The Synthesis of a Novel Carbazole-linked Cyclic Peptoid with Antibacterial Activity

John B. Bremner; Jonathan A. Coates; Paul A. Keller; Stephen G. Pyne; Helen M. Witchard

doi:10.1055/s-2002-19754

LETTER

The Synthesis of a Novel Carbazole-linked Cyclic Peptoid with Antibacterial Activity

John B. Bremner*^a, Jonathan A. Coates^b, Paul A. Keller*^a, Stephen G. Pyne*^a, Helen M. Witchard^a
^a Department of Chemistry, University of Wollongong, Wollongong, NSW, 2522, Australia
^b AMRAD Corporation Ltd, Richmond, Victoria, 3121, Australia
Fax: +61(2)42214287; e-Mail: john_bremner@uow.edu.au; e-Mail: paul_keller@uow.edu.au; e-Mail: stephen_pyne@uow.edu.au;

Abstract

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Abstract

This paper describes the synthesis of a novel cyclic peptoid 11, structurally comprising a tripeptide moiety linked through a carbazole scaffold. In a key step, a ring-closing metathesis reaction was used giving efficient access to a new class of cyclic peptoids.

Key words

cyclic peptoid - ring-closing metathesis - antibacterial activity

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References

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Physical properties, ¹H NMR and microanalytical/HRMS data for compounds in the Scheme were as follows:
1: Mp 108-110 °C. ¹H NMR (400 MHz, C₆D₆): δ = 7.78 (d, J = 2.0 Hz, 1 H, ArH-5), 7.41 (dd, J = 8.4, 2.0 Hz, 1 H, ArH-7), 6.77 (d, J = 8.4 Hz, 1 H, ArH-8), 6.23 (br s, 1 H, NH), 2.53 (dd, J = 15.0, 5.2 Hz, 1 H, H-4), 2.32-2.15 (m, 2 H, H-1 and H-2), 2.01 (dd, J = 15.2, 9.4 Hz, 1 H, H-4), 1.73-1.61 (m, 2 H, H-2 and H-3), 1.29 (m, 1 H, H-1), 0.99 (d, J = 6.8 Hz, 3 H, CH₃). HRMS (CI⁺) calcd for C₁₃H₁₄ ⁷⁹BrN + H: 264.0388; found: 264.0371. Anal. Calcd for C₁₃H₁₄BrN: C, 59.11; H, 5.34; N, 5.30. Found: C, 59.33; H, 5.38; N, 5.26.
2: Mp 120-122 °C. ¹H NMR (300 MHz, C₆D₆): δ = 8.27 (d, J = 8.7 Hz, 1 H, ArH-8), 7.61 (d, J = 2.1 Hz, 1 H, ArH-5), 7.44 (dd, J = 8.7, 2.1 Hz, 1 H, ArH-7), 3.06-2.94 (m, 1 H, H-1), 2.85-2.70 (m, 1 H, H-2), 2.36 (dd, J = 16.0, 5.4 Hz, 1 H, H-4), 1.90-1.78 (m, 1 H, H-4), 1.65 (m, 2 H, H-2 and H-3), 1.38 (s, 9 H, C(CH₃)₃), 1.30-1.16 (m, 1 H, H-1), 0.96 (d, J = 6.6 Hz, 3 H, CHCH₃). HRMS (EI⁺) calcd for C₁₈H₂₂ ⁷⁹BrNO₂: 363.0834; found: 363.0832. Anal. Calcd for C₁₈H₂₂BrNO₂: C, 59.35; H, 6.09; N, 3.85; O, 8.78. Found: C, 59.50; H, 6.20; N, 3.79; O, 8.81.
