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O=CHem Molecular Modeling I last updated 12/22/04


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O=CHem Molecular Modeling I




Last updated 12/22/04



Introduction-

In this exercise you will use a molecular modeling program called Spartan to create molecular models of four compounds, trans-stilbene, cis-stilbene, a cis-stilbene with substituent groups, G and G’, on the two aromatic rings, and combretastatin A-1, a highly substituted cis-stilbene that has been used in the treatment of certain types of cancer. Combretastatin A-1 was first isolated in 1981 and its structure established by Pettit and co-workers1 in 1987.

The Post-Laboratory Exercises that accompany this assignment ask you to determine specific angles and distances in each of the models you have made and, in the case of combretastatin A-1, to compare some of the theoretical results to experimental data. To save time you should have a copy of the Post-Laboratory Exercises available as you work your way through each modeling exercise.

The Chemistry Department has 10 licensed copies of Spartan. They are available from any computer running under Windows on the University’s network. The path to the program is Start/All Programs/Chemistry Applications/Spartan Student V2.0.0.


Starting Spartan

When you select New from the File menu in Spartan a window opens that contains four tool palettes; Entry, Expert, Peptide, and Nuc. At that point you should resize and reposition that window as well as this one so that your desktop looks something like this



Basic Operations

You can select a specific tool palette by clicking on the appropriate tab. Near the top of the Entry tool palette there are 20 tools, each of which corresponds to a particular type of atom. For example, the tool in the first column of the first row represents an sp3 hybridized (tetrahedral) carbon atom, while the one in the second column of the first row is an sp3 hybridized nitrogen atom. The tool in the first column of the second row is an sp2 (trigonal planar) hybridized carbon atom. The tool in the third column of the second row represents an sp3 hybridized (bent) oxygen atom, while the one in the third column of the third row is an sp2 hybridized (trigonal planar) oxygen atom. You activate a specific tool by clicking on it. You place an atom in the Spartan ST window by clicking the mouse anywhere within the window once you have activated a tool.

In the middle of the tool palette there are tools for creating pre-constructed functional groups and rings. You activate a specific tool by clicking either the Groups or the Rings button and then selecting an option from the drop-down menu associated with your selection. You place a functional group or ring in the Spartan ST window in the same way you do an atom.

Each atom or molecular fragment has at least one “free valence” associated with it. These appear as yellow lines. A “free valence” is assumed to be occupied by a hydrogen atom. You replace a hydrogen atom with another atom or group of atoms by clicking the appropriate tool on the end of a “free valence” in the Spartan ST window.

You can manipulate an object, i.e. change the perspective view, by click-dragging the mouse in the Spartan ST window. Four motions are possible: 1. Click-dragging horizontally rotates the object about the Y-axis. 2. Click-dragging vertically rotates the object about the X-axis. 3. Shift click-dragging vertically rotates the object around the Z-axis. 4. Right click-dragging the object moves it up or down, left or right.
Building New Molecules

The specific steps required to create each structure are itemized on the following pages. Comments are presented in red after a numbered instruction where appropriate. Figure 1 approximates what you should see on the computer screen after a specific step or group of steps involved in building trans-stilbene. Figures 2 and 3 provide comparable information for building cis-stilbene and combretastatin A-1, respectively.


trans-Stilbene


  1. Select New from the File menu in Spartan.

Presumably you have already done this.

  1. Activate the sp2 hybridized carbon atom tool.

  1. Click the mouse anywhere in the Spartan ST window.

  2. Click-drag the mouse vertically.

This action makes the “free valences” more obvious; the sphere that represents the carbon atom has two “single bond” valences and one “double bond” valence projecting from it.

  1. Click on the “double bond” valence.

At this point the model represents the structure of ethene. Each of the four “free valences” is assumed to be connected to a hydrogen atom.

  1. Click on the Rings button in the tool palette and select Benzene from the drop-down menu if it is not already selected.

  2. Click the mouse on a “free valence” of one carbon atom in your model.

The structure that you have created at this point is called styrene. You may want to manipulate the model to produce a perspective similar to that shown in Figure 1. Notice the red band around the bond between C-1 and C-1a. This indicates that free rotation around this bond is possible.

