One approach that will [most likely] work is hijacking the ClassLoader when Chrome starts and using a custom class loader that will ensure classes to be loaded are on the main dex list. Rough implementation idea for this is:
  - Modify build rules to add the main_dex_list as an asset
  - Subclass dalvik.system.PathListClassLoader and override loadClass() to check the main dex for the class to be loaded. If found, delegate class loading to the actual classloader, crash if not.
  - Don't do this in official builds

Not currently working on this.

A couple of hacky prototypes I wrote a while back:

1) Disable access to secondary dex files in isolated processes (https://codereview.chromium.org/2499923003/)

2) Fail when we try to load classes that aren't in the main_dex_list (https://codereview.chromium.org/2845773004/) 

This likely won't save us any disk space since optimized dex files will still be created with this approach so we're going to take the custom dex loading route.