Helma Wennemers

Tripeptides as Efficient Asymmetric Catalysts for 1,4-Addition Reactions of Aldehydes to Nitroolefins–A Rational Approach†

Peptides have become increasingly popular as asymmetric catalysts for a range of reactions. Features such as facile synthesis, modularity, and often high selectivity and activity render peptidic catalysts attractive alternatives to metal-based catalysts and other organocatalysts. One of the largest challenges in the development of peptidic catalysts is the prediction and incorporation of desirable catalytic properties into a given peptide. This is already a challenge for small rigid organocatalysts, but even more so for short peptidic catalysts bearing many more degrees of rotational freedom. As a result, combinatorial chemistry has proven to be a valuable tool for the identification of peptidic catalysts. In this study we used insight gained from conformational analysis to guide the development of tripeptides as efficient asymmetric catalysts for conjugate addition reactions of aldehydes to nitroolefins. Recently, we introduced the peptide H-Pro-Pro-AspNH2 (1) as a catalyst for direct asymmetric aldol

Peptide Catalyzed Asymmetric Conjugate Addition Reactions of Aldehydes to Nitroethylene—A Convenient Entry into γ2-Amino Acids

The peptide H-D-Pro-Pro-Glu-NH2 is a highly effective catalyst for conjugate addition reactions between aldehydes and nitroethylene. Only 1 mol % of H-d-Pro-Pro-Glu-NH2 and a 1.5-fold excess of aldehyde with respect to nitroethylene suffice to obtain gamma-nitroaldehydes and, after reduction, monosubstituted gamma-nitroalcohols in excellent yields and optical purities. The products can be readily converted into gamma2-amino acids, thereby opening an effective direct entry into this important class of compounds.

Enamine Catalysis with Low Catalyst Loadings - High Efficiency via Kinetic Studies

Kinetic studies on enamine catalysis provided insight into the rate determining step(s) of peptide catalyzed conjugate addition reactions between aldehydes and nitroolefins. They demonstrate that not enamine formation but both the reaction of the enamine with the electrophile and hydrolysis of the resulting imine are rate limiting. These results allowed for reducing the catalyst loading by a factor of 10 to as little as 0.1 mol %. This is the lowest catalyst loading that has been achieved so far in enamine catalysis with low molecular weight catalysts for a broad range of substrates.

Effects of terminal functional groups on the stability of the polyproline II structure : a combined experimental and theoretical study

The conformational stability of the polyproline II (PPII) helix with respect to the functional groups at the C- and N-termini was examined both experimentally and theoretically. Oligoprolines AcN-[Pro](12)-CONH(2) (1), HN-[Pro](12)-CONH(2) (2), AcN-[Pro](12)-CO(2)H (3), and HN-[Pro](12)-CO(2)H (4) with charged and capped termini served as model compounds, and the relative ease with which they switch from the PPII to the polyproline I (PPI) helix was used as a measure to analyze their conformational stabilities. CD spectroscopic studies demonstrate that a positively charged N-terminus and a negatively charged C-terminus destabilize the PPII helix and favor the PPI helix, whereas capped termini favor the PPII over the PPI helix. These experimental findings are supported by the energy differences between the PPII and PPI helices of oligoprolines 1-4 computed by ab initio methods including electron-correlation effects (second-order Møller-Plesset perturbation theory, MP2). Furthermore, these quantum-chemical calculations show that differences in charge-dipole interactions are responsible for the experimentally and computationally observed relative stabilities. Although these electrostatic interactions between the terminal charges and the amide dipoles stabilize both helices, they are significantly stronger in the PPI helix where the amide bonds are oriented almost linear to the helix axis as compared to the PPII helix in which the amides are nearly perpendicular to the axis. Moreover, we demonstrate that a negative charge at the C-terminus has a more pronounced effect on the relative stability as compared to a positive charge at the N-terminus due to destabilization of the PPII helix by repulsive interaction between the C-terminal carboxylate with the neighboring amide bond. Studies at different pH values verified the electrostatic nature of the observed effects and demonstrate how changes in the protonation state can be used to deliberately stabilize the PPII helix over the PPI helix or vice versa.

Tuning the cis/trans conformer ratio of Xaa-Pro amide bonds by intramolecular hydrogen bonds: the effect on PPII helix stability.

