Synthesis of a Malimide Analogue of the Telomerase Inhibitor UCS1025A Using a Dianionic Aldol Strategy

Abstract

The synthesis of a simplified analogue of UCS1025A via an aldol coupling is described.

Key words

aldol reactions - Diels-Alder reactions - imides - natural products - total synthesis

References and Notes

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11

Typical Procedure: THF (4.5 mL) was cooled to 0 °C and NaHMDS (1.02 mL, 2.0 M in THF, 2.05 mmol) was added. To this solution the benzyl-protected (S)-3-hydroxy-pyrrolidine-2,5-dione (0.20 g, 0.97 mmol) in THF (3.2 mL) was added dropwise and after complete addition the solution was stirred at 0 °C for an additional 5 min to give a yellowish suspension. The reaction mixture was cooled to -78 °C, cyclohexyl carbaldehyde (0.12 mL, 0.97 mmol) in THF (2.2 mL) was added dropwise and the resulting mixture was stirred at -78 °C for 1 h. The reaction was quenched with sat. NH₄Cl (5 mL) and diluted with Et₂O (30 mL) and CH₂Cl₂ (10 mL). The organic layer was washed with sat. NH₄Cl (2 × 5 mL), dried (Na₂SO₄) and concentrated. Purification by column chromatography (SiO₂; n-pentane-Et₂O, 1:1 → 1:3) gave 8a and 8b as a mixture of diastereomers in 31% and 25% yields, respectively.

12

Compound 8a: mp 135-137 °C; [α]²⁵ _D -49.8 (c = 1.01, acetone); R _f 0.19 (n-pentane-Et₂O, 1:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.18-7.27 (m, 5 H), 4.66 (d, J = 5.2 Hz, 1 H), 4.61 (d, J = 14.6 Hz, 1 H), 4.57 (d, J = 14.3 Hz, 1 H), 3.96 (dd, J = 2.2, 9.1 Hz, 1 H), 2.93 (dd, J = 2.3, 5.1 Hz, 1 H), 2.20 (br s), 1.95 (d, J = 12.4 Hz, 1 H), 1.58-1.76 (m, 4 H), 1.44-1.55 (m, 1 H), 1.02-1.26 (m, 3 H), 0.84-0.96 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 177.8, 176.2, 135.2, 128.7 (2 × C), 128.3 (2 × C), 127.9, 73.2, 67.3, 51.8, 42.7, 41.3, 29.3, 28.8,, 26.3, 25.9, 25.8. IR (KBr): 3462, 2924, 2851, 1696, 1438, 1407, 1356, 1168, 697 cm^-1. MS (EI): m/z (%) = 318 (26), 317 (83) [M⁺], 299 (23), 234 (77), 205 (74), 204 (36), 127 (17), 106 (26), 96 (25), 95 (31), 92 (23), 91 (100), 73 (26), 71 (18), 56 (30). Anal Calcd for C₁₈H₂₃NO₄: C, 68.12; H, 7.30; N, 4.41. Found: C, 67.84; H, 7.76; N, 4.26.

20

Compound 2: colorless oil; R _f 0.38 (pentane-EtOAc, 10:1). ¹H NMR (300 MHz, CDCl₃): δ = 11.51 (s), 7.18 (m), 5.38 (m), 5.22 (d, J = 9.9 Hz), 4.76 (s), 4.68 (d, J = 4.2 Hz), 4.54 (d, J = 14.3 Hz), 4.53 (d, J = 14.3 Hz), 4.44 (d, J = 14.1 Hz), 4.42 (d, J = 14.1 Hz), 3.65 (d, J = 4.2 Hz), 2.95 (dd, J = 5.4, 11.1 Hz), 2.62 (m), 2.18 (d, J = 8.2 Hz), 1.33-1.68 (m), 1.08-1.22 (m), 0.90 (d, J = 6.7 Hz, Me), 0.72 (s), 0.71 (s), 0.08 (s), 0.03 (s), 0.01 (s), 0.00 (s). ¹³C NMR (75 MHz, CDCl₃): δ = 204.8, 176.8, 174.7, 174.2, 173.5, 170.1, 135.6, 134.9, 131.4, 130.8, 130.4 (2 × C), 128.7 (2 × C), 128.6 (2 × C), 128.5 (4 × C), 127.9, 127.8, 101.7, 70.1, 68.1, 64.5, 57.4, 46.9, 42.9, 42.5, 42.3, 41.5, 37.3, 36.2, 34.6, 32.8 (2 × C), 30.5, 30.2, 29.8, 26.5, 26.4, 26.3, 26.2, 25.6 (3 × C), 25.4 (3 × C), 18.1, 17.9, 17.5, -3.9, -4.4, -4.9, -5.4. IR (CHCl₃): 3674, 3745, 2929, 2856, 2361, 2335, 1709, 1675, 1215, 839, 757 cm^-1. MS (EI): m/z (%) = 438 (100)[M - 57], 363 (11), 214 (7), 91 (46), 75 (42). HRMS: m/z [M - 57] calcd for C₂₅H₃₂NO₄Si: 438.21006; found: 438.21006.