A Simple Approach for the Synthesis of Thio-, Dithio- and Selenothiocarbamate-Tethered Peptidomimetics

Abstract

A simple and efficient method is described for the synthesis of thio-, dithio- and selenothiocarbamate-linked peptidomimetics. The nucleophilic addition of enantiopure N ^α-protected amino alkyl thiols to isocyanates, isothiocyanates or isoselenocyanates obtained from amino acid esters proceeds smoothly in the presence of catalytic amount of DMAP. The protocol was further extended for the synthesis of N,N′-orthogonally protected thio-, dithio- and selenothiocarbamate-linked peptidomimetics. The reaction is mild, free from racemization, and the products were obtained in good yield.

Key words

peptidomimetics - isocyanates - isothiocyanates and isoselenocyanates - amino alkyl thiols - thiocarbamates - dithiocarbamates - selenothiocarbamates

• References

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• 24 General Procedure for the Synthesis of Thio-, Dithio- and Selenothiocarbamate-Linked Peptidomimetics: To a solution of PgNH-CHR-ψ-[CH₂SH] (10.0 mmol) in anhyd CH₂Cl₂ (10.0 mL), isocyanato derivatives (10.0 mmol) and DMAP (0.2 equiv) were added. The reaction mixture was stirred for 30–50 min at r.t. After the completion of the reaction (TLC), the organic layer was washed with H₂O (10 mL), brine (10 mL) and dried over Na₂SO₄. The organic phase was evaporated under vacuo and the crude was recrystallized (Et₂O–THF) or purified through column chromatography using EtOAc–n-hexane (20:80) as eluent. Spectral data for compounds: Compound 5a: ¹H NMR (300 MHz, CDCl₃): δ = 0.98 (d, 6 H, J = 6.1 Hz), 1.59 (d, 3 H, J = 5.5 Hz), 2.90–3.11 (m, 3 H), 3.60 (s, 3 H), 3.91 (m, 1 H), 4.28 (m, 1 H), 4.20 (t, 1 H, J = 4.6 Hz), 5.01 (d, 2 H, J = 5.1 Hz), 5.16 (br, 2 H), 7.22–7.77 (m, 8 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.6, 20.1, 30.9, 37.4, 45.7, 47.1, 51.9, 58.3, 66.6, 126.8, 127.3, 128.2, 128.9, 141.4, 143.2, 155.7, 164.5, 171.8. HRMS: m/z [M + Na]⁺ calcd for C₂₅H₃₀N₂O₅S: 493.1773; found: 493.1775. Compound 5b: ¹H NMR (300 MHz, CDCl₃): δ = 2.70–3.02 (m, 2 H), 3.21–3.30 (m, 4 H), 3.62 (s, 3 H), 4.20 (m, 1 H), 4.83 (m, 1 H), 5.16 (br, 2 H), 5.32 (s, 2 