You have a few options, but starting from Cali definitely gives you more choices. I guess it depends on which border crossing you use. If you want to use the San Miguel crossing, then you should start in Cali. You can visit Cali and then head south to Popayan. From Popayan, you can cross the Cordillera to Pitalito and check out the San Augustin area. From Pitalito, you can head south to Mocoa. After Mocoa, the trip to the border (San Miguel) is an easy 4 hours. You wouldn't have to do any backtracking, and you'd see a very beautiful part of the country that most travelers skip.
If you want to do the Ipiales crossing, then you may or may not have to backtrack at some point (depends on the route). One itinerary is at the beginning, similar to the first itinerary explained above. Start with Cali and then head south to Popayan. From Popayan, cross the cordillera and head to the San Augustin area. From here, you have about 2 choices. You can either backtrack the same way you came going back to Popayan, or you can continue south from Pitalito, heading to Mocoa. Backtracking to Popayan would put you on the Pan American highway. From there, it's easy to catch a bus to Ipiales (the city on the Ecuador-Colombian border). If you don't want to go over the same tracks, then continue south to Mocoa (I'd do this instead of going back to Popayan). From Mocoa, it's easy to catch a bus to Pasto, where you can make your way to the Ipiales crossing.
If you can get service from Cali to Pitalito without having to pass through Popayan, then you could avoid having to backtrack to Popayan. From Pitalito (San Augustin area), you can head east over the Cordillera checking out Popayan, then going south to Ecuador, or you can continue south to Mocoa, making your way to the border from there.
If it were up to me, I'd do the San Miguel crossing. The Mocoa area is one of the prettiest places I've visited in Colombia and it's definitely worth a visit. Several years ago, the Putamayo region was not safe to visit. However, the situation has greatly improved and the region is a great place to see birds and animals, while experiencing Colombia's natural beauty. Due its past reputation as being an unsafe area, it doesn't receive a lot of tourists, and to most Colombians, Mocoa may as well be on the Moon. I'd go there before its stock eventually rises.