Exercise 1
Overview-
During the coming year you will undertake a research project that involves the synthesis of a group of compounds known as metalloles. The general structure of these compounds is shown in Figure 1. Here E stands for a phosphorous (P), silicon (Si), germanium (Ge), or tin (Sn) atom. G represents a variety of substituents that may be attached to various positions on the aromatic rings. Examples include -CH3, -OCH3, and -CF3. Most often R1 and R2, will be methyl groups (-CH3) or aromatic rings.
Figure 2 shows the structure that represents a series of compounds which we envision will be formed as intermediates during the synthesis of the target metalloles. The parent compound, where G=H, is called cis-stilbene or Z-stilbene.
A close structural analog of cis-stilbene known as combretastatin A-1 has been shown to inhibit the assembly of microtubules, cellular structures which play a central role in cell division. Such inhibitory activity suggests that combretastatin A-1 may be useful as a chemotherapeutic agent for the treatment of cancer. Figure 3 presents the structure of combretastatin A-1. Key carbon atoms are numbered according to the discussion that follows.
The structure shown in Figure 3 suggests that combretastatin A-1 is a planar molecule. It is not. Table 1 summarizes four experimentally measured torsional angles.
|
|
|
|
|
|
|
 |
|
|
|
 |
|
|
|
 |
|
|
|
 |
The torsional angle is defined as the angle between the plane made by the first three atoms specified and the plane made by the last three. For the first entry in Table 1 these planes are those defined by C(1)-C(1a)-C(1'a) and C(1a)-C(1'a)-C(1'), respectively. In the perspective of the first torsional angle, C(1a) is hidden behind C(1'a). Torsional angles are also called dihedral angles.
You will develop a better understanding of dihedral angles and molecular geometry as you work your way through this exercise. For now the main point is that there is generally a correlation between a molecule's shape and its biological activity.
In this exercise each group will use a program called MacSpartan to investigate the structure of the group's target compound. First, however, you will use cis-stilbene as a reference compound so that you can compare the theoretical results produced by MacSpartan with the experimental results described in the literature.
Getting Started-
1. Adjust the size and position of this window so that it fills the upper half of the screen.
2. Make the Launcher window active by clicking on it. Then click on the Chem Applications button on the Launcher. (If the Launcher is not visible on the desktop, you may select it from the Apple menu.)
3. Click the MacSpart... icon. After a brief delay a window entitled MacSpartan Plus will appear along with a "tool palette". Resize and reposition this window so it fills the lower half of the screen. Position the tool palette in the top left corner of the MacSpartan Plus window.
Building cis-Stilbene-
1. Select New from the File menu. A window entitled Builder-New Molecule will appear with another window called Model Kit to its right. The Model Kit tab labeled Entry should be highlighted. (Click on the Entry tab if either of the other two tabs, Expert or Peptide, is selected.) Resize and reposition these windows so that they occupy the bottom half of the screen.
2. Select the sp2 hybridized carbon tool: 
Then
click the mouse in the Builder-New Molecule window.
3. Click and drag the mouse until the molecular fragment you've
created looks like this: 
(Dragging
the mouse while holding down the Apple key rotates the molecule.)
4. Position the cursor over the right-hand end of the molecular
fragment and click the mouse. Your model should look approximately
like this 
without
the labels 1 and 2.
5. Click the Rings button in the tool pallette. The default value should be "Phenyl".
6. Position the cursor over the end of the single bond fragment labeled 1 above and click the mouse.
7. Manipulate the model until it looks something like this, again
without the label 2: 
8. Position the cursor over the end of the single bond fragment
that that was labeled 2 above and click the mouse. This completes the
construction of the model of cis-stilbene. It should look like
this: 
Compare
this drawing to the one in Figure 3.
If you manipulate it, you will see that all the atoms of the molecule lie in the same plane.
8. Click on the Dihedral Angle icon 
in
the tool palette. Position the dialog window that appears so it is
below the structure you have just created.
9. Click on the atoms that correspond to 1, 1a, 1'a, and 1' in Figure 3. Enter a value of -6 into the Dihedral text field. Press the return key, then click on the Done button. (Note that if you manipulate the molecule now that the hydrogen atoms attached to C-6 and C6' no longer contact each other.)
10. Select Save As... from the File menu. Select a destination for the file, either the Desktop or a floppy disk. Enter Stilbene in the text field that appears. Click the Save button.
11. Select Exit Builder from the File menu. Your structure should appear as a "wire-frame" model in a window entitled Stilbene (0).
Optimizing cis-Stilbene
1. Select Calculation from the Setup menu.
2. Select Geometry Optimization from the dropdown Task: menu and AM1 from the dropdown Level: menu. Then click the Save button.
3. Select Submit from the Setup menu. After a brief delay a dialog box stating "Analysis for "Stilbene" has started." will appear. Click OK. This calculation takes a bit more than 5 minutes.