This is a common thread I see among many clients: "Can I connect my sandbox/dev CRM environment using Multi-Org set up to a separate SFMC Business Unit?"
The short answer is yes, but the long answer is that it is a pain to maintain. There isn't any type of change management in SFMC, meaning no "push to production." That means essentially you'll have two separate business units (your Dev and Prod) where you need to manually maintain parity.
Automations and Journeys will have to be manually copied and even if you use Deployment Manager to copy between business units, this is still a manual effort.
Also even with test data in a separate Business Unit, those test records still end up in your All Subscribers list on your parent Business Unit level. One may argue that having a separate MID entirely for Dev use is a better solution. But, of course, that means more money thrown at Salesforce for a problem that they should have a solution for.
If you are having multiple business units and have to connect to only one Salesforce org, you should be able to do it. In this case, the Salesforce org and data will always be connected to the primary business unit. Other business units however cannot reference Salesforce data directly.
If you enable the Multi-Org feature, each business unit can be connected to a separate Salesforce org. With the Multi-Org feature, I don't think there is a way to connect same Salesforce org to multiple business units. The connection might work in Marketing Cloud but not in Salesforce as you would face issues in fetching the tracking data in Salesforce from multiple business units.
Best Answer
I've implemented multi-org before and it is fairly straightforward. You need to follow the help documentation regarding Marketing Cloud Connector and you should be able to integrate a Salesforce Orgs to each Business Unit.
Once multi-org is enabled, you can't undo it. That should not be a concern if you are going to use more than 1 Salesforce Orgs. The only thing I can say is that there will be some challenges initially. I've had to work with Salesforce support to resolve issues like Tracking information not going to Sales Cloud, Queries unable to access Data extensions and with Journey Builder not having Salesforce activities visible.
I've also had issues after a Marketing Cloud release when Integration stops working and you have to login to Sales Cloud and enter the API user credentials in the Integration to make it work again.
Each set up is different and I believe you'll face a different set of challenges while you work on it. That being said, move forward with multi-org, coz that's the only option :) Good Luck