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Synlett 2010(4): 551-554  
DOI: 10.1055/s-0029-1219155
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Richard J. G Black, Victoria J. Dungan, Rebecca Y. T. Li, Philip G. Young, Katrina A. Jolliffe*
School of Chemistry, The University of Sydney, 2006, NSW, Australia
Fax: +61(2)93513329; e-Mail: jolliffe@chem.usyd.edu.au;
Further Information

Publication History

Received 9 November 2009
Publication Date:
22 December 2009 (online)

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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

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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.

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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.