Kerr and Leduc. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200803257.
We’ve not got much to go in terms of biological activity (GABA receptor antagonism by a diastereoisomer…), so lets just assume that we’re in it for the chemistry.Â It’s quite a nice looking target, leaving me somewhat surprised that this is it’s first synthesis, so props to Michael Kerr for digging it out of the 1962 bag…
So, to the synthesis – and surprisingly to the very reaction, protection of butenol as it’s PMP ether.Â They used a Mitsunobu reaction to do this, which I found kinda interesting.Â I’ve never done a Mitsunobu reaction, but from what I’ve head, it seems like it isn’t the kind of reaction one wants at the start of a synthesis.Â Anyway, it was all Corey’s idea… I liked the formation of the cyclopropane, though; a very smart way to make enantiomerically pure cyclopropanes.Â Some protecting group shennigans were then required to replace the hydroxyl for an hydroxyl-amine (I wonder why they didn’t start with 1-amino-but-4-ene? *hits himself about the head*… durrr…), which they deprotected and cyclised in one pot.Â Quite a cyclisation too; working from a JACS paper on the methodology, Kerr suggests that one firstly gets formation of an imine, which opens the cyclopropane leaving the stabilised malonate anion and the first ring.Â The anion then shuts-down onto the iminium ion in a Mannich-sense, forming the cyclopentane.Â Nice.
To be fair, there’s quite a bit of leg-work between here and the next intermediate; eight steps isn’t unreasonable though.Â And I really like the way Kerr finishes-off the natural product, with two of the more important steps following each other to complete two more rings in direct succession.Â They actually had a bit of trouble with the order in which to complete these transformations, with the result I’ve shown being the most successful.Â Deprotections and cyclisation of the remaining ring by displacement of a mesylate then gave the natural product.
Nothing too dramatic, but that methodology is pretty damned nice, so it’s good to see it put to some use.