Research 

H-PPD-NH2 Molecular Recognition
Asymmetric Catalysis Molecular Recognition Molecular Scaffolds Peptide Cleavage

 

1. Peptides as Asymmetric Catalysts

In organic synthesis, enzymes and man-made catalysts of low molecular weight are commonly used catalysts. We are intrigued by the question whether peptides of intermediate complexity may be attractive alternative asymmetric catalysts.1

Peptides offer many sites for structural and functional diversification, thus, should allow for the generation of optimal catalysts. However, due to the many degrees of freedom of short chain peptides, the purely rational design of efficient peptidic catalysts has proven difficult. We therefore started the project by developing the screening method of "catalyst-substrate coimmobilization" which allows for the identification of catalysts among the members of combinatorial split-and-mix libraries (Figure 1).2 The method relies on the coimmobilization of one reaction partners (A) together with each library member, the potential catalysts, on the same bead. Incubation of the library with a labelled reaction partner (B), leads to its covalent attachment and thereby labeling only of those beads carrying compounds which mediate the reaction between A and B. Active compounds are therefore easily identified by visual inspection of the library under a low power microscope.

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Figure 1: Catalyst-substrate co-immobilisation for the discovery of catalysts within split-and-mix libraries.


Using this method we identified the peptides H-Pro-Pro-Asp-NH2 and H-Pro-D-Ala-D-Asp-NH2 as highly active and selective catalysts for aldol reactions.3-7 Only 1 mol% of H-Pro-Pro-Asp-NH2 is sufficient to catalyze aldol reactions with up to quantitative yields and enantioselectivities of up to 91% ee.

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Figure 2: H-Pro-Pro-Asp-NH2 and H-Pro-D-Ala-D-Asp-NH2, catalysts for asymmetric aldol reactions

These results demonstrated that the peptidic catalysts have a significantly higher activity compared to the rigid small organocatalyst proline which requires the use of 30 mol% for efficient catalysis. Thus, the higher complexity of peptidic catalysts is a good trade-off for higher complexity. Furthermore, the results demonstrated that the selectivity of peptidic catalysts can be easily tuned by varying their primary and thereby secondary structure.

Most recently, we used the closely related peptides H-D-Pro-Pro-Asp-NH2 and H-D-Pro-Pro-Glu-NH2 as catalysts for conjugate addition reactions between aldehydes and nitroolefins.8,9 1 mol% of either catalyst is sufficient to obtain the 1,4-addition products of a broad range of aldehyde and nitroolefin combinations in very good yields and stereoselectivities. Among the nitroolefins that can be reacted is the simplest possible nitroolefin, nitroethylene. The resulting monosubstituted nitroaldehydes offer a convenient entry into γ2-amino acids that are difficult to obtain by other methods.

For a highlight of our research on asymmetric catalysis click here or download the pdf.


Figure 3: H-D-Pro-Pro-Asp-NH2 and H-D-Pro-Pro-Glu-NH2 as catalysts for conjugate addition reactions

  1. J. D. Revell, H. Wennemers, Curr. Opin. Chem. Biol. 2007, 11, 269-278.
  2. P. Krattiger, C. McCarthy, A. Pfaltz, H. Wennemers, Angew. Chem. Int. Ed. 2003, 42, 1722-1724.
  3. P. Krattiger, R. Kovàsy, J. D. Revell, S. Ivan, H. Wennemers, Org. Lett. 2005, 7, 1101-1103.
  4. P. Krattiger, R. Kovàsy, J. D. Revell, H. Wennemers, QSAR Comb. Sci. 2005, 24, 1158-1163.
  5. J. D. Revell, D. Gantenbein, P. Krattiger, H. Wennemers, Biopolymers (Pept. Sci.) 2006, 84, 105-113.
  6. J. D. Revell, H. Wennemers, Tetrahedron 2007, 63, 8420-8424.
  7. J. D. Revell, H. Wennemers, Adv. Synth. Catal. 2008, in press.
  8. M. Wiesner, J. D. Revell, H. Wennemers, Angew. Chem. Int. Ed. 2008, 47, 1871-1874.
  9. M. Wiesner, J. D. Revell, S. Tonazzi, H. Wennemers, J. Am. Chem. Soc. 2008, ASAP.

