A Cyclooligomerisation Approach to Backbone-Modified Cyclic Peptides Bearing Guanidinium Arms

Abstract

Cyclooligomerisation of the pentafluorophenyl ester derivatives of oxazoles, derived from dipeptides containing protected ornithine, diaminobutanoic acid and diaminopropionic acid residues, gives the cyclic trimers as the major products. Deprotection and treatment with guanidinylating agents provides efficient access to backbone rigidified cyclic peptides with guanidinium functionalised side chains.

Key words

peptides - macrocycles - cyclisation - heterocycles - amides

References and Notes

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13

Representative cyclooligomerisation procedure: Compound 25 (1.19 g, 1.95 mmol) was dissolved in CH₂Cl₂ (5 mL) and TFA (15 mL) was added in one portion. The reaction mixture was stirred at r.t. for 2 h and the solvents were removed to give the trifluoroacetate salt 28 as a yellow foam. This was dissolved in DMF (39 mL) and DIPEA (1.5 mL, 8.78 mmol) was added in one portion. The pale-orange solution was stirred at r.t. for 3 d, then the DMF was removed in vacuo to give an orange oil. This was redissolved in EtOAc (50 mL) and washed with 1 M NaOH (2 × 3 mL), brine (2 × 7 mL) and H₂O (2 × 7 mL), dried (Na₂SO₄) and concentrated under reduced pressure to give a dark-orange foam. This was dissolved in EtOAc-hexane (1:2) and passed down a silica plug (EtOAc-hexane, 1:2→2:1) to give a mixture of cyclic oligomers. These were then separated by preparative HPLC {gradient 50→100% B [MeCN-TFA (100:0.1)] in A [H₂O-MeCN-TFA (95:5:0.1)] over 60 mins} to give the cyclic trimer 19, t _R = 28.0 min (225 mg, 42%) and cyclic tetramer 22, t _R = 30.1 min (58 mg, 9%) as colourless foams. Data for 19: [α]_D ^²0 -21.6 (c 1.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 8.33 (d, J = 4.4 Hz, 3 H), 7.42-7.24 (m, 15 H), 5.22 (m, 3 H), 5.14 (m, 3 H), 5.06 (s, 6 H), 3.24 (m, 6 H), 2.63 (s, 9 H), 2.12-1.90 (m, 12 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 160.79, 160.75, 156.4, 153.9, 136.5, 128.3, 128.2, 127.9, 127.8, 66.4, 47.5, 40.5, 32.0, 25.2, 11.5. MS (ESI): m/z = 1010 [M + Na]⁺. HRMS (ESI): m/z [M + Na]⁺ calcd. for C₅₁H₅₇N₉O₁₂Na: 1010.4019; found: 1010.3999. Data for 22: [α]_D ^²0 -73.3 (c 0.9, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.40 (d, J = 9.0 Hz, 4 H), 7.31-7.27 (m, 20 H), 5.36 (app dt, J = 9.0, 7.5 Hz, 4 H), 5.12 (m, 4 H), 5.04 (s, 8 H), 3.23 (m, 8 H), 2.60 (s, 12 H), 2.08 (m, 4 H), 1.95 (m, 4 H), 1.62-1.60 (m, 8 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 161.1, 161.0, 156.7, 154.3, 136.5, 128.6, 128.4, 128.2, 128.1, 66.7, 45.7, 40.6, 31.2, 26.3, 11.8. MS (ESI): m/z (%) = 1339 (100) [M + Na]⁺. HRMS: m/z [M + Na]⁺ calcd for C₆₈H₇₆N₁₂NaO₁₆: 1339.5395; found: 1339.5407.

16

Representative guanidinylation procedure: To a suspension of 31 (0.12 g, 0.15 mmol) in CH₂Cl₂ (5 mL), DIPEA (0.14 mL, 0.75 mmol) was added and the solution was stirred at r.t. for 15 min. N,N′-di-Boc-N′′-triflylguanidine (0.32 g, 0.83 mmol) in CH₂Cl₂ (2 mL) was added via cannula and the reaction mixture was stirred at r.t. for 21 h. The mixture was diluted with CH₂Cl₂ (10 mL) and washed with 2 M NaHSO₄ (10 mL), NaHCO₃ (10 mL), brine (10 mL), dried (MgSO₄) and concentrated under reduced pressure to give a pale-brown foam. The crude material was purified by flash chromatography (hexane-EtOAc, 2:3) to give 9 as a colourless foam (0.16 g, 82%); [α]_D ^²0 -1.0 (c 3.5, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 11.49 (s, 3 H), 8.32 (s, 3 H), 8.31 (s, 3 H), 5.14 (m, 3 H), 3.47-3.45 (m, 6 H), 2.66 (s, 9 H), 2.15 (m, 3 H), 1.98 (m, 3 H), 1.81 (m, 3 H), 1.55 (m, 3 H), 1.48 (s, 54 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 161.0, 160.8, 156.1, 154.2, 153.3, 128.5, 83.3, 79.5, 47.8, 40.6, 32.1, 28.3, 28.1, 24.7, 11.7. MS (ESI): m/z (%) = 1312 (100) [M + H]⁺, 1334 (20) [M + Na]⁺. HRMS: m/z [M + H]⁺ calcd for C₆₀H₉₄N₁₅O₁₈: 1312.6896; found: 1312.6900.