No biological data given as a raison d’etre, so we’ll focus on the fact that this is one bad-ass structure, ripe for a bit of aldol-bashing. Indeed, over the three communications outlined above (why not one article?), Evans et al go seriously aldol-tastic in the synthesis of this 41-member macrolide. So, to the retro (and probably the most complex I’ve drawn so far:
Now that’s what I call a disconnection approach! It’s all in the execution from here, and for the most part, it’s known chemistry. Their methods and retro ensure that the synthesis is very convergent, but I’m not going through much of it. However, two steps caught my eye:
Using a HWE, they built the diene SM, and were ready to hydrog the less-substituted alkene (the “trans Î”4 olefin”). However, various methods, including use of Lindar’s catalyst, resulted in over-reduction and inseparable byproducts. But they did get success using Crabtree’s catalyst (this JOC), which chelated to the free hydroxyl, allowing reduction of only the desired alkene. This did require deprotection of a TES group to free the hydroxyl in question, and then reprotect, but the managed an 80% yield over those three steps. Not new chemistry, but new to me…
Lastly, I really liked this aldol (one of the many), using Evan’s own methodology; a C2 symmetric copper catalyst to generate the chiral product in good e.e., on the “Chan Diene”. However, I couldn’t find a yield for this?!