H), 7.19–7.25 (m, 15 H). ¹³C NMR (100 MHz, CDCl₃): δ = 34.1, 36.2, 43.3, 52.3, 53.1, 56.5, 64.3, 126.1, 126.3, 126.8, 127.0, 127.2, 127.4, 127.8, 128.2, 129.0, 138.1, 139.0, 140.1, 155.2, 164.2, 171.7. HRMS: m/z [M + Na]⁺ calcd for C₂₈H₃₀N₂O₅S: 529.1773; found: 529.1770. Compound 5c: ¹H NMR (300 MHz, CDCl₃): δ = 0.94 (t, 3 H, J = 6.0 Hz), 1.02 (d, 3 H, J = 5.7 Hz), 1.22 (m, 2 H), 2.24 (m, 1 H), 2.92–3.24 (m, 4 H), 3.61 (s, 3 H), 3.75 (m, 2 H), 3.78 (m, 1 H), 4.81 (m, 1 H), 5.18 (br, 2 H), 5.32 (s, 2 H), 7.18–7.20 (m, 10 H). ¹³C NMR (100 MHz, CDCl₃): δ = 12.1, 15.0, 24.1, 32.2, 33.3, 39.0, 40.0, 52.1, 53.9, 55.7, 65.4, 126.4, 127.2, 128.1, 128.3, 128.5, 128.9, 137.4, 141.3, 155.8, 165.2, 171.8. HRMS: m/z [M + Na]⁺ calcd for C₂₆H₃₄N₂O₅S₂: 541.1807; found: 541.1805. Compound 5d: ¹H NMR (300 MHz, CDCl₃): δ = 2.20–2.30 (m, 4 H), 3.13 (d, 2 H, J = 5.2 Hz), 3.43–3.60 (m, 3 H), 3.63 (s, 3 H), 4.20 (t, 1 H, J = 3.5 Hz), 4.91 (d, 2 H, J = 5.8 Hz), 5.15 (br, 2 H), 5.21 (s, 2 H), 7.19–7.72 (m, 13 H). ¹³C NMR (100 MHz, CDCl₃): δ = 25.2, 28.3, 37.4, 40.6, 47.2, 51.8, 55.2, 68.1, 68.9, 126.2, 126.9, 127.5, 128.0, 128.4, 128.6, 129.0, 141.2, 143.2, 157.0, 171.1, 173.2, 196.2. HRMS: m/z [M + Na]⁺ calcd for C₃₁H₃₂N₂O₆S₂: 615.1599; found: 615.1595. Compound 5e: ¹H NMR (300 MHz, CDCl₃): δ = 0.90 (d, 6 H, J = 6.3 Hz), 1.25 (d, 3 H, J = 5.8 Hz), 1.70–1.75 (m, 3 H), 2.12–3.20 (m, 2 H), 3.63 (s, 3 H), 3.66 (m, 1 H), 3.85 (m, 1 H), 4.28 (t, 1 H, J = 4.8 Hz), 4.91 (d, 2 H, J = 6.7 Hz), 5.15 (br, 2 H), 7.26–7.78 (m, 8 H). ¹³C NMR (100 MHz, CDCl₃): δ = 18.5, 19.6, 20.7, 40.5, 43.8, 47.0, 47.5, 50.9, 52.4, 66.0, 126.7, 127.5, 128.0, 128.6, 141.4, 143.2, 154.7, 173.2, 195.7. HRMS: m/z [M + Na]⁺ calcd for C₂₆H₃₂N₂O₄S₂: 523.1701; found: 523.1705. Compound 5f: ¹H NMR (300 MHz, CDCl₃): δ = 0.95 (d, 6 H, J = 5.2 Hz), 2.15 (s, 3 H), 2.23–2.47 (m, 5 H), 2.95 (d, 2 H, J = 5.8 Hz), 3.45 (m, 1 H), 3.62 (s, 3 H), 3.86 (m, 1 H), 5.17 (br, 2 H), 5.22 (s, 2 H), 7.19–7.22 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.2, 17.3, 17.5, 29.0, 31.1, 33.2, 36.5, 52.1, 56.2, 58.4, 65.4, 126.1, 127.6, 128.3, 142.1, 155.7, 171.2, 197.0. HRMS: m/z [M + Na]⁺ calcd for C₂₀H₃₀N₂O₄S₃: 481.1265; found: 481.1261. Compound 