MacMillan, Jones, Simmons. JACS, 2009, ASAP. DOI: 10.1021/ja9052366.
Now this is a popular target; I’ve covered syntheses by both Qin and Overman (with a related synthesis of vincorine by Qin too), both of which contain some really nice chemistry, and aren’t exactly lengthy. However, this approach by MacMillan is incredibly concise, containing only nine steps, and starting with a commercially available indole. To get to the key cyclisation precursor, a process of carbonylating the C-2 position by lithiation and addition of DMF, followed by a Horner-Wadsworth-Emmons olefination provided the required diene ophile.
Diene ophile? Well that lets the cat out of the bag, so to speak. Yep, it’s [4+2] time, using propargyl aldehyde and a imidazolidinone catalyst. The catalyst and aldehyde do the rather expected imine formation (this is organocatalysis after all), and then the acetylene does the Diels-Alder thing, generating (as this is an alkyene) an enamine intermediate. This is of course in tautomeric equilibrium with an indolinium imine ion, trapped-out by addition of that conveniently situated pendant amine. Snaps that ring shut, giving them the product – two new rings and two stereocenters to the better. Both a cracking yield and example of stereochemical control. (BTW, TBA is tribromoaceticacid. Why’s it better than TFA?)
Completion of the target took another five steps (that’s called maths…) – a bit of protecting group shennanigans and a reductive amination provided the remaining carbon. The approach here was kinda interesting; they had two sulfides, one of which was propargylic. Treatment with t-butyl tin hydride (the bulk is important, apparently) promoted radical formation on the cyclohexene, and addition to the alkyene in a 6-exo-dig manner, loosing the extraneous thiol to give an allene. Not a bad yield, but that’s quite a chunk of initiator – 50 mol% relative to product.
Completion of the target from here required only loss of the protecting groups and a reduction of the allene – providing a bit of a selectivity headache there. However, simply dumping in a bit of palladium on carbon with a hydrogen atmosphere did a regioselective and diastereoselective reduction, providing the require exocyclic trans-ethylidene in over 90%, 20:1 d.r. There’s no discussion of this result, so I’m happy for them, but kinda bemused. However, it’s a rather fitting result to complete this sweet synthesis.