3: Mp 94-96 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.14 (d, J = 9.0 Hz, 1 H, ArH-1), 8.10 (d, J = 8.7 Hz, 1 H, ArH-8), 7.99 (d, J = 2.1 Hz, 1 H, ArH-4), 7.65 (br s, 1 H, ArH-5), 7.50 (dd, J = 8.9, 2.1 Hz, 1 H, ArH-2), 7.27 (dd, J = 8.4, 1.8 Hz, 1 H, ArH-7), 2.48 (s, 3 H, ArCH₃), 1.74 (s, 9 H, C(CH₃)₃). HRMS (CI⁺) calcd for C₁₈H₁₈ ⁷⁹BrNO₂ + H: 360.0599; found: 360.0600. Anal. Calcd for C₁₈H₁₈BrNO₂: C, 60.01; H, 5.04; N, 3.89; O, 8.88. Found: C, 59.89; H, 5.05; N, 3.86; O, 8.95.
4: Mp 150 °C(dec). ¹H NMR (400 MHz, CDCl₃): δ = 8.22 (d, J = 8.4 Hz, 1 H, ArH-8), 8.16 (d, J = 8.8 Hz, 1 H, ArH-1), 8.07 (d, J = 2.0 Hz, 1 H, ArH-4), 7.93 (d, J = 1.6 Hz, 1 H, ArH-5), 7.54 (dd, J = 8.8, 2.0 Hz, 1 H, ArH-2), 7.50 (dd, J = 8.8, 2.0 Hz, 1 H, ArH-7), 4.66 (s, 2 H, CH₂), 1.73 (s, 9 H, CH₃). HRMS (EI⁺) calcd for C₁₈H₁₇ ⁷⁹Br₂NO₂: 436.9626; found: 436.9670. Anal. Calcd for C₁₈H₁₇Br₂NO₂: C, 49.23; H, 3.90; N, 3.19; O, 7.29. Found: C, 49.30; H, 3.86; N, 3.11; O, 6.91.
5: Mp 173-175 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.49 (s, 1 H, ArNH), 8.05 (d, J = 1.8 Hz, 1 H, ArH-5), 7.69 (br s, 1 H, ArH-4), 7.43 (dd, J = 8.6, 1.8 Hz, 1 H, ArH-7), 7.25 (d, J = 9.0 Hz, 1 H, ArH-1), 7.23 (d, J = 8.4 Hz, 1 H, ArH-8), 7.12 (dd, J = 8.3, 1.5 Hz, 1 H, ArH-2), 6.05 (d, J = 7.5 Hz, 1 H, NH), 4.90 (dt, J = 7.8, 6.0 Hz, 1 H, CHN), 4.16 (q, J = 7.2 Hz, 2 H, OCH ₂CH₃) 3.27 (dd, J = 14.1, 6.3 Hz, 1 H, ArCH₂), 3.20 (dd, J = 14.0, 5.9 Hz, 1 H, ArCH₂), 1.96 (s, 3 H, COCH₃), 1.22 (t, J = 7.2 Hz, 3 H, OCH₂CH ₃). HRMS (CI⁺) calcd for C₁₉H₁₉ ⁷⁹BrN₂O₃ + H: 403.0657; found: 403.0664.