5g: ¹H NMR (300 MHz, CDCl₃): δ = 1.33 (d, 3 H, J = 4.6 Hz), 2.96–3.02 (m, 2 H), 3.04–3.31 (m, 2 H), 3.50 (s, 3 H), 3.81 (m, 1 H), 4.10 (m, 1 H), 4.12 (t, 1 H, J = 4.9 Hz), 4.99 (d, 2 H, J = 6.4 Hz), 5.22 (br, 2 H), 7.12–7.81 (m, 13 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.1, 36.2, 37.1, 47.2, 48.2, 52.0, 58.7, 67.2, 125.1, 126.7, 127.5, 127.9, 128.0, 128.2, 128.6, 139.0, 141.1, 143.4, 155.7, 171.2, 205.7. ⁷⁷Se NMR (76 MHz, Me₂Se–CDCl₃): δ = 322.0. HRMS: m/z [M + Na]⁺ calcd for C₂₉H₃₀N₂O₄SSe: 605.0989; found: 605.0984. Compound 5h: ¹H NMR (300 MHz, CDCl₃): δ = 0.95 (d, 6 H, J = 5.6 Hz), 2.30 (m, 1 H), 2.73–2.95 (m, 2 H), 2.98–3.21 (m, 2 H), 3.61 (s, 3 H), 3.80 (m, 1 H), 4.10 (m, 1 H), 4.21 (t, 1 H, J = 4.2 Hz), 4.80 (d, 2 H, J = 6.4 Hz), 5.21 (br, 2 H), 5.30 (s, 2 H), 7.12–7.81 (m, 13 H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.2, 17.4, 32.9, 34.3, 37.4, 47.2, 51.8, 52.1, 58.3, 67.1, 69.2, 125.3, 126.2, 127.2, 127.3, 128.0, 128.3, 128.6, 141.3, 142.1, 143.7, 155.1, 171.2, 173.2, 203.4. ⁷⁷Se NMR (76 MHz, Me₂Se–CDCl₃): δ = 322.0. HRMS: m/z [M + Na]⁺ calcd for C₃₃H₃₆N₂O₆SSe: 691.1357; found: 691.1352. Compound 5i: ¹H NMR (300 MHz, CDCl₃): δ = 0.94 (t, 3 H, J = 5.8 Hz), 1.01 (d, 3 H, J = 6.1 Hz), 1.37 (m, 2 H), 2.51 (m, 1 H), 2.60–2.81 (m, 2 H), 2.94–3.23 (m, 2 H), 3.41 (m, 1 H), 3.59 (s, 3 H), 4.21 (m, 1 H), 5.19 (br, 2 H), 5.29 (s, 2 H), 7.12–7.20 (m, 10 H). ¹³C NMR (100 MHz, CDCl₃): δ = 12.2, 15.2, 36.2, 37.1, 42.2, 51.2, 55.3, 58.9, 66.3, 125.4, 126.5, 127.4, 128.0, 128.3, 128.7, 139.1, 141.4, 155.2, 171.3, 202.4. ⁷⁷Se NMR (76 MHz, Me₂Se–CDCl₃): δ = 322.0. HRMS: m/z [M + Na]⁺ calcd for C₂₅H₃₂N₂O₄SSe: 559.1146; found: 559.1149. Compound 7a: ¹H NMR (300 MHz, CDCl₃): δ = 0.97 (d, 6 H, J = 6.0 Hz), 1.31 (d, 3 H, J = 5.4 Hz), 1.43 (m, 2 H), 1.76 (m, 1 H), 2.90–3.21 (m, 2 H), 3.01–3.35 (m, 2 H), 4.01–4.21 (m, 2 H), 4.25 (t, 1 H, J = 4.0 Hz), 5.01 (d, 2 H, J = 7.2 Hz), 5.31 (s, 2 H), 5.88 (br, 3 H), 7.19–7.82 (m, 13 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.2, 22.1, 23.4, 37.5, 42.2, 45.2, 47.0, 47.8, 48.9, 65.2, 67.2, 127.2, 127.4, 127.8, 128.1, 128.5, 128.8, 129.4, 141.2, 141.5, 143.1, 155.7, 163.1. HRMS: m/z [M + Na]⁺ calcd for C₃₃H₃₉N₃O₅S: 