Isomerizations between cis and trans conformers in Xaa–Pro amide bonds (Xaa = any amino acid, Pro = proline) are crucial in many natural processes such as protein folding and signal transduction. Both the understanding of the factors that determine the cis/trans conformer ratio and the development of tools that allow for the tuning of this equilibrium is therefore important. Proline derivatives with a substituent in the g position (C4) have proven useful in both respects (Scheme 1a). Conformational studies have shown that the nature of the substituent at C4 and the absolute configuration at this center critically influence both the pyrrolidine ring pucker and the cis/trans conformer ratio of the amide bond in Xaa–Pro bonds. In all of these proline derivatives, a correlation between the ring pucker and the cis/trans conformer ratio has been observed: A C4-exo ring pucker favors the trans conformation, whereas a C4-endo ring pucker leads to a higher population of the cis conformer. This observation has been attributed to a stronger noncovalent interaction between adjacent amide bonds through an n!p* interaction in the C4-exo compared to C4-endopuckered proline derivatives (Scheme 1 b). As a result, a variety of proline derivatives are available as tools to stabilize the trans conformer of Xaa–Pro bonds in which the proline ring adopts a C4-exo ring pucker. However, within many peptides and proteins the preferred ring pucker of proline with trans amide bonds is not C4-exo but C4-endo. Thus, proline derivatives that preferentially adopt a C4-endo conformation and favor the trans conformer are important alternative probes and have not been developed to date. Herein we present C4-endo ring-puckered proline derivatives in which the trans conformer is favored because of a hydrogen-bond-donating substituent in the g position. Furthermore, we demonstrate the versatility of these derivatives to stabilize trans amide bonds within longer peptides. We started our investigations by an analysis of the relative orientation of the carbonyl groups in acetylated methyl esters of proline derivatives with substituents at C4, which have proven as valuable model compounds for Xaa–Pro bonds. This orientation is crucial because the n!p* interaction that stabilizes the trans conformer requires a B rgi–Dunitz trajectory between the oxygen atom of the acetyl group (Oi 1) and the carbonyl group of the methyl ester (Ci=Oi) as well as a short distance between Oi 1 and Ci (Scheme 1b, right). [7,10]

Tripeptides of the type H-D-Pro-Pro-Xaa-NH2 as catalysts for asymmetric 1,4-addition reactions : structural requirements for high catalytic efficiency

Analysis of the structural and functional requirements within the asymmetric peptidic catalyst H-D-Pro-Pro-Asp-NH(2) led to the development of the closely related peptide H-D-Pro-Pro-Glu-NH(2) as an even more efficient catalyst for asymmetric conjugate addition reactions of aldehydes to nitroolefins. In the presence of as little as 1 mol % of H-D-Pro-Pro-Glu-NH(2), a broad range of aldehydes and nitroolefins react readily with each other. The resulting gamma-nitroaldehydes were obtained in excellent yields and stereoselectivities at room temperature. Within the structure of the peptidic catalysts, the D-Pro-Pro motif is the major contributor to the high stereoselectivities. The C-terminal amide and the spacer to the carboxylic acid in the side-chain of the C-terminal amino acid are responsible for the fine-tuning of the stereoselectivity. The peptidic catalysts not only allow for highly effective asymmetric catalysis under mild conditions, but also function in the absence of additives.

New ionic liquid-modified silica gels as recyclable materials for L-proline- or H–Pro–Pro–Asp–NH2-catalyzed aldol reaction

L-proline and the tripeptide H–Pro–Pro–Asp–NH2 (1) have been supported, by adsorption, onto the surface of modified silica gels functionalized with a monolayer of covalently attached 1,2-dimethyl-imidazolium chloride, tetrafluoroborate or hexafluorophosphate ionic moieties, respectively. Three different linkers were used to attach the ionic liquid moiety to the surface of these supports. The resulting materials have been used as catalysts for the aldol reaction between acetone and several substituted benzaldehydes. Good yields and enantioselectivities, comparable to or better than those obtained under homogeneous conditions, were obtained. These materials are easily recovered by filtration, and studies regarding their re-use have been carried out. Studies performed using L-proline-supported materials have shown that the re-use of these materials is dependent on the nature of the linker. The supported tripeptide H–Pro–Pro–Asp–NH2 gave higher enantioselectivities than those obtained with supported-proline. Recycling investigations using tripeptide-supported materials showed continued good selectivities but diminishing conversions over consecutive runs. L-proline-supported materials however, can be used at least nine times without loss of either conversion or selectivity.