6: Mp 98-100 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.13 (br s, 1 H, ArNH) 7.80 (br s, 1 H, ArH-5), 7.76 (br s, 1 H, ArH-4), 7.32 (d, J = 8.7 Hz, 1 H, ArH-8), 7.29 (d, J = 8.4 Hz, 1 H, ArH-1), 7.22 (dd, J = 8.7, 1.2 Hz, 1 H, ArH-7), 7.10 (dd, J = 8.4, 1.5 Hz, 1 H, ArH-2), 6.05 (ddt, J = 16.8, 10.2, 6.6 Hz, 1 H, CH₂CH=CH₂), 5.96 (d, J = 8.4 Hz, 1 H, NH), 5.11 (dd, J = 17.4, 1.8 Hz, 1 H, CH₂CH=CH ₂), 5.08 (dd, J = 9.3, 2.1 Hz, 1 H, CH₂CH=CH ₂), 4.90 (dt, J = 7.8, 6.3 Hz, 1 H, CHN), 4.17 (q, J = 7.2 Hz, 2 H, OCH ₂CH₃), 3.54 (d, J = 6.6 Hz, 2 H, CH ₂CH=CH₂), 3.26 (d, J = 5.7 Hz, 2 H, ArCH₂), 1.97 (s, 3 H, COCH ₃), 1.23 (t, J = 7.2 Hz, 3 H, OCH₂CH₃). HRMS (CI⁺) calcd for C₂₂H₂₄N₂O₃ + H: 365.1865; found: 365.1859.
7: Mp 123-125 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.18 (d, J = 8.1 Hz, 1 H, ArH-8), 8.16 (d, J = 8.1 Hz, 1 H, ArH-1), 7.71 (d, J = 1.2 Hz, 1 H, ArH-4), 7.68 (d, J = 1.5 Hz, 1 H, ArH-5), 7.27 (dd, J = 8.5, 1.5 Hz, 1 H, ArH-2), 7.17 (dd, J = 8.5, 1.8 Hz, 1 H, ArH-7), 6.03 (ddt, J = 16.5, 9.9, 6.9 Hz, 1 H, CH₂CH=CH₂), 5.11 (dd, J = 17.7, 1.8 Hz, 1 H, CH₂CH=CH ₂), 5.10 (dd, J = 10.2, 1.8 Hz, 1 H, CH₂CH=CH ₂), 4.90 (dt, J = 7.5, 6.0 Hz, 1 H, CHN), 4.17 (q, J = 7.2 Hz, 2 H, OCH ₂CH₃), 3.52 (d, J = 6.6 Hz, 2 H, CH ₂CH=CH₂), 3.28 (dd, J = 14.0, 5.7 Hz, 1 H, ArCH₂), 3.22 (dd, J = 14.1, 5.7 Hz, 1 H, ArCH₂), 1.98 (s, 3 H, COCH₃), 1.72 (s, 9 H, C(CH₃)₃), 1.23 (t, J = 7.2 Hz, 3 H, OCH₂CH₃). HRMS (ES⁺) calcd for C₂₇H₃₂N₂O₅ + H: 465.2389; found: 465.2408. Anal. Calcd for C₂₇H₃₂N₂O₅: C, 69.80; H, 6.94; N, 6.03; O, 17.22. Found: C, 69.87; H, 7.14; N, 5.88; O, 17.11.
8: Mp 175-177 °C. ¹H NMR (300 MHz, (CD₃)₂CO): δ = 8.21 (d, J = 8.4 Hz, 1 H, ArH-8); 8.20 (d, J = 8.7 Hz, 1 H, ArH-1), 7.96 (d, J = 1.2 Hz, 1 H, ArH-4), 7.89 (d, J = 0.9 Hz, 1 H, ArH-5), 7.39 (dd, J = 8.4, 1.5 Hz, 2 H, ArH-2 and CHN(obscured)), 7.33 (dd, J = 8.5, 1.8 Hz, 1 H, ArH-7), 6.07 (ddt, J = 16.9, 9.9, 6.9 Hz, 1 H, CH₂CH=CH₂), 5.14 (dd, J = 17.2, 1.5 Hz, 1 H, CH₂CH=CH ₂), 5.07 (dd, J = 9.9, 1.5 Hz, 1 H, CH₂CH=CH ₂), 4.80 (m, 1 H, CHN), 3.55 (d, J = 6.9 Hz, 2 H, CH ₂CH=CH₂), 3.34 (dd, J = 13.8, 5.4 Hz, 1 H, ArCH₂), 3.15 (dd, J = 13.8, 8.1 Hz, 1 H, ArCH₂), 1.89 (s, 3 H, COCH₃), 1.76 (s, 9 H, C(CH₃)₃). HRMS (ES⁺) calcd for C₂₅H₂₈N₂O₅ + H: 437.2076; found: 437.2072. Anal. Calcd for C₂₅H₂₈N₂O₅: C, 68.79; H, 6.47; N, 6.42; O, 18.33. Found: C, 68.90; H, 6.69; N, 6.34; O, 18.07.
