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Synlett 2004(7): 1270-1272  
DOI: 10.1055/s-2004-822915
LETTER
© Georg Thieme Verlag Stuttgart · New York

Functionalized Cyclotriproline - A Bowl-Shaped Tripodal Scaffold

Louis-Sebastian Sonntag, Stanislav Ivan, Michael Langer, Matteo M. Conza, Helma Wennemers*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax: +41(61)2671105; e-Mail: Helma.Wennemers@unibas.ch;
Further Information

Publication History

Received 18 March 2004
Publication Date:
28 April 2004 (online)

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Abstract

The synthesis and conformational analysis of C3-symmetric cyclotri[(4S)-aminoproline] as a bowl-shaped scaffold for three-armed receptors is described.

Key words

cyclic peptides - scaffolds - proline - cyclization - receptors

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7

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate; TBTU: N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium-tetrafluoroborate; PyBop: benzotriazole-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate.

10

Preparation of 1a: The HCl salt 5a (440 mg, 0.94 mmol) was dissolved in anhyd DMF (17 mL) and added within 1 h via syringe pump to a stirred solution of HATU (1.07 g, 2.81 mmol) and Hünig’s base (1.44 mL, 8.43 mmol) in anhyd DMF (90 mL). The reaction mixture was stirred for an additional hour before removal of all volatiles at reduced pressure. The remaining oil was extracted with CH2Cl2 (100 mL) and 2 M HCl (50 mL). The aqueous layers were extracted with CH2Cl2 (2 × 50 mL), the organic layers were washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent at reduced pressure followed by flash chromatography on silica gel (EtOAc) yielded the cyclotripeptide 1a (285 mg, 0.69 mmol, 73%) as a white solid. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 5.07 (dd, J = 8.1 Hz, 2.1 Hz, 3 H; Hα), 4.52 (dd, J = 12.5 Hz, 8.1 Hz, 3 H; Hδ), 4.04 (dtd, J = 9.9 Hz, 8.1 Hz, 5.3 Hz, 3 H; Hγ), 3.14 (dd, J = 12.5 Hz, 8.2 Hz, 3 H; Hδ), 2.64 (ddd, J = 13.9 Hz, 5.2 Hz, 2.1 Hz, 3 H; Hβ), 2.54 (ddd, J = 13.8 Hz, 10.0 Hz, 8.2 Hz, 3 H; Hβ). 13C NMR (125 MHz, CDCl3, 25 °C): δ = 165.9, 56.3, 55.7, 49.3, 34.1. FT-IR (NaCl): 2108, 1646, 1441, 1362, 1263, 1211 cm-1. ESI-MS: m/z Calcd for C15H18N12O3 [M + Na]+ 437. Found: 437 (100%). Elemental analysis calcd for C15H18N12O3 (414.16): C, 43.48; H, 4.38; N, 40.56. Found: C, 43.41; H, 4.34; N, 40.50.

11

Performing the cyclization at higher or lower dilution did not improve the yield any further.

17

The distance of 7-8 Å has proven to be an ideal distance between the attachment sites of the recognition elements of two-armed receptors, see ref 3.