 (EtOAc). Characterisation data for 4 are in accordance with reference 9. See the Supporting Information for comparison. ¹H NMR (500 MHz, DMSO-d₆): δ = 12.60 (s, 1 H), 11.73 (s, 1 H), 10.18 (s, 1 H), 7.95 (s, 1 H), 7.52 (s, 1 H), 6.60 (s, 1 H), 5.69 (d, J = 10.4 Hz, 1 H), 2.96 (dhept, J = 10.4, 6.5 Hz, 1 H), 0.97 (d, J = 6.5 Hz, 6 H); ¹³C NMR (126 MHz, DMSO-d ₆): δ = 157.3, 156.2, 136.5, 136.5, 125.4, 124.9, 124.7, 119.2, 104.4, 23.8, 22.2. HRMS (ESI): m/z [M – H]^– calcd for C₁₂H₁₃N₄O₂ ^–: 245.1044; found: 245.1041.
• 16 Use of 1.8 equiv of t-BuOK gave an estimated 1:0.6 ratio of 4 and deacetylated 6 in the crude product.