@Kappy - not the most useful of replies mate to be honest.After all, there is a strong possibility that this has everything to do with the way OS X and the thunderbolt interface handle wake from sleep states.
@kbrine:
I am having exactly the same problem but with slightly different hardware:
iMac 27 (mid-2011) with Mountain Lion 10.8.2
Booting from a Crucial M4 SSD in an OWC SATA enclosure connected to a Lacie eSata thunderbolt hub (which is connected to the iMac).
In normal use the drive is super fast and works really well.
But my problem is exactly as you describe, put the machine into sleep, and on wake everything appears to come back ok however you can't open apps from the dock and the spinning beachball appears. You can't do anything else and you have to reboot.
Now the interesting thing is that if I put the machine to sleep and then wake it up again within 1 minute everything works perfectly. After a longer period of time - and I'm presuming when the energy saving profile moves to a deeper sleep state (I don't know for sure so speculation from me here) - I get the problem we are having and I have to reboot.
Here's what I've tried so far:
Updated my SSD to the latest firmware.
No firmware updates available for the OWC enclosure nor the Lacie eSata hub (at least, not that I could find)
Turned off bluetooth (others on this forum had a problem with BT interfering with Thunderbolt displays coming back on after sleep)
Turned off 'Automatic Brightness Adjust' (again, based on Thunderbolt Display problems that others have reported)
I've tried out AutoEJECT and Jettison apps that unmount all external drives and re-mount them when waking from sleep. They've made absolutely no difference. Save yourself a few $$ and don't bother buying them from the App Store.
I've tried unplugging and re-inserting the Thunderbolt cable connecting my eSata hub to the iMac. No effect.
And that's as far as I've got. There are only two things left for me to try:: disable 'Power Nap' which - apparently - can also cause problems with Thunderbolt devices during sleep. But I'm not confident with that being the solution. Turn the power off to the Crucial M4 when the problem occurs and then re-power it in the hope that it causes some sort of refresh of the connection to happen. Again, not sure that's a good solution either as I don't want to be powering down my SSD every time I bring the iMac out of sleep!!!
So I too am open to ideas and opinions on what might be causing these wake-from-sleep problems arising when Mac OS is booted from an external thunderbolt drive.