The Skaggs Institute
for Chemical Biology

Scientific Report 2008

Filling Space at the Molecular Level

J. Rebek, Jr., D. Ajami, M. Ams, E. Barrett, S. Beer, T.J. Dale, R.J. Hooley, J.-L. Hou, H. Van Anda, S. Xiao, A. Lledo, H. Dube, P. Restorp, S. Kamioka

Molecular Mimicry

Protein-protein interactions are involved in many cell signaling events, and a large fraction of protein surfaces involve α-helices. This secondary structure presents side chains of the component amino acids along one face of the helix that are recognized by the partner protein. To interfere with these protein-protein interactions, several research groups have made α-helix mimetics. Our efforts have gone into those that have amphiphilic behavior, that is, ones that are hydrophobic on one side and hydrophilic on the other. We have found rapid and efficient ways of assembling these mimics by using a pyridizine-based scaffold. The mimics have good solubility, and their synthesis can be easily scaled up. The pyridizines and the scheme for their assembly are shown in Figure 1.

Fig. 1. A, Overlay of an idealized α-helix protein structure with a new scaffold. B, Synthetic scheme shows the component parts that present the amino acid side chains on the scaffold and the atoms that make up the hydrophilic surface.

Expanded Capsules

Reversible encapsulation complexes are synthetic receptors that more or less completely surround their target guests. They provide a window through which molecular behavior can be seen in extremely small spaces. They have revealed phenomena never before observed, such as coiled alkanes, stabilization of reactive intermediates, places where new forms of stereochemistry can emerge, and reaction chambers with well-defined shapes. We found that some capsules, such as shown in Figure 2, can incorporate spacer elements known as glycolurils in response to the presence of guests. The expanded capsules shown are present only when a suitable guest is able to fill the space inside. The shape of the space inside is shown in the figure, and narrow functional groups such as primary alkenes and acetylenes can fit in the tapered ends of the space.

Fig. 2. Size and shape of the space inside a capsule show the tapered ends and the constricted center. Center, Encapsulated 1-hexadecene inside the assembly. Right, Encapsulated 1-hexadecyne. The thin alkene and alkyne groups penetrate deep into the bottom of the capsule. The central parts of the guests are in fully extended conformations, and compression of the alkane appears near the top.

Coencapsulation

With 2 different guests inside a capsule, the contact points between the guests can be mapped out by using nuclear magnetic resonance techniques. For example, with ethane and heptane coencapsulated, as shown in Figure 3, we found that the 2 ends of heptane are alternately in contact with the ethane. This contact is achieved by the flipping of the heptane inside the capsule, rather than by the exchange of places of the 2 guests inside.

Fig. 3. Ethane (gray) and heptane (rainbow colored) are coencapsulated. Tumbling motions of the heptane can be detected by nuclear magnetic resonance techniques that show contact between the 2 ends of the longer guest with ethane.

Cavitands With Introverted Functionality

Cavitands are open-ended molecular vessels that allow relatively rapid motions of guests inside and out. Figure 4 shows a system held together by hydrogen bonding that features a seam of hydrogen bonds that maintain the vaselike shape. The cavitand is attached to an anthracene that delivers a carboxylic acid to the inside space. We have used this system to trap reactive intermediates such as those involved in reactions of isonitriles. The intermediates have only microsecond lifetimes in solution but are stabilized inside the cavitand for up to 15 minutes, long enough to characterize them by using nuclear magnetic resonance and infrared spectroscopic techniques.

Fig. 4. A deep vaselike structure presents a cavity, and the carboxylic acid (red) is directed into the space. Isonitriles are captured in the cavity and react with the acid to give stabilized intermediates, such as A.

Publications

Ajami, D., Rebek, J., Jr. Gas behavior in self-assembled capsules. Angew. Chem. Int. Ed. 47:6059, 2008.

Ajami, D., Rebek, J., Jr. Longer guests drive the reversible assembly of hyperextended capsules. Angew. Chem. Int. Ed. 46:9283, 2007.

Ajami, D., Rebek, J., Jr. Reversible encapsulation of terminal alkenes and alkynes. Heterocycles 76:169, 2008.

Ajami, D., Schramm, M.P., Rebek, J., Jr. Translational motion inside self-assembled encapsulation complexes. Tetrahedron, in press.

Mann, E., Moisan, L., Hou, J.-L., Rebek, J., Jr. Synthesis of pyridazines functionalized with amino acid side chains. Tetrahedron Lett. 49:903, 2008.

Moisan, L., Odermatt, S., Gombosuren, N., Carella, A., Rebek, J., Jr. Synthesis of an oxazole-pyrrole-piperazine scaffold as an α-helix mimetic. Eur. J. Org. Chem. 10:1673, 2008.

Restorp, P., Rebek, J., Jr. Reaction of isonitriles with carboxylic acids in a cavitand: observation of elusive isoimide intermediates. J. Am. Chem. Soc. 130:11850, 2008.

Restorp, P., Rebek, J., Jr. Synthesis of α-helix mimetics with four side-chains. Bioorg. Med. Chem. Lett. 18:5909, 2008.