Diketopiperazine Receptors - A Novel Class of Highly Selective Receptors for Binding Small Peptides

A novel class of receptors consisting of a rigid diketopiperazine backbone and peptidic side chains has been developed with the use of combinatorial chemistry. These diketopiperazine receptors interact with peptidic substrates with high specificity as shown in combinatorial on-bead assays. The central diketopiperazine moiety can be easily obtained from natural 4-hydroxyproline and serves as a rigidifying template for the peptidic modules which allow for structural as well as functional variations. Screenings of several dye-marked receptor prototypes against an encoded tripeptide library demonstrated not only the high binding specificities of the diketopiperazine receptors towards peptides but also revealed that small structural changes induce significant changes in their binding properties.

Enamine Catalysis in Flow with an Immobilized Peptidic Catalyst

Pep talk: An immobilized peptidic catalyst achieves more than 600 turnovers in a continuous-flow system, allowing the production of chiral γ-nitroaldehydes with excellent stereoselectivities on a scale of >450 mmol (>100 g). Such a high efficiency opens the way for more practical applications of enamine catalysis.

Importance of Ring Puckering versus Interstrand Hydrogen Bonds for the Conformational Stability of Collagen

The fibrous protein collagen is the most abundant protein in mammals and plays a crucial role both in numerous cellular activities and as a structural protein. Understanding the factors that govern the conformational stability of collagen is therefore important. In addition, there is a growing interest in collagen-based functional materials and as a result the development of synthetic collagen that bears functionalizable groups is important. 3] Collagen is built up of single strands that form triple helices which then further assemble into bundles and fibres. The single strands consist of repeating Xaa–Yaa–Gly units with all amide bonds in trans conformation. Proline (Pro) is most often found in the Xaa position and (4R)-hydroxyproline (Hyp) in the Yaa position. Within the triple helix the three strands are held together by hydrogen bonds between the NH group of glycine (Gly) of one strand and the C=O group of Pro of the adjacent strand (Figure 1a). Crystal structures show C(4)-endo ring puckers of the Pro residues in the Xaa and C(4)-exo ring puckers of the Hyp residues in the Yaa positions (Figure 1 a). 4] For the dihedral angles Y (NiCia-Ci-Ni+1) that are responsible for the directionality of the collagen strands average values of approximately 1558 (Xaa) and approximately 1508 (Yaa) are observed. Studies with collagen model peptides (CMPs) in which the natural Pro and Hyp residues were replaced by other proline derivatives led to the conclusion that both the ring puckering and the interstrand H bonds are crucial for the conformational stability of the collagen triple helix. 6] All of the studies that address the importance of the ring puckering were performed with proline derivatives in which the trans amide conformer is significantly favored over the cis conformer in the case of C(4)-exo ring-puckered derivatives, whereas the trans conformer is less favored in derivatives with C(4)-endo ring puckers. 5] In addition, the Y angles of the C(4)-endo ring puckered derivatives examined so far are typically approximately 1808 and are not close to those in collagen. Thus, any C(4)-endo ring-puckered derivative had an unfavorable bias towards the trans amide bond and the Y angle. We have recently introduced proline derivatives, such as (4S)-acetamido proline (Acp), in which intramolecular hydrogen bonding leads to a preference for the C(4)-endo ring pucker and the trans amide conformer in aqueous solutions (Figure 1b). This is due to an enforced dihedral angle Y at approximately 1408 by the intramolecular H bond, which allows for a stabilization of the trans isomer by a n!p* interaction. This dihedral angle Y within (4S)Acp is comparable to those observed in collagen and proline derivatives such as (4R)Hyp with a C(4)-exo ring pucker. Proline derivatives such as (4S)Acp therefore allow for the first time to investigate, whether a C(4)-endo ring pucker is tolerated in the Yaa position without a concomitant unfavorable bias on the trans amide bond and the Y angle. Furthermore, the combination of the C(4)-endo ring pucker and the intramolecular H bond allows for probing whether the ring pucker or the interstrand H bonds are more important in the Xaa position for the stability of the collagen triple helix. Herein, we demonstrate that a mismatched ring pucker is tolerated, whereas the interstrand H bonds are crucial for the conformational stability of the collagen triple helix. We started our investigations by analyzing the possible effects of the incorporation of (4S)Acp in the Yaa position on the properties of the collagen triple helix (Figure 2): The ring pucker of (4S)Acp is C(4)-endo and a mismatch to that of the C(4)-exo pucker of the natural (4R)Hyp residue. Thus, if the Figure 1. a) General structure of collagen. b) Ac–(4S)Acp–OCH3 with C(4)-endo conformation by intramolecular H bonding.