    1. Select Measure Dihedral from the Geometry menu and click on carbons 6, 1, 1a, and 1’a, in that order.

In the lower right corner of the window you should see a message dihedral (C5,C3,C1,C2) = 180.00o. Obviously Spartan uses a different numbering system than this document.

  1. Hold down the Alt key while click-dragging the mouse anywhere in the drawing window until the value of dihedral (C5,C3,C1,C2) = -58o.

This is the experimental value of the corresponding angle in combretastatin A-1.

  1. Select Minimize from the Build menu.

You should see Energy () = 22.2201 kcal/mol in the lower right hand corner of the window.

  1. Select Save from the File menu, navigate to your floppy disk or to the Desktop, and enter the name Styrene into the File name: text box.

The default file type is Spartan ST Doc (*.spartan). There is no need to add the extension to your file name. You will start the second exercise by opening this file. You will use the numbering shown in Figure 1 when you perform the Post-Laboratory Exercises.

  1. Click the mouse on the “free valence” of C-1’a that is “trans” to phenyl ring that you introduced in Step 7.

This is a model of trans-stilbene.

  1. Select Minimize from the Build menu

Along the bottom of the window you should see a text box labeled Energy() = . The value should be 38.7490 kcal/mol.

  1. Orient the model as shown in Figure 1 and use Save as… from the File menu to save this structure as trans-stilbene.

  1. Select Close from the File menu.

This clears the window.
Figure 1

Building trans-Stilbene



cis-Stilbene

In this exercise you will create a model of cis-stilbene in which you will set two dihedral angles to values that are reported in the literature for the cis-stilbene derivative combretastatin A-1. Subsequently you will use your model of cis-stilbene as the starting point for a building a model of combretastatin A-1. Refer to Figure 2 for steps 1-6.


1. Open the file named Styrene.spartan.

2. Select Add Fragment from the Build menu.

3. Connect a phenyl ring to the free valence on C-1’a that is “cis” to the phenyl ring on C-1a.


  1. Select the Minimize from the Build menu.

The energy of this conformation should be 41.2206 kcal/mol.

    1. Save your file as cis-stilbene and Close.


Figure 2

Building cis-Stilbene



Combretastatin A-1


1. Open your file named cis-stilbene.

2. Manipulate your model so that it looks approximately like the one shown in Figure 3.

3. Select Save as... from the File menu and enter the name Combretastatin A-1 in the text box. Click Save.


  1. Select Add Fragment from the Build menu.

5. Activate the sp3 hybridized oxygen atom tool (-O-, not O=).

6. Click on the “free valences” at C(3), C(4), C(5), C(2’), C(3’), and C(4’).

7. Activate the sp3 hybridized carbon atom tool.

8. Click on the “free valence” of each of the oxygen atoms attached to C(3), C(4), C(5), and C(4’).

Steps 4-7 add OCH3 groups to C(3), C(4), C(5) and C(5’). The groups attached to C(2’) and C(3’) are OH groups, not OCH3 groups.

9. Minimize the energy of the structure.

Energy() = 89.1511 kcal/mol

10. Save the changes your have made and Close your file.

Your model should look similar to the one shown in Figure 1 of the article entitled “Isolation, Structure, and Synthesis of Combretastatins A-1 and B-1, Potent New Inhibitors of Microtubule Assembly, Derived from Combretum Caffrum”.
Figure 3

Building Combretastatin A-1



A Disubstituted cis-Stilbene

In this exercise you will create a model of cis-stilbene that has a substituent group, G, on one of the aromatic rings and a second group, G’, on the other. A list of assignments of substituent groups is available on this page.



Repeat the procedure you followed in making combretastatin A-1, recording the information required for the Post-Laboratory Exercises as you proceed. Refer to the numbering of cis-stilbene shown in Figure 3 when you build your model: attach your group G to the appropriate carbon atom of the aromatic ring that is numbered without primes; attach your group G’ to the appropriate carbon of the aromatic ring that is numbered with primes.


1 Pettit, G.R., Singh, S.B., Niven, M.L., Hamel, E., and Schmidt, J.M. J. Natural Products 50, 119-131, 1987.


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