Silver-Ion-Mediated Macrocyclization To Form Cyclohexadepsipeptide

Abstract

A metal-ion-mediated cyclization of a linear peptide to the corresponding cyclohexadepsipeptide, a stereoisomer of ­hirsutellide A, was studied. The presence of AgBF₄ improved the cyclization yield from 14% to 61%. The effect of silver ion on the macrocyclization was further investigated by NMR and molecular mechanics calculations.

cyclization - ring closure - peptides - macrocycles - silver

References and Notes

<A NAME="RW04207ST-1">1</A> Vongvanich N. Kittakoop P. Iaska M. Trakulnaleamsai S. Vimuttipong S. Tanticharoen M. Thebtaranonth Y. J. Nat. Prod.  2002,  65:  1346 

<A NAME="RW04207ST-2A">2a</A> Xu YJ. Chen LG. Duan XM. Li ML. Jiang LQ. Zhao GL. Meng Y. Li Y. Tetrahedron Lett.  2005,  46:  4377 

<A NAME="RW04207ST-2B">2b</A> Xu YJ. Duan XM. Li ML. Jiang LQ. Zhao GL. Meng Y. Chen LG. Molecules  2005,  10:  259 

<A NAME="RW04207ST-2C">2c</A> The stereoconfiguration of the previously synthesized cyclopeptide^2a,b was corrected by X-ray crystallography: Xu YJ. Chen LG. Duan XM. Li ML. Jiang LQ. Zhao GL. Meng Y. Li Y. Tetrahedron Lett.  2007,  48:  733 

<A NAME="RW04207ST-3">3</A> Cui C. Kim KS. J. Phys. Chem. A  1999,  103:  2751 

<A NAME="RW04207ST-4">4</A> Ercolani G. Mandolini L. Masci B. J. Am. Chem. Soc.  1981,  103:  2780 

<A NAME="RW04207ST-5A">5a</A> Blake AJ. Hannam JS. Jolliffe KA. Pattenden G. Synlett  2000,  1515 

<A NAME="RW04207ST-5B">5b</A> Bertram A. Pattenden G. Synlett  2001,  1873 

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<A NAME="RW04207ST-6">6</A>

Experimental Procedure: A solution of 3 (0.13 g, 0.15 mmol) in EtOAc (15 mL) was treated with Pd-C (5%, 0.26 g), and then the black suspension was stirred at r.t. under an atmosphere of H₂ for 12 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give crude 8 (0.12 g, used in the next step without further purification). To a solution of 8 (0.12 g, 0.15 mmol) in anhyd CH₂Cl₂ (5 mL) was added TFA (0.2 mL, 1.5 mmol) dropwise at 0 °C with stirring. The mixture was then slowly warmed to r.t. and stirred for 12 h. The reaction mixture was concentrated, and then the residue was dried under high vacuum to give crude 4 (used directly in the next step).

<A NAME="RW04207ST-7">7</A> Davies JS. J. Peptide Sci.  2003,  9:  471 

<A NAME="RW04207ST-8">8</A>

Experimental Procedure: TFA salt 4 (0.15 mmol) was dissolved in anhyd MeCN (3 mL). FDPP (97%; 86.0 mg, 0.22 mmol) was added in one portion with stirring and cooled to 0 °C, followed by i-Pr₂NEt (0.12 mL, 0.74 mmol). The mixture was then warmed to r.t. and stirred for 36 h. The reaction was quenched by adding sat. aq NH₄Cl (1 mL) dropwise and evaporated in vacuo followed by dissolving in EtOAc (100 mL). The mixture was washed with sat. aq NH₄Cl (2 × 100 mL), sat. aq NaHCO₃ (2 × 100 mL) and brine (100 mL), dried (MgSO₄), filtered and evaporated in vacuo to leave a residue which was purified by column chromatography on silica gel using 30% EtOAc in PE as eluent to give cyclohexadepsipeptide 2 (13.8 mg, 14%) as a colorless oil.

<A NAME="RW04207ST-9">9</A>

Experimental Procedure: TFA salt 4 (0.18 mmol) was dissolved in anhyd MeCN (3.6 mL). AgBF₄ (52.6 mg, 0.27 mmol) and i-Pr₂NEt (0.2 mL, 0.9 mmol) were added and the mixture was stirred overnight. A solution of FDPP (97%; 107.0 mg, 0.27 mmol) in anhyd MeCN (2 mL) was added in one portion with stirring at 0 °C. The mixture was then warmed to r.t. and stirred for 36 h. The same workup procedure was carried out as described above. The crude product was purified by column chromatography on silica gel using 30% EtOAc in PE as eluent to give cyclohexadepsipeptide 2 (73.0 mg, 61%) as a colorless oil; [a]²⁵ _D -14.1° (c = 0.50, CHCl₃) {Lit.^2a [a]²⁰ _D -13.8° (c = 0.22, CHCl₃)}. ¹H NMR (300 MHz, CD₃CN): δ = 7.49 (d, J = 9.6 Hz, 2 H, 2 ¥ NH), 7.35-7.20 (m, 10 H), 5.43 (dd, J = 3.0, 11.4 Hz, 2 H), 4.89 (t, J = 9.9 Hz, 2 H), 4.26 (d, J = 17.1 Hz, 2 H), 3.54 (dd, J = 2.7, 14.1 Hz, 2 H), 3.42 (d, J = 17.1 Hz, 2 H), 3.28 (s, 6 H), 2.74 (dd, J = 11.4, 14.1 Hz, 2 H), 2.09-2.17 (m, 2 H), 1.45-1.53 (m, 2 H), 1.09-1.19 (m, 2 H), 0.88 (t, J = 7.2 Hz, 6 H), 0.85 (d, J = 6.6 Hz, 6 H). ¹³C NMR (75 MHz, CD₃CN): δ = 174.10, 168.76, 167.84, 136.95, 129.50, 128.77, 127.15, 74.37, 52.15, 51.79, 38.69, 37.59, 36.04, 24.16, 14.67, 9.88.

<A NAME="RW04207ST-10">10</A>

Based on its X-ray crystal structure,^2c the conformation of 2 was optimized with molecular mechanics calculations (gas-phase simulations with SYBYL 6.91). To examine the structure of the proposed complex 5, the silver ion was docked to the core domain of 2 by the Dock program.

<A NAME="RW04207ST-11">11</A>

Molecular modeling was performed using SYBYL 6.91 (Tripos). The initial structure of the molecule was drawn by hand and the peptide backbone was built up using the ‘sketch molecule’ feature. Chirality was assigned for all stereocenters but no further manual manipulation of the structure was undertaken. The lowest energy conformations were selected and refined by molecular mechanics minimization using Powell’s gradient algorithm method with the Tripos force field. The Gasteiger-Huckel charge was also selected. Due to the flexibility of the molecule, Systematic Search was selected to optimize the conformation by rotating the single bonds with an angle shift of 10°. Finally, from these refined conformations, the conformers with the lowest energy were selected to represent the most probable molecular configurations. The silver ion was also docked to the core domain of the optimized conformers by the Dock program.