Kerr and Carson. Org. Lett., 2009, ASAP. DOI: 10.1021/ol802870c.
After the ChemDraw marathon that was helicterin B, I was bloody glad to move on to a smaller target (even if the configurations are tightly packed…). This one has a pretty decent biological profile, and with a phosphate group hanging off it, no surprises that it interacts with the DNA machinary. I’m not going to blab on about it, but it’s certainly a worthy target; this’ll be why syntheses by Snider, Sorensen and Fukuyama (amongst others) are already out there.
So it’s going to take quite a bit of work to bring something new to the table, but Kerr makes a pretty good start with this enantioselective deprotonation. Again, it’s worth checking out Peter O’Brien’s work in this area, and probably this Tet. Lett. by EJ (back in the days when TL was worth reading). This proceedure established asymmetry at a quaternary centre with apparent ease.
The silyl-enol ether was then quenched with NIS to give the ?-iodo ketone (as a mixture of diastereomers, but this isn’t relevent), which participated in a pretty complex Reformatsky coupling. I say this as there are several factors – the aldehyde partner is chiral, so has a bearing, the iodide is also chiral, and the conformation of the cyclohexanone is going to muddy waters too. Kerr doesn’t try to rationalise the reaction too much – he was just happy to get a 4:1 mixture of diasteroisomers, which I reckon’s pretty good too.
A few more steps – a substrate controlled reduction and protecting group manipulations – and it was time to crack that cyclopropane open. Kerr’s been doing work on this kind of chemistry for years, with several publicaion on it, so there’s no real surprise that this goes like a charm. A bit of formaldehyde gives the N-methylene intermediate, which does a stepwise opening of the cyclopropane (nice, stablised malonate helping out a bit here). The malonyl anion then shuts down on the imine, building that pyrolidine nicely.
Seven(ish) more steps took the synthesis to fruition, but there were a few issues along the way. Mono-decarboxylation of malonate was a bit dissapointing, as no asymmetry could be induced at the common centre. This was saponified, Curtiused (protection with a Boc group in-situ), and methylated, giving them an intermediate that was close enough to those previously prepared that ‘formal’ methods were use to complete the synthesis. I would note though that the references for these steps are jumbled-up a bit – I think that 2f should read 2g.
Nice work on a compact target.