Functionalized Cyclotriproline - A Bowl-Shaped Tripodal Scaffold

Abstract

The synthesis and conformational analysis of C 3 -symmetric cyclotri[(4S)-aminoproline] as a bowl-shaped scaffold for three-armed receptors is described.Synthetic receptors are typically based on a template that is functionalized with recognition elements. 1 While the recognition elements can be regarded as the selectivity determining modules, the template is responsible for directing the recognition elements into a conformation that allows for intermolecular interactions. Thus, the choice of the template is crucial for the binding properties of synthetic receptors. Generally, templates with a defined curvature and attachment sites for the recognition elements that point into the same direction have proven superior to flexible, conformationally undefined templates. 2,3 Over the last decade, receptors based on templates that allow for the attachment of two peptides as recognition elements have shown good to excellent binding selectivities towards peptidic guest molecules. [2][3][4][5] Receptors with an additional third recognition element can be expected to exhibit even higher binding specificities and particularly affinities due to a three-point rather than a two-point binding motif. However, examples of peptide receptors with a parallel alignment of three recognition elements are still rare. 6Here we describe the synthesis of the cyclotriproline derivative 1 that allows for the attachment of three recognition elements after reduction of the azide functionalities. The acetylated cyclotriproline derivative 2 served as a minimal fragment of three-armed receptors for the conformational analysis of the tripodal scaffold.For the synthesis of 1 we envisioned the linear triprolines 3 and 4 as cyclization precursors ( Figure 1). Their synthesis starts from N-Boc-(4S)-N 3 -Pro-OCH 3 5 that was on one hand N-Boc deprotected to the HCl-salt 6 and on the other hand hydrolyzed to acid 7, which then was transformed to pentafluorophenyl (Pfp) ester 8. Mixing of 6 with 8 in the presence of Hünig's base provided dipeptide 9. The tripeptide 10 was obtained after methylester hydrolysis of 9 followed by coupling of the resulting acid and 6 with HATU. 7 Hydrolysis of the methylester 10 provided the acid 11 that was partially converted into the Pfpester 12. N-Boc deprotection of 11 and 12 with HCl in dioxane yielded the cyclization precursors 3 and 4 (Scheme 1).The formation of 1 was on one hand examined by the cyclization of the Pfp-ester 4 in pyridine and on the other hand by cyclizing the acid 3 in the presence of different coupling reagents. For the cyclization of the Pfp-ester, a solution of 4 in DMF containing 1% acetic acid was slowly added to a heated solution of pyridine to a final peptide Figure 1 Cyclotriproline derivatives 1 and 2 Scheme 1 Synthesis of the linear triprolines 3 and 4. Reagents and conditions: (a) 4 M HCl in dioxane, quant; (b) NaOH, quant.; (c) C 6 F 5 OH, EDC, 93%; (d) i-PrNEt 2 , 90%; (e) i. NaOH, ii. 5a, HATU, i-PrNEt 2 , 73%; (f) same as (b), 97%; (g) same as (c), 93%; (h) same as (a), quant.concentrati...