Application of the Radical Cascade of Acyclic Peptide-Based Precursors into Analogues of Type I β-Turn

Abstract

Radical cyclizations of di-, tri- and tetrapeptides containing N-2-bromobenzyl,N-methyl-substituted alanine or aspartic acid lead in good yields to α,β-unsaturated γ-lactams. The overall cascade, relying on a hydrogen atom transfer-elimination strategy could serve as a way to incorporate a flat and rigid five-membered ring into the peptide framework.

Key words

domino reactions - peptides - protecting groups - radicals - ring constructions

References

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16

Spectroscopic data of compounds 8-12:
2-[2-(3,4-Dimethyl-2-oxo-2,5-dihydro-pyrrol-1-yl)acetylamino]propionic Acid tert -Butyl Ester (8): IR (film): 3297, 3065, 2979, 2923, 1738, 1667, 1544, 1457, 1226, 1152 cm^-1. ¹H NMR: δ = 6.55 (1 H, br d, J = 6.7 Hz), 4.46-4.39 (1 H, quintet, J = 7.2 Hz), 4.21-3.96 (2 H, AB system, J = 16.3 Hz), 3.94-3.81 (2 H, AB system, J = 18.2 Hz), 1.98 (3 H, s), 1.82 (3 H, d, J = 0.9 Hz), 1.45 (9 H, s), 1.36 (3 H, d, J = 7.2 Hz) ppm. ¹³C NMR: δ = 173.4, 171.8, 168.2, 147.4, 128.3, 82.0, 55.3, 48.7, 46.5, 27.9, 18.4, 13.1, 8.6 ppm. MS (ESI): m/z = 319 [M⁺ + Na]. HRMS (ESI): m/z calcd for C₁₅H₂₄O₄N₂Na: 319.1628; found: 319.1644.
(3- tert -Butoxycarbonylmethyl-2-oxo-4-trimethylsilanyl-methyl-2,5-dihydropyrrol-1-yl)acetic Acid Methyl Ester (9): IR (film): 1736, 1687, 1456, 1368, 1327, 1251, 1214, 1148, 849 cm^-1. ¹H NMR: δ = 4.22 (2 H, s), 3.91 (2 H, s), 3.72 (3 H, s), 3.18 (2 H, s), 1.91 (2 H, s), 1.44 (9 H, s), 0.09 (9 H, s) ppm. ¹³C NMR: δ = 172.0, 170.0, 169.5, 153.5, 123.1, 80.9, 54.9, 52.1, 43.3, 30.7, 28.0, 20.1, -1.0 ppm. MS [LSIMS(+)]: m/z = 356 [M⁺ + H], 378 [M⁺ + Na]. HRMS [LSIMS(+)]: m/z calcd for C₁₇H₃₀O₅NSi: 356.1893; found: 356.1905.
2-[2-(1-Methoxycarbonylmethyl-2-oxo-4-trimethyl-silanylmethyl-2,5-dihydro-1 H -pyrrol-3-ylacetyl-amino]propionic Acid tert -Butyl Ester (10): IR (film): 3299, 3064, 1741, 1667, 1537, 1457, 1369, 1220, 1152 cm^-1. ¹H NMR: δ = 7.30 (1 H, m), 4.38-4.31 (1 H, quintet, J = 7.2 Hz), 4.29-4.19 (2 H, AB system, J = 17.8 Hz), 3.98 (2 H, s), 3.73 (3 H, s), 3.27 (2 H, s), 2.09 (3 H, s), 1.43 (9 H, s), 1.35-1.33 (3 H, d, J = 7.1 Hz) ppm. ¹³C NMR: δ = 172.6, 171.8, 169.5, 168.8, 128.8, 126.3, 81.6, 55.3, 52.2, 49.0, 43.5, 34.5, 27.9, 18.1, 13.3 ppm. MS (ESI): m/z = 377 [M⁺ + Na]. HRMS (ESI): m/z calcd for C₁₇H₂₆O₆N₂Na: 377.1683; found: 377.1697.
2-[2-(3- tert -Butoxycarbonylmethyl-4-methyl-2-oxo-2,5-dihydropyrrol-1-yl)acetylamino]propionic Acid Benzyl Ester (11): IR (film): 3297, 3066, 1734, 1670, 1541, 1457, 1326, 1151, 747 cm^-1. ¹H NMR: δ = 7.38-7.31 (5 H, m), 6.62-6.57 (1 H, br d, J = 7.5 Hz), 5.19-5.10 (2 H, AB system, J = 12.3 Hz), 4.63-4.57 (1 H, quintet, J = 7.3 Hz), 4.24-3.95 (2 H, AB system, J = 16.2 Hz), 3.97-3.85 (2 H, AB system, J = 18.7 Hz), 3.24 (2 H, s), 2.00 (3 H, s), 1.45 (9 H, s), 1.42-1.40 (3 H, d, J = 7.2 Hz) ppm. ¹³C NMR: δ = 172.4, 172.2, 169.3, 168.4, 151.2, 135.4, 128.6, 128.4, 128.1, 126.3, 81.2, 67.1, 55.5, 48.1, 46.6, 30.3, 28.0, 18.0, 13.5 ppm. MS [LSIMS(+)]: m/z = 431 [M⁺ + H], 453 [M⁺ + Na]. HRMS [LSIMS(+)]: m/z calcd for C₂₃H₃₁O₆N₂: 431.2182; found: 431.2189.
2-(2-{1-[(1- tert -Butoxycarbonylethylcarbamoyl)methyl]-4-methyl-2-oxo-2,5-dihydro-1 H -pyrrol-3-yl}acetyl-amino)propionic Acid tert -Butyl Ester (12): IR (film): 3299, 3065, 1736, 1659, 1543, 1455, 1368, 1226, 1152 cm^-1. ¹H NMR: δ = 7.30 (1 H, br s), 6.59 (1 H, br s), 4.60-3.90 (6 H, m), 3.26 (2 H, s), 2.09 (3 H, s), 1.45 (9 H, s), 1.44 (9 H, s), 1.37 (3 H, d, J = 7.2 Hz), 1.34 (3 H, d, J = 7.3 Hz) ppm. ¹³C NMR: δ = 172.8, 171.9, 171.8, 168.6, 167.7, 152.0, 128.7, 81.5 (2×), 55.8, 48.9, 48.8, 46.4, 32.5, 27.9 (2×), 18.3, 18.4, 13.4 ppm. MS (ESI): m/z = 468 [M⁺ + H], 490 [M⁺ + Na]. HRMS (ESI): m/z calcd for C₂₃H₃₇O₇N₃Na: 490.2524; found: 490.2542.