Well the main reason for the original Silk Road was that there weren't any sea lanes to get there until the 1500's when Magellan finally circumnavigated the globe. So my first thought is to stick a big continent in the way to block the sea lanes. Second, make the technology level low so that sea-worthy ships don't exist yet (coastal barques and trade cogs are ok, though). You could always stick a desert or mountains in there or a swamp. You've already mentioned the roving nomads.