Having never had an AMEX I know nothing about the rules of a 2-4-1 but are you sure about the open jaw return from a different zone than the outbound? Something doesn't sound right with that.
If it's true it certainly makes a 2-4-1 even better value than it is already.

We had our round the world trip of a lifetime three years ago....it'll never be bettered. We used a mixture of BA and DC miles which made finding availability much easier.