It depends how the CF card reports itself to the operating system. If it reports itself with 512 bytes physical blocksize, then it should work with AmigaOS. Then it's up to the user to know that the real physical blocksize is 4K. There is no support for this in AmigaOS.
First thing to do is to align partitions to physical blocks. The easiest way to do this is to choose a geometry where the cylinder size is divisible by 4K (this means the number of blocks per cylinder needs to be divisible by

.
Only after that you can choose to use 4K logical blocks for the file system. I don't think that PFS3 in its currently available version can be changed to use 4K blocks, therefore you might need to change to FFS or SFS.
Using 4K logical blocks on non-aligned partitions is even worse than to use 512 byte logical blocks, because accessing each logical block would need to access two physical blocks.
Fortunately with the usual IDE geometry of 1008 or 2016 blocks per cylinder, partitions are already aligned.