 

2. Selective Peptide Recognition

For the selective molecular recognition of peptides we developed the class of diketopiperazine receptors. These two-armed receptors consist of a structure-directing diketopiperazine template and peptidic side chains as "recognition modules“.1-6  Combinatorial and conventional binding studies revealed that such receptors bind tripeptides with excellent sequence selectivities and binding affinities in the range of ΔG = -5 - -6 kcal mol-1 in organic and aqueous solvents.

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Figure 4 : Diketopiperazine Receptors

We are currently using these highly selective interactions for the development of "artificial noses“ (collaboration with Prof. Joachim Bargon, University of Bonn),7 synthetic antibodies, the triggered self-assembly of supramolecular vesicular structures (collaboration with Prof. Wolfgang Meier, Uni Basel) and the development of liquid crystalline materials with tailor-made properties (collaboration with Dr. Charl Faul, Bristol University).8

  1. H. Wennemers, M. Conza, M. Nold, P. Krattiger, Chem. Eur. J. 2001, 7, 3342-3347.
  2. M. Conza, H. Wennemers, J. Org. Chem. 2002, 67, 2696-2698.
  3. H. Wennemers, M. Nold, M. Conza, K. J. Kulicke, M. Neuburger, Chem. Eur. J. 2003, 9, 442-448.
  4. M. Conza, H. Wennemers, Chem. Commun. 2003,866-867.
  5. P. Krattiger, H. Wennemers, Synlett 2005, 706-708.
  6. Bernard, H. Wennemers, Org. Lett. 2007, 9, 4283-4286.
  7. J. W. Lörgen, P. Krattiger, C. Kreutz, H. Wennemers, J. Bargon, Sensors and Actuators B: Chemical 2005,107, 366-371.
  8. C. F. J. Faul, P. Krattiger, B. Smarsly, H. Wennemers, J. Mater. Chem. 2008, in press.

 

3. Polyprolines as Molecular Scaffolds

The polyproline II (PPII) helix is a common secondary structure in many proteins (among them collagen) and plays important roles in numerous natural processes like . It is a highly symmetrical helix with every third residue stacked on top of each other. Oligoprolines adopt this PPII helix in water already at chain lengths as short as six residues and allow for a conformational switch to the more compact PPI helix in more hydrophobic environment.  We are engaged in a) understanding factors that influence the stability of the PPII helix and b) using the unique properties of oligoprolines for the development of functionalizable molecular scaffolds.

Towards these goals we incorporated (4S)- and (4R)-azidoprolines (Azp) into oligoprolines and demonstrated that the azido group allowed for facile further functionalization using “click chemistry”.1  In addition, (4S)Azp and (4R)Azp proved as valuable probes for tuning the conformational stability of the PPII helix: (4S)Azp destabilizes whereas (4R)Azp stabilizes the PPII helix.1,2

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Figure 5: Models of the PPII helix of oligoprolines with Azp residues in every third position.

We are currently applying these functionalizable molecular scaffolds for applications in material sciences (e.g. development of materials with defined electronic properties) and the life-sciences (e.g. development of cell-penetrating peptides and antibiotics).

  1. L.-S. Sonntag, S. Schweizer, C. Ochsenfeld, H. Wennemers, J. Am. Chem. Soc. 2006, 128, 14697-14703.
  2. M. Kümin, L.-S. Sonntag, H. Wennemers, J. Am. Chem. Soc. 2007, 129, 466-467.

 

4. Selective Peptide Cleavage

Radical mediated protein damage is considered to play a major role in several diseases and aging. Often these radicals are generated by reaction of Fe(II)-ions with hydrogenperoxide (Fenton reaction). We have addressed the question whether some peptides are more prone to backbone damage than others under such Fenton conditions. By a combination of combinatorial screenings and experiments with single peptides we found that peptides with two or more neighbouring acidic amino acids are cleaved preferentially to others.1,2

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Figure 6 : Detection of selective peptide damage within a split-and-mix library of tripeptides where each peptide is flanked by a fluorophore and quencher. 

Our studies indicate that the preferential damage of acid-rich peptides is due to the complexation of the Fe-ions by the carboxylates of the peptides which leads to the generation of radicals in close vicinity of the backbone of acidic peptides and thereby to the enhanced damage of these peptides.

  1. M. Nold, H. Wennemers, Chem. Commun. 2004, 1800-1801.
  2. M. Nold, K. Koch, H. Wennemers, Synthesis 2005, 1455-1458.

 

last update: 7.4.08