612.2508; found: 612.2505. Compound 7b: ¹H NMR (300 MHz, CDCl₃): δ = 1.21 (d, 3 H, J = 6.6 Hz), 1.25–1.60 (m, 6 H), 2.90–3.20 (m, 4 H), 3.25–3.45 (m, 2 H), 3.75 (m, 1 H), 5.01 (m, 1 H), 4.23 (t, 1 H, J = 4.5 Hz), 5.21 (d, 2 H, J = 6.1 Hz), 5.32 (s, 4 H), 5.81 (br, 4 H), 7.16–7.79 (m, 18 H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.7, 22.4, 29.2, 33.8, 35.0, 47.1, 47.4, 49.2, 49.4, 49.8, 67.4, 68.2, 68.5, 126.1, 126.3, 126.9, 127.2, 127.4, 127.7, 128.2, 128.6, 128.9, 129.4, 141.1, 141.4, 141.8, 143.4, 155.3, 155.7, 156.2, 167.5. HRMS: m/z [M + Na]⁺ calcd for C₄₁H₄₆N₄O₇S: 761.2985; found: 761.2980. Compound 7c: ¹H NMR (300 MHz, CDCl₃): δ = 1.02 (d, 6 H, J = 5.2 Hz), 1.49 (m, 2 H), 1.81 (m, 1 H), 3.01–3.32 (m, 4 H), 3.69 (m, 2 H), 4.32 (m, 1 H), 4.31 (t, 1 H, J = 5.2 Hz), 4.83 (d, 2 H, J = 6.2 Hz), 5.32 (s, 2 H), 5.80 (br, 3 H), 7.19–7.81 (m, 13 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.1, 22.4, 23.3, 32.5, 39.0, 41.7, 46.3, 47.2, 47.5, 64.2, 68.2, 126.2, 127.6, 127.3, 128.2, 128.7, 128.9, 129.4, 141.3, 141.8, 143.5, 155.2, 156.3, 169.1. HRMS: m/z [M + Na]⁺ calcd for C₃₂H₃₇N₃O₅S: 598.2352; found: 598.2350. Compound 7d: ¹H NMR (300 MHz, CDCl₃): δ = 0.95 (d, 6 H, J = 5.6 Hz), 1.20 (s, 9 H), 1.72 (m, 3 H), 2.40–2.49 (m, 4 H), 2.51 (d, 2 H, J = 4.9 Hz), 3.48 (m, 1 H), 3.99 (m, 1 H), 4.22 (t, 1 H, J = 4.2 Hz), 4.91 (d, 2 H, J = 6.7 Hz), 5.92 (br, 3 H), 7.21–7.78 (m, 13 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.1, 22.9, 27.7, 38.4, 40.1, 41.6, 46.9, 47.8, 49.1, 51.5, 65.7, 82.3, 127.5, 127.8, 127.9, 128.2, 128.6, 128.9, 129.5, 141.7, 142.3, 143.4, 155.6, 156.3, 194.5. HRMS: m/z [M + Na]⁺ calcd for C₃₆H₄₅N₃O₄S₂: 670.2749; found: 670.2745. Compound 7e: ¹H NMR (300 MHz, CDCl₃): δ = 0.99 (d, 6 H, J = 5.6 Hz), 1.40 (m, 2 H), 1.80 (m, 1 H), 2.74–3.10 (m, 6 H), 3.80 (m, 1 H), 4.19 (m, 1 H), 4.35 (t, 1 H, J = 4.2 Hz), 4.87 (d, 2 H, J = 6.7 Hz), 5.33 (s, 2 H), 5.82 (br, 3 H), 7.23–7.81 (m, 18 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.1, 23.1, 23.3, 39.4, 41.9, 42.3, 47.0, 47.8, 49.5, 55.5, 65.1, 67.4, 126.5, 126.8, 127.1, 127.5, 127.9, 128.2, 128.5, 128.7, 129.5, 139.2, 141.2, 143.3, 155.2, 155.8, 198.4. HRMS: m/z [M + Na]⁺ calcd for