9: Mp 156-158 °C. ¹H NMR (500 MHz, CDCl₃, ^* indicates signals for minor isomer): δ = 8.16 (d, J = 7.5 Hz, 0.7 H, ArH-1), 8.14^* (d, J = 7.5 Hz, 0.3 H, ArH-1), 8.10 (d, J = 8.0 Hz, 0.7 H, ArH-8), 8.08^* (d, J = 8.0 Hz, 0.3 H, ArH-8), 7.74 (s, 1 H, ArH-4), 7.70 (d, J = 7.5 Hz, 1.3 H, Fmoc ArH-4 and Fmoc ArH-5), 7.69^* (d, J = 7.5 Hz, 0.7 H, Fmoc ArH-4 and Fmoc ArH-5), 7.64^* (s, 0.3 H, ArH-5), 7.60 (s, 0.7 H, ArH-5), 7.54 (d, J = 7.5 Hz, 1.3 H, Fmoc ArH-1 and Fmoc ArH-8), 7.51^* (d, J = 7.5 Hz, 0.7 H, Fmoc ArH-1 and Fmoc ArH-8), 7.40-7.35^* (m, 0.3 H, NH-6), 7.34 (t, J = 7.5 Hz, 2 H, Fmoc ArH-3 and Fmoc ArH-6), 7.29-7.18 (m, 4 H, Fmoc ArH-2, Fmoc ArH-7, ArH-2 and ArH-7), 7.15^* (d, J = 7.0 Hz, 0.3 H, NH-3), 7.11 (d, J = 7.5 Hz, 0.7 H, NH-3), 7.05 (d, J = 7.5 Hz, 0.7 H, NH-6), 6.89^* (d, J = 7.5 Hz, 0.3 H, NHAc), 6.81 (d, J = 7.5 Hz, 0.7 H, NHAc), 5.98 (m, 1 H, ArCH₂CH=CH₂), 5.61 (m, 1 H, CH₂CH=CH₂), 5.41^* (br s, 1 H, NH-5), 5.12-4.98 (m, 5 H, NH-5, ArCH₂CH=CH ₂ and CH₂CH=CH ₂), 4.93^* (br d, J = 7.0 Hz, 0.3 H, CHN-8), 4.86 (dt, J = 7.5, 7.0 Hz, 0.7 H, CHN-8), 4.59^* (br d, J = 6.5 Hz, 0.3 H, CHN-5), 4.52 (br d, J = 6.0 Hz, 0.7 H, CHN-2), 4.51-4.41 (m, 1 H, CHN-5 and CHN-2^*), 4.32 (d, J = 7.0 Hz, 2 H, OCH₂), 4.13 (t, J = 6.5 Hz, 1 H, Fmoc CH), 3.64^* (s, 1 H, OCH₃), 3.62 (s, 2 H, OCH₃), 3.45^* (d, J = 5.5 Hz, 0.7 H, ArCH ₂CH=CH₂), 3.44 (d, J = 6.5 Hz, 1.3 H, ArCH ₂CH=CH₂), 3.24-3.12 (m, 2 H, ArCH₂-9), 3.08^* (br d, J = 6.0 Hz, 0.7 H, NCH ₂(CH₂)₃), 2.94-2.77 (m, 1.3 H, NCH ₂(CH₂)₃), 2.53-2.31 (m, 2 H, CH ₂CH=CH₂), 1.93 (s, 2 H, COCH₃), 1.92^* (s, 1 H, COCH₃), 1.84-1.55^* (m, 0.7 H, N(CH₂)₃CH ₂), 1.60-1.49 (m, 0.65 H, N(CH₂)₃CH ₂), 1.46-1.26 (m, 2.05 H, N(CH₂)₃CH ₂, N(CH₂)₂CH ₂CH₂ ^* and NCH₂CH ₂(CH₂)₂ ^*), 1.22-1.06 (m, 1.3 H, NCH₂CH ₂(CH₂)₂), 1.04-0.89 (m, 1.3 H, N(CH₂)₂CH ₂CH₂). HRMS (ES⁺) calcd for C₅₂H₅₉N₅O₉ + H: 898.4391; found: 898.4359. Anal. Calcd for C₅₂H₅₉N₅O₉: C, 69.55; H, 6.62; N, 7.80; O, 16.03. Found: C, 69.71; H, 6.78; N, 7.67; O, 15.84.
10: Mp 189-191 °C. HRMS (ES⁺) calcd for C₅₀H₅₅N₅O₉ + H: 870.4099; found: 870.4078.
11: Mp 230 °C(dec). HRMS (ES⁺) calcd for C₃₅H₄₅N₅O₇ + H: 648.3397; found: 648.3391.

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