Your latest layout looks a lot more usable than the first design, but I definitely think that P2 joystick is going to drive you nuts when trying to use the Defender buttons on the right side. IMO, it's best to just accept that a general-purpose cabinet is going to involve compromises on control layouts--in other words, I'd prefer controls that may be less accurate in spacing but are unobstructed and comfortable to use. I have to believe there is a good way of, for example, laying it out such that a dedicated up/down Defender stick is not needed.
I'm able to play Defender no problem using my P1 joystick, which has a generic 6-button layout next to it; the first button in the lower row is in just the right location for hitting with my thumb. For the "right side" Defender buttons (thrust, fire, smart bomb), I have variously mapped some of the P2-side buttons to those functions, or even other P1-side buttons. I never use hyperspace so I don't even bother mapping it. I'm able to play and enjoy the game just fine.
I guess I understand how you'd want a faithful layout if Defender is one of your top priorities, and in that case, I'd strongly suggest you consider swappable panels.
I'm in the process of doing just that right now; the panel is built and wired, just waiting for some last cables to come in the mail. After 6 years of playing Robotron on a generic layout, I decided to make a second panel with an accurate layout for that game. The cabinet was not originally designed with swappable panels in mind and it was not difficult to do; it would have been even easier had I worked it into the plan from the get-go. Both panels use the same i-Pac, although I found that I could have simply bought a second i-Pac for about the same amount of money I spent on the bits and pieces needed to share one.