C₃₉H₄₃N₃O₄S₂: 704.2593; found: 704.2595. Compound 7f: ¹H NMR (300 MHz, CDCl₃): δ = 0.91 (t, 3 H, J = 5.6 Hz), 1.08 (d, 3 H, J = 5.1 Hz), 1.32 (m, 2 H), 2.23 (m, 1 H), 2.81–3.32 (m, 6 H), 3.80 (m, 1 H), 4.37 (t, 1 H, J = 5.2 Hz), 4.99 (d, 2 H, J = 6.7 Hz), 5.30 (s, 2 H), 5.82 (br, 3 H), 7.20–7.78 (m, 13 H). ¹³C NMR (100 MHz, CDCl₃): δ = 12.2, 16.1, 25.5, 35.3, 40.2, 41.0, 43.2, 47.1, 54.2, 66.1, 68.4, 126.6, 127.4, 127.8, 128.5, 128.7, 129.0, 129.5, 141.0, 141.5, 144.3, 155.6, 156.0, 198.4. HRMS: m/z [M + Na]⁺ calcd for C₃₂H₃₇N₃O₄S₂: 614.2123; found: 614.2126. Compound 7g: ¹H NMR (300 MHz, CDCl₃): δ = 0.97 (d, 6 H, J = 5.4 Hz), 1.31 (d, 3 H, J = 5.8 Hz), 1.12 (s, 9 H), 2.40 (m, 1 H), 2.74–2.99 (m, 2 H), 3.04–3.22 (m, 2 H), 3.81–4.01 (m, 2 H), 5.01 (s, 2 H), 6.02 (br, 3 H), 7.10–7.26 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.2, 19.2, 29.0, 31.2, 39.1, 47.2, 48.2, 59.1, 65.2, 79.2, 127.5, 127.8, 128.2, 141.2, 155.7, 204.2. ⁷⁷Se NMR (76 MHz, Me₂Se–CDCl₃): δ = 320.0. HRMS: m/z [M + Na]⁺ calcd for C₂₂H₃₅N₃O₄SSe: 540.1411; found: 540.1416. Compound 7h: ¹H NMR (300 MHz, CDCl₃): δ = 0.95 (t, 3 H, J = 5.5 Hz), 0.99 (d, 3 H, J = 5.6 Hz), 1.10 (s, 9 H), 1.25 (m, 2 H), 1.32 (d, 3 H, J = 5.2 Hz), 2.12–3.32 (m, 5 H), 3.90 (m, 2 H), 4.30 (t, 1 H, J = 4.2 Hz), 4.92 (d, 2 H, J = 5.5 Hz), 5.69 (br, 3 H), 7.21–7.76 (m, 8 H). ¹³C NMR (100 MHz, CDCl₃): δ = 11.0, 14.3, 18.8, 26.5, 28.6, 32.1, 40.2, 48.1, 49.1, 52.3, 57.5, 68.2, 80.4, 126.0, 127.1, 127.8, 128.3, 141.3, 143.7, 155.1, 155.7, 202.3. ⁷⁷Se NMR (76 MHz, Me₂Se–CDCl₃): δ = 320.0. HRMS: m/z [M + Na]⁺ calcd for C₃₀H₄₁N₃O₄SSe: 642.1881; found: 642.1884. Compound 7i: ¹H NMR (300 MHz, CDCl₃): δ = 0.98 (d, 6 H, J = 6.5 Hz), 2.40 (m, 1 H), 2.60–3.22 (m, 6 H), 3.87 (m, 1 H), 4.30 (m, 1 H), 4.33 (t, 1 H, J = 4.3 Hz), 4.92 (d, 2 H, J = 6.6 Hz), 5.33 (s, 2 H), 5.99 (br, 3 H), 7.21–7.76 (m, 18 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.9, 32.8, 34.5, 40.9, 47.5, 49.6, 53.2, 59.9, 64.3, 68.4, 126.3, 126.8, 126.9, 127.0, 127.3, 127.9, 128.1, 128.3, 128.7, 129.0, 139.2, 140.3, 141.3, 143.9, 155.2, 155.9, 201.5. ⁷⁷Se NMR (76 MHz, Me₂Se–CDCl₃): δ = 320.0. HRMS: m/z [M + Na]⁺ calcd for C₃₈H₄₁N₃O₄SSe: 738.1881; found: 738.1884